Psychometric properties of Patient-Specific Functional Scale in patients with upper extremity disorders. A systematic review.
To identify, critically appraise, and synthesise the measurement properties of Patient-Specific Functional Scale (PSFS) in patients with upper extremity musculoskeletal disorders. Medline, Embase, PubMed, and Google Scholar databases from January 1999 to November 2020 were searched. Prospective measurement studies that included patients with upper extremity musculoskeletal disorders, that reported on the psychometric properties of PSFS were included. We used the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) 2018 guideline for systematic reviews to appraise the studies. Fourteen eligible studies were included. Three studies with adequate-very good quality and sufficient properties indicated excellent intra-class correlation coefficients (ICC) (≥0.75) in patients with shoulder pain (mean age 48 ± 11 years), multiple shoulder disorders (mean age 55 ± 16 years), and hand osteoarthritis (mean age 64 ± 9 years). The construct validity estimates of PSFS were moderate, when compared with Upper Extremity Functional Index (UEFI) (r = 0.50) and Numeric Pain Rating Scale (NPRS) (r = 0.51) in patients with combined upper extremity musculoskeletal disorders (shoulder/upper arm, wrist/hand and elbow/forearm). The patient-specific functional scale can be considered as a reliable, valid, and responsive tool in assessing functional change in patients with shoulder disorders/pain.Implications for rehabilitationThe Patient-Specific Functional Scale (PSFS) can be considered as: • a reliable outcome measure in assessing functional change in patients with shoulder pain and hand osteoarthritis; • a valid measure in assessing functional limitation in patients with upper extremity disorders; • a measure that is sensitive to change (displays longitudinal validity) in assessing functional change in patients with upper extremity disorders and in patients with shoulder pain; and • a responsive outcome measure in assessing functional change in patients with upper extremity disorders.


The evolution of surgical treatment for gastrointestinal cancers.
According to the latest Japanese nationwide estimates, over a million Japanese people are newly diagnosed with cancer each year. Since gastrointestinal cancers account for more than 40% of all cancer-related deaths, it is imperative to formulate effective strategies to control them. Basic drug discovery research Our research has revealed that the abnormal expression of regulators of chromosomal stability is a cause of cancers and identified an effective compound against cancers with chromosomal instability. We revealed the molecular mechanism of peritoneal dissemination of cancer cells via the CXCR4/CXCL12 axis to CAR-like cells and identified an MEK inhibitor effective against these tumors. Residual tumor cells after chemotherapy in colorectal cancer are LGR5-positive cancer stem cells and their ability to eliminate reactive oxygen species is elevated. The development of surgical procedures and devices In cases of gastric tube reconstruction for esophageal cancer, we determined the anastomotic line for evaluating the blood flow using ICG angiography and measuring the tissue O2 metabolism. We established a novel gastric reconstruction method (book-binding technique) for gastric cancer and a new rectal reconstruction method focusing on the intra-intestinal pressure resistance for rectal cancer. We established a novel tissue fusion method, which allows contact-free local heating and retains tissue viability with very little damage, and developed an understanding of the collagen-related processes that underpin laser-induced tissue fusion. Strategy to prevent carcinogenesis We succeeded in cleaving hepatitis B virus DNA integrated into the nucleus of hepatocytes using genome editing tools. The development of HCC from non-alcoholic steatohepatitis (NASH) may be prevented by metabolic surgery. We believe that these efforts will help to significantly improve the gastrointestinal cancer treatment and survival.


Age Differentiation within Gray Matter, White Matter, and between Memory and White Matter in an Adult Life Span Cohort.
It is well established that brain structures and cognitive functions change across the life span. A long-standing hypothesis called "age differentiation" additionally posits that the relations between cognitive functions also change with age. To date, however, evidence for age-related differentiation is mixed, and no study has examined differentiation of the relationship between brain and cognition. Here we use multigroup structural equation models (SEMs) and SEM trees to study differences within and between brain and cognition across the adult life span (18-88 years) in a large (N > 646, closely matched across sexes), population-derived sample of healthy human adults from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.org). After factor analyses of gray matter volume (from T1- and T2-weighted MRI) and white matter organization (fractional anisotropy from diffusion-weighted MRI), we found evidence for the differentiation of gray and white matter, such that the covariance between brain factors decreased with age. However, we found no evidence for age differentiation among fluid intelligence, language, and memory, suggesting a relatively stable covariance pattern among cognitive factors. Finally, we observed a specific pattern of age differentiation between brain and cognitive factors, such that a white matter factor, which loaded most strongly on the hippocampal cingulum, became less correlated with memory performance in later life. These patterns are compatible with the reorganization of cognitive functions in the face of neural decline, and/or with the emergence of specific subpopulations in old age.SIGNIFICANCE STATEMENT The theory of age differentiation posits age-related changes in the relationships among cognitive domains, either weakening (differentiation) or strengthening (dedifferentiation), but evidence for this hypothesis is mixed. Using age-varying covariance models in a large cross-sectional adult life span sample, we found age-related reductions in the covariance among both brain measures (neural differentiation), but no covariance change among cognitive factors of fluid intelligence, language, and memory. We also observed evidence of uncoupling (differentiation) between a white matter factor and cognitive factors in older age, most strongly for memory. Together, our findings support age-related differentiation as a complex, multifaceted pattern that differs for brain and cognition, and discuss several mechanisms that might explain the changing relationship between brain and cognition.


Guidance for otolaryngology health care workers performing aerosol generating medical procedures during the COVID-19 pandemic.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus disease 2019 (COVID-19) has a predilection for infecting the mucosa of the upper and lower airways. Otolaryngologists and supporting health care workers (HCWs) are particularly at high risk of becoming infected while treating patients as many in-office procedures and surgeries are Aerosol Generating Medical Procedures (AGMP). Based on a review of the literature and various guidelines, recommendations are made to mitigate the risk to health care workers of becoming infected with SARS-CoV-2 while providing clinical care. During the COVID-19 pandemic all elective and non-time sensitive Otolaryngology procedures should be deferred to mitigate the risk of transmission of infection to HCWs. For non-AGMPs in all patients, even COVID-19 positive patients Level 1 PPE (surgical mask, gown, gloves and face shield or goggles) is sufficient. If local prevalence is favourable and patients are asymptomatic and test negative for SARS-CoV-2, Level 1 PPE can be used during short duration AGMPs, with limited risk of infected aerosol spread. For AGMPs in patients who test positive for SARS-CoV-2 a minimum of Level 2 PPE, with adequate protection of mucosal surfaces, is recommended (N95/FFP2 respirator, gown, double gloves, goggles or face shield and head cover). For long duration AGMPs that are deemed high-risk in COVID-19 positive patients, Level 3 PPE can provide a higher level of protection and be more comfortable during long duration surgeries if surgical hoods or PAPRs are used. It is recommended that these procedures are performed in negative pressure rooms, if available. It is essential to follow strict donning and doffing protocols to minimize the risk of contamination. By following strict infection prevention recommendations, the risk of HCWs becoming infected with SARS-CoV-2 while treating patients can be minimized. As the COVID-19 pandemic evolves rapidly, these recommendations should serve as guidance and need to be interpreted based on local factors and availability of healthcare resources.


Two cases of plunging ranula managed by the intraoral approach.
Two cases of plunging ranula are reported. Treatment consisted of the total removal of the sublingual gland and evacuation of the cystic contents by the intraoral approach. The cyst remained just after the surgery in both cases, but then gradually regressed and disappeared within two months after the surgery. These findings support total removal of the sublingual gland as being the best method of treatment. We believe that complete dissection of the cyst with cervical incision as well as drainage of the cystic contents are unnecessary when the diagnosis of the plunging ranula is confirmed.


Constitutive activation of the N-methyl-D-aspartate receptor via cleft-spanning disulfide bonds.
Although the N-methyl-D-aspartate (NMDA) receptor plays a critical role in the central nervous system, many questions remain regarding the relationship between its structure and functional properties. In particular, the involvement of ligand-binding domain closure in determining agonist efficacy, which has been reported in other glutamate receptor subtypes, remains unresolved. To address this question, we designed dual cysteine point mutations spanning the NR1 and NR2 ligand-binding clefts, aiming to stabilize these domains in closed cleft conformations. Two mutants, E522C/I691C in NR1 (EI) and K487C/N687C in NR2 (KN) were found to exhibit significant glycine- and glutamate-independent activation, respectively, and co-expression of the two subunits produced a constitutively active channel. However, both individual mutants could be activated above constitutive levels in a concentration-dependent manner, indicating that cleft closure does not completely prevent agonist association. Interestingly, whereas the NR2 KN disulfide was found to potentiate channel gating and M3 accessibility, NR1 EI exhibited the opposite phenotype, suggesting that the EI disulfide may trap the NR1 ligand-binding domain in a lower efficacy conformation. Furthermore, both mutants affected agonist sensitivity at the opposing subunit, suggesting that closed cleft stabilization may contribute to coupling between the subunits. These results support a correlation between cleft stability and receptor activation, providing compelling evidence for the Venus flytrap mechanism of glutamate receptor domain closure.


N-glycoproteins bearing beta1-6 branched oligosaccharides from the A375 human melanoma cell line analysed by tandem mass spectrometry.
Tumour-associated alterations of cell surface glycosylation play a crucial role in the adhesion and metastasis of cancer cells. It is well known that the metastatic potential is associated with increased GlcNAc beta1-6 branching in N-glycans of tumour cells specifically recognized by a lectin from Phaseolus vulgaris leukoagglutinin (PHA-L). We identified proteins bearing GlcNAc beta1-6 branched N-glycans in the A375 human melanoma cell line by affinity chromatography separation on a PHA-L agarose column, followed by immunoidentification and tandem mass spectrometry (MS/MS) analysis. Amongst the proteins identified were integrin subunits alpha2, alpha3, alpha5 and beta1, as well as N-cadherin and lysosome-associated membrane proteins (LAMP-1 and LAMP-2). In addition, L1, Mac-2 binding protein (Mac-2-BP), activated leukocyte cell adhesion molecule/CD166 (ALCAM) and melanotransferrin were shown to react with PHA-L. Some of these proteins are connected mainly with nervous tissues or the immune system and play a crucial role in cell adhesion processes. The presence of GlcNAc beta1-6 branched oligosaccharides in these proteins may influence their adhesion properties, reducing adhesion of the cells to the extracellular matrix (ECM) and thus facilitating tumour cell invasion.


Steering most probable escape paths by varying relative noise intensities.
We demonstrate the possibility to systematically steer the most probable escape paths (MPEPs) by adjusting relative noise intensities in dynamical systems that exhibit noise-induced escape from a metastable point via a saddle point. With the use of a geometric minimum action approach, an asymptotic theory is developed that is broadly applicable to fast-slow systems and shows the important role played by the nullcline associated with the fast variable in locating the MPEPs. A two-dimensional quadratic system is presented which permits analytical determination of both the MPEPs and associated action values. Analytical predictions agree with computed MPEPs, and both are numerically confirmed by constructing prehistory distributions directly from the underlying stochastic differential equation.


Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome.
Apixaban is an oral, direct factor Xa inhibitor under development for secondary prevention in acute coronary syndrome (ACS). Apixaban's effect on D-dimer and prothrombin fragment 1.2 (F1.2) (coagulation activity biomarkers ) was determined in a randomised, double-blinded, placebo-controlled, phase 2 study. Patients (n=1,715) with either ST- segment elevation or non-ST-segment elevation ACS received either placebo or apixaban 2.5 mg twice daily, 10 mg once daily, 10 mg twice daily or 20 mg once daily for six months. Samples were obtained at baseline (before study drug administration), week 3 and week 26. Apixaban plasma concentrations were measured directly by liquid chromatography/mass spectometry, and anti-Xa activity was determined using apixaban as a reference standard. D-dimer and F 1.2 were measured using ELISA-based methods. Most patients had elevated D-dimer and F1.2 levels at baseline. Both coagulation activity biomarkers decreased by week 3 in all treatment groups, but to a greater degree with apixaban than placebo (p<0.001). In a multivariable analysis, apixaban was independently associated with a change in biomarkers over time (p<0.0001). While the overall decrease did not differ significantly among the three highest apixaban doses, F1.2 was suppressed more rapidly by the 10 mg once daily than the 2.5 mg twice daily dose (p<0.05). There was a strong and direct relationship between apixaban plasma concentrations and anti-Xa-apixaban levels, and an inverse relationship for both measures with coagulation activity biomarkers. In conclusion, the oral direct factor Xa inhibitor apixaban significantly reduced coagulation activity biomarkers among patients with ACS. The 10 mg once daily dose reduced thrombin generation (F 1.2) and fibrin formation (D-dimer) more rapidly and robustly than the 2.5 mg twice daily dose. The effect on both D-dimer and F 1.2 was apixaban concentration-and factor Xa inhibition dependent, durable and provided general guidance for dose selection in phase 3 investigation.


Efficiency of a self-administered outpatient parenteral antimicrobial therapy (s-opat) for infective endocarditis within the context of a shortened hospital admission based on hospital at home program.
This study aimed to evaluate the efficiency of treatment of infectious endocarditis (IE) via Self-administered Outpatient Parenteral Antimicrobial Therapy (S-OPAT) supported by a shortening hospital admission program in a hospitalization-at-home unit (HAH), including a short review of the literature. Ambispective cohort study of 57 episodes of IE in 54 patients treated in an HAH unit between 1988 and 2014 who receive S-OPAT after prior intra-hospital clinical stabilization. Characteristics of each episode of IE, safety and efficiency of the care model, were analyzed. Forty-three (76%) patients were males with a median age of 61 years (SD = 16.5). A total of 37 (65%) episodes affected the native valve (42% the aortic valve). In 75%, a micro-organism was isolated, of which 88% were Gram-positive bacteria. No deaths occurred during HAH program, clinical complications appeared in 30% of episodes, only 6 patients were re-admitted to hospital although no patient died. In the 12 months' follow-up 3 cases had a recurrence. The average cost of a day stay in HAH was €174 while in traditional cardiology hospitalization was €1100. The total average cost of treatment of each episode of IE managed entirely in hospital was calculated as €54,723. Application of the S-OPAT model based on HAH meant a cost reduction of 32.72%. In suitably selected patients, treatment of IE based on S-OPAT supported by a shortening hospital admission care program by means of referral to a HAH unit is a safe and efficient care model which entails a significant cost saving for the public healthcare system.


2-Benzisothiazolylimino-5-benzylidene-4-thiazolidinones as protective agents against cartilage destruction.
We report the synthesis, the antioxidant and the inhibitory activity (IC50) on metalloproteinases (MMPs) 3 and 13 of 2-benzo[d]isothiazolylimino-5-benzylidene-4-thiazolidinones. Their potential as protective agents in osteoarthritis (OA) was evaluated by biological assays on chondrocytes cultures, stimulated by IL-1β. The chondroprotective capability, related both to antioxidant activity and to inhibition of MMPs, was studied in vitro, by determining nitric oxide production and glycosaminoglycans release. Moreover, selected derivatives 1h and 1g was studied for nuclear factor kappaB (NF-κB) inhibition by Western Blot analysis and for MMP-3 protein release using ELISA test. The structure-activity relationship of tested compounds demonstrates a favorable effect of the para substitution on the 5-benzilydene ring. Compound 1g shows a potent and selective activity on MMP-3 versus MMP-13. Accordingly, 1g possesses high antioxidant effect, NO lowering and GAGs restoring capability and also reduces the production of MMPs and NF-κB expression. Thus 1g can be considered as new potential chondroprotective agents.


5-aryl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents: synthesis, bioevaluation and docking study.
The search for newer histone deacetylase (HDAC) inhibitors has attracted a great deal of interest of medicinal chemists worldwide, especially after the first HDAC inhibitor (Zolinza(®), widely known as SAHA or Suberoylanilide hydroxamic acid) was approved by the FDA for the treatment of Tcell lymphoma in 2006. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-aryl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. Most of the compounds in this series, e.g. compounds with 5-aryl moiety being 2- furfuryl (5a), 5-bromofuran-2-yl (5b), 5-methylfuran-2-yl (5c), thiophen-2-yl (5d), 5-methylthiophen-2-yl (5f) and pyridyl (5g-i), were found to have potent anticancer cytotoxicity with IC50 values of generally 5- to 10-fold lower than that of SAHA in 4 human cancer cell lines assayed. Those compounds with potent cytotoxicity were also found to have strong HDAC inhibition effects. Docking studies revealed that compounds 5a and 5d displayed high affinities towards HDAC2 and 8.


High-Throughput Automation in Chemical Process Development.
High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.


Small Molecule Modulation of the Integrated Stress Response Governs the Keratoconic Phenotype In Vitro.
The degenerative corneal disease keratoconus is a leading indicator for corneal transplant with an unknown etiology. We recently identified the activation of the integrated stress response (ISR) in ex vivo human corneas and in vitro cell culture. Utilizing small molecules to modulate the ISR we sought to investigate the effects of stimulating the ISR in healthy cells to recapitulate aspects of the in vitro keratoconic phenotype and whether relieving the ISR signaling would recover the disease phenotype. Corneal fibroblasts were extracted from patients undergoing corneal transplant or unaffected cadaverous donor limbal rings. Cells were exposed to the DNA damage-inducible protein (GADD34) inhibitor SAL003 to stimulate the ISR, or Trans-ISRIB to relieve ISR signaling pathway. Collagen production was assessed through hydroxyproline production, Sirius Red incorporation, or quantitative (q)PCR. Western blotting, hydroxyproline, and qPCR were used to assess components of the ISR pathway and collagen production. ISR stimulation through SAL003 resulted in significant decrease of hydroxyproline and COL1A1 transcription and eventual apoptosis in normal fibroblasts. Patient (KC) fibroblast production of hydroxyproline was increased in response to ISRIB, while matrix metalloproteinase (MMP)9 production was lowered. The prospective biomarker of keratoconus prolactin-inducible factor was also upregulated in KC fibroblast cultures in response to ISRIB. Inflammatory markers TNFα and IL-1β were unaffected. Activation of the ISR is sufficient to recapitulate many key aspects of the KC phenotype in unaffected cells in vitro. Inhibition of the ISR also relieves many of the hallmarks of KC in affected cells. Therefore, targeting of the ISR through small molecules is a potential therapeutic path for small molecule treatment of keratoconus.


Methods for comparative effectiveness based on time to confirmed disability progression with irregular observations in multiple sclerosis.
Real-world data sources offer opportunities to compare the effectiveness of treatments in practical clinical settings. However, relevant outcomes are often recorded selectively and collected at irregular measurement times. It is therefore common to convert the available visits to a standardized schedule with equally spaced visits. Although more advanced imputation methods exist, they are not designed to recover longitudinal outcome trajectories and typically assume that missingness is non-informative. We, therefore, propose an extension of multilevel multiple imputation methods to facilitate the analysis of real-world outcome data that is collected at irregular observation times. We illustrate multilevel multiple imputation in a case study evaluating two disease-modifying therapies for multiple sclerosis in terms of time to confirmed disability progression. This survival outcome is derived from repeated measurements of the Expanded Disability Status Scale, which is collected when patients come to the healthcare center for a clinical visit and for which longitudinal trajectories can be estimated. Subsequently, we perform a simulation study to compare the performance of multilevel multiple imputation to commonly used single imputation methods. Results indicate that multilevel multiple imputation leads to less biased treatment effect estimates and improves the coverage of confidence intervals, even when outcomes are missing not at random.


Accelerating root system phenotyping of seedlings through a computer-assisted processing pipeline.
There are numerous systems and techniques to measure the growth of plant roots. However, phenotyping large numbers of plant roots for breeding and genetic analyses remains challenging. One major difficulty is to achieve high throughput and resolution at a reasonable cost per plant sample. Here we describe a cost-effective root phenotyping pipeline, on which we perform time and accuracy benchmarking to identify bottlenecks in such pipelines and strategies for their acceleration. Our root phenotyping pipeline was assembled with custom software and low cost material and equipment. Results show that sample preparation and handling of samples during screening are the most time consuming task in root phenotyping. Algorithms can be used to speed up the extraction of root traits from image data, but when applied to large numbers of images, there is a trade-off between time of processing the data and errors contained in the database. Scaling-up root phenotyping to large numbers of genotypes will require not only automation of sample preparation and sample handling, but also efficient algorithms for error detection for more reliable replacement of manual interventions.


Treatment of diffuse diabetic maculopathy with intravitreal triamcinolone and laser photocoagulation: randomized clinical trial with morphological and functional evaluation.
Treatment of diffuse macular edema in diabetes mellitus is currently unsatisfactory. The purpose of this double blind randomized clinical trial was to compare the treatment of diffuse diabetic macular edema with intravitreal triamcinolone or laser in type 2 diabetes mellitus patients using a morphofunctional assessment. Fourteen patients (21 eyes) with clinically significant diffuse macular-edema, previously untreated and with a macular thickness >250 µm at optical coherence tomography were randomized for treatment with laser or intravitreal injection of triamcinolone acetate. Optical coherence tomography, biomicroscopy, fundoscopy, fluorescein angiography, tonometry, scotometry, visual and contrast acuities were performed at 0, 1, 3 and 6 months. At pre-treatment stage, Laser (n=9) and Triamcinolone (n=12) groups did not differ regarding retinal thickness, visual and contrast acuities. In Triamcinolone group macular thickness decreased after 1 month (424.1 ± 19.9 µm to 358.4 ± 18.2 µm; p=0.04) and started to return to the initial values in the 3(rd) month (p=0.02). No changes occurred in macular scotometry and visual and contrast acuities. No side effects were observed with both treatments. During the study macular thickness diminished in the triamcinolone group, especially in the first month of treatment. At 3 and 6 months there was no difference. Macular thickness did not change during the study in the laser group. In the study sample it was not possible to demonstrate differences relates to visual acuity and scotometry between the two groups. CLINICALTRIALS.GOV IDENTIFIER: NCT00668239.


Down's syndrome and Alzheimer's dementia: defining an association.
The typical neuropathological features of Alzheimer's disease, plaques and tangles, appear in virtually all patients with Down's Syndrome after the age of 40. Clinically, changes in cognitive performance and behavior appear to correlate with these neuropathological changes, although a satisfactory operational definition of dementia in a context of mental retardation is not available. It is unknown whether the cholinergic losses in the nucleus basalis, which are a feature of early onset Alzheimer's disease, also occur late in Down's syndrome. Two family studies have supported a greater than expected incidence of Down's cases among relatives of probands dying with Alzheimer-type dementia, but the association is not strong. It is noteworthy that in both studies, phenotypically normal carriers of the rare 15/21 translocation had severe early onset dementia, although this translocation is responsible for less than 0.4 per cent of Down's cases. An increased incidence of dementia among carriers of the more common 14/21 translocation has not been reported. In any case, it is proposed that a gene product originating from the long arm of chromosome 21 (21q) is necessary for Alzheimer-type pathology, since a segregating gene could not be responsible for the 100 per cent incidence of these changes among 21q trisomics.


A dynamic approach for outpatient scheduling.
Patient no-show is a recurrent problem in medical centers and, in conjunction with cancellation of appointments, often results in loss of productivity and excessive patient time to appointment. The purpose of this study was to develop a dynamic procedure for scheduling patients within an outpatient clinic where patients are expected to have multiple appointments, such as physical therapy, occupational therapy, primary care, and dentistry. This retrospective study involved the year 2014 de-identified patient records from an outpatient clinic affiliated with a large university hospital. A number of patient characteristics, appointment data, and historical attendance records were examined to determine whether they significantly impacted patients who missed scheduled appointments (no-shows). Patient attendance behaviors over multiple appointments were examined to determine whether their no-show and cancellation patterns differed from one appointment to the next. Decision tree analysis was applied to those predictors that significantly correlated with patient attendance behavior to assess the likelihood of a patient no-show. A sample dynamic appointment scheduling procedure that utilized different overbooking strategies for different appointment numbers was then developed. Computer simulation was used to assess the effectiveness of the dynamic procedure versus two other methods consisting of randomly assigned and uniformly assigned appointments. The dynamic scheduling procedure resulted in increased scheduling efficiency through overbooking but with less than 5% risk of appointment conflicts (i.e. two patients showing at the same time), equating to approximately 0.16 conflicts per clinician per day. It also increased clinic utilization by about 6.7%. It consistently outperformed the other two methods with respect to the percentage of appointment conflicts. The study is limited with respect to potential clinician cost increase resulting from possible appointment conflicts. A second limitation is that patients experiencing appointment conflicts might not wait for treatment, resulting in potential loss of revenue. A third limitation is that the model does not take into account patient satisfaction, nor the ethics of overbooking patients. A dynamic appointment scheduling procedure was developed using actual patient characteristics. The procedure resulted in creation of more efficient appointment schedules thereby increasing the clinic utilization.


Incidence of Metamorphopsia After Successful Rhegmatogenous Retinal Detachment Surgery: A Systematic Review and Meta-Analysis.
To investigate the incidence and factors influencing the occurrence of metamorphopsia in patients with simple rhegmatogenous retinal detachment (RRD) after surgery. Relevant studies of metamorphopsia were identified by searching in PubMed, Embase, and Cochrane until August 2022. Meta-analysis of the incidence of metamorphopsia after rhegmatogenous retinal detachment surgery was performed using Review Manager 5.4 statistical software. A total of 12 studies reported 1133 participants with 469 patients with postoperative metamorphopsia. The meta-analysis showed a higher incidence of metamorphopsia in macular-off cases compared with macular-on RRD (RR = 2.88, 95% CI: 2.35 to 3.52). The use of perfluorocarbon liquid (PFCL) during pars plana vitrectomy (PPV) reduced the incidence of metamorphopsia (RR = 0.61, 95% CI: 0.41 to 0.92). There was no evidence of any important difference in metamorphopsia between participants in the PPV group and the scleral buckling (SB) group (RR = 1.04, 95% CI: 0.82 to 1.33). There was little or no difference in metamorphopsia between gas and silicon oil (SO) in the PPV group (RR = 0.89, 95% CI: 0.69 to 1.13). The incidence of postoperative metamorphopsia is higher in macular-off RRD, and PFCL should be a preferred choice to prevent postoperative metamorphopsia in macula-off RRD cases.


Panax notoginseng saponins attenuates cisplatin-induced nephrotoxicity via inhibiting the mitochondrial pathway of apoptosis.
The goal of this experiment was to investigate the protective effect and the molecular mechanism of Panax Notoginseng Saponins (PNS) on cisplatin-induced nephrotoxicity through mitochondrial pathway of apoptosis. The rats underwent intraperitoneal injection with a single dose of cisplatin, a subset of rats were also intraperitoneally injected with 31.35 mg/kg PNS once a day for 8 days. At day 1, 4 and 8 after exposure to cisplatin, the concentrations of blood urea nitrogen (BUN), serum creatinine (Scr) and urinary N-acetyl-β-D-Glucosaminidase (NAG) were determined using commercial kits. The pathological change of renal tissue were examined using H & E staining and transmission electron microscopy. The rate of apoptosis and the expression of Bcl-2 in rat renal tissue were detected by using TUNEL staining and Western bloting, respectively. And the expressions of Bax and caspases 9 were detected by immunnohistochemistry. The results showed that PNS significantly protected against cisplatin-induced nephrotoxicity, as evidenced by the decrease in concentration of blood BUN, Scr and urinary NAG, as well as the attenuation of renal histopathological damage. Furthermore, PNS reduced the rate of apoptosis, and the mechanism studies showed that PNS inhibited the expression of Bax and caspase 9, while increased the expression of Bcl-2. This study first demonstrated that PNS can protect against cisplatin-induced nephrotoxicity and reduce renal tissue apoptosis via inhibiting the mitochondrial pathway.


Patient vulnerability is associated with poor prognosis following upfront hepatectomy for colorectal liver metastasis.
With the rapid aging of populations worldwide, the number of vulnerable patients with liver metastasis from colorectal cancer has increased. This study aimed to examine the association between vulnerability and clinical outcomes in patients with colorectal liver metastasis (CRLM). Consecutive 101 patients undergoing upfront hepatectomy for CRLM between 2004 and 2020 were included. The preoperative vulnerability was assessed using the Clinical Frailty Scale (CFS) score ranging from one (very fit) to nine (terminally ill), and frailty was defined as a CFS score of ≥ 4. A multivariable Cox proportional hazard regression model was utilized to investigate associations of frailty with disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). Of the 101 patients, 12 (12%) had frailty. Associations between frailty and surgical outcomes, namely, the incidence of 90-day mortality and postoperative complications, were not statistically significant (P > 0.05). In the multivariable analyses, after adjusting for clinical risk scores calculated using six factors (timing of liver metastasis, primary tumor lymph node status, number of liver tumors, size of the largest tumor, extrahepatic metastatic disease, and carbohydrate antigen 19-9 level) to predict recurrence following hepatectomy for CRLM, preoperative frailty was found to be an independent risk factor for DFS (hazard ratio [HR]:2.37, 95% confidence interval [CI] 1.06-4.72, P = 0.036), OS (HR:4.17, 95% CI 1.43-10.89, P = 0.011), and CSS (HR:3.49, 95% CI 1.09-9.60, P = 0.036). Preoperative frailty was associated with worse DFS, OS, and CSS after upfront hepatectomy for CRLM. Assessment and improvement of patient vulnerability may provide a favorable prognosis for patients with CRLM.


Research Hotspots and Trends of Social Robot Interaction Design: A Bibliometric Analysis.
(1) Background: Social robot interaction design is crucial for determining user acceptance and experience. However, few studies have systematically discussed the current focus and future research directions of social robot interaction design from a bibliometric perspective. Therefore, we conducted this study in order to identify the latest research progress and evolution trajectory of research hotspots in social robot interaction design over the last decade. (2) Methods: We conducted a comprehensive review based on 2416 papers related to social robot interaction design obtained from the Web of Science (WOS) database. Our review utilized bibliometric techniques and integrated VOSviewer and CiteSpace to construct a knowledge map. (3) Conclusions: The current research hotspots of social robot interaction design mainly focus on #1 the study of human-robot relationships in social robots, #2 research on the emotional design of social robots, #3 research on social robots for children's psychotherapy, #4 research on companion robots for elderly rehabilitation, and #5 research on educational social robots. The reference co-citation analysis identifies the classic literature that forms the basis of the current research, which provides theoretical guidance and methods for the current research. Finally, we discuss several future research directions and challenges in this field.


Miconazole Contributes to NRF2 Activation by Noncanonical P62-KEAP1 Pathway in Bladder Cancer Cells.
Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated expression and cytoprotective proteins, plays critical roles in chemoprevention, inflammation and aging. NRF2 has recently been proposed as a novel target for cancer chemoprevention. The fungicide miconazole has shown promising antiproliferative effects in cancer cells. After miconazole treatment, the p62-KEAP1-NRF2 activation was analyzed by qPCR and Western blot. The nuclear translocation indicating NRF2 activation was further confirmed by immunofluorescence. Finally, the ROS production was detected by CM-H2DCFDA staining. We demonstrate in this study that miconazole dramatically increases NRF2 activation in bladder cancer cells, in a dose- and time-dependent manner. Interestingly, levels of expression of p62, a noncanonical pathway that mediates NRF2 activation, appeared to increase in accordance with NRF2. We also investigated levels of the negative regulator kelch-like ECH-associated protein 1 (KEAP1), which is involved in NRF2 activation. As expected, a decrease in KEAP1 expression was found after miconazole exposure. Confirmation of NRF2 nuclear translocation was monitored by immunofluorescence. Miconazole-induced generation of reactive oxygen species (ROS) promoted NRF2 activation. Pretreatment of bladder cancer cells with ROS scavengers abolished NRF2 expression and nuclear translocation, indicating that miconazole activates the noncanonical p62-KEAP1-NRF2 pathway, which is regulated by ROS production. Our study elucidates the mechanisms through which miconazole stimulates NRF2 which may contribute to cancer chemopreventive effects.


Multidrug resistance protein P-gp interaction with nanoparticles (fullerenes and carbon nanotube) to assess their drug delivery potential: a theoretical molecular docking study.
P-glycoprotein (P-gp)-mediated efflux system plays an important role to maintain chemical balance in mammalian cells for endogenous and exogenous chemical compounds. However, despite the extensive characterisation of P-gp potential interaction with drug-like molecules, the interaction of carbon nanoparticles with this type of protein molecule is poorly understood. Thus, carbon nanoparticles were analysed, such as buckminsterfullerenes (C20, C60, C70), capped armchair single-walled carbon nanotube (SWCNT or C168), and P-gp interactions using different molecular docking techniques, such as gradient optimisation algorithm (ADVina), Lamarckian genetic algorithm (FastDock), and shape-based approach (PatchDock) to estimate the binding affinities between these structures. The theoretical results represented in this work show that fullerenes might be P-gp binders because of low levels of Gibbs free energy of binding (ΔG) and potential of mean force (PMF) values. Furthermore, the SWCNT binding is energetically unfavourable, leading to a total decrease in binding affinity by elevation of the residual area (Ares), which also affects the π-π stacking mechanisms. Further, the obtained data could potentially call experimental studies using carbon nanostructures, such as SWCNT for development of drug delivery vehicles, to administer and assess drug-like chemical compounds to the target cells since organisms probably did not develop molecular sensing elements to detect these types of carbon molecules.


Determining the efficacy of the bovine amniotic membrane homogenate during the healing process in rabbits' ex vivo corneas.
To evaluate the efficacy of bovine amniotic membrane homogenate (BAMH) on wounded ex vivo rabbit corneas. Eighteen corneas obtained from normal rabbit eyes were wounded equally using a 6 mm trephine and cultured into an air-liquid interface model. Corneas were treated with phosphate-buffered saline (PBS) (n = 6, control group), 0.2% ethylenediaminetetraacetic acid (EDTA; n = 6), or BAMH (n = 6). All treatments were applied topically 6 times/day. Each cornea was macrophotographed daily with and without fluorescein stain to assess epithelialization and haziness. After 7 days, corneal transparency was evaluated, and the tissues prepared for histologic analysis of viability, and total and epithelial thickness. The mean epithelialization time was 6.2 ± 0.82 days for the control group, 6.2 ± 0.75 days for the EDTA-treated group, and 5.1 ± 0.40 days for the BAMH-treated group, demonstrating a significant difference between the BAMH and the other groups. The corneas that received EDTA had better transparency compared with the other groups. Histologically, all corneas had adequate morphology and architecture after healing. Analysis of corneal and epithelial thickness revealed no significant difference among groups. Bovine amniotic membrane homogenate is an effective and promising treatment for stromal and epithelial ulcers.


Intron evolution as a population-genetic process.
Debate over the mechanisms responsible for the phylogenetic and genomic distribution of introns has proceeded largely without consideration of the population-genetic forces influencing the establishment and retention of novel genetic elements. However, a simple model incorporating random genetic drift and weak mutation pressure against intron-containing alleles yields predictions consistent with a diversity of observations: (i) the rarity of introns in unicellular organisms with large population sizes, and their expansion after the origin of multicellular organisms with reduced population sizes; (ii) the relationship between intron abundance and the stringency of splice-site requirements; (iii) the tendency for introns to be more numerous and longer in regions of low recombination; and (iv) the bias toward phase-0 introns. This study provides a second example of a mechanism whereby genomic complexity originates passively as a "pathological" response to small population size, and raises difficulties for the idea that ancient introns played a major role in the origin of genes by exon shuffling.


Electrocatalysis at graphite and carbon nanotube modified electrodes: edge-plane sites and tube ends are the reactive sites.
Carbon, and particularly graphite in its various forms, is an attractive electrode material. Two areas of particular interest are modified carbon electrodes and carbon nanotube electrodes. In this article we focus on the relationship between surface structure and electrochemical and chemical reactivity of electrodes based on these materials. We overview recent work in this area which has led us to believe that much of the catalytic activity, electron transfer and chemical reactivity of graphitic carbon electrodes is at surface defect sites, and in particular edge-plane-like defect sites. We also question the claimed special "catalytic" properties of carbon nanotube modified electrodes.


DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity.
Dipeptidyl-peptidase 4 (DPP-4) cleaves and inactivates the insulinotropic hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide, collectively termed incretins. DPP-4 inhibitors entered clinical practice as approved therapeutics for type-2 diabetes in 2006. However, inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). Fourteen common (minor allele frequencies ≥0.05) DPP4 tagging single nucleotide polymorphisms (SNPs) were genotyped in 1,976 non-diabetic TÜF participants characterized by oral glucose tolerance tests and bioimpedance measurements. In a subgroup of 168 subjects, plasma incretin levels were determined. We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. A common variant, i.e., SNP rs6741949, in the DPP4 gene interacts with body adiposity and negatively affects glucose-stimulated GLP-1 levels, insulin secretion, and glucose tolerance. Whether this SNP underlies the reported inter-individual variance in responsiveness to DPP-4 inhibitors, at least in subjects with high body fat content, remains to be shown.


Monkeypox: the resurgence of forgotten things.
Monkeypox, a rare zoonotic disease, is primarily prevalent in Central and Western Africa. However, monkeypox is emerging as a worldwide concern due to the 2022 monkeypox outbreak, which is the first instance of widespread community transmission outside Africa. Monkeypox is caused by the monkeypox virus, which belongs to the genus Orthopoxvirus and presents as a vesicular-pustular disease that may be preceded by fever, malaise, and other constitutional symptoms. If present, lymphadenopathy may distinguish it from chickenpox or smallpox. However, contrary to previous manifestations, most monkeypox patients presented with atypical features during the 2022 outbreak. Monkeypox is usually a self-limiting disease with symptoms lasting between 2 weeks and 4 weeks and is mainly transmitted when a person comes into contact with an infected animal, person, or fomites contaminated with the virus. Very few treatment options are available for this disease. Tecovirimat has been licensed in some countries for the treatment of smallpox and monkeypox infections. Two other medications, cidofovir and brincidofovir, have been found to be effective against poxviruses in in vitro and animal studies, but data on human cases of monkeypox are limited. Although Imvamune (JYNNEOS), a vaccine against monkeypox, is authorized in the United States, there are currently no established routine vaccination programs. Current preventive strategies focus on the detection of probable cases and containment of the outbreak through the implementation of selected ring vaccination programs. Fundamental principles to prevent the spread of monkeypox, including maintaining personal hygiene and avoiding close contact with symptomatic patients, are of paramount importance.


Ranking predictors of a sustained viral response for patients with chronic hepatitis C treated with pegylated interferon and ribavirin in Scotland.
From the literature on the hepatitis C virus, the existence of a gap between a sustained virologic response (SVR) attainable in randomized clinical trials (RCTs) versus routine practice is not clear. Further, in terms of the pretreatment prediction of SVR, to date, studies have focused only on reporting the magnitude of association (MOA) between each predictor and an SVR. They fail to acknowledge that a predictor with a large MOA is of little value to clinicians if it has low variability in the treatment population. Hepatitis C virus clinical databases were used to derive a large, representative cohort of Scottish pegylated interferon and ribavirin initiates. Overall, 39% [123/315, 95% confidence interval (CI) 34-45%] of genotype 1 and 70% (414/594, 95% CI 66-73%) of genotype 2/3 patients achieved an SVR; this compares with the pooled estimates of 47% for genotype 1 (95% CI 41-52%) and 80% for genotype 2/3 (95% CI 75-85%) RCT participants. Significant predictors of SVR identified from logistic regression were ranked on the basis of the akaike information criteria (reflecting an approach that will account for each predictor's MOA and variability) as follows: (i) genotype, % increase in akaike information criteria of the final model when variables are excluded, 58.49%; (ii) γ-glutamyl transferase, 18.64%; (iii) platelet count, 6.48%; (iv) alanine aminotransferase quotient, 4.63%; (v) ever infected with hepatitis B virus, 4.31% and (vi) sex, 3.10%. (i) The proportion of patients attaining an SVR in Scottish routine practice is marginally lower than in RCTs and (ii) other than genotype, γ-glutamyl transferase emerges as a valuable predictor of an SVR in routine practice. Further, we demonstrate an approach to more clearly discern the predictive value of response predictors.


Pneumatosis cystoides intestinalis mimicking acute abdomen.
Pneumatosis cystoides intestinalis (PCI) is a rare disease. It was first described by Du Vernoy in 1793 during a cadaver dissection. Air-filled bubble-like lesions are located in the submucosa or the subserosa of the digestive tract. A 55-year-old Turkish male presented to the emergency department with complaints of recurrent abdominal pain and vomiting. Free air was detected in abdominal x-ray and abdominal computed tomography (CT). In exploration, a grape-like lesion consisting of hundreds of cysts was detected on the surface of the small intestine. Bowel resection was performed successfully. The surgical findings and pathological result confirmed the diagnosis of pneumatosis cystoides intestinalis.


Digital Cognitive Assessment Tests for Older Adults: Systematic Literature Review.
The global health pandemic has affected the increasing older adult population, especially those with mental illnesses. It is necessary to prevent cases of cognitive impairment in adults early on, and this requires the support of information and communication technologies for evaluating and training cognitive functions. This can be achieved through computer applications designed for cognitive assessment. In this review, we aimed to assess the state of the art of the current platforms and digital test applications for cognitive evaluation, with a focus on older adults. A systematic literature search was conducted on 3 databases (Web of Science, PubMed, and Scopus) to retrieve recent articles on the applications of digital tests for cognitive assessment and analyze them based on the methodology used. Four research questions were considered. Through the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology, following the application of inclusion and exclusion criteria, a total of 20 articles were finally reviewed. Some gaps and trends were identified regarding the types of digital applications and technologies used, the evaluated effects on cognitive domains, and the psychometric parameters and personal characteristics considered for validation. Computerized tests (similar to paper-and-pencil tests) and test batteries (on computers, tablets, or web platforms) were the predominant types of assessments. Initial studies with simulators, virtual environments, and daily-life activity games were also conducted. Diverse validation methods and psychometric properties were observed; however, there was a lack of evaluations that involved specific populations with diverse education levels, cultures, and degrees of technology acceptance. In addition, these evaluations should consider emotional and usability aspects.


[Adrenoreceptive structures in the early embryos of the clawed toad (Xenopus laevis)].
Studies have been made on the binding of labeled ligands to beta-adrenoreceptor--3H-dihydroalprenolol (DHA) and 125I-iodocyanopindolol (ICP--in crude homogenate and subcellular fractions of toad embryos during cleavage divisions. Specific binding of these ligands was observed which is confirmed by a decrease of the activity after addition of cold propranolol or adrenalin. The value of Kd for DHA is equal to 3 x 10(-9) M for ICP--to 1.5 x 10(-9) M. In addition to this high-affinity pool of binding with a low capacity, a low-affinity and high-capacity pool was also found. Cooling of the preparation up to 4 degrees C for 2 h increases the specific binding simultaneously with a decrease of the affinity of adrenoreceptive structures of the embryo. The data obtained are discussed in relation to the criteria of intracellular transmitter process.


Registered Nurses' attitudes towards end-of-life care: A sequential explanatory mixed method study.
To examine registered nurses' attitudes about end-of-life care and explore the barriers and facilitators that influence the provision of high-quality end-of-life care. A sequential explanatory mixed methods research design was used. An online cross-sectional survey was distributed to 1293 registered nurses working in five different hospitals in the Kingdom of Saudi Arabia. The Frommelt Attitudes Towards Care of the Dying Scale was used to assess nurses' attitudes towards end-of-life care. Following the survey, a subset of registered nurses were interviewed using individual semi-structured interviews. Four hundred and thirty-one registered nurses completed the online survey, and 16 of them participated in individual interviews. Although nurses reported positive attitudes towards caring for dying patients and their families in most items, they identified negative attitudes towards talking with patients about death, their relationship with patients' families and controlling their emotions. The individual interview data identified the barriers and facilitators that registered nurses experience when providing end-of-life care. Barriers included a lack of communication skills and family and cultural and religious resistance to end-of-life care. The facilitators included gaining support from colleagues and patients' families. This study has identified that while registered nurses hold generally favourable attitudes towards end-of-life care, they have negative attitudes towards talking with patients and families about death and managing their emotional feelings. Education providers and leaders in healthcare settings should consider developing programmes for undergraduate nurses and nurses in clinical practice to raise awareness about the concept of death in a cross-section of cultures. Nurses' attitudes towards dying patients will be enhanced with culture-specific knowledge which will also enhance communication and coping methods. This study used the Mixed Methods Article Reporting Standards (MMARS).


Trans-cinnamaldehyde improves memory impairment by blocking microglial activation through the destabilization of iNOS mRNA in mice challenged with lipopolysaccharide.
Microglia activation and neuroinflammation are critically involved in pathogenesis of neurodegenerative disorders. Patients with neurodegenerative disorders often suffer memory impairment and currently there is no effective treatment for inflammation-led memory impairment. Trans-cinnamaldehyde (TCA) isolated from medicinal herb Cinnamomum cassia has been shown to exhibit anti-inflammatory capability. However, the potential of TCA to be used to improve memory impairment under neuroinflammation has not been explored. Primary microglia stimulated by lipopolysaccharide (LPS) were used to evaluate the potential anti-neuroinflammatory effects of TCA by examining the production of nitric oxide (NO), expression of inducible nitric oxide synthase (iNOS), pro-inflammatory cytokines, and activation of MAPKs. A mouse model of LPS-induced memory impairment was established to assess the neuroprotective effects of TCA against memory deficit and synaptic plasticity inhibition by both behavioral tests and electrophysiological recordings. TCA pretreatment decreased LPS-induced morphological changes, NO production and IL-1β release in primary microglia. Decreased NO production was due to the accelerated degradation of iNOS mRNA in LPS-stimulated microglia through TCA's inhibitory effect on MEK1/2-ERK1/2 signaling pathway. TCA was able to reduce the levels of iNOS and phosphorylated ERK1/2 in hippocampus of mice challenged with LPS. Most importantly, TCA significantly lessened memory deficit and improved synaptic plasticity in LPS-challenged mice. This study demonstrates that TCA suppressed microglial activation by destabilizing iNOS mRNA, which leads to improved memory impairment in mice suffering neuroinflammation.


Causal associations between COVID-19 and childhood mental disorders.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can invade both the peripheral and central nervous systems and impact the function of the brain. Therefore, it is necessary to evaluate the mutual influences between COVID-19 outcomes and childhood mental disorders. We examined genetic correlations and potential causalities between three childhood mental disorders and three COVID-19 phenotypes by genetically proxied analyses. The three mental disorders included attention-deficit/hyperactivity disorder (ADHD, N = 292,548), Tourette's syndrome (TS, N = 14,307), and autism spectrum disorder (ASD, N = 46,350). The three COVID-19 traits included SARS-CoV-2 infection (N = 2,597,856), hospitalized COVID-19 (N = 2,095,324), and critical COVID-19 (N = 1,086,211). Literature-based analysis was used to build gene-based pathways connecting ADHD and COVID-19. ADHD was positively correlated with the three COVID-19 outcomes (Rg: 0.22 ~ 0.30). Our Mendelian randomization (MR) analyses found that ADHD confers a causal effect on hospitalized COVID-19 (odds ratio (OR): 1.36, 95% confidence interval (CI): 1.10-1.69). TS confers a causal effect on critical COVID-19 (OR: 1.14, 95% CI: 1.04-1.25). Genetic liability to the COVID-19 outcomes may not increase the risk for the childhood mental disorders. Pathway analysis identified several immunity-related genes that may link ADHD to COVID-19, including CRP, OXT, IL6, PON1, AR, TNFSF12, and IL10. Our study suggests that both ADHD and TS may augment the severity of COVID-19 through immunity-related pathways. However, our results did not support a causal role of COVID-19 in the risk for the childhood mental disorders.


Cross-cultural similarities and differences in the experience of awe.
Current research on awe is limited to Western cultures. Thus, whether the measurement, frequency, and consequences of awe will replicate across non-Western cultures remains unanswered. To address this gap, we validated the dispositional awe scale (Shiota, Keltner, & John, 2006) in 4 countries (United States, Iran, Malaysia, and Poland; N = 1,173) with extensive variations in cultural values (i.e., power distance) and personality profiles (i.e., extraversion and openness). Multigroup factor analyses demonstrated that, across all cultures, a 3-factor model that treats awe, amusement, and pride as 3 unique emotions is superior to a single-factor model that clusters all 3 emotions together. Structurally, the scales of awe, amusement and pride were invariant across all countries. Furthermore, we found significant country-level differences in dispositional awe, with the largest discrepancy between the United States and Iran (d = 0.79); these differences are not likely due to cultural response biases. Results are discussed in terms of possible explanations for country-level differences and suggestions for future research. (PsycINFO Database Record


CRISPR/Cas9: an advanced tool for editing plant genomes.
To meet current challenges in agriculture, genome editing using sequence-specific nucleases (SSNs) is a powerful tool for basic and applied plant biology research. Here, we describe the principle and application of available genome editing tools, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeat associated CRISPR/Cas9 system. Among these SSNs, CRISPR/Cas9 is the most recently characterized and rapidly developing genome editing technology, and has been successfully utilized in a wide variety of organisms. This review specifically illustrates the power of CRISPR/Cas9 as a tool for plant genome engineering, and describes the strengths and weaknesses of the CRISPR/Cas9 technology compared to two well-established genome editing tools, ZFNs and TALENs.


Ventilator-associated pneumonia in extracorporeal membrane oxygenation-assisted patients.
Extracorporeal membrane oxygenation (ECMO) provides a circulatory and/or respiratory assistance in case of refractory cardiogenic shock or acute respiratory distress syndrome (ARDS). Due to their extreme critical illness, these patients usually require prolonged mechanical ventilation, which is an inherent risk of ventilator-associated pneumonia (VAP). Although microorganisms responsible of VAP on ECMO are similar to those found in non-ECMO patients, classical suspicion criteria of VAP are no longer relevant on ECMO. Frequent severe chest X-Ray impairments, and poor specificity of the classical biomarkers on ECMO make VAP diagnosis challenging. In addition, significant drug pharmacokinetic modifications by the device may lead to low plasmatic antibiotic concentration and potential treatment failure. Consequently, rate of treatment failure and relapse appear high in that population (up to 30%), with significant impact on mortality and on the ECMO duration.


Treatment noncompliance in randomized experiments: statistical approaches and design issues.
Treatment noncompliance in randomized experiments threatens the validity of causal inference and the interpretability of treatment effects. This article provides a nontechnical review of 7 approaches: 3 traditional and 4 newer statistical analysis strategies. Traditional approaches include (a) intention-to-treat analysis (which estimates the effects of treatment assignment irrespective of treatment received), (b) as-treated analysis (which reassigns participants to groups reflecting the treatment they actually received), and (c) per-protocol analysis (which drops participants who did not comply with their assigned treatment). Newer approaches include (d) the complier average causal effect (which estimates the effect of treatment on the subpopulation of those who would comply with their assigned treatment), (e) dose-response estimation (which uses degree of compliance to stratify participants, producing an estimate of a dose-response relationship), (f) propensity score analysis (which uses covariates to estimate the probability that individual participants will comply, enabling estimates of treatment effects at different propensities), and (g) treatment effect bounding (which calculates a range of possible treatment effects applicable to both compliers and noncompliers). The discussion considers the areas of application, the quantity estimated, the underlying assumptions, and the strengths and weaknesses of each approach.


An overview of generalized anxiety disorder: disease state--appropriate therapy.
This article reviews the prevalence, diagnosis, and treatment of generalized anxiety disorder (GAD). Patients with GAD often present to primary care physicians; frequently the disorder manifests with somatic symptoms that have no identifiable physiologic foundation. Accurate diagnosis and treatment often prove elusive, and health care resources are inappropriately consumed in the management of a wide array of complaints, including headache, noncardiac angina, fatigue, insomnia, or abdominal discomfort. Early diagnosis and intervention are critical; GAD is frequently associated with other anxiety and mood disorders, major depressive disorder among them. The differential diagnosis of GAD is complex, including medication side effects and substance-related dependence or withdrawal phenomena, as well as endocrine, neurologic, cardiorespiratory, and autoimmune disorders. GAD is differentiated from adjustment disorder with anxiety because only GAD can manifest without identifiable emotional stressors; it is differentiated from panic disorder largely on the basis of the chronicity of GAD and the episodic, abrupt nature of panic attacks, with the involvement of at least 4 autonomic, cardiopulmonary, neurologic, or other symptoms. In addition to psychotherapy, education, lifestyle modifications, and social support, several pharmacologic agents may be appropriate therapy for GAD. Given the chronic, nonremitting, relapsing character of GAD, use of benzodiazepines, which confer short-term relief, is usually ill-advised in long-term treatment because these agents can impair cognitive and psychomotor function, interact with various central nervous system depressants (eg, alcohol), and exhibit substantial potential for abuse, tolerance, dependence, and withdrawal effects. Buspirone and certain antidepressants, including the dual noradrenergic-serotonergic reuptake inhibitor venlafaxine, represent first-line therapy for GAD.


Social prescribing of nature therapy for adults with mental illness living in the community: A scoping review of peer-reviewed international evidence.
Social prescribing of nature therapy "green social prescribing" facilitates access to local nature-based activities that improve biopsychosocial wellbeing outcomes, are affordable, accessible, and can be adapted to context. These are becoming increasingly popular and gray literature is emerging, however, peer-reviewed scientific evidence is exiguous. This scoping review aimed to identify and critique peer-reviewed evidence for green social prescribing interventions and develop recommendations for research and clinical practice. Included studies were published in peer-reviewed journals in English on/after 1 January 2000. Participants were community-living adults with mental illness; Intervention was any green social prescribing program; Comparator was not restricted/required; Outcomes were any biopsychosocial measures; and any/all Study Designs were included. Twelve databases were searched on 15 October 2022; these were Academic Search Premier, APA PsycArticles, APA PsycINFO, CINAHL, Cochrane Library, Google Scholar, JSTOR, ProQuest, PubMed, Science Direct, Scopus, and Web of Science. The Mixed Methods Appraisal Tool was used to assess quality. Seven publications describing 6 unique studies (5 UK, 1 Australia) were identified including 3 mixed-methods, 2 qualitative, and 1 RCT. Participants included 334 adults (45% female, aged 35-70 years); sample sizes ranged from 9 to 164. All studies showed improvements in biopsychosocial wellbeing, and participants from most studies (n = 5) reported increased connection to the earth and intention to further access nature. Participant demographics and diagnoses were poorly reported, and intervention activities and assessments varied considerably. However, MMAT scores were good overall suggesting these studies may reliably demonstrate intervention outcomes. We conclude that socially prescribed nature therapy can improve biopsychosocial wellbeing and is a potentially important intervention for mental illness. Recommendations for research and clinical practice are provided.


MFQE 2.0: A New Approach for Multi-Frame Quality Enhancement on Compressed Video.
The past few years have witnessed great success in applying deep learning to enhance the quality of compressed image/video. The existing approaches mainly focus on enhancing the quality of a single frame, not considering the similarity between consecutive frames. Since heavy fluctuation exists across compressed video frames as investigated in this paper, frame similarity can be utilized for quality enhancement of low-quality frames given their neighboring high-quality frames. This task is Multi-Frame Quality Enhancement (MFQE). Accordingly, this paper proposes an MFQE approach for compressed video, as the first attempt in this direction. In our approach, we first develop a Bidirectional Long Short-Term Memory (BiLSTM) based detector to locate Peak Quality Frames (PQFs) in compressed video. Then, a novel Multi-Frame Convolutional Neural Network (MF-CNN) is designed to enhance the quality of compressed video, in which the non-PQF and its nearest two PQFs are the input. In MF-CNN, motion between the non-PQF and PQFs is compensated by a motion compensation subnet. Subsequently, a quality enhancement subnet fuses the non-PQF and compensated PQFs, and then reduces the compression artifacts of the non-PQF. Also, PQF quality is enhanced in the same way. Finally, experiments validate the effectiveness and generalization ability of our MFQE approach in advancing the state-of-the-art quality enhancement of compressed video.


The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression.
Tumorigenesis is associated with enhanced cellular glucose uptake and increased metabolism. Because the p53 tumor suppressor is mutated in a large number of cancers, we evaluated whether p53 regulates expression of the GLUT1 and GLUT4 glucose transporter genes. Transient cotransfection of osteosarcoma-derived SaOS-2 cells, rhabdomyosarcoma-derived RD cells, and C2C12 myotubes with GLUT1-P-Luc or GLUT4-P-Luc promoter-reporter constructs and wild-type p53 expression vectors dose dependently decreased both GLUT1 and GLUT4 promoter activity to approximately 50% of their basal levels. PG(13)-Luc activity, which was used as a positive control for functional p53 expression, was increased up to approximately 250-fold by coexpression of wild-type p53. The inhibitory effect of wild-type p53 was greatly reduced or abolished when cells were transfected with p53 with mutations in amino acids 143, 248, or 273. A region spanning -66/+163 bp of the GLUT4 promoter was both necessary and sufficient to mediate the inhibitory effects of p53. Furthermore, in vitro translated p53 protein was found to bind directly to two sequences in that region. p53-DNA binding was completely abolished by excess unlabeled probe but not by nonspecific DNA and was super-shifted by the addition of an anti-p53 antibody. Taken together, our data strongly suggest that wild-type p53 represses GLUT1 and GLUT4 gene transcription in a tissue-specific manner. Mutations within the DNA-binding domain of p53, which are usually associated with malignancy, were found to impair the repressive effect of p53 on transcriptional activity of the GLUT1 and GLUT4 gene promoters, thereby resulting in increased glucose metabolism and cell energy supply. This, in turn, would be predicted to facilitate tumor growth.


High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21.
The AML1 gene, situated in 21q22, is often rearranged in acute leukemias through t(8;21) translocation, t(12;21) translocation, or less often t(3;21) translocation. Recently, point mutations in the Runt domain of the AML1 gene have also been reported in leukemia patients. Observations for mutations of the Runt domain of the AML1 gene in bone marrow cells were made in 300 patients, including 131 with acute myeloid leukemia (AML), 94 with myelodysplastic syndrome (MDS), 28 with blast crisis chronic myeloid leukemia (CML), 3 with atypical CML, 41 with acute lymphoblastic leukemia (ALL), and 3 with essential thrombocythemia (ET). Forty-one of the patients had chromosome 21 abnormalities, including t(8;21) in 6 of the patients with AML, t(12;21) in 8 patients with ALL, acquired trisomy 21 in 17 patients, tetrasomy 21 in 7 patients, and constitutional trisomy 21 (Down syndrome) in 3 patients. A point mutation was found in 14 cases (4.7%), including 9 (22%) of the 41 patients with AML of the Mo type (MoAML) (none of them had detectable chromosome 21 rearrangement) and 5 (38%) of the 13 myeloid malignancies with acquired trisomy 21 (1 M1AML, 2 M2AML, 1 ET, and 1 atypical CML). In at least 8 of 9 mutated cases of MoAML, both AML alleles were mutated: 3 patients had different stop codon mutations of the 2 AML1 alleles, and 5 patients had the same missense or stop codon mutation in both AML1 alleles, which resulted in at least 3 of the patients having duplication of the mutated allele and deletion of the normal residual allele, as shown by FISH analysis and by comparing microsatellite analyses of several chromosome 21 markers on diagnosis and remission samples. In the remaining mutated cases, with acquired trisomy 21, a missense mutation of AML1, which involved 2 of the 3 copies of the AML1 gene, was found. Four of the 7 mutated cases could be reanalyzed in complete remission, and no AML1 mutation was found, showing that mutations were acquired in the leukemic clone. In conclusion, these findings confirm the possibility of mutations of the Runt domain of the AML1 gene in leukemias, mainly in MoAML and in myeloid malignancies with acquired trisomy 21. AML1 mutations, in MoAML, involved both alleles and probably lead to nonfunctional AML1 protein. As AML1 protein regulates the expression of the myeloperoxidase gene, the relationship between AML1 mutations and Mo phenotype in AML will have to be further explored. (Blood. 2000;96:2862-2869)


Technique for continuous tuning of optical fiber lasers.
For the first time to the authors' knowledge, we have demonstrated how thermally controlled overcoupled fused fiber couplers and fiber loop mirrors based on these couplers can be used as broadband tuning elements in a fiber laser cavity. No bulk optical elements play any role in this technique. Temperature tuning the coupler results in a shift in the coupling ratio or in the effective output coupler transmission. For a fixed pump source, and for a given laser cavity, this shift causes the lasing wavelength to shift. We have continuously tuned an Er silica fiber laser in this manner over the range of 1527-1570 nm in a ring configuration, and, using a fiber loop mirror with these couplers in a linear Tm silica fiber laser cavity, we have achieved more than 50-nm broadband tuning over the range of 1850-1910 nm. The tuning range and the sensitivity to temperature depend on the degree of overcoupling of the loop mirror coupler.


Phonation threshold pressure measurements during phonation by airflow interruption.
Most methods to measure phonation threshold pressure (PTP) are clinically impractical because they are invasive. This report concerns an airflow interruption system developed to allow noninvasive estimation of (PTP) at different levels of vocal intensity. An estimation of PTP was made for normal subjects with normal larynges and no voice complaints and for individuals who had dysphonia associated with vocal polyps to compare the estimated minimal pressure across the glottis that was required to sustain phonation in the two conditions. This was a methodological study designed to measure an unanticipated PTP from a subject. Subjects sustained a constant tone and the airflow was directed into a section of pipe with an airtight mask over the mouth and nose. The airflow, intramask pressure, and intensity of the acoustic output were recorded. A PTP was predicted from a difference between an estimate of the subglottal pressure and the vocal tract pressure at the point that phonation ceased after interruption of airflow. Eleven control subjects and 13 patients with vocal fold polyps were studied. In each population there were eight men and five women. The individuals in the group with vocal fold polyps averaged 39 years of age, and the control subject group averaged 49 years of age. Normal subjects produced a steady vowel /a/ at 75, 80, and 85 dB. Patients with polyps were unable to sustain phonation at these levels but were able to produce phonation at 65, 70, and 75 dB. The validity of the system was tested using a laryngeal model and in a patient with a normal larynx and voice who had a tracheotomy (placed for sleep apnea syndrome) which allowed direct measurement of subglottal pressure. The measured mean PTP levels (with standard deviation [SD]) for the control subjects were 2.38 (1.273), 2.67 (1.879), and 2.98 (2.23) cm H2O at 75, 80, and 85 dB, respectively. The measured mean PTP levels (with SD) for the patients with polyps were 4.79 (2.67), 5.85 (2.34), and 7.37 (3.26) cm H2O at 75, 80, and 85 dB, respectively. The differences in mean PTP between groups at 75, 80, and 85 dB were significant at P = .013, P = .017, and P = .010, respectively. The estimations of PTP for patients with vocal fold polyps were significantly higher than for the control subjects at three phonation levels.


Multiclass kernel-imbedded Gaussian processes for microarray data analysis.
Identifying significant differentially expressed genes of a disease can help understand the disease at the genomic level. A hierarchical statistical model named multiclass kernel-imbedded Gaussian process (mKIGP) is developed under a Bayesian framework for a multiclass classification problem using microarray gene expression data. Specifically, based on a multinomial probit regression setting, an empirically adaptive algorithm with a cascading structure is designed to find appropriate featuring kernels, to discover potentially significant genes, and to make optimal tumor/cancer class predictions. A Gibbs sampler is adopted as the core of the algorithm to perform Bayesian inferences. A prescreening procedure is implemented to alleviate the computational complexity. The simulated examples show that mKIGP performed very close to the Bayesian bound and outperformed the referred state-of-the-art methods in a linear case, a nonlinear case, and a case with a mislabeled training sample. Its usability has great promises to problems that linear-model-based methods become unsatisfactory. The mKIGP was also applied to four published real microarray data sets and it was very effective for identifying significant differentially expressed genes and predicting classes in all of these data sets.


Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells.


[Irreversible loss of the substantia compacta in metabolic bone diseases based on roentgenogrammetric data].
A study was made of gram roentgenographic indices of the compact substance (CS) in metabolic skeletal diseases: of the cortical layer summary thickness (CST) and a cortical area (CA) of the metacarpal bone II in 310 patients and the femoral cortical index (FCI) in 184 patients. Three components in CS loss were singled out: involution, metabolic and inert. Irreversibility of endocortical loss of the osseous tissue was shown and interpreted as fast developing involution osteoporosis. CST is a more sensitive index of CS loss than FCI though the combination of both indices provides more information on CS loss.


Microfluidic tuning of distributed feedback quantum cascade lasers.
In this Letter, we report the tuning of the emission wavelength of a single mode distributed feedback quantum cascade laser by modifying the mode effective refractive index using fluids. A fabrication procedure to encapsulate the devices in polymers for microfluidic delivery is also presented. The integration of microfluidics with semiconductor laser (optofluidics) is promising for new compact and portable lab-on-a-chip applications.


Sub-100 μW Multispectral Riemannian Classification for EEG-Based Brain-Machine Interfaces.
Motor imagery (MI) brain-machine interfaces (BMIs) enable us to control machines by merely thinking of performing a motor action. Practical use cases require a wearable solution where the classification of the brain signals is done locally near the sensor using machine learning models embedded on energy-efficient microcontroller units (MCUs), for assured privacy, user comfort, and long-term usage. In this work, we provide practical insights on the accuracy-cost trade-off for embedded BMI solutions. Our multispectral Riemannian classifier reaches 75.1% accuracy on a 4-class MI task. The accuracy is further improved by tuning different types of classifiers to each subject, achieving 76.4%. We further scale down the model by quantizing it to mixed-precision representations with a minimal accuracy loss of 1% and 1.4%, respectively, which is still up to 4.1% more accurate than the state-of-the-art embedded convolutional neural network. We implement the model on a low-power MCU within an energy budget of merely 198 μJ and taking only 16.9 ms per classification. Classifying samples continuously, overlapping the 3.5 s samples by 50% to avoid missing user inputs allows for operation at just 85 μW. Compared to related works in embedded MI-BMIs, our solution sets the new state-of-the-art in terms of accuracy-energy trade-off for near-sensor classification.


Verprolin function in endocytosis and actin organization. Roles of the Las17p (yeast WASP)-binding domain and a novel C-terminal actin-binding domain.
Vrp1p (verprolin, End5p) is the yeast ortholog of human Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP). Vrp1p localizes to the cortical actin cytoskeleton, is necessary for its polarization to sites of growth and is also essential for endocytosis. At elevated temperature, Vrp1p becomes essential for growth. A C-terminal Vrp1p fragment (C-Vrp1p) retains the ability to localize to the cortical actin cytoskeleton and function in actin-cytoskeleton polarization, endocytosis and growth. Here, we demonstrate that two submodules in C-Vrp1p are required for actin-cytoskeleton polarization: a novel C-terminal actin-binding submodule (CABS) that contains a novel G-actin-binding domain, which we call a verprolin homology 2 C-terminal (VH2-C) domain; and a second submodule comprising the Las17p-binding domain (LBD) that binds Las17p (yeast WASP). The LBD localizes C-Vrp1p to membranes and the cortical actin cytoskeleton. Intriguingly, the LBD is sufficient to restore endocytosis and growth at elevated temperature to Vrp1p-deficient cells. The CABS also restores these functions, but only if modified by a lipid anchor to provide membrane association. Our findings highlight the role of Las17p binding for Vrp1p membrane association, suggest general membrane association may be more important than specific targeting to the cortical actin cytoskeleton for Vrp1p function in endocytosis and cell growth, and suggest that Vrp1p binding to individual effectors may alter their physiological activity.


A linear noise approximation for stochastic epidemic models fit to partially observed incidence counts.
Stochastic epidemic models (SEMs) fit to incidence data are critical to elucidating outbreak dynamics, shaping response strategies, and preparing for future epidemics. SEMs typically represent counts of individuals in discrete infection states using Markov jump processes (MJPs), but are computationally challenging as imperfect surveillance, lack of subject-level information, and temporal coarseness of the data obscure the true epidemic. Analytic integration over the latent epidemic process is impossible, and integration via Markov chain Monte Carlo (MCMC) is cumbersome due to the dimensionality and discreteness of the latent state space. Simulation-based computational approaches can address the intractability of the MJP likelihood, but are numerically fragile and prohibitively expensive for complex models. A linear noise approximation (LNA) that approximates the MJP transition density with a Gaussian density has been explored for analyzing prevalence data in large-population settings, but requires modification for analyzing incidence counts without assuming that the data are normally distributed. We demonstrate how to reparameterize SEMs to appropriately analyze incidence data, and fold the LNA into a data augmentation MCMC framework that outperforms deterministic methods, statistically, and simulation-based methods, computationally. Our framework is computationally robust when the model dynamics are complex and applies to a broad class of SEMs. We evaluate our method in simulations that reflect Ebola, influenza, and SARS-CoV-2 dynamics, and apply our method to national surveillance counts from the 2013--2015 West Africa Ebola outbreak.


Metabolically Healthy and Unhealthy Normal Weight and Obesity.
Increased fat mass is an established risk factor for the cardiometabolic diseases type 2 diabetes and cardiovascular disease (CVD) and is associated with increased risk of all-cause and CVD mortality. However, also very low fat mass associates with such an increased risk. Whether impaired metabolic health, characterized by hypertension, dyslipidemia, hyperglycemia, insulin resistance, and subclinical inflammation, may explain part of the elevated risk of cardiometabolic diseases that is found in many subjects with very low fat mass, as it does in many obese subjects, is unknown. An important pathomechanism of impaired metabolic health is disproportionate fat distribution. In this article the risk of cardiometabolic diseases and mortality in subjects with metabolically healthy and unhealthy normal weight and obesity is summarized. Furthermore, the change of metabolic health during a longer period of follow-up and its impact on cardiometabolic diseases is being discussed. Finally, the implementation of the concept of metabolic health in daily clinical practice is being highlighted.


Care coordination for CSHCN: associations with family-provider relations and family/child outcomes.
To examine the association between receiving adequate care coordination (CC) with family-provider relations and family/child outcomes. We analyzed data from the 2005-2006 National Survey of Children With Special Health Care Needs. Eligible subjects were the 88% of families asked about experience with CC, service use, and communication. Respondents also reported on demographic characteristics, health status, family-provider relations, and family/child outcomes. Weighted, multivariate logistic regression models were constructed to assess independent associations of adequate CC with outcomes. Among families with children with special health care needs asked about CC, 68.2% reported receiving some type of CC help. Of these, 59.2% reported receiving adequate CC help, and 40.8% reported inadequate CC. Families that reported adequate compared with inadequate CC had increased odds of receiving family-centered care, experiencing partnerships with professionals, and satisfaction with services. They had decreased odds of having problems with referrals for specialty care, missing >6 school days because of illness (previous year), and visiting the emergency department more than twice in the previous 12 months (P < .001). Those who reported adequate compared with inadequate CC had decreased odds of the following: more than $500/y of out-of-pocket expenses, family financial burden, spending more than 4 hours/week coordinating care, and stopping/reducing work hours. Parental report of adequate CC was associated with favorable family-provider relations and family/child outcomes. Additional efforts are needed to discern which aspects of CC are most beneficial and for which subgroups of children with special health care needs.


Preoperative CA 125 is significant indicator of curative resection in gastric cancer patients.
To investigate the correlation among tumor markers, curative resection, and recurrence in gastric cancer. The patients with preoperative tumor makers [Carcinoembryonic antigen, Carbohydrate antigen (CA) 19-9, and CA 125] and elective gastrectomy between January 2000 and December 2009 at Chungbuk National University Hospital were enrolled in this study. We analyzed the relationship among the tumor makers, curative resection and recurrence, retrospectively. Among the 679 patients with gastric cancer, curative resection was 93.6% (n=636) and non-curative resection was 6.4% (n=43). The independent risk factors for the non-curative resection were tumor location and the positivity of preoperative serum CA 19-9 and CA 125 levels. After curative resection, the independent prognostic risk factors for recurrence in curative resection were gender, stage, and preoperative increased serum CA 125 level (HR=2.431, P=0.020), in a multivariate analysis. Preoperative CA 125 is a useful predictive biomarker for curative resection and prognostic biomarker for recurrence in gastric cancer patients.


Fibrillar structure of methylcellulose hydrogels.
It is well established that aqueous solutions of methylcellulose (MC) can form hydrogels on heating, with the rheological gel point closely correlated to the appearance of optical turbidity. However, the detailed gelation mechanism and the resulting gel structure remain poorly understood. Herein the fibrillar structure of aqueous MC gels was precisely quantified with a powerful combination of (real space) cryogenic transmission electron microscopy (cryo-TEM) and (reciprocal space) small-angle neutron scattering (SANS) techniques. The cryo-TEM images reveal that MC chains with a molecular weight of 300 000 g/mol associate into fibrils upon heating, with a remarkably uniform diameter of 15 ± 2 nm over a range of concentrations. Vitrified gels also exhibit heterogeneity in the fibril density on the length scale of hundreds of nanometers, consistent with the observed optical turbidity of MC hydrogels. The SANS curves of gels exhibit no characteristic peaks or plateaus over a broad range of wavevector, q, from 0.001-0.2 Å(-1). The major feature is a change in slope from I ∼ q(-1.7) in the intermediate q range (0.001 - 0.01 Å(-1)) to I ∼ q(-4) above q ≈ 0.015 Å(-1). The fibrillar nature of the gel structure was confirmed by fitting the SANS data consistently with a model based on the form factor for flexible cylinders with a polydisperse radius. This model was found to capture the scattering features quantitatively for MC gels varying in concentration from 0.09-1.3 wt %. In agreement with the microscopy results, the flexible cylinder model indicated fibril diameters of 14 ± 1 nm for samples at elevated temperatures. This combination of complementary experimental techniques provides a comprehensive nanoscale depiction of fibrillar morphology for MC gels, which correlates very well with macro-scale rheological behavior and optical turbidity previously observed for such systems.


Gene expression regulation and lineage evolution: the North and South tale of the hybrid polyploid Squalius alburnoides complex.
The evolution of hybrid polyploid vertebrates, their viability and their perpetuation over evolutionary time have always been questions of great interest. However, little is known about the impact of hybridization and polyploidization on the regulatory networks that guarantee the appropriate quantitative and qualitative gene expression programme. The Squalius alburnoides complex of hybrid fish is an attractive system to address these questions, as it includes a wide variety of diploid and polyploid forms, and intricate systems of genetic exchange. Through the study of genome-specific allele expression of seven housekeeping and tissue-specific genes, we found that a gene copy silencing mechanism of dosage compensation exists throughout the distribution range of the complex. Here we show that the allele-specific patterns of silencing vary within the complex, according to the geographical origin and the type of genome involved in the hybridization process. In southern populations, triploids of S. alburnoides show an overall tendency for silencing the allele from the minority genome, while northern population polyploids exhibit preferential biallelic gene expression patterns, irrespective of genomic composition. The present findings further suggest that gene copy silencing and variable expression of specific allele combinations may be important processes in vertebrate polyploid evolution.


Pharmacokinetics of N-acetylcysteine after oral and intravenous administration to healthy cats.
To describe the pharmacokinetics of N-acetylcysteine (NAC) in healthy cats after oral and IV administration. 6 healthy cats. In a crossover study, cats received NAC (100 mg/kg) via IV and oral routes of administration; there was a 4-week washout period between treatments. Plasma samples were obtained at 0, 5, 15, 30, and 45 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours after administration, and NAC concentrations were quantified by use of a validated high-performance liquid chromatography-mass spectrometry protocol. Data were analyzed via compartmental and noncompartmental pharmacokinetic analysis. Pharmacokinetics for both routes of administration were best described by a 2-compartment model. Mean ± SD elimination half-life was 0.78 ± 0.16 hours and 1.34 ± 0.24 hours for the IV and oral routes of administration, respectively. Mean bioavailability of NAC after oral administration was 19.3 ± 4.4%. The pharmacokinetics of NAC for this small population of healthy cats differed from values reported for humans. Assuming there would be similar pharmacokinetics in diseased cats, dose extrapolations from human medicine may result in underdosing of NAC in cats with acute disease. Despite the low bioavailability, plasma concentrations of NAC after oral administration at 100 mg/kg may be effective in the treatment of chronic diseases.


Self-Assembled Enzyme Nanoparticles for Carbon Dioxide Capture.
Enzyme-based processes have shown promise as a sustainable alternative to amine-based processes for carbon dioxide capture. In this work, we have engineered carbonic anhydrase nanoparticles that retain 98% of hydratase activity in comparison to their free counterparts. Carbonic anhydrase was fused with a self-assembling peptide that facilitates the noncovalent assembly of the particle and together were recombinantly expressed from a single gene construct in Escherichia coli. The purified enzymes, when subjected to a reduced pH, form 50-200 nm nanoparticles. The CO2 capture capability of enzyme nanoparticles was demonstrated at ambient (22 ± 2 °C) and higher (50 °C) temperatures, under which the nanoparticles maintain their assembled state. The carrier-free enzymatic nanoparticles demonstrated here offer a new approach to stabilize and reuse enzymes in a simple and cost-effective manner.


Single-Step Hydrothermal Synthesis of Biochar from H3PO4-Activated Lettuce Waste for Efficient Adsorption of Cd(II) in Aqueous Solution.
Developing an ideal and cheap adsorbent for adsorbing heavy metals from aqueous solution has been urgently need. In this study, a novel, effective and low-cost method was developed to prepare the biochar from lettuce waste with H3PO4 as an acidic activation agent at a low-temperature (circa 200 °C) hydrothermal carbonization process. A batch adsorption experiment demonstrated that the biochar reaches the adsorption equilibrium within 30 min, and the optimal adsorption capacity of Cd(II) is 195.8 mg∙g-1 at solution pH 6.0, which is significantly improved from circa 20.5 mg∙g-1 of the original biochar without activator. The fitting results of the prepared biochar adsorption data conform to the pseudo-second-order kinetic model (PSO) and the Sips isotherm model, and the Cd(II) adsorption is a spontaneous and exothermic process. The hypothetical adsorption mechanism is mainly composed of ion exchange, electrostatic attraction, and surface complexation. This work offers a novel and low-temperature strategy to produce cheap and promising carbon-based adsorbents from organic vegetation wastes for removing heavy metals in aquatic environment efficiently.