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Purpose: There is some evidence that trace element and mineral deficiencies may promote the occurrence of febrile seizures. However, the role of these elements in the occurrence of complex seizures in children with FS has not been comprehensively investigated. The present study was conducted to evaluate this issue., Methods: In a cross-sectional study, 220 patients including 110 febrile and 110 FS children aged 6-60 months were studied. Blood samples were taken and serum zinc, potassium, sodium, magnesium and calcium levels were measured. Demographic and clinical characteristics were also recorded., Results: The patients were similar in age and sex. Higher serum zinc levels decreased the risk of seizure (RR = 0.95, p-value = 0.0001) and complex seizure (OR = 0.96, p-value = 0.03). Higher serum sodium levels decreased the risk of complex seizures (OR = 0.85, p-value = 0.023). Higher serum potassium levels were associated with a lower risk of seizure (OR = 0.55, p-value = 0.035). Serum calcium and magnesium levels were not associated with the risk of seizure and complex seizure. A BMI at the upper end of the normal range decreased the risk of complex seizures (OR = 0.83, p-value = 0.05). Male sex increased the risk of complex seizure (OR = 4.14, p-value = 0.016)., Conclusions: Low serum levels of zinc, potassium and sodium are risk factors for seizure and complex seizure in febrile children. Male sex is also a risk factor for complex seizures. The time from fever to seizure was shorter in younger children. Children with a BMI at the upper end of the normal range have a lower risk of having a complex seizure., Competing Interests: Declarations Ethical approval The ethics committee of Mashhad University of Medical Sciences approved the study protocol (code: IR.MUMS.MEDICAL.REC.1399.261). Consent to participate The written informed consent was obtained from patients or their parents. Consent of publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Highly crystallized Co and Co 3 O 4 nanoparticles embedded in an N-doped amorphous carbon matrix have been successfully fabricated by the molten-salt-assisted method using KClO 3 and zeolitic imidazolate framework-12 (ZIF-12). Pyrolysis of ZIF-12 with different concentrations of KClO 3 leads to embedded Co and Co 3 O 4 nanoparticles in a conductive amorphous carbon network. The impact of salt concentration on the morphology and electrochemical performance of these composites was investigated for electrochemical sensor applications. By employing a straightforward and efficient technique, Co/Co 3 O 4 heterostructures were successfully synthesized in N-doped porous amorphous carbon. The Co/Co 3 O 4 carbon heterostructures were optimized by varying the salt concentration, resulting in a significant electrochemical sensor performance for detecting ALC in both bulk and biological fluids. The sensor demonstrates excellent sensitivity (62.97 nmol/L) and selectivity toward ALC, with a wide linear range (0.2-2 μM) and a low detection limit (18.89 nM). Furthermore, it displays remarkable stability and reproducibility, positioning it as a strong contender for practical use in pharmaceutical analysis and biomedical research. This study presents a significant advancement in electrochemical sensing technology and underscores the potential of Co/Co 3 O 4 heterostructures in the development of high-performance sensors for detecting bioactive compounds in complex matrices., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

A new fluorescent sensor based on diethylaminosalicylaldehyde-thiosemicarbazide (DST) was studied using a combination of density functional theory calculations and experimental investigations. DST was able to detect the metal ions Ag + and Hg 2+ in the presence of various competing metal ions and anions, with detection limits of 0.45 and 0.34 µM, respectively. The DST sensor could operate in a fully aqueous environment and within a wide pH range from 5 to 9. Density functional theory studies supported the experimental findings in determining the stable structures of the DST sensor and the complexes between DST and the Ag + and Hg 2+ ions, as well as elucidating the fluorescence ON-OFF mechanism in the DST sensor and the complexes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Carbapenem-resistant Acinetobacter baumannii (CRAB) are increasingly reported worldwide and a leading cause of mortality associated with antimicrobial resistance. Their early detection, particularly in the cases of bloodstream infections, is crucial in attempting to initiate effective antibiotic treatment. The immunochromatographic assay RESIST ACINETO (Coris BioConcept) is a new test developed for the detection of OXA-23, OXA-40/58, and New-Delhi Metallo-beta-lactamase (NDM) carbapenemases in Acinetobacter spp. We evaluated this test on a collection of 121 Acinetobacter spp. clinical isolates, including 104 carbapenemase producers (97 carbapenemases targeted by the test) and 17 non-carbapenemase producers. The performance of the RESIST ACINETO test was evaluated according to the manufacturer's recommendations from bacterial and blood cultures. The strains producing the carbapenemases OXA-23, -40, -58, or/and NDM were accurately detected from bacterial cultures and directly from blood cultures, with the exception of one OXA-23/NDM-1-positive Acinetobacter radioresistens isolate (only detected through standard culture). None of the non-carbapenemase producers tested positive. The RESIST ACINETO test demonstrated sensitivity/specificity of 100%/100% and 99%/100% on bacterial and blood cultures, respectively., Importance: The incidence of bloodstream infections with carbapenem-resistant Acinetobacter baumannii (CRAB) could be very high in some countries such as the Balkans or Southeast Asia. In case of positive blood cultures with Gram-negative bacteria, the use of the RESIST ACINETO test could prove highly beneficial for the rapid identification of these imipenem-resistant bacteria and their antibiotic resistance mechanisms. In addition, it is now well established that New-Delhi Metallo-beta-lactamase (NDM) carbapenemase-producing isolates can have increased MICs of cefiderocol, which is an alternative treatment for these infections. This test may also allow the optimization of treatment based on the type of carbapenemase present. Finally, the RESIST ACINETO test is a rapid, easy-to-use, and cost-effective assay that demonstrates excellent performance in detecting the major acquired carbapenemases present in the Acinetobacter species ., Competing Interests: The authors declare no conflict of interest.

Purpose: To evaluate the potential benefit of adding a low frequency vascular probe to the conventional pre-operative ultrasound examination of patients with primary hyperparathyroidism., Methods: A prospective cohort of 136 patients with primary hyperparathyroidism underwent a conventional ultrasound examination of the neck with a high frequency ( > 10 MHz) linear ultrasound probe, followed by an add-on examination with a low frequency vascular probe. For each ultrasound probe, and for every potential parathyroid lesion, the presence of a feeding vessel, a polar placement of the feeding vessel, and the presence of a vascular arch was recorded., Results: A total of 146 ultrasound lesions were evaluated for vascularity by each probe. For both ultrasound probes, the odds of a hyperfunctioning parathyroid gland being correctly identified increased with the number of visible vascular features. The vascular probe identified a significantly higher number of vascular features among ultrasound true positive glands compared with the conventional probe (p < 0.0001). Among histopathologically verified pathological parathyroid glands, the vascular probe identified 20% more feeding vessels, 27% more polar placements of the feeding vessel, and 65% more vascular arches than the high frequency probe. However, the diagnostic confidence score for true positive glands did not differ significantly between the probes (p = 0.11)., Conclusion: The addition of a low frequency vascular probe increases the number of visible vascular features in hyperfunctioning parathyroid glands, which facilitates their preoperative detection. Whether or not this can increase the diagnostic confidence of ultrasound examiners has yet to be substantiated., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests. Ethics approval The study was carried out in accordance with the ethical principles of the 1964 Declaration of Helsinki and its later amendments. The study is registered at ClinicalTrials.gov (NCT04305561) and has been approved by the Regional Committees on Health Research Ethics for Southern Denmark (project ID S-20190077). Consent to participate Written informed consent was obtained from all participants in this study., (© 2024. The Author(s).)

General anesthetics exposure, particularly prolonged or repeated exposure, is a crucial cause of neurological injuries. Notably, isoflurane (ISO), used in pediatric anesthesia practice, is toxic to the developing brain. The relatively weak antioxidant system at early ages needs antioxidant support to protect the brain against anesthesia. Cerium oxide nanoparticles (CeO 2 -NPs, nanoceria) are nano-antioxidants and stand out due to their unique surface chemistry, high stability, and biocompatibility. Although CeO 2 -NPs have been shown to exhibit neuroprotective and cognitive function-facilitating effects, there are no reports on their protective effects against anesthesia-induced neurotoxicity and cognitive impairments. Herein, Wistar albino rat pups were exposed to ISO (1.5 %, 3-h) at postnatal day (P)7+P9+P11, and the protective properties of CeO 2 -NP pretreatment (0.5 mg/kg, intraperitoneal route) were investigated for the first time. The control group at P7+9+11 received 50 % O 2 (3-h) instead of ISO. Exposure to nanoceria one-hour before ISO protected hippocampal neurons of the developing rat brain against apoptosis [determined by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC) analysis with caspase-3, and immunoblotting with Bax/Bcl2, cleaved caspase-3 and PARP1] oxidative stress, and inflammation [determined by immunoblotting with 4-hydroxynonenal (4HNE), nuclear factor kappa-B (NF-κB), and tumor necrosis factor-alpha (TNF-α)]. CeO 2 -NP pretreatment also reduced ISO-induced learning (at P28-32) and memory (at P33) deficits evaluated by Morris Water Maze. However, memory deficits and thigmotactic behaviors were detected in the agent-control group; elimination of these harmful effects will be possible with dose studies, thus providing evidence supporting safer use. Overall, our findings support pretreatment with nanoceria application as a simple strategy that might be used for pediatric anesthesia practice to protect infants and children from ISO-induced cell death and learning and memory deficits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Journal name] and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Human cone photoreceptors differ from rods and serve as the retinoblastoma cell-of-origin, yet the developmental basis for their distinct behaviors is poorly understood. Here, we used deep full-length single-cell RNA-sequencing to distinguish post-mitotic cone and rod developmental states and identify cone-specific features that contribute to retinoblastomagenesis. The analyses revealed early post-mitotic cone- and rod-directed populations characterized by higher THRB or NRL regulon activities, an immature photoreceptor precursor population with concurrent cone and rod gene and regulon expression, and distinct early and late cone and rod maturation states distinguished by maturation-associated declines in RAX regulon activity. Unexpectedly, both L/M cone and rod precursors co-expressed NRL and THRB RNAs, yet they differentially expressed functionally antagonistic NRL and THRB isoforms and prematurely terminated THRB transcripts. Early L/M cone precursors exhibited successive expression of several lncRNAs along with MYCN , which composed the seventh most L/M-cone-specific regulon, and SYK , which contributed to the early cone precursors' proliferative response to RB1 loss. These findings reveal previously unrecognized photoreceptor precursor states and a role for early cone-precursor-intrinsic SYK expression in retinoblastoma initiation., Competing Interests: Competing interests: The authors declare that they have no competing interests.

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. Studies carried out in recent years suggest that extracellular vesicles (EVs) may be a potential biomarker in cancer. Tyro3-Axl-Mertk (TAM) Receptor Tyrosine Kinases (RTKs) and Phosphatidylserine (PS) have crucial roles in macrophage-mediated immune response under normal conditions. In the tumor microenvironment, these molecules contribute to immunosuppressive signals and prevent the formation of local and systemic antitumor immune responses. Based on this, we aimed to evaluate the amount of PS and TAM RTK in plasma and on the surface of EVs in CLL patients and healthy volunteers in this study. In this study, 25 CLL (11 F/14 M) patients in the Rai (O-I) stage, newly diagnosed or followed up without treatment, and 15 healthy volunteers (11 F/4 M) as a control group were included. For all samples, PS and TAM RTK levels were examined first in the plasma and then in the EVs obtained from the plasma. We detected a significant decrease in plasma PS, and TAM RTK levels in CLL patients compared to the control. Besides, we determined a significant increase in TAM RTK levels on the EV surface in CLL, except for PS. In conclusion, these receptor levels measured by ELISA in plasma may not be effective for the preliminary detection of CLL. However, especially TAM RTKs on the surface of EVs may be good biomarkers and potential targets for CLL therapies., (© 2024 John Wiley & Sons Ltd.)

Background: Currently, integrase inhibitors (INIs)-based ART regimens are the preferred initial therapy for AIDS patients. There is scarce information on the use of dolutegravir (DTG) among late-presenter people living with HIV (PLHIV)., Objectives: To compare the effect of DTG- or efavirenz (EFV)-based regimens on the outcomes of patients with advanced AIDS., Methods: We compared two cohorts of consecutive symptomatic AIDS patients (WHO stage 4, CD4 count<50 cells/mL) starting therapy with DTG-based (2018-2021, prospective cohort) or EFV-based regimens (2013-2016, retrospective cohort) from five Brazilian cities. The main endpoints were early (all-cause) mortality, viral suppression at 24 and 48 weeks, changes in CD4 count, and changes in initial therapy (for any reason)., Results: We included all eligible patients in a consecutive way (in both groups) until we reached 92 individuals per arm. The median baseline CD4 count (20 vs. 21 cells/mL) and the median HIV plasma viral load (5.5 copies/mL log 10 ) were identical across the groups. Viral suppression rates were higher in the DTG group than in the EFV group at 24 (67.4% vs. 42.4%,) and 48 weeks (65.2% vs. 45.7%, p  < 0.001 for both comparisons). More patients in the DTG group presented with CD4 > 200 cells/mL compared to the EFV group at 48 weeks (45% vs. 29%, p  = 0.03). Treatment changes (ITT, M = F) were significantly more frequent in the EFV group (1% vs. 17%, p  < 0.0001). The relative mortality rate was 25% lower in the DTG group, but without statistical significance., Conclusion: We detected a higher rate of virological suppression and greater treatment durability in patients with advanced AIDS treated with DTG than in those treated with EFV., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Brites, Lacerda, Sprinz, Bay, Pinto, Azevedo, Luz, Lins-Kusterer and Netto.)

Background: Effective teamwork is critical to the mission of Child Advocacy Center (CAC) multidisciplinary teams. Team interventions designed to fit the unique cross-organizational context of CAC teams may improve teamwork in CACs., Methods: A collaborative, community-engaged approach was used to adapt TeamSTEPPS, an evidence-based team training for healthcare, for CAC multidisciplinary teams. The adapted training was piloted with one team and evaluated using mixed methods. Team members completed pre-training (n = 26) and follow-up surveys (n = 22) and participated in qualitative interviews (n = 9)., Results: The adaptation process resulted in the creation of TeamTRACS (Team Training in Roles, Awareness, Communication, and Support). Participants rated TeamTRACS as highly acceptable, appropriate, feasible, relevant, and useful for CAC teams. They identified positive and negative aspects of the training, ideas for improvement, and future uses for TeamTRACS., Conclusions: TeamTRACS is a feasible approach to team training in CACs, and team members find the content and skills relevant and useful. Additional research is needed to test the effectiveness of TeamTRACS and identify appropriate implementation strategies to support its use., Competing Interests: Declarations of interest: None.

Purpose: The preferred nuclear medicine method for identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT) develops continuously in relation to the technological progress. Diagnostic methods based on PET/CT have during recent years evolved with new tracer possibilities competing with traditional scintigraphic methods. This investigation is a head-to-head comparison of Tc-99m-sestamibi SPECT/CT gamma camera scintigraphy (sestamibi SPECT/CT) and C-11-L-methionin PET/CT imaging (methionine PET/CT) for preoperative identification of hyperfunctioning parathyroid glands., Procedures: The study is a prospective cohort study including 27 patients diagnosed with primary hyperparathyroidism (PHPT). Two nuclear medicine physicians assessed all examinations independently and blinded. All scanning assessments were matched to the final surgical diagnosis as confirmed by histopathology. Biochemical monitoring of the therapeutical effects was performed preoperatively by PTH-measurements and followed postoperatively for up to 12 months. Comparisons were made for differences in sensitivity and positive predictive value (PPV)., Results: Twenty-seven patients (18 females, 9 males; mean age (range): 58.9 years (34.1-79)) were enrolled into the study. The 27 patients had a total of 33 identified sites of lesions of which 28 (85%) turned out to be histopathological verified hyperfunctioning parathyroid glands. The sensitivity and PPV for sestamibi SPECT/CT were 0.71 and 0.95; that of methionine PET/CT was 0.82 and 1, respectively. Both sensitivity and PPV were slightly lower for sestamibi SPECT/CT than for methionine PET PET/CT (-0.11, 95% confidence interval (95% CI): -0.29 to 0.08; -0.05, 95% CI: -0.14 to 0.04, respectively), but not to a statistically significant extent (p=0.38 and p=0.31). The sensitivity and PPV for diagnostic CT were 0.64 (95% CI: 0.44 to 0.81) and 1 (95% CI: 0.81 to 1)., Conclusions: Methionine PET/CT performed comparable to sestamibi SPECT/CT with respect to identification and localization of hyperfunctioning parathyroid glands prior to surgery., (© 2023. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Automatic document classification is a common problem that has successfully been addressed with machine learning methods. However, these methods require extensive training data, which is not always readily available. Additionally, in privacy-sensitive settings, transfer and reuse of trained machine learning models is not an option because sensitive information could potentially be reconstructed from the model. Therefore, we propose a transfer learning method that uses ontologies to normalize the feature space of text classifiers to create a controlled vocabulary. This ensures that the trained models do not contain personal data, and can be widely reused without violating the GDPR. Furthermore, the ontologies can be enriched so that the classifiers can be transferred to contexts with different terminology without additional training. Applying classifiers trained on medical documents to medical texts written in colloquial language shows promising results and highlights the potential of the approach. The compliance with GDPR by design opens many further application domains for transfer learning based solutions.

Importance: Scintigraphy and ultrasonography are common imaging modalities for the preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism. When comparing the 2 modalities, the benefits of ultrasonography in terms of convenience, patient comfort, duration, cost, and lack of radiation should be taken into account., Objective: To investigate whether surgeon-performed ultrasonography, with or without contrast-enhanced ultrasonography (CEUS), is noninferior to scintigraphy for localizing pathological parathyroid glands in patients with primary hyperparathyroidism., Design, Setting, and Participants: Prospective, paired, noninferiority cohort study performed at a high-volume tertiary referral center for parathyroidectomy with blinded examiners and a 6-month follow-up. Participants were adults (age ≥18 years) referred for parathyroidectomy due to primary hyperparathyroidism. Of 207 eligible patients, 35 were excluded, leaving 172 enrolled in the study. Inclusion lasted from September 2019 until February 2021. Follow-up ended in December 2021., Exposures: 99mTechnetium-pertechnetate/99mtechnetium-sestamibi subtraction scintigraphy with 99mtechnetium-sestamibi single-photon emission computed tomography/computed tomography, followed by surgeon-performed ultrasonography and CEUS., Main Outcomes and Measures: The sensitivity of each imaging modality in localizing pathological parathyroid glands, calculated on a per-quadrant and a per-patient basis, respectively. The a priori noninferiority margin was a lower 95% confidence limit for the difference in sensitivity not falling below -10%., Results: Out of 172 participants, 139 (80.8%) were women, the median (range) age was 65 (24-87) years, and the median (IQR) follow-up was 200.5 (181-280.25) days. Quadrant sensitivity (95% CI) was 70.9% (63.2%-78.5%) for ultrasonography, 68.4% (60.4%-76.5%) for ultrasonography plus CEUS, and 67.0% (60.0%-74.0%) for scintigraphy. The sensitivity difference (95% CI) compared with scintigraphy was 3.9% (-4.1% to 11.8%) for ultrasonography and 1.5% (-6.4% to 9.3%) for ultrasonography plus CEUS, establishing noninferiority for both modalities. Per-patient sensitivity was 81.4% (74.8%-86.9%) for ultrasonography and 79.1% (72.2%-84.9%) for both scintigraphy and ultrasonography plus CEUS. The sensitivity difference compared with scintigraphy was 2.3% (-6.8% to 11.4%) for ultrasonography and 0.0% (-9.1% to 9.1%) for ultrasonography plus CEUS, establishing noninferiority for both modalities., Conclusions and Relevance: In this cohort study, conventional ultrasonography by an experienced parathyroid surgeon-sonographer was noninferior to scintigraphy and may constitute a valid first-line imaging modality in patients with primary hyperparathyroidism, even without the addition of CEUS. Further imaging should be reserved for cases that are equivocal or nonlocalizing on ultrasonography.

Damage to hippocampus, cerebellum, and cortex associated with cognitive functions due to anesthetic-induced toxicity early in life may cause cognitive decline later. Aquaporin 4 (AQP4), a key protein in waste clearance pathway of brain, is involved in synaptic plasticity and neurocognition. We investigated the effects of single and repeated isoflurane (Iso) anesthesia on AQP4 levels and brain damage. Postnatal-day (P)7 Wistar albino rats were randomly assigned to Iso or Control (C) groups. For single-exposure, pups were exposed to 1.5% Iso in 30% oxygenated-air for 3-h at P7 (Iso 1 ). For repeated-exposure, pups were exposed to Iso for 3 days, 3-h each day, at 1-day intervals (P7 + 9 + 11) starting at P7 (Iso 3 ). C 1 and C 3 groups received only 30% oxygenated-air. Based on HE-staining and immunoblotting (Bax/Bcl-2, cleaved-caspase3 and PARP1) analyses, Iso exposures caused a higher degree of apoptosis in hippocampus. Anesthesia increased 4-hydroxynonenal (4HNE), oxidative stress marker; the highest ROS accumulation was determined in cerebellum. Increased inflammation (TNF-α, NF-κB) was detected. Multiple Iso-exposures caused more significant damage than single exposure. Moreover, 4HNE and TNF-α contributed synergistically to Iso-induced neurotoxicity. After anesthesia, higher expression of AQP4 was detected in cortex than hippocampus and cerebellum. There was an inverse correlation between increased AQP4 levels and apoptosis/ROS/inflammation. Correlation analysis indicated that AQP4 had a more substantial protective profile against oxidative stress than apoptosis. Remarkably, acutely increased AQP4 against Iso exhibited a more potent neuroprotective effect in cortex, especially frontal cortex. These findings promote further research to understand better the mechanisms underlying anesthesia-induced toxicity in the developing brain.

Studies of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) shows divergence in frequency, disease definition, reporting of clinical characteristics and traces of selection bias. This is a nationwide population-based retrospective study of PHPT in MEN 2A, suggesting a representative frequency, with complete reporting and a strict PHPT definition. The Danish MEN 2A cohort 1930-2021 was used. Of 204 MEN 2A cases, 16 had PHPT, resulting in a frequency of 8% (CI, 5-12). Age-related penetrance at 50 years was 8% (CI, 4-15). PHPT was seen in the American Thyroid Association moderate (ATA-MOD) and high (ATA-H) risk groups in 62% and 38% of carriers, respectively. Median age at PHPT diagnosis was 45 years (range, 21-79). A total of 75% were asymptomatic and 25% were symptomatic. Thirteen underwent parathyroid surgery, resulting in a cure of 69%, persistence in 8% and recurrence in 23%. In this first study with a clear PHPT definition and no selection bias, we found a lower frequency of PHPT and age-related penetrance, but a higher age at PHPT diagnosis than often cited. This might be affected by the Danish RET p.Cys611Tyr founder effect. Our study corroborates that PHPT in MEN 2A is often mild, asymptomatic and is associated with both ATA-MOD and ATA-H variants. Likelihood of cure is high, but recurrence is not infrequent and can occur decades after surgery.

The prevalence of inflammatory bowel disease (IBD) continues to rise around the globe. Although the percentage of pediatric IBD patients seems to be increasing, rates are surprisingly heterogeneous among different populations. Although the pathogenesis of IBD is believed to be multifactorial, a genetic predisposition may be especially relevant in pediatric-onset IBD. Phenotypic characteristics can also be significantly different when comparing pediatric and adult-onset IBD. Patients that develop the disease at a younger age usually present with more extensive and more aggressive disease and develop complications faster when compared to those that develop it during adulthood. Children with IBD are found to have frequent mood disorders and have a higher risk of developing socio-economic hardship, failing to meet development milestones. Therefore, IBD management should always involve a multidisciplinary team that is not limited to medical providers. Most institutions do not have an established transition protocol and lack the resources and training for transition care. Although there is no consensus on an optimal timing to transition the patient's care to an adult team, it is usually accepted they should be eligible for adult care when most of the key transition points have been met. Management strategies should be tailored to each patient's developmental level and environment. A successful transition can improve the long-term outcomes such as sustained remission, medication adherence, mental health and social and academic performance, while decreasing healthcare utilization. Every institution that manages pediatric IBD patients should have a well-established transition protocol in order to make sure to maintain continuity of care., (Copyright © 2022 Elsevier España, S.L.U. All rights reserved.)

Glycozolidol was isolated from the root of Glycosmis pentaphylla (6-hydroxy-2-methoxy-3-methylcarbazole, GLD). This molecule attracted considerable interest due to its beneficial biological activities that likely stem from its antioxidant activity; yet, the radical scavenging action of GLD has not been investigated thus far. In this study, DFT calculations were used to estimate the radical scavenging activity of GLD against a variety of biologically significant radical species in physiological environments. The findings demonstrated that GLD exerts significant antiradical activity in water at pH = 7.40 and in pentyl ethanoate (as a model of lipidic media) with k overall = 8.23 × 10 6 M 4 M -1 s -1 , respectively. In aqueous solution, the sequential proton-loss electron transfer mechanism made the highest contribution to the activity, whereas in nonpolar solvents the formal hydrogen transfer mechanism dominated the activity. GLD is predicted to have strong antiradical activity against CH 3 O˙, CH 3 OO˙, CCl 3 OO˙, NO 2 , SO 4 ˙ - , DPPH and ABTS + ˙ k M app ≈ 10 9 M -1 s -1 M k f ≈ 10 6 M -1 s -1 . The results suggest that GLD is a good radical scavenger in physiological environments., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The ability of a new compound, Wal, (walterolactone A/B 6- O -gallate-β-d-pyranoglucoside) originating from Euonymus laxiflorus Champ. as a hydroperoxyl radical scavenger and pro-oxidant enzyme inhibitor was studied in silico . Different mechanisms, reaction locations, and chemical species of Wal in aqueous solution were taken into consideration. Formal hydrogen transfer from the OH group has been discovered as the chemical process that contributes most to the antioxidant properties of Wal in nonpolar and aqueous solutions. The overall rate coefficients for polar and non-polar environments are expected to have values of 7.85 × 10 6 M -1 s -1 and 4.84 × 10 5 M -1 s -1 , respectively. According to the results of the investigation, Wal has greater scavenging activity against the HOO˙ radical than the reference antioxidant Trolox at physiological pH (7.4). In addition, docking results indicate that Wal's antioxidant properties involve the inhibition of the activity of enzyme families (CP450, MP, NO, and XO) that are responsible for ROS production., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Background: The COVID-19 pandemic uniquely affects patients with neurologic and developmental disabilities at the Kennedy Krieger Institute. These patients are at increased risk of co-morbidities, increasing their risk of contracting COVID-19. Disruptions in their home and school routines, and restrictions accessing crucial healthcare services has had a significant impact., Methods: A Pandemic Intake questionnaire regarding COVID-19 related medical concerns of guardians of patients was distributed using Qualtrics. Data from May-December 2020 were merged with demographic information of patients from 10 clinics (Center for Autism and Related Disorders (CARD), Neurology, Epigenetics, Neurogenetics, Center for Development and Learning (CDL) Sickle Cell, Spinal Cord, Sturge-Weber syndrome (SWS), Tourette's, and Metabolism). A provider feedback survey was distributed to program directors to assess the effectiveness of this intervention., Results: Analysis included responses from 1643 guardians of pediatric patients (mean age 9.5 years, range 0-21.6 years). Guardians of patients in more medically complicated clinics reported perceived increased risk of COVID-19 ( p  < 0.001) and inability to obtain therapies ( p  < 0.001) and surgeries ( p  < 0.001). Guardian responses from CARD had increased reports of worsening behavior ( p  = 0.01). Providers increased availability of in-person and virtual therapies and visits and made referrals for additional care to address this. In a survey of medical providers, five out of six program directors who received the responses to this survey found this questionnaire helpful in caring for their patients., Conclusion: This quality improvement project successfully implemented a pre-visit questionnaire to quickly assess areas of impact of COVID-19 on patients with neurodevelopmental disorders. During the pandemic, results identified several major areas of impact, including patient populations at increased risk for behavioral changes, sleep and/or disruptions of medical care. Most program directors reported improved patient care as a result., 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., (© 2022 Vedmurthy, Murray, Chen, Asiedu, Baranano, Bay, Belcher, Burton, Conlon, Fine, Gill, Harris, Hart, Inches, Johnson, Lance, Lipkin, Menon, McIntyre, Rajaprakash, Recio, Singer, Smegal, Smith-Hicks, Vernon, Wilms Floet, Wong, Yelin, Leppert, Zabel and Comi.)

Purpose: The COVID-19 pandemic created novel challenges for school systems and students, particularly students with disabilities. In the shift to remote/distance learning, this report explores the degree to which children with disabilities did not receive the special education and related services defined in their individualized education program (IEP)., Methods: Patients attending an outpatient tertiary care center for neurodevelopmental disabilities in Maryland were surveyed on the impact of the pandemic on educational services provision., Results: Nearly half (46%) of respondents qualified for special education and related services through an IEP before the start of the COVID-19 pandemic. Among those with IEPs, 48% attested to reduced frequency and/or duration of special education and/or related services during the pandemic. The reduction was greatest in occupational therapy services (47%), followed physical therapy services (46%), and special education services (34%)., Conclusion: This survey of children with disabilities observes a substantial reduction in IEP services reported in their completed surveys. To address the observed reduction in IEP services, we sought additional education for clinicians on the rights of students with disabilities in anticipation of students' re-entry to the classroom. A special education law attorney provided an instructional session on compensatory education and recovery services to prepare clinicians to properly inform parents about their rights and advocate for patients with unmet IEP services during the pandemic., 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., (© 2022 Chen, Rasmussen, Legg, Alexander, Vedmurthy, Asiedu, Bay, Belcher, Burton, Conlon, Fine, Gill, Lance, Lipkin, Wong, Wilms Floet, Doerrer, Glattfelder, Kordek, Pertman, Murray, Zabel, Comi and Leppert.)

Automated coding of diseases can support hospitals in the billing of inpatient cases with the health insurance funds. This paper describes the implementation and evaluation of classification methods for two selected Rare Diseases. Different classifiers of an off-the-shelf system and an own application are applied in a supervised learning process and comparatively examined for their suitability and reliability. Using Natural Language Processing and Machine Learning, disease entities are recognized from unstructured historical patient records and new billing cases are coded automatically. The results of the performed classifications show that even with small datasets (≤ 200), high correctness (F1 score ∼0.8) can be achieved in predicting new cases.

Mexidol ( MD , 2-ethyl-6-methyl-3-hydroxypyridine) is a registered therapeutic agent for the treatment of anxiety disorders. The chemical structure suggests that MD may also act as an antioxidant. In this study, the hydroperoxyl radical scavenging activity of MD was studied to establish baseline antioxidant activity, followed by an investigation of the effect of MD on the copper-catalysed oxidative damage in biological systems, using computational methods. It was found that MD exhibits moderate radical scavenging activity against HOO • in water and pentyl ethanoate solvents following the single electron transfer and formal hydrogen transfer mechanisms, respectively. MD can chelate Cu(II), forming complexes that are much harder to reduce than free Cu(II): MD chelation completely quenches the Cu(II) reduction by ascorbic acid and suppresses the rate of reduction reaction by O 2 ⋅ - that are the main reductants of Cu(II) in biological environments. Therefore, MD exerts its anti-HO • activity primarily as an OIL-1 inhibitor., (© 2022 The Authors.)

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to promote tissue function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term NSCs (ST-NSCs) and long-term NSCs (LT-NSCs). ST-NSCs divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months but are pushed out of homeostasis by lengthening quiescence. Single-cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC aging factor. Treatment with the Abl inhibitor imatinib increased NSC activation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable and adaptable to cellular aging., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Intraventricular conduction disturbances are associated with an increased risk of adverse cardiovascular outcomes. However, data about factors associated with intraventricular conduction disturbances are sparse. We aimed to identify the clinical factors associated with intraventricular conduction disturbances in the general population., Methods: Cross-sectional study in a sample of 3704 participants (age range 45-86 years, 55.2% women). Intraventricular conduction disturbances were defined as QRS > 110 ms on electrocardiograms, and classified into right bundle branch block (RBBB), left bundle branch block (LBBB), left anterior fascicular block (LAFB) and non-specific intraventricular conduction disturbances (NIVCD)., Results: The number of participants, the resulting prevalence (square brackets) and 95% CI (round brackets) of intraventricular conduction disturbances and subtypes (RBBB, LBBB, LAFB and NIVCD) were 187 [5.1% (4.4-5.8%)], 103 [2.9%, (2.3-3.4%)], 29 [0.8% (0.6-1.1%)], 31 (0.9% [0.6-1.2%]), and 47 [1.3% (0.9-1.7)], respectively. Multivariable logistic regression identified male sex [odds ratio and (95% CI): 2.55 (1.34-4.86)] and increasing age (p-value for trend <0.001) as being associated with RBBB; hypertension [3.08 (1.20-7.91)] and elevated NT-proBNP [3.26 (1.43-7.41)] as being associated with LBBB; elevated NT-proBNP [3.14 (1.32-7.46)] as being associated with LFAB; and male sex [5.97 (1.91-18.7)] and increased height [1.31 (1.06-1.63)] as being associated with NIVCD., Conclusion: In a sample of the Swiss middle-aged population, the clinical factors associated with intraventricular conduction disturbances differed according to the intraventricular conduction disturbances subtype: male sex and ageing for RBBB; hypertension and elevated NT-proBNP for LBBB; elevated NT-proBNP for LAFB; and male sex and increased height for NIVCD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Herein, a novel fluorescent sensor has been developed for the detection of biothiols based on theoretical calculations of the stability constant of the complex between a Cu 2+ ion and ( E )-3-((2-(benzo[ d ]thiazol-2-yl)hydrazono)methyl)-7-(diethylamino) coumarin (BDC) as a fluorescent ligand. In this study, on the basis of density functional theory method, the Gibbs free energy of ligand-exchange reaction and the solvation model were carried out using thermodynamic cycles. The obtained results are in good agreement with the experimental data. The BDC-Cu 2+ complex can be used as a fluorescent sensor for the detection of biothiols in the presence of non-thiol containing amino acids, with a detection limit for cysteine at 0.3 μM. Moreover, theoretical calculations of excited states were used to elucidate variations in the fluorescence properties. The computed results show that the excited doublet states D 2 and D 1 are dark doublet states, which quench the fluorescence of the complex., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This study aimed to analyse the survival of patients admitted to Brazilian hospitals due to the COVID-19 and estimate prognostic factors. This is a retrospective, multicentre cohort study, based on data from 46 285 hospitalisations for COVID-19 in Brazil. Survival functions were calculated using the Kaplan-Meier's method. The log-rank test compared the survival functions for each variable and from that, hazard ratios (HRs) were calculated, and the proportional hazard model was used in Cox multiple regression. The smallest survival curves were the ones for patients at the age of 68 years or more, black/mixed race, illiterate, living in the countryside, dyspnoea, respiratory distress, influenza-like outbreak, O2 saturation <95%, X-ray change, length of stay in the intensive care unit (ICU), invasive ventilatory support, previous heart disease, pneumopathy, diabetes, Down's syndrome, neurological disease and kidney disease. Better survival was observed in the influenza-like outbreak and in an asthmatic patient. The multiple model for increased risk of death when they were admitted to the ICU HR 1.28, diabetes HR 1.17, neurological disease HR 1.34, kidney disease HR 1.11, heart disease HR 1.14, black or mixed race of HR 1.50, asthma HR 0.71 and pneumopathy HR 1.12. This reinforces the importance of socio-demographic and clinical factors as a prognosis for death.

Usnic acid (UA) is a natural product found in the lichen genera. Because of the phenolic groups in its structure, UA is suspected to be an antioxidant. Therefore, in this study, the radical scavenging of UA was investigated in physiological environments in silico by using kinetic calculations. It was found that the overall rate constant for the hydroxyl radical scavenging activity was approximately 10 9 M -1 s -1 in all environments, whereas the HOO • and CH 3 OO • radical scavenging activities were only significant in the polar environments with k in the range of 10 3 -10 4 M -1 s -1 . The results also revealed that the HO • scavenging activity followed the single electron transfer (SET) and radical adduct formation mechanisms; however, the SET pathway (for the dianion HU 2- ) played a dominant role in the scavenging of other studied radicals, including CH 3 O • , CCl 3 O • , CCl 3 OO • , NO 2 , SO 4 •- , and N 3 • . The activity of UA against these radicals was as high as that of typical phenolic acids such as ferulic acid, p M k f ∼ 10 8 M -1 s -1 ) in polar solvents. Thus, UA is a promising natural antioxidant in aqueous environments., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Background: Prolonged PR interval (PRi) is associated with adverse outcomes. However, PRi determinants are poorly known. We aimed to identify the clinical determinants of the PRi duration in the general population., Hypothesis: Some clinical data are associated with prolonged PRi., Methods: Cross-sectional study conducted between 2014 and 2017. Electrocardiogram-derived PRi duration was categorized into normal or prolonged (>200 ms). Determinants were identified using stepwise logistic regression, and results were expressed as multivariable-adjusted odds ratio (OR) (95% confidence interval). A further analysis was performed adjusting for antiarrhythmic drugs, P-wave contribution to PRi duration, electrolytes (kalemia, calcemia, and magnesemia), and history of cardiovascular disease., Results: Overall, 3655 participants with measurable PRi duration were included (55.6% females; mean age 62 ± 10 years), and 330 (9.0%) had prolonged PRi. Stepwise logistic regression identified male sex (OR 1.41 [1.02-1.97]); aging (65-74 years: OR 2.29 [1.61-3.24], and ≥ 75 years: OR 4.21 [2.81-6.31]); increased height (per 5 cm, OR 1.15 [1.06-1.25]); hypertension (OR 1.37 [1.06-1.77]); and hs troponin T (OR 1.67 [1.15-2.43]) as significantly and positively associated, and high resting heart rate (≥70 beats/min, OR 0.43 [0.29-0.62]) as negatively associated with prolonged PRi. After further adjustment, male sex, aging and increased height remained positively, and high resting heart rate negatively associated with prolonged PRi. Hypertension and hs troponin T were no longer associated., Conclusion: In a sample of the Swiss middle-aged population, male sex, aging and increased height significantly increased the likelihood of a prolonged PRi duration, whereas a high resting heart rate decreased it., (© 2020 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Diterpenes that were isolated from Crossopetalum gaumeri (Loes.) Lundell (Celastraceae) plants are reported to exhibit a range of biological activities, in particular as radical scavengers. Thus further insight into the antioxidant activity of diterpenes in physiological environments is much needed but not studied yet. In this study, the antioxidant activity of nine natural diterpenes was evaluated using kinetic and thermodynamic calculations. It was found that the sequential proton loss electron transfer (SPLET) mechanism is favored in polar environments, whereas formal hydrogen transfer (FHT) is the main pathway for the radical scavenging of these diterpenes in the gas phase as well as in lipid media. The rate constants for the HOO˙ radical scavenging of these compounds in the gas phase, polar and nonpolar solvents are in the range of 2.29 × 10 -2 to 4.58 × 10 7 , 9.74 × 10 -3 to 1.67 × 10 8 and 3.54 × 10 -5 to 1.31 × 10 5 M -1 s -1 , respectively. 7-Deoxynimbidiol (6), exhibits the highest HOO˙ radical scavenging with k overall M 8 M -1 s -1 M 4 M -1 s -1 in water and pentyl ethanoate solvents, respectively, that is about 1300 times higher than that of Trolox in polar environments. It is thus a promising natural antioxidant in physiological environments., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Functionalized fullerene is one of the most advantageous nanotechnologies to develop novel materials for potential biomedical applications. In this study, we applied the ONIOM-GD3 approach to explore the nucleophilic addition reaction mechanism between polyaniline (emeraldine and leucoemeraldine forms) and fullerene. Potential energy surfaces were also analyzed to predict the predominantly formed products of the functionalized reaction. The themoparameters, such as bond dissociation enthalpy (BDE), ionization energy (IE), and electron affinity (EA), characterized by two mechanisms HAT and SET, were used to evaluate the antioxidant activities of the selected compounds. Moreover, the calculated HOMO, LUMO, and DOS results indicate that the electronic structures of polyaniline-fullerene were significantly affected by the presence of fullerene. The computational results show that C60-L1 seems to be the best antioxidant following the SET mechanism., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Indolinonic hydroxylamine (IH) is known as a potential artificial antioxidant in apolar environments. Here, a library of 108 monosubstituted derivatives was screened in silico to identify a lead compound for increased antioxidant activity, following a strategy of shortlisting based on thermochemical and kinetic properties. It was found that the presence of substituents at the 2, 4, and 7 positions increased, while substituents in other positions decreased the BDE(O-H) values, in good correlation to the electron-donating ability of substituents. Among the studied compounds, the N and 5 amine-substituted derivatives have the lowest BDE(O-H) values (62.4-64.0 kcal mol -1 ). The presence of the strong electron-withdrawing substituents can decrease the proton affinities of the derivatives, whereas the decrease of ionization energies correlates to the electron-donating ability of the substituents. It was also found that the formal hydrogen transfer (FHT) mechanism is the favored pathway for the HOO · radical scavenging. Kinetic calculations showed that the rate constant of the reaction between N-NHMe-IH compound and HOO · radical following the FHT mechanism ( k = 3.00 × 10 7 M -1 s -1 ) is about 8223 and 5253 times higher than those of Trolox and ascorbic acid, respectively, in the pentyl ethanoate solvent. Thus, N-NHMe-IH is expected to be the most powerful antioxidant reported to date in lipid environments.

Indole-3-carbinol (I3C) is the product of the enzymatic hydrolysis of glucobrassicin in the human body. I3C exhibits diverse bioactivities. It is used as a supplement to enhance the efficiency of some cancer therapies and is available as an over-the-counter dietary supplement described as a potential antioxidant, among other health benefits. Thus, it is important to develop an in-depth understanding of its antioxidant activity. In this study, the hydroxyl radical scavenging of I3C has been investigated in silico under physiologically relevant conditions (aqueous and lipid-mimetic pentyl ethanoate environment) using thermochemical and kinetic calculations. For benchmarking purposes, the results were compared to known experimental data. The overall reaction rate constant of the HO • radical scavenging of I3C in water was found to be 2.30 × 10 10 M -1 s -1 and over two times lower in lipid-mimetic pentyl ethanoate solvent at 7.74 × 10 9 M -1 s -1 . The results also highlighted that the HO • radical scavenging follows almost exclusively the radical adduct formation mechanism (>94%) in a lipid mimetic medium, whereas this mechanism contributes about 60% in aqueous environments. I3C is considered a dopamine-like antioxidant, its main function being prevention of oxidative degradation of lipids; our study supports this view., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

The objective of this study was to evaluate the chemical composition, and the trypanocidal and antibacterial activities of the essential oils from four species of Annonaceae: Bocageopsis multiflora (Mart.) R.E.Fr., Duguetia quitarensis Benth., Fusaea longifolia (Aubl.) Saff., and Guatteria punctata (Aubl.) R.A.Howard. The chemical composition of the essential oils from the aerial parts yielded 23, 20, 21 and 23 constituents, respectively, which were identified by GC/MS. The trypanocidal activity was evaluated against the amastigote and trypomastigote forms of T. cruzi. The antibacterial activity was evaluated by the microdilution method against enterohemorrhagic Escherichia coli, Pseudomonas aeruginosa, Streptococcus mutans, Streptococcus pyogenes, and methicillin-resistant Staphylococcus aureus. The results of trypanocidal activity showed that the essential oils of the four species were active at the tested concentrations, with G. punctata essential oil being the most active, with IC 50 =0.029 μg/mL, and selectivity index (SI)=32, being 34 times more active than the reference drug benznidazole. All EOs showed strong antibacterial activity (minimum inhibitory concentrations of 4.68-37.5 μg/mL) against strains of S. mutans., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Due to a substantial risk of malignancy, patients with focal FDG-avid thyroid incidentalomas (FFTIs) on PET/CT are in most of Denmark referred to Head and Neck Cancer (HNC) fast track programs. The aim of this study was to determine the risk of malignancy in FFTI managed in a HNC fast track program., Methods: A prospective cohort study including all patients with FFTI referred to the HNC fast track program, Odense University Hospital between September 1, 2016 and August 31, 2017. Ultrasonography (US) and fine-needle aspiration biopsy (FNAB) were intended to be done in all patients. Nodules with cytology of Bethesda 1, 3, 4, 5, or 6 were planned for surgical removal., Results: A total of 104 patients were included. All patients had US and 101 patients (97%) had FNAB. Forty-two patients had benign cytology classified as Bethesda 2. The remaining 62 patients underwent surgery except from 11 patients, mainly due to comorbidity. The overall risk of malignancy for patients with FFTI referred to our HNC fast track program was calculated to be 24% (23/95) based on patients with unequivocal cytology and/or histology. The only statistically significant US characteristic to predict malignancy was the appearance of irregular margins with a sensitivity of 47% and specificity of 96%., Conclusion: The risk of malignancy of FFTIs handled in our HNC fast track program is 24%.

Indolinonic hydroxylamine (IH) is a new-generation artificial antioxidant that, due to its ability to fractionate into apolar environments, is considered for prevention against lipid peroxidation. For this reason, it is important to understand, and compare, its activity in polar and nonpolar environments. In this study, the antioxidant activity of IH has been evaluated against HO • and HOO • radicals in water and, for a lipid-mimetic environment, pentyl ethanoate solvent, using kinetic calculations. It was found that the overall reaction rate constant of the HO • radical scavenging is more than 7 times higher in aqueous (8.98 × 10 9 M -1 s -1 ) than in apolar (1.22 × 10 9 M -1 s -1 ) media. However, HOO • scavenging was 35 times faster in apolar media (1.00 × 10 5 M -1 s -1 vs 2.80 × 10 3 M -1 s -1 ). In a lipid environment, the HAT mechanism was favored for the antioxidant activity for both radical species, whereas in aqueous solution the SET mechanism defined the HO • scavenging, while HAT described the HOO • scavenging. IH was shown to be one of the most active antioxidants in lipid environment, an essential characteristic for the protection of biological systems.

Objective: Reliable and pratique methods are essential for rapid and accurate determination of post thawing viability of peripheral blood stem cell (PBSC) graft before hematopoietic stem cell transplantation. In this study, Trypan Blue (TP) Eosin Y (EO), and Acridine-orange-ethidium bromide (AO/EB), which are of the methods commonly used for the assessment of viability in clinic practice, were compared with the flow cytometry-7AAD (7AAD) method, which is a more sensitive method. The aim of this study is to examine which method evaluates postthawing viability in a more compatible manner with 7AAD., Materials-Methods: Postthawing viability rates were examined simultaneously by means of four different methods before hematopoietic stem cell transplantation in a total of 20 PBSC graft. The results obtained from the AO/EB, TP, EO methods were evaluated with the flow cytometry-7AAD in terms of concordance., Results: The AO / EB was determined to be the method having the best concordance with the flow cytometry-7AAD method. Although, at a lower level compared to the AO/EB method, the EO method had a statistically significant concordance with the flow cytometry-7AAD method. No statistically significant concordance was detected between the TP method and 7AAD method in terms of viability results., Conclusion: The AO/EB method was identified to be the method having the best compatibility with the flow cytometry -7AAD method in showing the viability of the cryopreserved PBSC graft. In the viability assessment of PBCS graft using light microscopy, the EO may be preferred since is more sensitive compared to the TP method., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Allogeneic stem cell transplantation applications have improved tremendously over the past quarter of a century. The use of new immunosuppressive protocols and elimination of T cells by CD34+ cell enrichment or T cell depletion on apheresis products increases the chance of using partially matched or haploidentical grafts. This is without increasing the risk of graft-versus-host disease, which is observed as a major complication of hematopoietic stem cell transplantation. The aim of this protocol is to evaluate the results obtained from 6 different process cycles performed on 6 different days. We used the CliniMACS Plus system located in our Cell and Tissue Manufacturing Center Quality Control Unit which is already calibrated as a class D room and includes a class A microbiological safety cabinet inside. The average purity of the end products was 95.66%, excluding only one end product which was 70%; this was higher than the values in current studies in the field. Superior to the reported studies, the CD3 quantity in each end product was below the dedicated thresholds. BactecTM FX40 blood culture system test results were detected as negative for each end product. Endotoxin testing suggested the absence of endotoxin within the products. The consistent outcomes obtained from these 6 different process cycles confirmed that the CliniMACS® Plus process cycles performed in accordance with our well-defined quality management system procedure is sufficient for the routine application of high-quality and safe CD34+ enrichment processes within our clean room area., (© 2019 S. Karger AG, Basel.)

Objectives: Spiral ganglion neurons (SGNs) include potential endogenous progenitor populations for the regeneration of the peripheral auditory system. However, whether these populations are present in adult mice is largely unknown. We examined the presence and characteristics of SGN-neural stem cells (NSCs) in mice as a function of age., Methods: The expression of Nestin and Ki67 was examined in sequentially dissected cochlear modiolar tissues from mice of different ages (from postnatal day to 24 weeks) and the sphere-forming populations from the SGNs were isolated and differentiated into different cell types., Results: There were significant decreases in Nestin and Ki67 double-positive mitotic progenitor cells in vivo with increasing mouse age. The SGNs formed spheres exhibiting self-renewing activity and multipotent capacity, which were seen in NSCs and were capable of differentiating into neuron and glial cell types. The SGN spheres derived from mice at an early age (postnatal day or 2 weeks) contained more mitotic stem cells than those from mice at a late age., Conclusion: Our findings showed the presence of self-renewing and proliferative subtypes of SGN-NSCs which might serve as a promising source for the regeneration of auditory neurons even in adult mice.

Tissue-specific gene expression defines cellular identity and function, but knowledge of early human development is limited, hampering application of cell-based therapies. Here we profiled 5 distinct cell types at a single fetal stage, as well as chondrocytes at 4 stages in vivo and 2 stages during in vitro differentiation. Network analysis delineated five tissue-specific gene modules; these modules and chromatin state analysis defined broad similarities in gene expression during cartilage specification and maturation in vitro and in vivo, including early expression and progressive silencing of muscle- and bone-specific genes. Finally, ontogenetic analysis of freshly isolated and pluripotent stem cell-derived articular chondrocytes identified that integrin alpha 4 defines 2 subsets of functionally and molecularly distinct chondrocytes characterized by their gene expression, osteochondral potential in vitro and proliferative signature in vivo. These analyses provide new insight into human musculoskeletal development and provide an essential comparative resource for disease modeling and regenerative medicine.

Background: Tuberculosis (TB) is a major health problem worldwide. In TB, the immune and central nervous systems modulate each other. The two main components of this network are the hypothalamic-pituitary-adrenal axis (HPA) and autonomic nervous system (ANS)., Objective: To elucidate neuro-endocrine-immune (NEI) interactions in pulmonary (PTB) or pleural (PLTB) TB, we analysed the relationship among compounds from these systems., Methods: We quantified levels of catecholamines, hormones and cytokines in plasma from patients with PTB (n = 46) or PLTB (n = 12) and controls (n = 32), and in the pleural fluid from PLTB patients. Transcript expression for genes involved in glucocorticoid-related function (quantitative real-time polymerase chain reaction) was also analysed in mononuclear cells (MCs) from peripheral blood (PBMC) or pleural effusion (PEMC) compartments., Results: Both patient groups had increased plasma levels of pro- and anti-inflammatory cytokines, cortisol, growth hormone (GH) and dopamine, whereas insulin-like growth factor 1 (IGF-1) and dehydroepiandrosterone levels were decreased. The pleural fluid contained increased levels of pro-inflammatory cytokines, GH and IGF-1 and reduced levels of steroid hormones compared with their plasma counterparts. PBMCs from PTB patients had increased expression of transcripts for 11β-hydroxysteroid dehydrogenase (11βHSD1) and a decreased glucocorticoid receptor (GR) ratio (GRα/GRβ). In PLTB cases, expression of 11βHSD1 and GRα transcripts was higher in PEMCs., Conclusion: PTB patients seem to display adverse NEI dysregulation. Changes in pleural fluid are compatible with a more effective NEI reaction.

Inflammation contributes to the development of cancer, yet acute inflammatory responses are also needed to eradicate tumorigenic cells and activate adaptive immune responses to combat cancer. Physical exercise has direct immunomodulatory effects, and in line with this, exercise has been demonstrated to inhibit tumor growth, including diethylnitrosamine-(DEN)-induced hepatocarcinoma. Having observed a sex-dependent development of DEN-induced hepatocarcinoma, we aimed to evaluate the effect of exercise and sex on the acute inflammatory response to DEN. Thus, we randomized male and female mice to cages with or without running wheels for 6 weeks, whereafter DEN was administered and the inflammatory response was evaluated for up to 96 hours. DEN administration caused marked acute inflammatory responses in female mice with weight loss, reduced food intake, release of liver enzymes, and increased systemic levels of IL6. Moreover, DEN caused increased hepatic expression of cytokines, immune cell markers, and components of the toll-like receptor signaling pathway. In male mice, DEN administration provoked similar physiologic effects with weight loss and reduced food intake, but less systemic and hepatic acute inflammation, which was associated with a higher baseline expression of the detoxifying enzyme glutathione S-transferase and lower expression of ERα in male mice. Voluntary wheel running attenuated systemic and hepatic inflammation, in particular in the female mice, and shifted the peak time of the inflammatory response. In conclusion, DEN elicited an acute inflammatory response in particular in female mice, and this response was attenuated by prior exercise. Cancer Prev Res; 10(12); 719-28. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Patterning of the facial skeleton involves the precise deployment of thousands of genes in distinct regions of the pharyngeal arches. Despite the significance for craniofacial development, how genetic programs drive this regionalization remains incompletely understood. Here we use combinatorial labeling of zebrafish cranial neural crest-derived cells (CNCCs) to define global gene expression along the dorsoventral axis of the developing arches. Intersection of region-specific transcriptomes with expression changes in response to signaling perturbations demonstrates complex roles for Endothelin 1 (Edn1) signaling in the intermediate joint-forming region, yet a surprisingly minor role in ventralmost regions. Analysis of co-variance across multiple sequencing experiments further reveals clusters of co-regulated genes, with in situ hybridization confirming the domain-specific expression of novel genes. We then created loss-of-function alleles for 12 genes and uncovered antagonistic functions of two new Edn1 targets, follistatin a ( fsta ) and emx2 , in regulating cartilaginous joints in the hyoid arch. Our unbiased discovery and functional analysis of genes with regional expression in zebrafish arch CNCCs reveals complex regulation by Edn1 and points to novel candidates for craniofacial disorders., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Diabetes is a risk factor for the development of pulmonary tuberculosis (TB) and both diseases present endocrine alterations likely to play a role in certain immuno-endocrine-metabolic associated disorders. Patients with TB, or with TB and type 2 diabetes (TB + T2DM) and healthy controls (HCo) were assessed for plasma levels of cortisol, dehydroepiandrosterone (DHEA), estradiol, testosterone, growth hormone (GH), prolactin, insulin-like growth factor-1 (IGF-1), cytokines (IL-6, IL-10, IFN-γ) and the specific lymphoproliferative capacity of peripheral blood mononuclear cells. All patients had higher levels of cortisol with a reduction in DHEA, thus resulting in an increased cortisol/DHEA ratio (Cort/DHEA). Increased prolactin and particularly GH levels were found in both groups of TB patients. This was not paralleled by increased concentrations of IGF, which remained within the levels of HCo. Estradiol levels were significantly augmented in patients TB, and significantly more in TB + T2DM, whereas testosterone levels were decreased in both groups of patients. IFN- γ and IL-6 concentrations were significantly increased in all TB, even further in TB + T2DM; while IL-10 was equally increased in both groups of TB patients. The in vitro specific proliferative capacity was decreased in both groups of patients as compared to that of HCo. The adverse immune-endocrine profile of TB seems to be slightly more pronounced in patients who also have T2DM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Different cortical areas are organized into distinct intracortical subnetworks. The manner in which descending pathways from the entire cortex interact subcortically as a network remains unclear. We developed an open-access comprehensive mesoscale mouse cortico-striatal projectome: a detailed connectivity projection map from the entire cerebral cortex to the dorsal striatum or caudoputamen (CP) in rodents. On the basis of these projections, we used new computational neuroanatomical tools to identify 29 distinct functional striatal domains. Furthermore, we characterized different cortico-striatal networks and how they reconfigure across the rostral-caudal extent of the CP. The workflow was also applied to select cortico-striatal connections in two different mouse models of disconnection syndromes to demonstrate its utility for characterizing circuitry-specific connectopathies. Together, our results provide the structural basis for studying the functional diversity of the dorsal striatum and disruptions of cortico-basal ganglia networks across a broad range of disorders.

The purpose of this study was to characterize children with Down syndrome and attention-deficit hyperactivity disorder (ADHD) with disruptive behaviors using the Aberrant Behavior Checklist (ABC), and to measure the treatment effects of guanfacine on maladaptive behaviors. Subjects were enrolled from a group of outpatients who visited our clinic between 2002 and 2007. Subjects (N = 23) were children with Down syndrome ages 4 to 12 years (mean 7.4 ± 4.1), who met criteria for ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition The Aberrant Behavior Checklist Irritability and Hyperactivity subscales each showed a significant decrease (P < .0001) at follow-up. The mean decline on Hyperactivity was 25% (-7.8 points), and for Irritability, 25% (-3.5 points). The mean composite score also declined by 24% (-12 points). Effect size differences on Irritability were moderate, whereas differences on Hyperactivity and composite score appeared large. Clinically important target behaviors were reduced. Medication was generally well tolerated and the incidence of treatment emergent side effects remained low., (© The Author(s) 2016.)

Recently, two-dimensional monolayer molybdenum disulfide (MoS 2 ), a transition metal dichalcogenide, has received considerable attention due to its direct bandgap, which does not exist in its bulk form, enabling applications in optoelectronics and also thanks to its enhanced catalytic activity which allows it to be used for energy harvesting. However, growth of controllable and high-quality monolayers is still a matter of research and the parameters determining growth mechanism are not completely clear. In this work, chemical vapor deposition is utilized to grow monolayer MoS 2 flakes while deposition duration and temperature effect have been systematically varied to develop a better understanding of the MoS 2 film formation and the influence of these parameters on the quality of the monolayer flakes. Different from previous studies, SEM results show that single-layer MoS 2 flakes do not necessarily grow flat on the surface, but rather they can stay erect and inclined at different angles on the surface, indicating possible gas-phase reactions allowing for monolayer film formation. We have also revealed that process duration influences the amount of MoO 3 /MoO 2 within the film network. The homogeneity and the number of layers depend on the change in the desorption-adsorption of radicals together with sulfurization rates, and, inasmuch, a careful optimization of parameters is crucial. Therefore, distinct from the general trend of MoS 2 monolayer formation, our films are rough and heterogeneous with monolayer MoS 2 nanowalls. Despite this roughness and the heterogeneity, we observe a strong photoluminescence located around 675 nm.

Background: Hyponatraemia is a prognostic marker of increased mortality and morbidity in selected groups of hospitalised patients. The aim of the present study was to examine the prevalence and prognostic significance of hyponatraemia at hospital admission in an unselected population with a broad spectrum of medical and surgical diagnoses., Methods: Consecutive patients >40 years of age admitted to a general district hospital in Greater Copenhagen between 1 April 1998 and 31 March 1999. Median follow-up time was 5.16 years (range 0-4372 days). Plasma sodium measurements were available in 2960 patients, and hyponatraemia defined as P-Na(+) <137 mmol/L at hospital admission was present in 1105 (37.3 %) patients., Results: One-year mortality was higher for hyponatraemic patients than for normonatraemic patients: 27.5% versus 17.7%. Moreover, hyponatraemia was an independent predictor of short and long-term all-cause mortality after 1 year and after the entire observation period respectively: hazard ratio (HR) 1.6 (95 % confidence interval (CI) 1.4-1.9, P < 0.0001) and HR 1.4 (95 % CI 1.3-1.6, P < 0.0001). Patients with hyponatraemia had longer hospitalisations than patients with normonatraemia: 7.6 (±0.38) days vs 5.6 (±0.21) days, P < 0.001. There was no interaction between hyponatraemia at admission and any admission diagnoses (P > 0.05 for all interaction analyses)., Conclusion: Hyponatraemia is associated with increased all-cause mortality and longer admission length independently of diagnosis and clinical variables., (© 2014 Royal Australasian College of Physicians.)