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Objective. Clinical diagnosis of epilepsy relies partially on identifying interictal epileptiform discharges (IEDs) in scalp electroencephalograms (EEGs). This process is expert-biased, tedious, and can delay the diagnosis procedure. Beyond automatically detecting IEDs, there are far fewer studies on automated methods to differentiate epileptic EEGs (potentially without IEDs) from normal EEGs. In addition, the diagnosis of epilepsy based on a single EEG tends to be low. Consequently, there is a strong need for automated systems for EEG interpretation. Traditionally, epilepsy diagnosis relies heavily on IEDs. However, since not all epileptic EEGs exhibit IEDs, it is essential to explore IED-independent EEG measures for epilepsy diagnosis. The main objective is to develop an automated system for detecting epileptic EEGs, both with or without IEDs. In order to detect epileptic EEGs without IEDs, it is crucial to include EEG features in the algorithm that are not directly related to IEDs. Approach. In this study, we explore the background characteristics of interictal EEG for automated and more reliable diagnosis of epilepsy. Specifically, we investigate features based on univariate temporal measures (UTMs), spectral, wavelet, Stockwell, connectivity, and graph metrics of EEGs, besides patient-related information (age and vigilance state). The evaluation is performed on a sizeable cohort of routine scalp EEGs (685 epileptic EEGs and 1229 normal EEGs) from five centers across Singapore, USA, and India. Main results. In comparison with the current literature, we obtained an improved Leave-One-Subject-Out (LOSO) cross-validation (CV) area under the curve (AUC) of 0.871 (Balanced Accuracy (BAC) of 80.9%) with a combination of three features (IED rate, and Daubechies and Morlet wavelets) for the classification of EEGs with IEDs vs. normal EEGs. The IED-independent feature UTM achieved a LOSO CV AUC of 0.809 (BAC of 74.4%). The inclusion of IED-independent features also helps to improve the EEG-level classification of epileptic EEGs with and without IEDs vs. normal EEGs, achieving an AUC of 0.822 (BAC of 77.6%) compared to 0.688 (BAC of 59.6%) for classification only based on the IED rate. Specifically, the addition of IED-independent features improved the BAC by 21% in detecting epileptic EEGs that do not contain IEDs. Significance. These results pave the way towards automated detection of epilepsy. We are one of the first to analyze epileptic EEGs without IEDs, thereby opening up an underexplored option in epilepsy diagnosis., (© 2022 IOP Publishing Ltd.)

Background: Many rapid nucleic acid testing systems have emerged to halt the development and spread of COVID-19. However, so far relatively few studies have compared the diagnostic performance between these testing systems and conventional detection systems. Here, we performed a retrospective analysis to evaluate the clinical detection performance between SARS-CoV-2 rapid and conventional nucleic acid detection system., Methods: Clinical detection results of 63,352 oropharyngeal swabs by both systems were finally enrolled in this analysis. Sensitivity (SE), specificity (SP), and positive and negative predictive value (PPV, NPV) of both systems were calculated to evaluate their diagnostic accuracy. Concordance between these two systems were assessed by overall, positive, negative percent agreement (OPA, PPA, NPA) and κ value. Sensitivity of SARS-CoV-2 rapid nucleic acid detection system (Daan Gene) was further analyzed with respect to the viral load of clinical specimens., Results: Sensitivity of Daan Gene was slightly lower than that of conventional detection system (0.86 vs. 0.979), but their specificity was equivalent. Daan Gene had ≥98.0% PPV and NPV for SARS-CoV-2. Moreover, Daan Gene demonstrated an excellent test agreement with conventional detection system (κ = 0.893, p = 0.000). Daan Gene was 99.31% sensitivity for specimens with high viral load (C t  < 35) and 50% for low viral load (C t  ≥ 35)., Conclusions: While showing an analytical sensitivity slightly below than that of conventional detection system, rapid nucleic acid detection system may be a diagnostic alternative to rapidly identify SARS-CoV-2-infected individuals with high viral loads and a powerful complement to current detection methods., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

The sole clinicopathological characteristic is not enough for the prediction of survival of patients with clear cell renal cell carcinoma (ccRCC). However, the survival prediction model constructed by machine learning technology for patients with ccRCC using clinicopathological features is rarely reported yet. In this study, a total of 5878 patients diagnosed as ccRCC from four independent patient cohorts were recruited. The least absolute shrinkage and selection operator analysis was implemented to identify optimal clinicopathological characteristics and calculate each coefficient to construct the prognosis model. In addition, weighted gene co-expression network and gene enrichment analysis associated with risk score were also carried out. Three clinicopathologic features were selected for the construction of the prognosis risk score model as the prognostic factors of ccRCC, including tumor size, tumor grade, and tumor stage. In the CPTAC (Clinical Proteomic Tumor Analysis Consortium) cohort, the General cohort, the SEER (Surveillance, Epidemiology, and End Results) cohort, and the Huashan cohort, patients with high-risk score had worse clinical outcomes than patients with low-risk score (hazard ratio 5.15, 4.64, 3.96, and 5.15, respectively). Further functional enrichment analysis demonstrated that our machine learning-based risk score was significantly connected with some cell proliferation-related pathways, consisting of DNA repair, cell division, and cell cycle. In summary, we developed and validated a machine learning-based prognosis prediction model, which might contribute to clinical decision-making for patients with ccRCC., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

UpToDate is an evidence-based resource to support clinical decisionmaking created by doctors. UpToDate has a wide dissemination in Germany. In a multicenter study, physicians, students, scientists and other healthcare professionals at four German universities were asked about their use of UpToDate. The survey was answered 1,083 times, including 540 doctors. 76% of the surveyed physicians (but only 54% of chief physicians) used UpToDate. The lack of knowledge about Up-ToDate amounted to 10-41%, depending on the user group. 90 to 95% of all clinically active persons named the quick, general overview of diagnosis and therapy of diseases as the main advantage of UpToDate. Every fourth senior doctor pointed to reduced length of stay as a result of UpToDate, (almost) every fourth chief physician stated that UpToDate saved costs. UpToDate is an important but expensive resource in patient care and should be promoted more aggressively by the librarians - given the existing lack of knowledge about the existence of this resource. [ABSTRACT FROM AUTHOR]

Background: Stroke-related complications are barriers to patients'ecovery leading to increasing morbidity, mortality, and health care costs, decreasing patient's quality of life. The purpose of this study was to quantify incidence and risk factors of stroke-related complications during the first year after discharge from rehabilitation ward. Methods: A prospective observational study was conducted in nine tertiary-care rehabilitation centers. We evaluated the incidence of morbidities during the first year after stroke, including musculoskeletal pain, neuropathic pain, pneumonia, deep vein thrombosis (DVT), pressure ulcer, spasticity, shoulder subluxation, joint contracture, dysphagia, urinary incontinence, anxiety and depression. The complications at discharge and at month-12 were compared using the McNemar test. Univariate analysis and multiple logistic regression analysis by forward stepwise method were used to determine factors predicting the complications at month-12. Results: Two hundred and fourteen from 327 patients (65.4%) were included. The age was 62.1 ± 12.5 years, and 57.9% were male. In 76.8% of the patients at least one complication was found during the first year after stroke. Those complications were musculoskeletal pain (50.7%), shoulder subluxation (29.3%), depression (21.2%), spasticity (18.3%), joint contracture (15.7%) and urinary incontinence (14.4%). Other complications less than 5% were dysphagia (3.5%), pressure ulcer (2.6%), infection (1.5%), and neuropathic pain (3.0%). Nearly 60% of patients with complications at discharge still had the same complaints after one year. Only 7.6% were without any complication. Morbidity was significantly associated with age and type of stroke. Using multiple logistic regression analysis, age and physical complications at discharge were significant risk factors for physical and psychological morbidities after stroke respectively (OR = 2.1, 95% CI 1.2, 3.7; OR = 3.1, 95% CI 1.3, 7.1). Conclusion: Long-term complications are common in stroke survivors. More than three-fourths of the patients developed at least one during the first year after rehabilitation. Strategies to prevent complications should be concerned especially on musculoskeletal pain which was the most common complaint. Physical complications at discharge period associated with psychological complications at 1 year followed up. More attention should be emphasized on patients age older than 60 years who were the major risk group for developing such complications. [ABSTRACT FROM AUTHOR]

Background: Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Electroconvulsive therapy and pharmacotherapy are each efficacious in the treatment of PD. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the acute pharmacologic treatment of PD. However, little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical importance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder. Methods/design: The primary goal of this multicenter randomized placebo-controlled trial is to assess the risks and benefits of continuing antipsychotic medication in persons with PD once the episode of depression has responded to treatment with an antidepressant and an antipsychotic. Secondary goals are to examine age and genetic polymorphisms as predictors or moderators of treatment variability, potentially leading to more personalized treatment of PD. Individuals aged 18-85 years with unipolar psychotic depression receive up to 12 weeks of openlabel treatment with sertraline and olanzapine. Participants who achieve remission of psychosis and remission/nearremission of depressive symptoms continue with 8 weeks of open-label treatment to ensure stability of remission. Participants with stability of remission are then randomized to 36 weeks of double-blind treatment with either sertraline and olanzapine or sertraline and placebo. Relapse is the primary outcome. Metabolic changes are a secondary outcome. Discussion: This trial will provide clinicians with much-needed evidence to guide the continuation and maintenance treatment of one of the most disabling and lethal of psychiatric disorders. [ABSTRACT FROM AUTHOR]

We propose a hierarchical Bayesian model for analyzing multi-site experimental fMRI studies. Our method takes the hierarchical structure of the data (subjects are nested within sites, and there are multiple observations per subject) into account and allows for modeling between-site variation. Using posterior predictive model checking and model selection based on the deviance information criterion (DIC), we show that our model provides a good fit to the observed data by sharing information across the sites. We also propose a simple approach for evaluating the efficacy of the multi-site experiment by comparing the results to those that would be expected in hypothetical single-site experiments with the same sample size. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to investigate whether it is possible to pool together diffusion spectrum imaging data from four different scanners, located at three different sites. Two of the scanners had identical configuration whereas two did not. To measure the variability, we extracted three scalar maps (ADC, FA and GFA) from the DSI and utilized a region and a tract-based analysis. Additionally, a phantom study was performed to rule out some potential factors arising from the scanner performance in case some systematic bias occurred in the subject study. This work was split into three experiments: intra-scanner reproducibility, reproducibility with twin-scanner settings and reproducibility with other configurations. Overall for the intra-scanner and twin-scanner experiments, the region-based analysis coefficient of variation (CV) was in a range of 1%–4.2% and below 3% for almost every bundle for the tract-based analysis. The uncinate fasciculus showed the worst reproducibility, especially for FA and GFA values (CV 3.7–6%). For the GFA and FA maps, an ICC value of 0.7 and above is observed in almost all the regions/tracts. Looking at the last experiment, it was found that there is a very high similarity of the outcomes from the two scanners with identical setting. However, this was not the case for the two other imagers. Given the fact that the overall variation in our study is low for the imagers with identical settings, our findings support the feasibility of cross-site pooling of DSI data from identical scanners. [Copyright &y& Elsevier]

Abstract: The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126μmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p <0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population. [Copyright &y& Elsevier]

Research on treatments for patients with co-occurring psychiatric and substance use disorders is of core importance and at the same time highly challenging as it includes patients that are normally excluded from clinical studies. Such research may require methodological adaptations which in turn create new challenges. However, the challenges that arise in such studies are insufficiently discussed in the literature. The aim of this methodology paper is, firstly, to discuss the methodological adaptations that may be required in such research; secondly, to describe how such adaptations created new challenges in a group-randomized clinical trial on Integrated Treatment amongst patients with co-occurring psychiatric and substance use disorders. We also discuss how these challenges might be understood and highlight lessons for future research in this field. Trial registration: NCT00447733. [ABSTRACT FROM AUTHOR]

Abstract: Modified Zelen''s approach is a randomization technique useful in multi-center trials where balance in treatment assignments within a center is desired. It has great balancing properties in a study with equal allocation to several treatment arms. This technique can also be used in studies with unequal allocation, where it would provide an allocation ratio close to the targeted one within centers as well as across centers. However, the implementation of the modified Zelen''s approach for unequal allocation involves more than just imposing a constraint on within-center imbalance in treatment assignments, as is the case with equal allocation. Failure to account for this might provide a potential for accidental bias and (even in a double-blind study) selection and evaluation bias. The naive expansion of the modified Zelen''s approach to unequal allocation can also lead to a shift in the re-randomization distribution of the between-group difference in treatment means. This paper will explain why and will offer an easy way to expand the modified Zelen''s approach to unequal allocation that allows one to avoid these issues. The expansion to unequal allocation of another very useful in multi-center trials technique where partial blocks of supplies are sent to the centers will be offered. [Copyright &y& Elsevier]

Abstract: The inter-site and intra-site variability of system performance of MRI scanners (due to site-dependent and time-variant variations) can have significant adverse effects on the integration of multi-center DTI data. Measurement errors in accuracy and precision of each acquisition determine both the inter-site and intra-site variability. In this study, multiple scans of an identical isotropic diffusion phantom and of the brain of a traveling human volunteer were acquired at MRI scanners from the same vendor and with similar configurations at three sites. We assessed the feasibility of multi-center DTI studies by direct quantification of accuracy and precision of each dataset. Accuracy was quantified via comparison to carefully constructed gold standard datasets while precision (the within-scan variability) was estimated by wild bootstrap analysis. The results from both the phantom and human data suggest that the inter-site variation in system performance, although relatively small among scanners of the same vendor, significantly affects DTI measurement accuracy and precision and therefore the effectiveness for the integration of multi-center DTI measurements. Our results also highlight the value of a DTI-specific phantom in identifying and quantifying measurement errors due to site-dependent variations in the system performance, and its usefulness for quality assurance/quality control in multi-center DTI studies. In addition, we observed that the within-scan variability of each data acquisition, as assessed by wild bootstrap analysis, is of the same magnitude as the inter-site and intra-site variability. We propose that by weighing datasets based on their variability, as evaluated by wild bootstrap analysis, one can improve the quality of the dataset. This approach will provide a more effective integration of datasets from multi-center DTI studies. [Copyright &y& Elsevier]

Objective: To evaluate the clinical value of 2-[F]fluoro-2-deoxy- d-glucose positron emission tomography (FDG-PET) for the diagnosis of fever of unknown origin (FUO), we performed a Japanese multi-center retrospective survey. Methods: A total of 81 consecutive patients with FUO who underwent FDG-PET at 6 institutions between July 2006 and December 2007 were retrospectively evaluated. FDG uptake was visually evaluated using a 4-grade scale. The efficacy of FDG-PET for the evaluation of FUO, the provision of additional diagnostic information, the clinical impact on therapeutic decisions (4-grade scale), and the diagnostic performance compared with the final diagnosis were evaluated. Results: The diagnostic results were analyzed according to 4 groups of final diagnoses: infection, arthritis/vasculitis/autoimmune/collagen disease (A/V), tumor/granuloma (T/G), and other/unknown (O/U). Sensitivity was highest in T/G, followed by infection, A/V and O/U [100%(7/7), 89%(24/27), 65%(11/17), 0%(0/1) respectively]. Clinical impact and mean FDG score showed the same tendency. Additional information was highest in infection followed by T/G, A/V, and O/U [76%(22/29), 75%(6/8), 43%(9/21), 23%(5/22), respectively]. The O/U group showed a high specificity (84%, 16/19) and accurately excluded active focal inflammatory diseases and malignancy. The use of steroids for the treatment of fever seemed to mask the lesions and modified the results, especially in the A/V group (4 false negatives in 8 steroid users out of 21 A/V patients). The prevalence of each disease in each hospital significantly affected the effectiveness of FDG-PET for the diagnosis of FUO. The mean FDG uptake score and additional information (70%, 31/44 vs. 30%, 11/37, respectively) in national hospital (NH) was significantly higher than in university hospitals (UH). A Grade 3 clinical impact, in which the FDG PET results changed the clinical decision, was seen in 50% (22/44) of the patients in the NH group and 13.5% (5/37) of the patients in the UH group. The sensitivity (91%, 30/33; 63%, 12/19) and specificity (60%, 6/10; 86%, 12/14) of the results in the NH and UH groups differed. The total sensitivity was 81% (42/52), specificity was 75% (18/24). The NH group included a large number of cases with infectious diseases (50%, 23/44), while the UH group included a large number of A/V cases (38%, 14/37) and O/U cases (41%, 15/37). Conclusion: FDG-PET for the diagnosis of FUO provided additional diagnostic information and had a high clinical impact, especially among patients with infectious diseases. It was also helpful in cases with unknown or other miscellaneous diseases by allowing the exclusion of focally active diseases. The prevalence of diseases in hospitals significantly affected the effectiveness of FDG-PET for the diagnosis of FUO. FDG-PET is a useful examination providing various degrees of clinical impact for the management of FUO, depending on the characteristics of the patient and the hospital. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To estimate the cumulative incidence of self-reported influenza vaccination (“vaccination coverage”) and investigate predictors in HIV-infected women. Methods: In an ongoing cohort study of HIV-infected women in five US cities, data from two influenza seasons (2006–2007 n =1209 and 2007–2008 n =1161) were used to estimate crude and adjusted prevalence ratios (aPR) and 95% confidence intervals ([,]) from Poisson regression with robust variance models using generalized estimating equations (GEE). Results: In our study, 55% and 57% of HIV-infected women reported vaccination during the 2006–2007 and 2007–2008 seasons, respectively. Using data from both seasons, older age, non-smoking status, CD4 T-lymphocyte (CD4) count ≥200 cells/mm3, and reporting at least one recent healthcare visit was associated with increased vaccination coverage. In the 2007–2008 season, a belief in the protection of the vaccine (aPR=1.38 [1.18, 1.61]) and influenza vaccination in the previous season (aPR=1.66 [1.44, 1.91]) most strongly predicted vaccination status. Conclusion: Interventions to reach unvaccinated HIV-infected women should focus on changing beliefs about the effectiveness of influenza vaccination and target younger women, current smokers, those without recent healthcare visits, or a CD4 count <200 cells/mm3. [Copyright &y& Elsevier]

To determine the prognostic value of myocardial ischemia, function and coronary risk factors on total and hard cardiac events using myocardial perfusion imaging in a Japanese population. A prospective cohort study was performed in 117 Japanese hospitals, each with a nuclear cardiology facility. A total of 4,031 patients with suspected or confirmed ischemic heart disease were registered. The patients were followed up for a year to investigate total and hard events, and those who had any events were followed up for 3 years to evaluate subsequent hard events. A stress-rest gated myocardial perfusion study was performed with 99mTc-tetrofosmin using gated single-photon emission computed tomography (SPECT) and analyzed by semi-quantitative scores. During the 1-year follow-up period, 263 (6.5%) patients had total events comprising all-cause death, non-fatal myocardial infarction (MI), heart failure, unstable angina, angina pectoris and coronary revascularization. Cardiac death occurred in 23 patients (0.6%) and non-fatal MI in 11 (0.3%). Among patients with ejection fraction (EF) of <45% and a summed difference score (SDS) of ≥2, 18.7% (2.4% for cardiac death and 0.6% for non-fatal MI) experienced total events compared with 3.9% (0.3% for cardiac death and 0.2% for non-fatal MI; P < 0.0001) of those with EF ≥ 45% and SDS < 2. Multivariate analysis identified EF, SDS, age, history of revascularization and diabetes as significant predictors of all events, while the significant predictors were age and EF for hard events. When the patients who had heart failure in the first year were followed up, 9 of 41 (22.0%) experienced cardiac death in the subsequent 3-year follow-up period. Myocardial ischemia defined by SDS and ventricular function were the main predictors of total events despite the relatively low incidence of hard events in this Japanese population. In patients with cardiac events in a year, closer attention should be paid to subsequent hard events particularly in patients with heart failure. [ABSTRACT FROM AUTHOR]

A retrospective analysis was performed of 12,888 cases of larynx and hypopharynx carcinoma diagnosed in 19 ENT Departments in Poland during an 11-year period from 1991 to 2001. An assessment of basic epidemiological data, including also tumor site and disease stage at the time of diagnosis, was conducted. Epidemiological trends over the 11-year period of the analysis were examined. The average M:F proportion was 8:1, with a significant increase in the number of female patients during the analyzed period. The predominant localization of carcinoma was in the glottis (47.2%), followed by the supraglottis (40.3%) and pyriform sinus (7.8%). A significant increase in pyriform sinus tumors was observed in the analyzed period. Majority of cases (57.4%) presented with local advanced stage (T3 + T4) carcinoma of the larynx and hypopharynx, with the highest rate (81.0%) for the pyriform sinus carcinomas, and with the lowest rate for glottic tumors (41.8%). Regional lymph node metastases were diagnosed in 47.7% of the analyzed cases, with the highest rate (82.2%) in cases of pyriform sinus carcinomas, and the lowest (31.7%) in glottic carcinomas. In the 11-year period, a significant drop in N0 cases and a tendency toward increased rates of N2 and N3 lymph nodes metastases cases of supraglottic carcinoma were observed. Distant metastases at the time of diagnosis were registered in 2.2% of the analyzed cases, with the highest percentage in the posterior pharyngeal wall (7.6%) and pyriform sinus (7.4%) carcinomas. [ABSTRACT FROM AUTHOR]

An international collaborative study of 45 transplant centers was undertaken at the 14th International HLA (human leukocyte antigen) and Immunogenetics Workshop to see if HLA antibodies detected posttransplant are predictive of chronic graft failure. With the newly developed assay, MICA (major histocompatibility complex class I-related chain A) antibodies were also measured and their effect analyzed. Total of 5219 sera from patients who were more than 6 months posttransplant with functioning graft were tested for HLA antibodies by enzyme-linked immunosorbent assay, flow cytometry, or Luminex. HLA antibodies were found in 27.2% of kidney patients, 23.6% in the liver, 52.7% in the heart, and 21.7% in the lung. The method of antibody testing did not have a marked influence on the frequency of antibodies detected. MICA antibodies were detected in 15% of kidneypatients, 30% of heart patients, and 31% of liver patients. Among 948 kidney patients who had HLA antibodies, 7.3% had rejected their graft within 1 year of testing, compared with 1.7% in 2615 patients without HLA antibodies ( P= 0.8 × 10−17). Death occurred in 1.4% of total kidney patients and did not correlate to the presence of antibodies. We conclude that patients with posttransplant HLA antibodies indeed have a higher rate of chronic graft failure and that posttransplant antibodies are predictive of chronic rejection. [ABSTRACT FROM AUTHOR]

Abstract: Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal–parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory. [Copyright &y& Elsevier]

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and an increased risk of fragility fractures. Bone mineral density (BMD) is the most important determinant of osteoporotic fracture risk, but the genes responsible for BMD regulation and fracture are incompletely defined. To enable multi-center studies to examine the genetic influences on BMD there is a requirement to standardize measurements across different manufacturers of bone densitometers, different versions of machines and different normative ranges. This paper describes a method developed to allow near-identical subjects with low age-adjusted BMD (based on Z-scores) to be recruited in 17 centers using 27 different densitometers. Cross-calibration was based on measurements using a European spine phantom circulated to all centers and measured ten times on each individual machine. From theses values an individual exponential curve, based on nominal versus observed BMD, was derived for each machine. As expected, there were large and significant variations in nominal BMD values, not only between scanners from different manufacturers but also between different versions of scanners from the same manufacturer. Hologic scanners tended to underestimate the nominal BMD, while Lunar scanners overestimated the value. Norland scanners gave mixed values over estimating BMD at the lower nominal value (0.5 g/cm2) while underestimating the value at the higher value (1.5 g/cm2). The validity of the exponential equations was tested using hip and spine measurements on 991 non-proband women from a familial osteoporosis study (FAMOS). After cross-calibration there was a considerable reduction in variation between machines. This observation, coupled with the absence of a similar reduction in variation attributable to a linear regression on age, demonstrated the validity of the cross-calibration approach. Use of the cross-calibration curves along with a standard normative range (in the case of this study, the Hologic normative range) allowed age-specific Z-scores to be used as an inclusion criterion in this genetic study, a method that will be useful for other trials where age-specific BMD inclusion criteria are required. [ABSTRACT FROM AUTHOR]

Serum lipid responses to dietary modification are partly determined by genetic factors. The objective of the present study was to investigate the influence of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene on serum lipid and lipoprotein responses to n−3 fatty acid supplementation. A total of 76 men and 74 women (age 49±8 years, body mass index 26.5±3.0 kg/m2) participated in a controlled multi-center study. Subjects were randomly assigned to consume either fish oil supplements (3.6 g n−3 fatty acids/day containing 2.4 g of EPA and DHA) or placebo capsules containing olive oil for 3 months. At baseline, the Pro12Ala polymorphism was not associated with serum total and lipoprotein lipid concentrations or lipoprotein lipase activity in the fasting state. After the 3-month study period, carriers of the Ala12 allele presented a greater decrease in serum triacylglycerol concentration in response to n−3 fatty acid supplementation than did subjects with the Pro12Pro genotype when the total dietary fat intake was below 37 E% (p=0.003) or the intake of saturated fatty acids was below 10 E% (p=0.006). Changes in serum total cholesterol, serum LDL cholesterol and HDL cholesterol concentrations were similar among the genotypes in the n−3 fatty acid supplementation group and in the placebo group. In conclusion, the Pro12Ala polymorphism of the PPAR-γ2 gene may modify the inter-individual variability in serum triacylglycerol response to n−3 fatty acid supplementation. [Copyright &y& Elsevier]

Background: Human coronaviruses (HCoVs) are associated with upper respiratory tract infections. Although studies have analyzed the clinical and epidemiological characteristics of HCoV-associated infections, no multi-center studies have been conducted in Korean children. We aimed to describe the epidemiology and clinical characteristics of HCoV-associated infection in children., Methods: We retrospectively reviewed medical records of children in whom HCoVs were detected using multiplex reverse transcriptase-polymerase chain reaction amplification in five centers from January 2015 to December 2019., Results: Overall, 1,096 patients were enrolled. Among them, 654 (59.7%) patients were male. The median age was 1 year [interquartile range (IQR), 0-2 years]. HCoVs were identified mainly in winter (55.9%). HCoV-229E, HCoV-OC43, and HCoOV-NL63 were detected mainly in winter (70.9, 55.8, and 57.4%, respectively), but HCoV-HKU1 was mainly identified in spring (69.7%). HCoV-OC43 (66.0%) was detected most frequently, followed by HCoV-NL63 (33.3%), and HCoV-229E (7.7%). Two different types of HCoVs were co-detected in 18 samples, namely. Alphacoronavirus-betacoronavirus co-infection ( n = 13) and, alphacoronavirus-alphacoronavirus co-infection ( n = 5). No betacoronavirus-betacoronavirus co-infection was detected. Patients were diagnosed with upper respiratory tract infection (41.4%), pneumonia (16.6%), acute bronchiolitis (15.5%), non-specific febrile illness (13.1%), croup (7.3%), and acute gastroenteritis (5.1%). There were 832 (75.9%) hospitalized patients with a median duration of hospitalization of 4 days (IQR, 3-5 days); 108 (9.9%) patients needed supplemental oxygen with 37 (3.4%) needing high-flow nasal cannula or mechanical ventilation. There were no deaths., Conclusion: HCoV-associated infections exhibit marked seasonality with peaks in winter. Patients with lower respiratory tract infection, a history of prematurity, or underlying chronic diseases may progress to a severe course and may need oxygen therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jo, Choi, Oh, Kim, Choi, Jo and Park.)

International literature reports that nursing students feel unprepared when facing patients and families within dying care. They consider their curricula inadequate in teaching end-of-life care and promoting the attitudes required to care for dying patients. Findings of recent studies exploring nursing students' attitudes towards care of the dying patient are often contradictory. To explore Italian nursing students' attitudes towards caring for dying patients. A multicenter cross-sectional study was conducted. The Bachelor's Degree in Nursing courses of four Universities of the Lazio Region. The sample included 1193 students. Data were collected between September 2017 and March 2018 using the Italian version of FATCOD-B-I. The differences between the mean scores were compared through t -test or ANOVA. Associations between scores and participant characteristics were evaluated through generalized linear regression. The mean score of FATCOD-B-I was 115.3 (SD = 9.1). Higher scores were significantly associated with training in palliative care (p < 0.0001) and experience with terminally ill patients (p < 0.0001). Students manifested more negative attitudes when they perceived patients losing hope of recovering, and patient's family members interfering with health professionals' work. Uncertainties emerged around knowledge of opioid drugs, decision-making, concepts of death and dying, management of mourning, and relational aspects of patient care. Italian nursing students seem to have more positive attitudes towards care of dying patients than most other countries. They believe that caring for a terminal patient is a formative, useful experience but they do not feel adequately prepared in practice. Deeper palliative care education, integrated with practical training, would prepare students better, enabling them to discover their own human and professional capacity to relieve suffering. • Italian nursing students have more positive attitudes than those of other countries. • For Italian nursing students, the experience with dying patients is formative. • Education and experience can model and transform students' attitudes. • Students do not feel adequately prepared to deal with end-of-life care. • Palliative care education is needed to prepare students to empathize with patients. [ABSTRACT FROM AUTHOR]

Background: The accumulation of risk for the development of rheumatoid arthritis (RA) is regarded as a continuum that may start with interacting environmental and genetic factors, proceed with the initiation of autoimmunity, and result in the formation of autoantibodies such as anti-citrullinated peptide antibodies (ACPA). In parallel, at-risk individuals may be asymptomatic or experience joint pain (arthralgia) that is itself non-specific or clinically suspicious for evolving RA, even in the absence of overt arthritis. Optimal strategies for the management of people at-risk of RA, both for symptom control and to delay or prevent progression to classifiable disease, remain poorly understood., Methods: To help address this, groups of stakeholders from academia, clinical rheumatology, industry and patient research partners have collaborated to advance understanding, define and study different phases of the at-risk state. In this current report we describe different European initiatives in the field and the successful effort to build a European Registry of at-risk people to facilitate observational and interventional research., Results: We outline similarities and differences between cohorts of at-risk individuals at institutions spanning several countries, and how to best combine them within the new database. Over the past 2 years, besides building the technical infrastructure, we have agreed on a core set of variables that all partners should strive to collect for harmonization purposes., Conclusion: We emphasize to address this process from different angles and touch on the biologic, epidemiologic, analytic, and regulatory aspects of collaborative studies within a meta-database of people at-risk of RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Studenic, Hensvold, Kleyer, van der Helm-van Mil, Pratt, Sieghart, Krönke, Williams, de Souza, Karlfeldt, Johannesson, Krogh, Klareskog and Catrina.)

Objective: The purpose of this study was to investigate the accuracy of one-step automated orthodontic diagnosis of skeletodental discrepancies using a convolutional neural network (CNN) and lateral cephalogram images with different qualities from nationwide multi-hospitals., Methods: Among 2,174 lateral cephalograms, 1,993 cephalograms from two hospitals were used for training and internal test sets and 181 cephalograms from eight other hospitals were used for an external test set. They were divided into three classification groups according to anteroposterior skeletal discrepancies (Class I, II, and III), vertical skeletal discrepancies (normodivergent, hypodivergent, and hyperdivergent patterns), and vertical dental discrepancies (normal overbite, deep bite, and open bite) as a gold standard. Pre-trained DenseNet-169 was used as a CNN classifier model. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis, t-stochastic neighbor embedding (t-SNE), and gradientweighted class activation mapping (Grad-CAM)., Results: In the ROC analysis, the mean area under the curve and the mean accuracy of all classifications were high with both internal and external test sets (all, > 0.89 and > 0.80). In the t-SNE analysis, our model succeeded in creating good separation between three classification groups. Grad-CAM figures showed differences in the location and size of the focus areas between three classification groups in each diagnosis., Conclusions: Since the accuracy of our model was validated with both internal and external test sets, it shows the possible usefulness of a one-step automated orthodontic diagnosis tool using a CNN model. However, it still needs technical improvement in terms of classifying vertical dental discrepancies.

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Background: Due to the absence of specific symptoms and low survival rate, efficient biomarkers for hepatocellular carcinoma (HCC) diagnosis are urgently required. The purpose of this study was to evaluate the diagnostic performance of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and to determine the optimal cutoff values for HBV infection-related HCC., Methods: We conducted a cross-sectional, multi-center study in China to ascertain the cutoff value for HCC patients in the context of CHB- and HBV-related cirrhosis. The receiver operating characteristic curve (ROC) and the area under the curve (AUC) were used to evaluate the diagnostic performance of PIVKA-II., Results: This study enrolled 784 subjects and demonstrated that PIVKA-II had a sensitivity of 84.08% and a specificity of 90.43% in diagnosis HCC from chronic liver diseases. PIVKA-II at a cutoff of 37.5 mAU/mL yielded an AUC of 0.9737 (sensitivity 91.78% and specificity 96.30%) in discriminating HCC from chronic hepatitis B (CHB) patients. PIVKA-II at a cutoff of 45 mAU/mL yielded an AUC of 0.9419 (sensitivity 77.46% and specificity 95.12%) in discriminating HCC- from HBV-related cirrhosis patients. Furthermore, using a cutoff value of 40 mAU/mL for PIVKA-II as an HCC marker, only 4.81% (15/312) was positive in chronic hepatitis and 12.80% (37/289) in cirrhosis patients, revealing the satisfactory specificity of PIVKA-II in chronic liver disease of different etiologies., Conclusion: Our data indicated that PIVKA-II had satisfactory diagnostic efficiencies and could be used as a screening or surveillance biomarker in HCC high-risk population., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Limited evidence is available on the associations of long-term exposure to various fine particulate matter (PM 2.5) constituents with sub-clinical outcomes of cardiovascular disease (CVD) in China. We aimed to explore the associations of PM 2.5 and its constituents with blood pressure (BP), fasting glucose, and cardiac electrophysiological (ECG) properties based on a national survey of 5852 Chinese adults, who participated in the Sub-Clinical Outcome of Polluted Air study, from July 2017 to March 2019. Annual residential exposure to PM 2.5 and its constituents of each subject was predicted by a satellite-based mode. We assessed the associations between five main constituents [organic matter (OM), black carbon (BC), sulfate (SO 4 2−), nitrate (NO 3 −), ammonium (NH 4 +)] of PM 2.5 and systolic BP (SBP), diastolic BP (DBP), fasting glucose, and ECG measurements (PR, QRS, QT, and QTc interval) using multivariable linear regression models. Long-term PM 2.5 exposure was significantly associated with increased levels of fasting glucose, DBP, and ECG measurements. An IQR increase in OM (8.2 μg/m3) showed considerably stronger associations with an elevated fasting glucose of 0.39 mmol/L (95%CI confidence interval: 0.28, 0.49) compared with other PM 2.5 constituents. Meanwhile, an IQR increase in NO 3 −, NH 4 + and OM had stronger associations with DBP and ECG parameters compared with BC and SO 4 2−. This nationwide multi-center study in China indicated that some constituents (i.e., OM, NO 3 −, and NH 4 +) might be mainly responsible for the association of PM 2.5 with sub-clinical outcomes of CVD including BP, fasting glucose, and ECG measurements. Unlabelled Image • Few studies explore the associations of PM 2.5 constituents with sub-clinical outcomes. • PM 2.5 constituents were significantly associated with sub-clinical outcomes. • Some constituents may dominate the association of PM 2.5 with sub-clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: It has been widely reported that the prognostic nutritional index (PNI) played a pivotal role in nutritional assessment of surgical patients and tumor prognosis. In order to improve the accuracy of evaluation in Western China, we established reference intervals (RIs) of PNI in healthy controls., Methods: A retrospective cohort study on healthy ethnic Han adults (18-79 years) was conducted to explore the influences of age, gender, study centers, and instruments on PNI and to establish RIs. The data came from a healthy routine examination center database and laboratory information system (LIS) of four centers in Western China, and there were 200 persons selected randomly for verification of RIs., Results: Five thousand eight hundred and thirty-nine healthy candidates were enrolled. PNI showed a marked gender dependence, and males had significantly higher PNI than females across all ages (p < 0.01). We found that PNI is significantly different between age groups (p < 0.01), the value of PNI tended to decrease with age increasing. There is also an obvious influence of centers and instruments on PNI (p < 0.01)., Conclusions: We established reference intervals of PNI in healthy Han Chinese population in Western China and validated successfully. Further established RIs will lead to better standardizations of PNI for clinical applications., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Two hundred and fifty-three non-duplicate toxigenic Clostridium difficile isolates, collected from February 2012 to December 2014, were evaluated for phenotypic resistance to ten antimicrobial drugs with the E-test gradient diffusion method. All strains of C. difficile were susceptible to metronidazole, vancomycin, and tigecycline. The metronidazole MIC values of the hyperepidemic PCR-ribotypes RT027 and RT176 were higher than those of non-epidemic PCR-ribotypes (p < 0.05, as evidenced by Mann-Whitney U test). In contrast, vancomycin susceptibility did not differ between hyperepidemic and non-epidemic strains, although the difference was almost significant (p = 0.065). Clostridium difficile RT027 and RT176 isolates could be assessed to five and four different susceptibility patterns, respectively, representing various combinations of resistance to different antimicrobial classes. A single point mutation (Thr82Ile) in the gyrA gene was detected in 11 (78.6%) of 14 isolates with high level of resistance to ciprofloxacin and moxifloxacin and four different types of single point mutations (Arg447Lys, Ser416Ala, Asp426Val, Asp426Asn) in the gyrB gene were detected in 4 strains, also with high level of resistance to ciprofloxacin and moxifloxacin. Four different point mutations were detected in the rpoB gene in 21 rifampicin-resistant strains of which one has not been reported previously, Gln489Leu. This study demonstrates the presence of multidrug-resistant C. difficile strains in Polish hospitals over the study period, irrespective of geographical location or reference level of the hospital. • We demonstrates highly diversified susceptibility patterns of Polish C. difficile. • We clarified that MDR C. difficile strains dominated in hospital setting. • Higher percentage of RI resistant strains was observed. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.

Background . Pre-school children are at a higher risk to acquire infectious diseases such as hand, foot and mouth disease due to their immature immune system. Good hand hygiene prevents transmission of infectious diseases. This study aimed to determine the knowledge and practices of hand hygiene among pre-schoolers. Methods . In this prospective, multi-center study, the pre-schools were selected according to the selection criteria. A questionnaire consisting of socio-demographics, knowledge and practices of hand hygiene were administered via face-to-face interview during the pre- and post-intervention period. A total of 435 pre-schoolers aged 5 and 6 years old from 2 pre-schools within Klang Valley, School P (test group) and School C (control group) were involved in this study. The test group was provided with comprehensive hand hygiene education including video on proper handwashing technique during the 2 months intervention period, whereas the control group did not receive any form of intervention. The data were statistically analyzed using descriptive analysis and independent t -test. Results . Majority of pre-schoolers gained knowledge of handwashing from their parents. However, only 63% demonstrated good handwashing technique. Test group were significantly better ( P  < 0.05) in handwashing technique and hand hygiene routine score. Conclusion . A comprehensive hand hygiene education program should include proper handwashing facilities, resources, and awareness of the care-givers in instilling and sustaining good hand hygiene behavior., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: To improve the early diagnosis of hepatocellular carcinoma (HCC), more effective diagnostic biomarkers are needed. A combination of biomarkers is reported to distinguish individuals with early-stage HCC from at-risk individuals., Methods: Participants in this study were recruited from six hospitals in China. Literature review was used to choose 19 candidate proteins, a case-control study in the discovery stage was used to identify five proteins (P5) that constituted a diagnostic model. In the training and validation stages, the effectiveness of P5 for detecting early-stage HCC was tested (cross-sectional study). Finally, a nested case-control study independent of the other stages was set up to evaluate the P5 in the preclinical diagnosis of HCC., Findings: Between February 2013 and June 2017, a total of 1396 participants were recruited. A panel of 5 proteins (P5: OPN, GDF15, NSE, TRAP5 and OPG) showed high diagnostic accuracy when differentiating the early-stage HCC from the at-risk group, with AUCs of 0·892, 0·907 and 0·852 for the training stage, validation cohort 1 and cohort 2 data sets, respectively. In the prediction set, the sensitivity of P5 for diagnosing preclinical HCC increased with time, starting from 12 months before to the time of definitive clinical diagnosis (range, 46·15% to 86·67%)., Interpretation: The P5 panel has the potential to screen populations at high risk of developing HCC and can enable the early diagnosis of HCC., Funding: Research supported by grants from eight funds. All sources of funding were declared at the end of the text., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)