Harmonized-Multinational qEEG Norms (HarMNqEEG)

This paper extends our frequency domain quantitative electroencephalography (qEEG) methods pursuing higher sensitivity to detect Brain Developmental Disorders. Prior qEEG work lacked integration of cross-spectral information omitting important functional connectivity descriptors. Lack of geographical diversity precluded accounting for site-specific variance, increasing qEEG nuisance variance. We ameliorate these weaknesses. i) Create lifespan Hermitian Riemannian multinational qEEG norms for cross-spectral tensors. These norms result from the HarMNqEEG project fostered by the Global Brain Consortium. We calculate the norms with data from 9 countries, 12 devices, and 14 studies, including 1564 subjects. Instead of raw data, only anonymized metadata and EEG cross-spectral tensors were shared. After visual and automatic quality control developmental equations for the mean and standard deviation of qEEG traditional and Hermitian Riemannian descriptive parameters were calculated using additive mixed-effects models. We demonstrate qEEG "batch effects" and provide methods to calculate harmonized z-scores. ii) We also show that the multinational harmonized Hermitian Riemannian norms produce z-scores with increased diagnostic accuracy to predict brain dysfunction at school-age produced by malnutrition only in the first year of life. We provide data and software for constructing norms. iii) We offer open code and data to calculate different individual z-scores from the HarMNqEEG dataset. These results contribute to developing bias-free, low-cost neuroimaging technologies applicable in various health settings.

Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for Hepatocellular Carcinoma

Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis. However, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including HCC. In this study, we evaluated the prognostic value of plasma hPG80 in patients with HCC, alone or in combination with AFP. A total of 168 HCC patients were tested prospectively for hPG80 and analyzed retrospectively. The prognostic impact of hPG80 and AFP levels on patient survival was assessed using Kaplan-Meier curves and log-rank tests. hPG80 was detected in 84% of HCC patients. There was no correlation between hPG80 and AFP levels in the training and validation cohorts. Both cohorts showed higher sensitivity of hPG80 compared to AFP, especially at early stages. Patients with high hPG80 (hPG80+) levels (optimal cutoff value 4.5 pM) had significantly lower median overall survival (OS) compared to patients with low hPG80 (hPG80−) levels (12.4 months versus not reached respectively, p < 0.0001). Further stratification by combining hPG80 and AFP levels (cutoff 100 ng/mL) improved prognosis in particular for those patients with low AFP level (hPG80−/AFP+ and hPG80−/AFP−, 13.4 months versus not reached respectively, p < 0.0001 and hPG80+/AFP+ and hPG80+/AFP−, 5.7 versus 26 months respectively, p < 0.0001). This was corroborated when analyses were performed using the BCLC staging especially at early stages. Our findings show that hPG80 could serve as a new prognostic biomarker in HCC. Used in combination with AFP, it improves the stratification of the patients in good and poor prognosis, especially for those patients with negative AFP and early-stage HCC.

Control of Expression of Key Cell Cycle Enzymes Drives Cell Line-Specific Functions of CDK7 in Human PDAC Cells

Inhibition of the dual function cell cycle and transcription kinase CDK7 is known to affect the viability of cancer cells, but the mechanisms underlying cell line-specific growth control remain poorly understood. Here, we employed a previously developed, highly specific small molecule inhibitor that non-covalently blocks ATP binding to CDK7 (LDC4297) to study the mechanisms underlying cell line-specific growth using a panel of genetically heterogeneous human pancreatic tumor lines as model system. Although LDC4297 diminished both transcription rates and CDK T-loop phosphorylation in a comparable manner, some PDAC lines displayed significantly higher sensitivity than others. We focused our analyses on two well-responsive lines (Mia-Paca2 and Panc89) that, however, showed significant differences in their viability upon extended exposure to limiting LDC4297 concentrations. Biochemical and RNAseq analysis revealed striking differences in gene expression and cell cycle control. Especially the downregulation of a group of cell cycle control genes, among them CDK1/2 and CDC25A/C, correlated well to the observed viability differences in Panc89 versus Mia-Paca2 cells. A parallel downregulation of regulatory pathways supported the hypothesis of a feedforward programmatic effect of CDK7 inhibitors, eventually causing hypersensitivity of PDAC lines.

The ‘critical trochanter angle’ does not show superiority over the CCD angle in predicting varus stem alignment in cementless short-stem total hip arthroplasty

Purpose Varus positioning of the femoral stem can affect the hip offset (HO). The critical trochanter angle (CTA) was introduced in 2019 as a novel geometric angle, to predict varus stem alignment in cementless straight stem THA. The aim of this study was to evaluate the applicability of the CTA as a predictor for stem alignment in THA with a cementless neck resecting short stem. Patients and methods In this retrospective study, 106 patients (index surgery 2014–2019) with unilateral THA and a morphologically healthy contralateral hip as a reference (Kellgren–Lawrence ≤ 1) were included. A cementless short stem with meta-diaphyseal fixation and press-fit cup was implanted in all cases. Stem alignment, CCD angle, CTA and offset reconstruction were measured on preoperative and 3 months postoperative AP radiographs of the pelvis. Results Preoperative lower CTA and lower CCD angle were positively correlated (r = 0.472; p < 0.001). Higher varus stem alignment is correlated with lower CTA (r = − 0.384; p < 0.001) and lower CCD angle (r = − 0.474; p < 0.001). A CTA of 23.1° or lower showed a sensitivity of 59.1% and a specificity of 87.1% (AUC: 0.733) and a CCD angle of 132.75° or lower a sensitivity of 68.2% and a specificity of 80.6% (AUC: 0.77) for a varus stem alignment > 3°. Conclusion The CTA is also applicable in cementless THA with a neck resecting short stem to evaluate risk of intraoperative varus stem positioning. The CCD angle shows higher sensitivity with marginally lower specificity. Therefore, the CTA is not superior in predicting varus stem alignment in short-stem THA. Level of evidence IV.

Validation of Urinary Charged Metabolite Profiles in Colorectal Cancer Using Capillary Electrophoresis-Mass Spectrometry

This study aimed to validate and reanalyze urinary biomarkers for detecting colorectal cancers (CRCs). We previously conducted urinary metabolomic analyses using capillary electrophoresis-mass spectrometry and found a significant difference in various metabolites, especially polyamines, between patients with CRC and healthy controls (HC). We analyzed additional samples and confirmed consistency between the newly and previously analyzed data. In total, we included 36 HC, 34 adenoma (AD), and 214 CRC samples, which were used for subsequent analyses. Among the 132 quantified metabolites, 16 exhibited consistent differences in both datasets, which included polyamines, etc. Pathway analyses of the integrated data revealed significant differences in many metabolites, such as glutamine, and metabolites of the TCA and urea cycles. The discrimination ability of the combination of multiple metabolites among the three groups was evaluated, which yielded higher sensitivity than tumor markers. The Mann–Whitney test was employed to evaluate the prognosis predictivity of the assessed metabolites and the difference between the patients with or without recurrence, which yielded 16 significantly different metabolites. Among these 16 metabolites, 11 presented significant prognosis predictivity. These data indicated the potential of metabolite-based discrimination of patients with CRC and AD from HC and prognosis predictivity of the monitored metabolites.

A rapid phage assay for detection of viable Mycobacterium avium subsp. paratuberculosis in milk

Paratuberculosis is an incurable gastroenteritis among ruminants that is promoted by Mycobacterium avium subsp. paratuberculosis (MAP), an acid-fast mycobacterium. To accelerate the detection of viable pathogen, a conventional (peptide mediated magnetic separation: PMS) and novel (phage-bead qPCR: PBQ) phage based assay was optimized. A superior limit of detection (LOD) of 10 MAP per 10 mL milk was suggested for PBQ compared to 100 cells/10 mL for PMS-phage assay. Via PBQ, viable MAP was found in 48.78% out 41 unpasteurized sheep and goat milk samples. Sheep milk samples (n = 29) that were tested by PMS-phage assay contained no viable MAP. The absence of viable MAP in milk collected from 21 of the recent sheep animals was also confirmed by PBQ after a 2-week gap. Although, the two phage assays comparably detected no viable MAP in the milk samples, MAP DNA and antibodies against MAP were recognized in milk and sera of some of these animals within two instances of sampling representing that some sheep animals were MAP shedders. In conclusion, PBQ and PMS-phage could be promising methods for the assessment of MAP viability in milk samples. However, PBQ was privileged over the PMS-phage assay due to the lower LOD, rapidity, higher sensitivity, lack of need to M. smegmatis and consequent virucidal treatment that are essential in PMS-phage assay for making lawn and inactivation of exogenous mycobacteriophages respectively.

A Comparative Study of the Electrical and Electromechanical Responses of Carbon Nanotube/Polypropylene Composites in Alternating and Direct Current

The electrical and electromechanical responses of ~200 µm thick extruded nanocomposite films comprising of 4 wt.% and 5 wt.% multiwall carbon nanotubes mixed with polypropylene are investigated under an alternating current (AC) and compared to their direct current (DC) response. The AC electrical response to frequency (f) and strain (piezoimpedance) is characterized using two configurations, namely one that promotes resistive dominance (resistive configuration) and the other that promotes the permittivity/capacitive contribution (dielectric configuration). For the resistive configuration, the frequency response indicated a resistive–capacitive (RC) behavior (negative phase angle, θ), with a significant contribution of capacitance for frequencies of 104 Hz and above, depending on the nanotube content. The piezoimpedance characterization in the resistive configuration yielded an increasing impedance modulus (|Z|) and an increasing (negative) value of θ as the strain increased. The piezoimpedance sensitivity at f = 10 kHz was ~30% higher than the corresponding DC piezoresistive sensitivity, yielding a sensitivity factor of 9.9 for |Z| and a higher sensitivity factor (~12.7) for θ. The dielectric configuration enhanced the permittivity contribution to impedance, but it was the least sensitive to strain.

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

HAS2 is a member of the gene family encoding the hyaluronan synthase 2, which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for increased susceptibility to adult asthma. However, whether HAS2 dysfunction affects airway remodeling and steroid insensitivity is still limited. Therefore, this study aimed to clarify the Has2 dysfunction, triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Has2 heterozygous-deficient (Has2+/−) mice and their wild-type littermates have been evaluated in a model of chronic ovalbumin (OVA) sensitization and challenge. Mice present a higher sensitivity to OVA and higher IL-17 release as well as eosinophilic infiltration. RNA sequencing demonstrated the downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2+/−-OVA mice. The combined treatment with anti-IL-17A antibody and dexamethasone reduces steroid insensitivity in Has2+/−-OVA mice. Has2 attenuation worsens eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling and could potentially be exploited for their therapeutic benefits in patients with asthma.

The respect pyramid: A model of respect based on lay knowledge in two cultures

Respect is a common social concept, yet how lay people define it has not been thoroughly investigated. This study used a grounded theory approach, using in-depth interviews, to conceptualize respect according to lay knowledge. 40 participants from two cultures in the Middle East—20 Jewish Israelis and 20 Palestinians—reported how they define respect ( Kavod in Hebrew and Ihtiram in Arabic). The findings define respect as a complex, multidimensional concept. Based on the findings, a respect pyramid model was developed, which includes four dimensions: avoiding disrespect, deserved/normative respect, conditional respect, and considerate respect. Each dimension indicates an increase in aspects that make the respect less conditional and more intrinsic, while requiring higher sensitivity and greater effort. The implications of the respect pyramid for relationships and the cultural differences regarding definitions of respect are discussed.

Performance of Rapid Antigen Tests for COVID-19 Diagnosis: A Systematic Review and Meta-Analysis

The identification of viral RNA using reverse transcription quantitative polymerase chain reaction (RT-qPCR) is the gold standard for identifying an infection caused by SARS-CoV-2. The limitations of RT-qPCR such as requirement of expensive instruments, trained staff and laboratory facilities led to development of rapid antigen tests (RATs). The performance of RATs has been widely evaluated and found to be varied in different settings. The present systematic review aims to evaluate the pooled sensitivity and specificity of the commercially available RATs. This review was registered on PROSPERO (registration number: CRD42021278105). Literature search was performed through PubMed, Embase and Cochrane COVID-19 Study Register to search studies published up to 26 August 2021. The overall pooled sensitivity and specificity of RATs and subgroup analyses were calculated. Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used to assess the risk of bias in each study. The overall pooled sensitivity and specificity of RATs were 70% (95% CI: 69–71) and 98% (95% CI: 98–98), respectively. In subgroup analyses, nasal swabs showed the highest sensitivity of 83% (95% CI: 80–86) followed by nasopharyngeal swabs 71% (95% CI: 70–72), throat swabs 69% (95% CI: 63–75) and saliva 68% (95% CI: 59–77). Samples from symptomatic patients showed a higher sensitivity of 82% (95% CI: 82–82) as compared to asymptomatic patients at 68% (95% CI: 65–71), while a cycle threshold (Ct) value ≤25 showed a higher sensitivity of 96% (95% CI: 95–97) as compared to higher Ct value. Although the sensitivity of RATs needs to be enhanced, it may still be a viable option in places where laboratory facilities are lacking for diagnostic purposes in the early phase of disease.