Genetic Testing in Kid Epilepsy

Advance care planning (ACP) is considered a pivotal aid in the decision-making process, especially for many people living with dementia, who inevitably will lose the capacity to make decisions at the end of life. In Italy, ACP has been recently regulated by law 219/2017, leading to the investigation of how physicians deal with ACP in dementia. In order to comprehend the perception of physicians who provide care for patients with dementia regarding ACP and to describe their difficulties and needs, this study presents the results of a qualitative research study performed within a local health authority in northern Italy. Data were collected by semi-structured interviews with 11 physicians dealing with patients with dementia and were analysed using interpretative phenomenological analysis. Four superordinate themes were identified, describing both the difficulties and challenges perceived by physicians in performing shared ACP in their daily activities. This study demonstrates that physicians experience troubles synchronizing the time of shared ACP with the more rapid development of dementia. Results also suggest that further training about communication on ACP is urgently required to ease the implementation of shared ACP. A broader involvement of institutions and other professionals is also important in spreading ACP among healthcare institutions.Data used to estimate the burden of diseases (BOD) are usually sparse, noisy, and heterogeneous. These data are collected from surveys, registries, and systematic reviews that have different areal units, are conducted at different times, and are reported for different age groups. In this study, we developed a Bayesian geo-statistical model to combine aggregated sparse, noisy BOD data from different sources with misaligned areal units. Our model incorporates the correlation of space, time, and age to estimate health indicators for areas with no data or a small number of observations. The model also considers the heterogeneity of data sources and the measurement errors of input data in the final estimates and uncertainty intervals. We applied the model to combine data from nine different sources of body mass index in a national and sub-national BOD study. The cross-validation results confirmed a high out-of-sample predictive ability in sparse and noisy data. The proposed model can be used by other BOD studies especially at the sub-national level when the areal units are subject to misalignment.
Research shows that sensitivity to certain alcohol responses conveys risk for problem drinking. This study aimed to determine if high-risk adolescent drinkers infuse more alcohol and experience greater alcohol-induced stimulation and wanting and less sedation than low-risk adolescent drinkers.
Ninety-two low- (n=38) and high-risk (n=54) adolescent drinkers, as determined by Alcohol Use Disorders Identification Test scores of <6 or ≥6, respectively, participated in the Dresden Longitudinal Study on Alcohol Use in Young Adults in which intravenous alcohol self-administration was examined in a mixed within- and between-subjects design.
Technische Universität Dresden. Dresden, Germany.
Predictors were drinking status (high- versus low-risk), time and their interactions. Outcomes were arterial blood alcohol concentration (aBAC); alcohol-induced stimulation, sedation and wanting assessed at baseline, 10 (alcohol prime), 45, 65, 85, 105, 125 and 145minutes. Covariates were family history of alcohol use disorder, sex and aBAC.
The alcohol prime dose produced similar sharp increases in stimulation and sedation in high- and low-risk drinkers (time P < 0.001; group×time P > 0.05). During self-administration, high-risk drinkers reached higher aBACs (P=0.028) at a faster rate (group×time P<0.001), and experienced further increases in stimulation (group×time P=0.005) but with similar sedation (group×time P=0.794) than in low-risk drinkers. High-risk drinkers also exhibited greater tonic alcohol wanting (group P=0.003) throughout the session.
High-risk adolescent drinkers appear to have heightened sensitivity to alcohol-induced stimulation and tonic high levels of wanting compared with low-risk adolescent drinkers.
High-risk adolescent drinkers appear to have heightened sensitivity to alcohol-induced stimulation and tonic high levels of wanting compared with low-risk adolescent drinkers.
Endoscopic evaluation of disease activity, including mucosal healing, is poorly established in Crohn's disease. We previously reported that patients with a Lewis score (LS) on capsule endoscopy <270 had a lower risk of exacerbation without additional treatment. This study investigated prognostic predictors in patients undergoing capsule endoscopy and determined the optimal LS cut-off value.
In a retrospective single-center study, 102 patients with Crohn's disease who underwent capsule endoscopy were reviewed. We reviewed the clinical course and the patients' characteristics, Crohn's Disease Activity Index, laboratory findings, LS, and Prognostic Nutritional Index (PNI) for factors potentially associated with Crohn's disease-related emergency hospitalization. Subsequently, we prospectively enrolled 66 patients with Crohn's disease and analyzed clinical outcomes according to these factors.
In the retrospective study, LS≥270 and PNI<45 were identified as independent predictors of Crohn's disease-relahould be considered for this group.Covalency in actinides has emerged as a resounding research topic on account of the technological importance in separating minor actinides from lanthanides for spent nuclear fuel processing, and utilization of their distinct bonding properties has been realized as a route towards overcoming this challenge. Because of the limited radial extent of the 4f orbitals, there is almost no 4f electron participation in bonding in lanthanides; this is not the case for the actinides, which have extended 5f orbitals that are capable of overlapping with ligand orbitals, although not to the degree of overlap as in the d orbitals of transition metals. In this concept paper, a general description of covalency in actinide compounds is provided. After introducing two main approaches to enhance covalency, either by exploiting increased orbital overlap or decreasing energy differences between the orbitals causing orbital energy degeneracy, the current state of the field is illustrated by using several examples from the recent literature. This paper is concluded by proposing the use of actinide chalcogenides as a convenient auxiliary tool to study covalency in actinide compounds.Low-intensity resistance exercise with blood flow restriction exercise is an emerging type of exercise recognition worldwide. This systematic review evaluated the effects of low-intensity resistance exercise performed with concurrent blood flow restriction (LIRE-BFR) on acute and chronic measures of arterial stiffness in humans. A systematic search in six healthcare science databases and reference lists was conducted. Data selected for primary analysis consisted of post-intervention changes in arterial stiffness markers. This systematic review included randomized and non-randomized controlled trials of LIRE-BFR in humans. 156 articles were initially identified, 15 of which met inclusion criteria. Ten studies were excluded because they did not match predefined arterial stiffness markers. Thus, five articles were included in this review two acute studies (N = 39 individuals, age = 20-30 years old, 30.8% women and 69.2% men) and three longitudinal studies (N = 51 individuals, age = 24-86-years old, 41.2% women and 58.8% men). Acute LIRE-BFR demonstrated both positive and negative effects on arterial stiffness in healthy young people. In contrast, longitudinal studies reported neutral effects in healthy young and older people. In conclusion, LIRE-BFR applied to the upper and lower limbs may acutely induce increases in central blood pressure and pulse wave velocity in healthy young people, whereas LIRE-BFR for the lower limbs may elicit positive effects related to indirect markers of arterial stiffness. Moreover, longitudinal LIRE-BFR studies showed no changes in arterial stiffness in young and older people. Hence, LIRE-BFR should be prescribed with a degree of caution to avoid non-intended responses in arterial stiffness markers in humans.
Drug resistance is a common phenomenon frequently observed in countries where leishmaniasis is endemic. Due to the production of the pteridine reductase enzyme (PTR1), drugs lose their efficacy, and consequently, the patient becomes unresponsive to treatment. This study aimed to compare the in vitro effect of meglumine antimoniate (MA) on non- healing Leishmania tropica isolates and on MA transfected non-healing one to PTR1.
Two non-healing and one healing isolates of L. tropica were collected from patients who received two courses or one cycle of intralesional MA along with biweekly liquid nitrogen cryotherapy or systemic treatment alone, respectively. After confirmation of L. tropica isolates by polymerase chain reaction (PCR), the recombinant plasmid pcDNA-rPTR (antisense) was transfected via electroporation and cultured on M199. Isolates in form of promastigotes were treated with different concentrations of MA and read using an enzyme-linked immunosorbent assay (ELISA) reader and the half inhibitory cf the drug, and its inhibition by antisense and could improve the treatment of non-healing cases. These findings have future implications in the prophylactic and therapeutic modality of non- healing Leishmania isolates to drug.Controlling magnetic states by a small current is essential for the next-generation of energy-efficient spintronic devices. However, it invariably requires considerable energy to change a magnetic ground state of intrinsically quantum nature governed by fundamental Hamiltonian, once stabilized below a phase-transition temperature. Here, it is reported that, surprisingly, an in-plane current can tune the magnetic state of the nanometer-thin van der Waals ferromagnet Fe3 GeTe2 from a hard magnetic state to a soft magnetic state. It is a direct demonstration of the current-induced substantial reduction of the coercive field. This surprising finding is possible because the in-plane current produces a highly unusual type of gigantic spin-orbit torque for Fe3 GeTe2 . In addition, a working model of a new nonvolatile magnetic memory based on the principle of the discovery in Fe3 GeTe2 , controlled by a tiny current, is further demonstrated. The findings open up a new window of exciting opportunities for magnetic van der Waals materials with potentially huge impact on the future development of spintronic and magnetic memory.Radix Gentianae Macrophyllae (RGM) is a traditional Chinese medicine belonging to the Gentiana genus and including four species of herbs. Owing to the lack of characteristic constituents, it is difficult to discriminate RGMs of different origins or even differentiate between herbs in the same genus. The current research aimed to explore the characteristic aromatic compounds, verify their significance in distinguishing different origins of RGM herbs and provide a simple and effective quality evaluation method. A selective extraction method was developed for noniridoid compounds and the extract was then subjected to UPLC-QTOF-MS analysis to obtain the RGM-MS ion pair database for noniridoid components. An HPLC-DAD quantitative analysis method was further developed based on characteristic aromatic compounds (2-phenylethyl β-d-glucopyranoside, 2-methoxyanofinic acid and gentioxepine) after the ion screening in the MS database. By means of principal component analysis and hierarchical clustering analysis analysis, the significant relationship between aromatic compounds contents and different species of RGM was revealed. As a result, the significance of 2-phenylethyl β-d-glucopyranoside, 2-methoxyanofinic acid and gentioxepine in distinguishing four species of RGM herbs was verified and a sensitive and reproducible HPLC-DAD method was established using these markers, which can be used for the classification and quantitative analysis of RGMs.A 61-year-old woman with acute myocardial infarction (MI), cardiogenic shock, and Impella CP support underwent emergency coronary artery bypass grafting. Postoperatively venous-arterial extracorporeal membrane oxygenation (va-ECMO) became necessary, followed by Impella 5.0 insertion on 7th postoperative day (POD), the addition of right ventricular support by TandemHeart due to inadequate flow of Impella system, which then allowed for va-ECMO weaning. Impella und TandemHeart were removed on 14th POD, 31st POD, respectively. Biventricular decompensation following MI was successfully treated by a sequence of different mechanical circulatory support systems allowing an adaptive weaning strategy.Systemic cytokine concentrations have been extensively studied in implant-associated infections, providing sensitive diagnostic markers. However, less is known about the relationships of tissue-level cytokines surrounding the joint. The aim of this study was to define the cytokine profiles of tissues to investigate the use of these cytokines as markers of debridement in chronic joint infection. Using a rodent model, muscle samples were obtained from rats following Kirschner wire implantation and infection with Staphylococcus aureus to determine if (1) differences exist in cytokine concentrations with proximity to infection, and (2) localized infection-specific markers can be identified on a tissue level to potentially serve as debridement markers in the future. Samples were collected from 4 distinct locations, and the concentrations of interleukin(IL)-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, granulocyte-macrophage colony-stimulating factor, interferon-γ, and tumor necrosis factor-α were quantified in each sample, relative to the amount of tissue. Cytokine concentrations differed with proximity to the joint when implant or infection was present, and tissues at the operative knee joint showed the highest levels of most cytokines. Additionally, IL-1β, IL-4, and IL-6 showed promise, beyond diagnostics, as tissue-level indicators of infection response. Ultimately, this study illustrated that tissue-level evaluation provided insight into infection-specific response, and these markers may be useful for guiding the debridement of implant-associated infections.
Patent ductus arteriosus (PDA) is an important cause of morbidity and mortality, especially in very-low-birth-weight infants. The aim of the present study was to evaluate the outcomes of bedside surgical ligation of PDA via limited upper ministernotomy as an alternative approach to thoracotomy.
A total of 23 low-birth-weight premature infants, who underwent bedside ligation of PDA in the neonatal intensive care unit between January 2017 and April 2020, were enrolled. The patients were divided into two groups those with thoracotomy (n = 13) and those with limited upper ministernotomy (n = 10). These patients were evaluated retrospectively in terms of clinical and preoperative, intraoperative, postoperative parameters between the groups.
Mean birth weight was 1059 ± 275 g in the thoracotomy group and 1035 ± 285 g in the ministernotomy group. There was no statistically significant difference in the age at surgery, weight at surgery, preoperative mechanical ventilation (MV) support, inotropic score onset of surgery, and total procedure time between the groups. There was a statistically significant difference in the hospital length of stay, postoperative MV time, and complications in the intensive care unit in favor of the ministernotomy group (p = .04,p = .03,p = .034, respectively). The study showed no statistically significant difference in the mortality rate between the two groups (two patients in the thoracotomy group and one patient in the ministernotomy group).
The limited upper ministernotomy is an anatomically and technically feasible alternative to classical left posterolateral thoracotomy for bedside surgical PDA ligation.
The limited upper ministernotomy is an anatomically and technically feasible alternative to classical left posterolateral thoracotomy for bedside surgical PDA ligation.
The management of Graves' disease (GD) in the US is shifting towards increased use of anti-thyroid drugs (ATD). If patients fail to achieve remission after a standard course of therapy of 12-18months, long-term treatment with ATD (≥24months) may be chosen over definitive therapy with radioiodine (RAI) or surgery. Clinicians will need to contrast this strategy to ablative therapies as they help patients in decision making.
Review of the literature illustrates that long-term ATD delivers euthyroidism with minimal complications, low financial cost and with an advantageous profile regarding quality of life (QoL) and other biological outcomes.
Long-term ATD is a viable alternative to ablative therapies in the management of GD offering advantages across multiple patient centred outcomes. Decision making must factor differences in this approach compared to ablative therapies and ultimately be tailored to individualized patient situations.
Long-term ATD is a viable alternative to ablative therapies in the management of GD offering advantages across multiple patient centred outcomes. Decision making must factor differences in this approach compared to ablative therapies and ultimately be tailored to individualized patient situations.
Infective issues about anti-tumor necrosis factor (TNF)-α agents in inflammatory bowel disease (IBD) remain controversial, especially when compared with nonbiological treatments. This study aimed to evaluate the incidence and prevalence of several infections in anti-TNF-α-exposed patients compared with nonbiological treatments.
All naïve IBD subjects treated with anti-TNF-α and matched nonbiologic-exposed patients were included.
Among 3453 patients in the database, 288 anti-TNF-α-exposed subjects and 288 nonbiologic-exposed IBD controls met inclusion criteria. Fifty-eight infections (20.1%) occurred during anti-TNF-α treatment versus 23 (8%) in the matched group (odds ratio [OR] 2.9, P<0.001) (incidence 5.72 vs 0.96/100 patient-years, incidence ratio [IR] 6, P<0.001). IR was higher for anti-TNF-α versus mesalamine/sulfasalazine (IR 40.8, P<0.001), similar to azathioprine/6-mercaptopurine/methotrexate (IR 0.78, P=0.32) and lower than corticosteroids (IR 0.05, P<0.001). The incidence rate of serious infections was 1.3 in the anti-TNF-α-exposed versus 0.38/100 patient-years in nonexposed subjects (IR 3.44, P=0.002), without significant difference between anti-TNF-α and azathioprine/6-mercaptopurine/methotrexate (1.3 vs 3.03/100 patient-years, IR 0.43, P=0.1). Predictors of infections in anti-TNF-α-exposed patients were concomitant use of systemic steroids (OR 1.9, P=0.02) or azathioprine (OR 2.6, P=0.01) and a body mass index<18.5 at time of infection (OR 2.2, P=0.01).
The risk of developing infections during anti-TNF-α therapy remains high, although not dissimilar to that found for other immunosuppressants, while concomitant immunosuppression and malnutrition appear the most important causes of infection.
The risk of developing infections during anti-TNF-α therapy remains high, although not dissimilar to that found for other immunosuppressants, while concomitant immunosuppression and malnutrition appear the most important causes of infection.
The aim was to investigate socio-economic risk factors for maternal underweight before pregnancy and then associations of underweight with neonatal outcomes.
Data of 3401 mother-child dyads from the population-based birth cohort Survey of Neonates in Pomerania (SNiP) were analysed.
Bivariate analysis showed that underweighted mothers were younger, smoked more often, had a lower equivalent income and lower socio-economic status (employment status and/or educational level) compared to women with normal weight. The final prediction model revealed that only younger maternal age (OR=0.93; 95%-CI=0.90-0.97) and maternal smoking during pregnancy (OR=2.52; 95%-CI=1.74-3.66) were associated with underweight. Compared to women with normal pre-pregnancy BMI, underweight women had an increased chance of premature labour (OR=1.73; 95% CI 1.29-2.31) and a reduced placental weight. The offspring of underweight women had an increased risk of late preterm birth (OR=1.82; 95% CI 1.21-2.74) and birthweight<2500g (OR=1.91; 95% CI 1.23-2.95).
Smoking during pregnancy and a younger age were identified as risk factors for maternal pre-pregnancy underweight which then was associated with late preterm birth and low birthweight.
Smoking during pregnancy and a younger age were identified as risk factors for maternal pre-pregnancy underweight which then was associated with late preterm birth and low birthweight.
Firefighters have an increased risk of cancer, but variations in reported results could be due to differences in occupational case ascertainment. This study compares cancer risk estimates generated by identifying firefighters from their occupational title available in the Florida Cancer Data System (FCDS) versus identification by a linkage method between the FCDS and the Florida State Fire Marshal's Office.
Florida firefighter employment records (1972-2012; n = 109,009) were linked with FCDS data (1981-2014; ~3.3 million records), identifying 3760 primary cancers in male firefighters. Using the FCDS occupational data field we identified 1831 male cancer cases in those classified as firefighters, first-line supervisors of firefighting and prevention workers, fire inspectors, emergency medical technicians, or paramedics. Age and calendar year-adjusted odds ratios (aOR) and 95% confidence intervals for firefighters versus non-firefighters were calculated for both groups.
For skin cancers the risk estimate and certification or other administrative records, which are a vital resource for firefighter cancer research.Aortopulmonary window (APW) is a rare but serious congenital cardiac malformation, most patients with APW will die from congestive heart failure within one year after birth. In fact, patients with large APW is rarely seen in childhood or adult life. However, we report an older child with a large anomalous "window" on the ascending aorta, with discontinuous pulmonary arteries, and the left pulmonary artery (LPA) arising via a left-sided arterial duct in the presence of a right aortic arch. Preoperative diagnosis made by echocardiography and chest computerized tomography revealed anatomical futures clearly. Cardiac catheterization indicated that the pulmonary resistances indices were 2.92 Wood unit/m2 in LPA and 3.35 Wood unit/m2 in RPA, Q p Q s was 3.26. This patient underwent surgical correction at the age of 10 and successfully survived.The pharmacokinetics of fluoroquinolones in chelonians are well described but this does not extend to pradofloxacin, a broad-spectrum veterinary fluoroquinolone available as an oral suspension for cats and dogs. The aim of this study was to investigate the single-dose pharmacokinetic profile of pradofloxacin oral suspension at 7.5 mg/kg in eastern long-necked turtles (Chelodina longicollis). Eight treated turtles were sampled at multiple time points up to 168 hr. Plasma concentrations were measured using high-performance liquid chromatography. Pradofloxacin was quantifiable for up to 48 hr after drug administration. The Tmax (9.0 hr) and T½ to 48 hr (13.16 hr) were longer, and the Cmax (0.2 μg/ml) and AUC0-24 (2.2 hr*μg/ml) lower, than previously reported in cats and dogs. Pradofloxacin was measurable in tank water samples for up to 48 hr. No adverse effects were observed in six turtles administered 7.5 mg/kg sid for 7 days. Using mammalian MIC data, the AUC0-24 /MIC ratios for a range of bacterial isolates suggest that this dose of pradofloxacin in turtles is unlikely to be effective against many bacterial pathogens.The Danish physicist Niels Bohr is best known for two major achievements first, his model of the quantum atom, published in 1913, for which he received the Nobel Prize in 1922; and second, the "Copenhagen interpretation" of quantum mechanics developed together with colleagues at his institute in the latter half of the twenties. Having turned his institute toward nuclear physics, making it a pioneer institution in this emerging field, Bohr escaped from Nazi-occupied Denmark in 1943. Learning in England about the advanced state of the secret project to develop an atomic bomb, which Bohr had so far considered impracticable in a foreseeable future, he agreed to join the project. Bohr decided instantly that the prospect of such a weapon of mass destruction would require what he came to call an "open world" among nations, and he worked conscientiously toward this end until he died in 1962. In the process, statesmen, including Winston Churchill and Franklin D. Roosevelt, as well as diplomats from several countries, came to encounter Bohr and his political mission. Although not as successful as his scientific achievements, his mission was considered by Bohr himself as equally important. Yet it constitutes a hitherto relatively neglected part of Bohr's career.1.AMG 510 is the first-in-class KRASG12C inhibitor, currently in phase 2 clinical trials as an orphan drug to treat non-small cell lung cancer patients. We developed and validated a sensitive, selective, and high-throughput HPLC-MS/MS method for the quantitation of AMG 510 in mouse plasma per the regulatory guideline of the US Food and Drug and Administration. AMG 510 and the IS (MRTX-1257) were extracted from mouse plasma using tert-butyl methyl ether and chromatographed using an isocratic mobile phase (0.2% formic acidacetonitrile; 2575, v/v) at a flow rate of 0.65 mL/min on an Atlantis dC18 column. AMG 510 and the IS eluted at ~0.95 and 0.73 min, respectively. AMG 510 and the IS were detected by positive electrospray ionization in multiple reaction monitoring using transition pair (Q1 → Q3) m/z 561.1 → 134.1 and m/z 566.5 → 98.2, respectively. Excellent linearity was achieved in the concentration range of 1.08-5040 ng/mL (r > 0.0996). No matrix effect and carryover were observed. Intra- and inter-day accuracies and precisions were within the acceptance range. AMG 510 was demonstrated to be stable under the tested storage conditions. This novel method has been applied to a pharmacokinetic study in mice.
Medical school accreditation is recognised internationally as an important quality control process for programmes that lead to the Medical Doctor (MD) degree. Accreditation standards govern the accreditation process which in turn drives educational objectives. Given the power of these standards to shape what becomes valued in the curricula, it is therefore imperative to ensure that core values and ideals of the profession are meaningfully incorporated. As the provision of compassionate care has long been a central medical value, this value should be clearly articulated in MD programme accreditation standards.
We conducted a Critical Discourse Analysis of compassionate care within Undergraduate Medical Education (UME) Accreditation Standards governing North American medical schools since 1957. We explored how and to what extent the written language of the accreditation standards incorporated compassionate care.
References to compassionate care in the UME Accreditation Standards were few and far between. .
The relative absence of language pertaining to compassionate care in accreditation standards is troubling as compassion is integral to good medical care. This absence is particularly important to attend to in the current era of competency-based training where we must be explicit about all important curricular objectives lest essential values and practices be unintentionally lost.Itai-itai (Japanese, "It hurts! It hurts!") disease (IID), a form of osteomalacia, can be induced in ovariectomized rats by long-term administration of cadmium (Cd). This IID rat model shows severe anemia, severe nephropathy, and osteomalacia accompanied by iron (Fe) deposition at the mineralization front. We characterized the pathogenesis of Cd-induced bone lesions by investigating the relationship between Fe deposition and osteoid tissue formation in ovariectomized rats. The rats were injected with CdCl2 (0.5 mg/kg) for 70 weeks, with or without co-injection of erythropoietin (EPO) for varying lengths of time to elucidate whether EPO prevents and/or cures anemia, and, with the restoration from anemia, lessens the osteoid tissue formation. Necropsies were performed at 25, 50, or 70 weeks. Fe deposition at the mineralization front of bone was found at 50 weeks and increased thereafter. Animals injected with EPO showed decreased Fe deposition, although there was no relation between EPO administration and osteoid formation in the femur. Because the increase in bone lesion severity was independent of the amount of Fe deposition, we suggest that Fe deposition is not involved in the etiology of Cd-induced femoral bone lesions.Notoginsenoside Ft1 (NGFt1), a dammarane triterpene glycoside isolated from Panax notoginseng, showed potent effective in stimulating platelet aggregation in our previous assay, yet its pharmacokinetic behavior is still unclear. This study describes a rapid and sensitive ultra-high-pressure LC-tandem mass spectrometry assay for determining of NGFt1 in rat plasma. Methanol-mediated precipitation was used for sample pre-treatment. Chromatographic separation was achieved on a C18 column with gradient elution using water and acetonitrile as mobile phase. Determination was obtained using an electrospray ionization source in negative selected reaction monitoring (SRM) mode at the transitions of m/z 915.9 → m/z 783.8 and m/z 799.8 → m/z 637.8 for NGFt1 and internal standard, respectively. The assay was linear over the concentration range 0.25-2500 ng/mL (r > 0.995) with the lower limit of quantification of 0.25 ng/mL. The intra- and inter-day precisions (relative standard deviation, %) ranged 1.65%-9.84% and 2.46%-13.49%, respectively, whereas accuracy (relative recovery, %) ranged from 96.21% to 99.45%, respectively. The recovery ranged from 95.09% to 102.22% and the matrix effect from 98.29% to 100.13%. The analyte was stable under tested storage conditions. The method has been successfully applied to a preclinical pharmacokinetic study in rats after a single intravenous (2 mg/kg) and oral (50 mg/kg) administration.This study evaluated four bridged-ethylene hybrid (BEH) columns containing C18 (130 Å), peptide C18 (300 Å), phenyl, or a mixed-mode charged surface hybrid (CSH C18 ) using a wide range of antisense oligonucleotide therapeutics. The BEH C18 , peptide, and phenyl columns were all capable of providing significant retention of oligonucleotide samples across multiple ion-pairing systems using alkylamines and 1,1,1,3,3,3,-hexafluoroisopropanol (HFIP). The retention of the oligonucleotides varied depending on the choice of alkylamine, with the order of retention being dimethylcyclohexylamine > diisopropylethylamine > triethylamine. The selectivity of these columns for several closely eluting impurities was similar. Although overall the C18 , peptide, and phenyl columns were all found to be capable of analyzing oligonucleotide therapeutics, the phenyl column was found to be the most retentive and the C18 column provided the best peak shape. The CSH C18 column was found to be degraded by the alkylamine-HFIP mobile phase despite the mobile phase being within the pH stability range of the column.Hemorrhagic shock (HS) is a medical emergency during trauma. Significant loss of tissue perfusion may result in cellular hypoxia, organ damage and death. The primary treatment of HS is control of the source of bleeding as soon as possible and fluid replacement (crystalloid solutions and blood transfusion). Metabolomics can identify novel biomarkers for various functional and organic diseases. Therefore, systematic exploration of the biological mechanisms of HS and blood transfusion enables the optimization of treatments for HS to reduce the occurrence of organ damage. In this study, a global metabolic profiling strategy is applied to evaluate metabolic changes in the HS rat model. A serum metabolic network with 58 significant metabolites was constructed for HS and resuscitation. Our investigation will offer insights into the pathogenesis.It is widely accepted that there exists a "resting" or "quiescent" state where a growing cell leaves the cell cycle to enter what is often called the "G0-phase." I propose that there is no biological reality to the "G0-phase." The experimental basis for proposing a G0-phase is re-examined and re-analyzed here showing that the G0-phase is an anthropomorphic construct with no biological reality.
Asthma exacerbations are inflammatory events that rarely result in full hospitalization following an ER visit. Unfortunately, certain patients require prolonged support, including occasional external lung support through ECMO or ECCOR (with subsequent further exposure to other life-threatening issues), and some die. In parallel, biologics are revolutionizing severe asthma management, mostly in T2 high patients.
We extensively reviewed the current unmet needs surrounding ICU-admitted asthma exacerbations, with a focus on currently available drugs and the underlying biological processes involved. We explored whether currently available T2-targeting drugs can reasonably be seen as potential players not only for relapse prevention but also as candidate drugs for a faster resolution of such episodes. The patient's perspective was also sought.
About 30% of asthma exacerbations admitted to the ICU do not resolve within five days. Persistent severe airway obstruction despite massive doses of corticosteroids and maximal pharmacologically induced bronchodilation is the main cause of treatment failure. Previous ICU admission is the main risk factor for such episodes and may eventually be considered as a T2 surrogate marker. Fatal asthma cases are hallmarked by poorly steroid-sensitive T2-inflammation associated with severe mucus plugging. New, fast-acting T2-targeting biologics (already used for preventing asthma exacerbations) have the potential to circumvent steroid sensitivity pathways and decrease mucus plugging. This unmet need was confirmed by patients who reported highly negative, traumatizing experiences.
There is room for improvement in the management of ICU-admitted severe asthma episodes. Clinical trials assessing how biologics might improve ICU outcomes are direly needed.
There is room for improvement in the management of ICU-admitted severe asthma episodes. Clinical trials assessing how biologics might improve ICU outcomes are direly needed.Cardiac resynchronization therapy with His-bundle pacing is evolving rapidly as a viable cardiac device strategy for the treatment of severe chronic heart failure. The success of this technique in patients with congenital heart disease is facilitated by advanced integrated imaging modalities. We report a case of cardiac resynchronization therapy with His-bundle pacing with defibrillator for the management of a patient with heart failure with severely reduced ejection fraction, left bundle branch block, and congenital heart disease characterized by Scimitar syndrome with cardiac dextroposition. We highlight the contribution of integrated imaging modalities to guide accurate lead positioning.
Focal cortical dysplasia (FCD) is a malformation of cortical development that often causes pharmacologically intractable epilepsy. However, FCD lesions are frequently characterized by minor structural abnormalities that can easily go unrecognized, making diagnosis difficult. Therefore, many epileptic patients have had pathologically confirmed FCD lesions that appeared normal in pre-surgical fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) studies. Such lesions are called "FLAIR-negative." This study aimed to improve the detection of histopathologically verified FCD in a sample of patients without visually appreciable lesions.
The technique first extracts a series of features from a FLAIR image. Then, three naive Bayesian classifiers with probability (NBCP) are trained based on different numbers of feature maps to classify voxels as lesional or healthy voxels and assign the lesions a probability of correct classification. This method classifies the three-dimensional (3D) images of all pan-temporal lobe epilepsy (non-TLE) patients, lesions could be accurately located, although there were still false-positive areas.The nucleotide-binding domain leucine-rich repeat containing receptors (NLRs) are a family of evolutionarily conserved proteins. Several members of NLRs, notably NLRP1, NLRP3 and NLRC4, are able to form cytosolic oligomeric signalling platforms termed inflammasomes to mediate immune response towards pathogens, damage and stress. However, the functions of many NLRs still remain elusive. In the past few years, a couple of less-characterized NLR members are emerging as important signalling molecules with fundamental functions in host defence and inflammation. Among them, NLRP9 is an NLR originally proposed to be expressed and function solely in the reproductive system. Recent evidence has suggested that NLRP9 is also capable of initiating inflammasome formation in the intestine to restrict replication and damage brought by rotavirus infection. Here, we highlight the latest progress in characterization of the role of NLRP9 in infectious and inflammatory diseases, as well as the newest crystallographic and biochemical studies on NLRP9. Finally, we discuss some important questions remained to be answered regarding the molecular and cellular mechanisms governing NLRP9's function in innate immunity and inflammation.
Aldehyde dehydrogenase-2 (ALDH2) plays an important role in the alcohol detoxification and acetaldehyde metabolism. Published studies have demonstrated some inconsistent associations between ALDH2 rs671 G>A polymorphism and head and neck cancer (HNC) risk.
A meta-analysis was performed to provide pooled data on the association between the ALDH2 rs671 G>A polymorphism and HNC risk. Electronic databases were searched to identify relevant studies. Odds ratios and 95% confidence intervals (CIs) were used to examine the pooled effect size of each genetic model. In addition, heterogeneity test, accumulative analysis, sensitivity analysis, and publication bias were conducted to test the statistical power.
Thirteen publications (14 independent case-control studies) involving 10,939 subjects were selected. The stratified analysis indicated that both light/moderated drinking (e.g., GA vs. GG OR=1.47, 95% CI=1.16 to 1.86, p<0.01, I
=81.1%) and heavy drinking would increase HNC risk with rs671 G>A mutation (e.g., GA vs. GG OR=2.30, 95% CI=1.11 to 4.77, p=0.03, I
=81.9%).
In summary, this meta-analysis suggested that the ALDH2 rs671 G>A polymorphism may play an important synergistic effect in the pathogenesis of HNC development in East Asians.
A polymorphism may play an important synergistic effect in the pathogenesis of HNC development in East Asians.Women, more so than men, are using social media activism to respond to sexism. However, when they do, they are also faced with gendered criticisms 'hashtag feminism' that may instead serve to silence them. Based on social identity theory, this research examined how women's social media activism, in response to sexism, may be a first step towards further activism. Two studies used a simulated Twitter paradigm to expose women to sexism and randomly assign them to either tweet in response, or to a no-tweet control condition. Both studies found support for a serial mediation model such that tweeting out after sexism strengthened social identity, which in turn increased collective action intentions, and in turn, behavioural collective actions. Study 2 further showed that validation from others increases the indirect effect of tweeting on behavioural collective action through collective action intentions, but group efficacy did not moderate any indirect effects. It was concluded that social media activism in response to sexism promotes an enactment of women's social identity, thereby mobilizing them to further action.In his book Coercion and Its Fallout Murray Sidman argued against the use of punishment based on concerns about its shortcomings and side effects. Among his concerns were the temporary nature of response suppression produced by punishment, the dangers of conditioned punishment, increases in escape and avoidance responses, punishment-induced aggression, and the development of countercontrol. This paper revisits Sidman's arguments about these putative shortcomings and side effects by examining the available data. Although Sidman's concerns are reasonable and should be considered when using any form of behavioral control, there appears to be a lack of strong empirical support for the notion that these potential problems with punishment are necessarily ubiquitous, long-lasting, or specific to punishment. We describe the need for additional research on punishment in general, and especially on its putative shortcomings and side effects. We also suggest the need for more effective formal theories of punishment that provide a principled account of how, why, and when lasting effects of punishment and its potential side effects might be expected to occur or not. In addition to being necessary for a complete account of behavior, such data and theories might contribute to improved interventions for problems of human concern.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which may result in acute respiratory distress syndrome (ARDS), multiorgan failure, and death. The alveolar epithelium is a major target of the virus, but representative models to study virus host interactions in more detail are currently lacking. Here, we describe a human 2D air-liquid interface culture system which was characterized by confocal and electron microscopy and single-cell mRNA expression analysis. In this model, alveolar cells, but also basal cells and rare neuroendocrine cells, are grown from 3D self-renewing fetal lung bud tip organoids. These cultures were readily infected by SARS-CoV-2 with mainly surfactant protein C-positive alveolar type II-like cells being targeted. Consequently, significant viral titers were detected and mRNA expression analysis revealed induction of type I/III interferon response program. Treatment of these cultures with a low dose of interferon lambda 1 reduced viral replication. Hence, these cultures represent an experimental model for SARS-CoV-2 infection and can be applied for drug screens.
Dermatomyositis (DM) and polymyositis (PM) are two rare autoimmune disorders occasionally described with dysthyroidism; however, no solid evidence still proves such an association.
To evaluate the prevalence of dysthyroidism among DM/PM patients.
A nation-wide case-control study was conducted.
From the Clalit Health Services health records database, we extracted 2085 (DM=1475 (70.7%), PM=610 (29.3%)) PM/DM cases and 10193 sex-age matched controls in the period 2000-2018. Both univariate and multivariate analyses were performed to evaluate the link dysthyroidism and PM/DM. Survival analysis was also performed.
The rate of hyperthyroidism was significantly (P=.0097) higher in cases (n=40, 1.9%) with respect to controls (n=123, 1.2%). Similarly, the rate of hypothyroidism was significantly (P<.0001) associated with cases (n=234, 11.2%) when compared to controls (n=853, 8.4%). At the multivariate logistic regression analysis, both DM (OR 1.31 [95%CI 1.07-1.60], P=.0087) and PM (OR 1.54 [95%CI 1.21-1.95], P=.004) were significantly associated with hypothyroidism, whereas DM (OR 1.70 [95%CI 1.10-2.61], P=.0165) but not PM (OR 1.45 [0.83-2.55], P=.1947) was found to be associated with hyperthyroidism. Subjects with PM and positive for anti-Sjögren's syndrome-related antigen A (SSA) auto-antibody displayed a significant risk of developing hyperthyroidism (OR 5.85 [95%CI 1.02-33.74], P=.0480), whereas individuals with DM and positive for antinuclear antibody (ANA) had a higher risk of developing hyperthyroidism (OR 2.65 [95%CI 1.00-7.03], P=.0498).
Physicians treating PM/DM patients should consider screening for thyroid dysfunction on a regular basis.
Physicians treating PM/DM patients should consider screening for thyroid dysfunction on a regular basis.Although public debates on cannabis are ongoing in many countries, there are currently no EU-wide rules for either medical or recreational use of cannabis. Numerous studies have illustrated that creating such rules is a complex challenge. The battle over the legalisation of medical use of cannabis in Poland is a good example for analysing the mutual impact of the social practices that various actors perform through and by the discourses in the field of health care how they discursively create their own roles and take positions and how they shape the coalitions and opposition in trying to achieve their strategic goals. This article aims to reconstruct and explain how different types of knowledge are discursively used to sustain or question power relations in the healthcare field. The dispersed knowledge-power influences social actors, who try to define or redefine social practices and aspire to guide them in the healthcare field. The presented approach allows authors to go beyond the social actors' perception vs institutional regulations and to analyse discursive actions as elements of the complex networks of meanings activating various type of resources. Those dynamic networks, involving the different (and sometimes the same) actors in the different actions, open the new fields of rationality. Starting by identifying the crucial actors and their discursive actions visible in the mainstream press discourse, we will reconstruct three types of groups related to medical cannabis. We will then investigate three types of dispositives - law, discipline and security - to investigate the relations between discursive and non-discursive elements. The proposed analysis belongs to the Critical Discourse Analysis (CDA) paradigm and includes investigation of the media discourses and in-depth interviews with the identified actors.
Assessment of image quality directly in clinical image data is an important quality control objective as phantom-based testing does not fully represent image quality across patient variation. Computer algorithms for automatically measuring noise in clinical computed tomography (CT) images have been introduced, but the accuracy of these algorithms is unclear. This work benchmarks the accuracy of the global noise (GN) algorithm for automatic noise measurement in contrast-enhanced abdomen CT exams in comparison to precise reference noise measurements. The GN algorithm was further optimized compared to the previous report in the literature.
Reference values of noise were established in a public image dataset of 82 contrast-enhanced abdomen CT exams. The reference noise values were obtained by manual regions-of-interest measurements of pixel standard deviation in the liver parenchyma according to an instruction protocol. Noise measurements taken by six observers were averaged together to improve reference noisn of automatic clinical image quality measurement methods. The GN algorithm was optimized and validated for automatic measurement of soft-tissue noise in abdomen CT exams.
The performance of automatic noise measurement was benchmarked in a large clinical CT dataset. The study provides a framework for thorough validation of automatic clinical image quality measurement methods. The GN algorithm was optimized and validated for automatic measurement of soft-tissue noise in abdomen CT exams.A 44-year-old lady, a follow-up case of idiopathic dilated cardiomyopathy and cardiac resynchronization therapy defibrillator device implantation with epicardial left ventricular (LV) lead, underwent a transvenous LV lead revision in view of epicardial lead malfunction. A chest X-ray after this, done for worsening dyspnea, revealed pneumopericardium along with left pneumothorax. The computed tomography (CT) revealed a communication between the left pleural and pericardial cavities, around the old epicardial lead. Drainage of the left pleural cavity resolved both the pneumothorax and pneumopericardium and the patient remained well on follow up.This case report describes a procedure of retrieval of a leadless transcatheter pacemaker from the right pulmonary artery 3 days after device implantation. An 80-year-old man affected by ischemic cardiomyopathy and sinus node dysfunction was implanted with a leadless transcatheter pacemaker in the low septum of the right ventricle. Three days after the procedure, the leadless pacemaker migrated into a side branch of the right pulmonary artery. The device was successfully removed using two snares hooked to a tine via the proximal retrieval feature.
Toxoplasmosis is a zoonotic disease that affects humans and warm-blooded animals. This study describes an outbreak of toxoplasmosis in howler monkeys (Alouatta sp.) and survival of capuchins (Sapajus apella), under the same environmental conditions.
Howler monkeys were submitted to post-mortem examination. Tissue samples were processed to histopathology and immunohistochemistry to detect lesions and tachyzoites of Toxoplasma gondii. Tissue samples were also frozen and submitted to PCR and genotyping of T. gondii.
Typical lesions were observed in several organs including the liver, lymph node, and brain, with intralesional cysts and tachyzoites of T. gondii demonstrated by immunohistochemistry. T. gondii genomic sequences were amplified by PCR, and genotyping characterized the same T. gondii clone in all howler monkeys.
Our results support the notion that some species of neotropical primates are highly susceptible to toxoplasmosis and the hypothesis that capuchins (S. apella) may be resistant.
Our results support the notion that some species of neotropical primates are highly susceptible to toxoplasmosis and the hypothesis that capuchins (S. apella) may be resistant.Killer cell immunoglobulin-like receptors (KIRs) interact with polymorphic human leucocyte antigen (HLA) class I molecules, modulating natural killer (NK) cell functions and affecting both the susceptibility and outcome of immune-mediated diseases. The KIR locus is highly diverse in gene content, copy number and allelic polymorphism within individuals and across geographical populations. To analyse currently under-represented Asian and Pacific populations, we investigated the combinatorial diversity of KIR and HLA class I in 92 unrelated Malay and 75 Malaysian Chinese individuals from the Malay Peninsula. We identified substantial allelic and structural diversity of the KIR locus in both populations and characterized novel variations at each analysis level. The Malay population is more diverse than Malay Chinese, likely representing a unique history including admixture with immigrating populations spanning several thousand years. Characterizing the Malay population are KIR haplotypes with large structural variants present in 10% individuals, and KIR and HLA alleles previously identified in Austronesian populations.