Notes

Frugal Ferroptosis Inhibitor Liproxstatin-1 Attenuates Neural Cutbacks and Neuroinflammation Following Subarachnoid Hemorrhage.
Carbon neutral is among the possible ways of solving the problem of climate change. Many scholars have utilized different single indicators such as CO2 and methane with different variables to mitigate the possible ways of solving the problem of global warming. The present study employs a specific country (UAE) approach to investigate the possible way of solving climate change. The author utilized 1980-2018 annual data of the UAE to investigate the possibility of carbon neutral in the UAE as to suggest ways of limiting climate change. Both linear and non-linear (squared) foreign direct investment (FDI) and GDP per capita were added to the study and considered as the variables of interest and other control variables (energy use and population). Among the findings of this study are inverted U-shaped relationship between economic growth (GDP per capita) and ecological footprint which confirms EKC for the UAE, positive relationship between energy use and ecological footprint, negative relationship between FDI and preventive in nature towards FDI so as to maintain this positive trend towards sustainable development. The analytical abstract demonstrates the interactions that exist among the employed variables in Granger causality analysis. The big arrows denote two-way transmission while the small arrows show one-way causal transmissions passing to the variables where they are pointing at.Environmental arsenic exposure in adults and children has been associated with a reduction in the expression of club cell secretory protein (CC16) and an increase in the expression of matrix metalloproteinase-9 (MMP-9), both biomarkers of lung inflammation and negative respiratory outcomes. The objectives of this study were to determine if the levels of serum CC16 and MMP-9 and subsequent respiratory infections in children are associated with the ingestion of arsenic by drinking water. This cross-sectional study included 216 children from three Yaqui villages, Potam, Vicam, and Cocorit, with levels of arsenic in their ground water of 70.01 ± 21.85, 23.3 ± 9.99, and 11.8 ± 4.42 μg/L respectively. Total arsenic in water and urine samples was determined by inductively coupled plasma/optical emission spectrometry. Serum was analyzed for CC16 and MMP-9 using ELISA. The children had an average urinary arsenic of 79.39 μg/L and 46.8 % had levels above of the national concern value of 50 μg/L. Increased arsenic concentrations in drinking water and average daily arsenic intake by water were associated with decreased serum CC16 levels (β = - 0.12, 95% CI - 0.20, - 0.04 and β = - 0.10, 95% CI - 0.18, - 0.03), and increased serum MMP-9 levels (β = 0.35, 95% CI 0.22, 0.48 and β = 0.29, 95% CI 0.18, 0.40) at significant levels (P less then 0.05). However, no association was found between levels of these serum biomarkers and urinary arsenic concentrations. In these children, reduced serum CC16 levels were significantly associated with increased risk of respiratory infections (OR = 0.34, 95% CI 0.13, 0.90). In conclusion, altered levels of serum CC16 and MMP-9 in the children may be due to the toxic effects of arsenic exposure through drinking water.
Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and one of the most common preventable forms of mental retardation worldwide. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). TD accounts for about 65% of CH, however a genetic cause is identified in less than 5% of patients.

The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development, function and pathways.

We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.
We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.Defective thyroid hormone transport due to deficiency in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) results in severe neurodevelopmental delay due to cerebral hypothyroidism and in clinical negative sequelae following a chronic thyrotoxic state in peripheral tissues. The life expectancy of patients with MCT8 deficiency is severely impaired. Increased mortality is associated with lack of head control and being underweight at young age. Treatment options are available to alleviate the thyrotoxic state; particularly, treatment with the thyroid hormone analogue triiodothyroacetic acid seems a promising therapy. This review provides an overview of key clinical features and treatment options available and under development for this rare disorder.Social phobia is one of the most common anxiety disorders in youth yet still under-recognized and undertreated. This study purposed to evaluate the level of social phobia and examine correlating selected socio-demographic factors (age, gender, marital status, working status, and educational level) among Syrian refugees' youth in Jordan. A cross-sectional, descriptive correlation design was selected to carry out this study. The convenience sample composed of 290 youth aged 15-25 years were recruited from Amman and Mafraq cities. The data was collected using a questionnaire which consists of socio-demographic data and social phobia scale. The findings found that the participants had a high level of social phobia. There was a correlation between social phobia and age (r = 0.64; p 19-25 years), and having low educational level had a higher level of social phobia. Age was the main significant predictor of social phobia. The current findings confirm the necessity of developing social and psychological strategies and interventions to minimize this problem among youth affected by social phobia.Sclerosing angiomatoid nodular transformation (SANT) is a rare vascular lesion of the spleen. Although several hypotheses have been suggested, the etiopathogenesis of SANT remains unknown. It is also unclear whether SANT is a reactive or a neoplastic lesion. Since CTNNB1 (β-catenin gene) exon 3 mutations were frequently detected in some rare fibrovascular lesions, we aimed to investigate the presence of oncogenic CTNNB1 mutations in SANT cases. For this purpose, 7 cases of SANT with typical histopathological features were retrieved. First, the presence of CTNNB1 exon 3 alterations was examined with a recently described immunohistochemistry-based method. Then, the findings were confirmed with polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), and Sanger sequencing. In all cases, immunochemistry of β-catenin gave a staining pattern that was suggestive of exon 3 alteration; however, no missense mutations were found in any case at the CTNNB1 exon 3 hotspot region. Subsequently, we screened for large interstitial deletions of CTNNB1 exon 3 which revealed short PCR products in three cases. Sequencing confirmed that these cases had large interstitial deletions, resulting in loss of the entire exon 3 of CTNNB1. In the remaining four cases, loss of exon 3 was documented at the cDNA level, although genomic deletion was not identified. These results demonstrate that loss of CTNNB1 exon 3 and stabilization of β-catenin with activation of Wnt signaling pathway might have a significant role in the pathogenesis of SANT. Through this study, we provided important evidence for the neoplastic nature and pathogenesis of this disorder.Follicular helper T-cell-derived peripheral T-cell lymphoma (TFH-derived PTCL) initially present in the Waldeyer's ring is a rare condition with a challenging diagnosis. This study aimed to evaluate the clinicopathological characteristics and diagnosis of Waldeyer's ring TFH-derived PTCL and raise awareness of this type of lymphoma. A series of 13 cases of Waldeyer's ring TFH-derived PTCL were retrospectively analyzed. Clinically, most patients presented with localized manifestations, such as painless cervical lymphadenopathy (7/13), pharyngalgia (6/13), and nasal obstruction (3/13), and systemic symptoms were uncommon. Macroscopically, plump mass (9/13) and nodular lesions (3/13) covered with intact and tense mucosa were the main findings on fiberoptic laryngoscopy examination. Pathologically, diffuse infiltration with atypical lymphocytes in the lamina propria (10/13) was the most common growth pattern. Clear cells (9/13) and vascular proliferation (11/13) within a polymorphic inflammatory background (11/13) were frequently observed. All cases expressed at least two TFH markers PD-1 in 92.3% (12/13), BCL6 in 69.2% (9/13), CXCL13 in 53.8% (7/13), and CD10 in 46% (6/13). Targeted next-generation sequencing analysis identified frequent mutations, including TET2 (10/11), RHOA (6/11), DNMT3A (3/11), and IDH2 (2/11). The overall survival rate at 2 years was 35.5%, and survival analysis revealed that patients with localized disease showed better overall survival (P = 0.022). In conclusion, careful morphological observation combined with immunohistochemistry and molecular analysis would help in diagnosis of TFH-derived PTCL involving the Waldeyer's ring, which is a rare condition that frequently presents with atypical clinical manifestations.Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.Reliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213-231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation.In situ mantle cell neoplasia (ISMCN) is a rare entity of disputed clinical significance. We report an additional case, unusual by its presentation in the large intestine and its multifocal involvement of several nodal and extranodal sites. The diagnosis was made in a 46-year-old male patient from a surgical specimen resected for cecal adenocarcinoma. Gross examination showed multiple small polypoid lesions surrounding the ileocecal valve, corresponding to lymphoid aggregates with hyperplastic follicles. Numerous cyclin D1/SOX11+ lymphoid cells, harboring the t(11;14)(q13;q32) translocation, were present in the inner layers of mantle zones. The same lesions were found in the ileum, the appendix, and the regional lymph nodes. The final diagnosis was multifocal ISMCN of the ileocecal region, with both nodal and extra-nodal involvement. A simple surveillance was decided. Our observation expands the clinical spectrum of the disease and underlines the necessity to closely examine even normal-appearing reactive lymphoid tissues.If generated from water using renewable energy, hydrogen could serve as a carbon-zero, environmentally benign fuel to meet the needs of modern society. Photoelectrochemical cells integrate the absorption and conversion of solar energy and chemical catalysis for the generation of high value products. Tandem photoelectrochemical devices have demonstrated impressive solar-to-hydrogen conversion efficiencies but have not become economically relevant due to high production cost. Dye-sensitized solar cells, those based on a monolayer of molecular dye adsorbed to a high surface area, optically transparent semiconductor electrode, offer a possible route to realizing tandem photochemical systems for H2 production by water photolysis with lower overall material and processing costs. This review addresses the design and materials important to the development of tandem dye-sensitized photoelectrochemical cells for solar H2 production and highlights current published reports detailing systems capable of spontaneous H2 formation from water using only dye-sensitized interfaces for light capture.
The relative age effect (RAE) is a worldwide phenomenon, allowing sport participation and elite selection to be based on birthdate distribution. Negative consequences include both a narrow, non-optimal elite selection and negative health effects on entire populations. This study investigated the RAE and athletic performance in multiple individual sports in Sweden.

Birthdates of athletes born between the years 1922 and 2015 were collected across 4-month periods (tertiles T1, T2, T3) from cross-country skiing (N = 136,387), orienteering (N = 41,164), athletics (N = 14,503), alpine skiing (N = 508), E-sports (N = 47,030), and chess (N = 4889). In total, data from 244,560 athletes (women N = 79,807, men N = 164,753) was compared to the complete parent population of 5,390,954 births in Sweden during the same years. Chi-squared statistics compared parent and cohort distributions stratified by sport, sex, and age.

A significantly skewed distribution of birthdates was present in all sports, both sexes, and most will result not only in a narrow and arbitrary selection for adult elite athletes but also in a negative impact on public health.
Solid pseudopapillary neoplasm of the pancreas is a rare tumor in young women, metastasizing in only 5-15% of cases, and most commonly to the liver. Although treatment guidelines have not been established, surgical resection is usually performed. We report a rare case of repeat hepatectomy for liver metastases after distal pancreatectomy with solid pseudopapillary neoplasm.

The patient was a 71-year-old woman who underwent distal pancreatectomy for solid pseudopapillary neoplasm, and liver metastasis occurred 4years after the first surgery. Partial liver resection was performed for four liver metastases, and histopathological examination revealed a diagnosis of liver metastasis from solid pseudopapillary neoplasm. However, 18months later, liver metastases were detected again; three tumors were identified, and partial resection was performed, which has provided 18months' recurrence-free survival.

Long-term prognosis can be expected following R0 resection for resectable liver metastasis from solid pseudopapillary neoplasm.
Long-term prognosis can be expected following R0 resection for resectable liver metastasis from solid pseudopapillary neoplasm.The field of vaccinology underwent massive advances over the past decades with the introduction of virus-like particles (VLPs), a supra-molecular nanoparticle vaccine platform that resembles viral structures without the ability to replicate in hosts. This innovative approach has been remarkably effective, as evidenced by its profound immunogenicity and safety. These highly desirable intrinsic properties enabled their further development as vaccines against a multitude of diseases. To date, several VLP-based vaccines have already been commercialized and many more are undergoing clinical evaluation prior to FDA approval. However, efficacious vaccines against a plethora of pathogens are still lacking, which imposes a tremendous socioeconomic burden and continues to threaten public health throughout the globe. This is especially the case for several respiratory pathogens and protozoan parasites. In this review, we briefly describe the fundamentals of VLP vaccines and the unique properties that enable these to be such valuable vaccine candidates and summarize current advances in VLP-based vaccines targeting respiratory and parasitic diseases of global importance.
Our objective was to investigate the predictors of falls requiring a visit to the emergency department in patients with nonvalvular atrial fibrillation (AF) receiving different types of anticoagulants and to investigate the clinical consequences of falling in the same population.

A total of 1217 patients with nonvalvular AF from two institutions were retrospectively evaluated. Each patient underwent a physical examination, and clinical histories and medication profiles were taken from each patient at baseline.

The median age of our cohort was 71 years; 52.3% were males, and 86.1% of patients were receiving anticoagulation at study baseline. The 5-year freedom-from-falling rate was 81.6%. The use and type of anticoagulation was not significantly associated with the risk of falling (P = 0.222), whereas higher Morse Fall Scale (MFS), CHA
DS
-VAS
(congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65-74 years, sex categoring benzodiazepines had the highest risk of falls. The type and quality of anticoagulation did not seem to affect the risk of falling but did significantly affect survival after the first fall.
Older patients who had comorbidities and were taking amiodarone, diuretics, or short- or medium-acting benzodiazepines had the highest risk of falls. The type and quality of anticoagulation did not seem to affect the risk of falling but did significantly affect survival after the first fall.
The beta EQ-5D-Y-5L is a new patient-reported outcome measure (PROM) for children aged 8-15 years that is currently under development by the EuroQol Group. The EQ-5D-Y-5L is similar to the EQ-5D-Y but has five levels of severity per dimension rather than three. The increased number of levels increases the granularity of the responses but possibly has also increased the difficulty of distinguishing between levels. The EuroQoL's Version Management Committee (VMC) required a robust method to determine how well children distinguish between the five EQ-5D-Y-5L ordinal severity qualifiers (i.e. 'no problems' through to 'extreme problems'), which are a critical aspect of both health measurement and the valuation of health states.

This paper describes the development, testing, selection, and piloting of such a method.

Following a literature review and consultation with the wider VMC and a Language Support Services agency, a range of exercises were developed to assess the ordering and comprehension of the five sfiers among children. Additional formal testing of the exercise in other countries and languages is now underway. The approach developed and tested by the VMC for cognitive debriefing of beta EQ-5D-Y-5L language/country versions may also be useful in determining the adequacy of translated qualifiers in debriefing of adult EQ-5D-5L versions and other PROMs.
The card ranking exercise was found to be a preferred and acceptable means of testing the ordering of translations of severity qualifiers among children. Additional formal testing of the exercise in other countries and languages is now underway. The approach developed and tested by the VMC for cognitive debriefing of beta EQ-5D-Y-5L language/country versions may also be useful in determining the adequacy of translated qualifiers in debriefing of adult EQ-5D-5L versions and other PROMs.A variety of dihydroquinazolin-4(1H)-one derivatives (1-37) were synthesized via "one-pot" three-component reaction scheme by treating aniline and different aromatic aldehydes with isatoic anhydride in the presence of acetic acid. Chemical structures of compounds were deduced by different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C-NMR. Compounds were subjected to α-amylase and α-glucosidase inhibitory activities. A number of derivatives exhibited significant to moderate inhibition potential against α-amylase (IC50 = 23.33 ± 0.02-88.65 ± 0.23 μM) and α-glucosidase (IC50 = 25.01 ± 0.12-89.99 ± 0.09 μM) enzymes, respectively. Results were compared with the standard acarbose (IC50 = 17.08 ± 0.07 μM for α-amylase and IC50 = 17.67 ± 0.09 μM for α-glucosidase). Structure-activity relationship (SAR) was rationalized by analyzing the substituents effects on inhibitory potential. Kinetic studies were implemented to find the mode of inhibition by compounds which revealed competitive inhibition for α-amylase and non-competitive inhibition for α-glucosidase. However, in silico study identified several important binding interactions of ligands (synthetic analogues) with the active site of both enzymes.
Our goal was to evaluate the association between neonatal blood brain-derived neurotrophic factor (BDNF) level and autism spectrum disorder (ASD) diagnosis later in life.

MEDLINE and Web of Science databases were searched from inception until September 16, 2020. Reference lists of all relevant articles also were reviewed. Mean blood BDNF concentrations, standard deviations, sample sizes, and other data needed for calculation of effect sizes were extracted by two independent investigators. The quality of the included studies was appraised using the Newcastle-Ottawa Scale for case-control studies. Data were pooled using the random-effects model.

Five case-control studies involving 1341 cases and 3395 controls were included in the meta-analysis. The meta-analysis of all included studies showed no significant difference in blood BDNF levels between neonates diagnosed with ASD later in life and healthy controls [standardized mean difference (SMD) = 0.261; 95% confidence interval (CI) - 0.052 to 0.573; P = 0.102], with high level of heterogeneity (Q = 64.346; I
 = 93.784; P < 0.001). A subgroup analysis by assay type showed decreased blood BDNF levels in ASDs compared to controls (SMD = - 0.070; 95% CI - 0.114 to - 0.026; P = 0.002), with high level of homogeneity (Q = 0.894; I
 = 0.000; P = 0.827). No evidence of publication bias was observed.

Neonates diagnosed with ASD later in life have decreased blood levels of BDNF measured by double-antibody immunoassay. More studies are warranted to facilitate a more robust conclusion.
Neonates diagnosed with ASD later in life have decreased blood levels of BDNF measured by double-antibody immunoassay. More studies are warranted to facilitate a more robust conclusion.
The aim of our systematic review was to assess the role of interventional radiotherapy (IRT, brachytherapy) in the management of primary and/or recurrent vulvar carcinoma.

A systematic research using PubMed, Scopus and Cochrane library was performed. ClinicalTrials.gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews. Only full-text English-language articles related to IRT for treatment of primary or recurrent VC were identified and reviewed. Conference paper, survey, letter, editorial, book chapter and review were excluded. Time restriction (1990-2018) as concerns the years of the publication was considered.

Primary disease the median 5-year LC was 43.5% (range 19-68%); the median 5-year DFS was 44.5% (range 44-81%); the median 5-year OS was 50.5% (range 27-85%). Recurrent disease the median 5-year DFS was 64% (range 56-72%) and the median 5-year OS was 45% (range 33%-57%). Acute ≥ grade 2 toxicity was reported in three patients (1.6%). The severe late toxicity rates (grade 3-4) ranged from 0% to 14.3% (median 7.7%).

IRT as part of primary treatment for primary and/or recurrent vulvar cancer is associated with promising clinical outcomes.
IRT as part of primary treatment for primary and/or recurrent vulvar cancer is associated with promising clinical outcomes.
The glucocorticoid receptor (GR) is a member of the nuclear receptor family that controls key biological processes in the cardiovascular system and has recently been shown to modulate Wnt signaling in endothelial cells. Wnt/β-catenin signaling has been demonstrated to be crucial in the process of angiogenesis. In the current study, we studied whether GR could regulate angiogenesis via the Wnt/β-catenin pathway.

Key components of the Wnt/β-catenin pathway were evaluated using quantitative PCR and Western blot in the presence or absence of GR. Enhanced angiogenesis was found in GR deficiency in vitro and confirmed with cell viability assays, proliferation assays and tube formation assays. Consistent with these in vitro findings, endothelial cell-specific GR loss GR in vivo promoted angiogenesis in both a hind limb ischemia model and sponge implantation assay. Results were further verified in a novel mouse model lacking endothelial LRP5/6, a key receptor in canonical Wnt signaling, and showed substantially suppressed angiogenesis using these same in vitro and in vivo assays. To further investigate the mechanism of GR regulation of Wnt signaling, autophagy flux was investigated in endothelial cells by visualizing auto phagolysosomes as well as by assessing P62 degradation and LC3B conversion. Results indicated that potentiated autophagy flux participated in GR-Wnt regulation.

Lack of endothelial GR triggers autophagy flux, leads to activation of Wnt/β-catenin signaling and promotes angiogenesis. There may also be a synergistic interaction between autophagy and Wnt/β-catenin signaling.
Lack of endothelial GR triggers autophagy flux, leads to activation of Wnt/β-catenin signaling and promotes angiogenesis. There may also be a synergistic interaction between autophagy and Wnt/β-catenin signaling.Store-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient's lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.Severe combined immune deficiency (SCID) caused by RAG1 or RAG2 deficiency is a genetically determined immune deficiency characterized by the virtual absence of T and B lymphocytes. Unless treated with hematopoietic stem cell transplantation (HSCT), patients with RAG deficiency succumb to severe infections early in life. However, HSCT carries the risk of graft-versus-host disease. Moreover, a high rate of graft failure and poor immune reconstitution have been reported after unconditioned HSCT. Expression of the RAG genes is tightly regulated, and preclinical attempts of gene therapy with heterologous promoters have led to controversial results. Using patient-derived induced pluripotent stem cells (iPSCs) and an in vitro artificial thymic organoid system as a model, here we demonstrate that gene editing rescues the progressive T cell differentiation potential of RAG2-deficient cells to normal levels, with generation of a diversified T cell repertoire. These results suggest that targeted gene editing may represent a novel therapeutic option for correction of this immunodeficiency.
The COVID-19 pandemic is a global crisis impacting population health and the economy. We describe a cost-effectiveness framework for evaluating acute treatments for hospitalized patients with COVID-19, considering a broad spectrum of potential treatment profiles and perspectives within the US healthcare system to ensure incorporation of the most relevant clinical parameters, given evidence currently available.

A lifetime model, with a short-term acute care decision tree followed by a post-discharge three-state Markov cohort model, was developed to estimate the impact of a potential treatment relative to best supportive care (BSC) for patients hospitalized with COVID-19. The model included information on costs and resources across inpatient levels of care, use of mechanical ventilation, post-discharge morbidity from ventilation, and lifetime healthcare and societal costs. Published literature informed clinical and treatment inputs, healthcare resource use, unit costs, and utilities. The potential health imfectiveness framework expands beyond current models to include societal costs and post-discharge ventilation morbidity effects of potential COVID-19 treatments.
Effective COVID-19 treatments for hospitalized patients may not only reduce disease burden but also represent good value for the health system and society. Though data limitations remain, this cost-effectiveness framework expands beyond current models to include societal costs and post-discharge ventilation morbidity effects of potential COVID-19 treatments.
Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant disorder characterized by mucocutaneous telangiectasia and arteriovenous malformations (AVMs). There are some anesthetic considerations for cesarean delivery in a parturient with HHT.

A 27-year-old parturient with pulmonary hemorrhage was admitted to our tertiary perinatal center. She was first diagnosed with HHT and a cesarean delivery using spinal anesthesia at 37 weeks of gestation was initially planned. However, magnetic resonance imaging (MRI) at 32 weeks of gestation revealed spinal AVM ranging from the thoracic to the lumbar levels. Thus, elective cesarean delivery under general anesthesia was planned. The parturient had an uneventful perioperative course.

HHT should be considered as a differential diagnosis when parturients develop pulmonary hemorrhage. In a cesarean delivery of parturients with HHT, spinal MRI during pregnancy can help in deciding the anesthetic procedure to be used.
HHT should be considered as a differential diagnosis when parturients develop pulmonary hemorrhage. In a cesarean delivery of parturients with HHT, spinal MRI during pregnancy can help in deciding the anesthetic procedure to be used.In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.Intentional forgetting of unwanted items is effortful, yet directed forgetting seems to improve when a secondary task is performed. According to the cognitive load hypothesis of directed forgetting, allocating attentional resources to another task improves forgetting by restricting unwanted encoding of to-be-forgotten (TBF) items. Alternatively, it might be that anything that makes studying more difficult will encourage greater effort to perform the task well and therefore lead to improved intentional forgetting. To assess these proposals we imposed data-processing limitations on study words in an item-method directed forgetting paradigm. Across six experiments, the perceptual quality of study words was manipulated by varying (1) the duration of study word presentation (Experiments 1-4); (2) the contrast of the displayed word against its visual background (Experiment 5); or (3) the amount of visual background noise on which the word was presented (Experiment 6). In Experiments 4-6, a lexical decision task corroborated the difficulty of study word processing. Despite evidence that relatively low visual contrast and relatively high visual background noise, in particular, create challenging conditions, we found no evidence that perceptual quality impacts the magnitude of the directed forgetting effect. This work suggests that data limitations have no discernible effect on forgetting and corroborate that only attentional resource limitations improve directed forgetting.I propose a model that places episodic, semantic, and other commonly studied forms of memory into the same conceptual space. The space is defined by three dimensions required for Tulving's episodic and semantic memory. An implicit-explicit dimension contrasts both episodic and semantic memory with common forms of implicit memory. A self-reference dimension contrasts episodes that occurred to one person with semantic knowledge. A scene dimension contrasts episodes that occurred in specific contexts with context-free semantic information. The three dimensions are evaluated against existing behavioral and neural evidence to evaluate both the model and the concepts underlying the study of human memory. Unlike a hierarchy, which has properties specific to each category, the dimensions have properties that extend throughout the conceptual space. Thus, the properties apply to all forms of existing and yet-to-be-discovered memory within the space. Empty locations in the proposed space are filled with existing phenomena that lack a clear place in current theories of memory, including reports of episodic-like memories for events reported to but not witnessed by a person, fictional narrative accounts, déjà vu, and implicit components contributing to personality, the self, and autobiographical memory.Recent evidence suggests that some simulations of future events are encoded in memory and later recalled as "memories of the future," but the factors that determine the memorability of future simulations remain poorly understood. The current research aimed to test the hypothesis that imagined future events are better memorized when they are integrated in autobiographical knowledge structures. Across two experiments, we found that future events that involved the self were better recalled than future events that involved an acquaintance (Experiment 1), and that future events that were related to personal goals were better recalled than future events that were unrelated to goals (Experiment 2). Although self-reference and personal goals influenced the phenomenological characteristics of future simulations (e.g., their vividness and the clarity of event components), the enhanced recall of self-relevant and goal-relevant simulations was not simply due to these differences in the characteristics of simulations. Taken together, these findings suggest that the integration of simulated events with preexisting autobiographical knowledge is an important determinant of memories of the future.It still remains unclear how the functional organisation of the adrenal cortex arises. One aim of this study was to create a setup which allows for the establishment of a concentration gradient in vitro. This was achieved by a continuous flow of medium through the culture flask which caused differences in glucose and cortisol concentrations as well as in pH values between the sites of inflow and outflow of medium. Using real-time polymerase chain reaction, we found that a continuous supply of 1 ml medium per hour significantly increased the expression of MC2R, CYP11B1 and CYP17A1 genes of NCI-H295R cells in the distal area of the flask as compared with the proximal part. The expression of the AT1R showed a reverse regulation. The addition of dexamethasone to the medium led to an increase in gene expression of MC2R while AT1R was downregulated. Moreover, we detected a higher expression of CYP11B2 and a decreased expression of CYP11B1 when endothelial cell-conditioned medium (ECCM) was added to the inflow. Our experiments show that a directed medium delivery system creates different gradients and affects the functional differentiation of the NCI-H295R cells. Also, our results emphasise that products of endothelial cells have additional effects on the differentiation of the cultured adrenal cortical cells. Our results are in support that the regulation of the adrenal zonation is possible through different concentration gradients.Endometrial-related disorders including Asherman's syndrome, thin endometrium, pelvic organ prolapse, and cesarean scar pregnancies can be accompanied by different symptoms such as amenorrhea, infertility, abnormal placental implantation and recurrent miscarriage. Different methods have been introduced to overcome these problems such as surgery and hormonal therapy but none of them has shown promising outcomes. On the other hand, the development of novel regenerative therapeutic strategies has opened new avenues for the treatment of endometrial-related deficiencies. In this regard, different types of scaffolds, acellular matrices and also cell therapy with adult or stem cells have been investigated for the treatment of endometrial-related deficiencies. In this paper, we review the current status of cell-based endometrium regeneration using scaffold dependent and scaffold-free methods and future perspectives in this field. Moreover, we discuss the endometrial diseases that can be candidates for cell-based treatments. Also, the cells with the potential for endometrial regeneration are explained.
Observational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip.

We selected 35 SNPs strongly associated with fasting glucose (p < 5 × 10
) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men.

In a meta-analysis of the three cohorts, a genetically predicted 1mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (-0.67cm
[95% CI -1.30, -0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040g/cm
[95% CI -0.00, 0.07; p = 0.060]).

Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings.
Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings.This commentary begins by describing the author's research and expert witness practice serving sex and gender minorities, especially practitioners of BDSM/kinky sex. Then, it reviews the three most common reasons that BDSM is legally prosecuted. First, consent was this assault, rape, and/or kidnapping, or was it consensual kinky sex that either got out of hand or is now being strategically employed to punish the other partner? Second, age play was this adult trying to have sex with children or was he (and it is virtually always men) intending to age play with an adult who is pretending to be an adolescent? Third, death by kinky sex was this a person who murdered their lover or was this an accidental death? Finally, this article concludes with recommendations for kinksters who wish to assure consent and safe play, and for litigators involved in the prosecution of kinky sex.To evaluate whether a peculiar plasma profile of fatty acids and endocannabinoidome (eCBome)-related mediators may be associated to longevity, we assessed them in octogenarians (Old; n=42) living in the east-central mountain area of Sardinia, a High-Longevity Zone (HLZ), compared to sexagenarian (Young; n=21) subjects from the same area, and to Olds (n=22) from the Northern Sardinia indicated as Lower-Longevity Zone (LLZ). We found significant increases in conjugated linoleic acid (CLA) and heptadecanoic acid (170) levels in Old-HLZ with respect to younger subjects and Old-LLZ subjects. Young-HLZ subjects exhibited higher circulating levels of pentadecanoic acid (150) and retinol. Palmitoleic acid (POA) was elevated in both Young and Old subjects from the HLZ. eCBome profile showed a significantly increased plasma level of the two endocannabinoids, N-arachidonoyl-ethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in Old-HLZ subjects compared to Young-HLZ and Old-LLZ respectively. In addition, we found increased N-oleoyl-ethanolamine (OEA), 2-linoleoyl-glycerol (2-LG) and 2-oleoyl-glycerol (2-OG) levels in Old-HLZ group with respect to Young-HLZ (as for OEA an d 2-LG) and both the Old-LLZ and Young-HLZ for 2-OG. The endogenous metabolite of docosahexaenoic acid (DHA), N-docosahexaenoyl-ethanolamine (DHEA) was significantly increased in Old-HLZ subjects. In conclusion, our results suggest that in the HLZ area, Young and Old subjects exhibited a favourable, albeit distinctive, fatty acids and eCBome profile that may be indicative of a metabolic pattern potentially protective from adverse chronic conditions. These factors could point to a suitable physiological metabolic pattern that may counteract the adverse stimuli leading to age-related disorders such as neurodegenerative and metabolic diseases.
In patients with spontaneous cerebellar intracerebral hemorrhage (ICH) guidelines advocate evacuation when the hematoma diameter is > 3cm. We studied outcome in patients with cerebellar ICH > 3cm who did not undergo immediate hematoma evacuation.

We included consecutive patients with cerebellar ICH > 3cm at two academic hospitals between 2008 and 2017. Patients who died < 24h (h) were excluded because of probable confounding by indication. We determined patient characteristics, hematoma volumes, EVD placement, secondary hematoma evacuation, in-hospital and 3-month case-fatality, and functional outcome.

Of 130 patients with cerebellar ICH, 98 (77%) had a hematoma > 3cm of whom 22 (23%) died < 24h and 28 (29%) underwent hematoma evacuation < 24h. Thus, 48 patients were initially treated conservatively (mean age 70 ± 13, 24 (50%) female). Of these 48 patients, 7 (15%) underwent secondary hematoma evacuation > 24h, of whom 1 (14%) had received an EVD < 24h. Five others also received an EVD < 24h without subsequent hematoma evacuation. Of the 41 patients without secondary hematoma evacuation, 11 (28%) died and 20 (51%) had a favorable outcome (mRS of 0-3) at 3months. The 7 patients who underwent secondary hematoma evacuation had a decrease in GCS score of at least two points prior to surgery; two (29%) had deceased at 3months; and 5 (71%) had a good functional outcome (mRS 0-3).

While cerebellar ICH > 3cm is often considered an indication for immediate hematoma evacuation, there may be a subgroup of patients in whom surgery can be safely deferred. Further data are needed to assess the optimal timing and indications of surgical treatment in these patients.
 3 cm is often considered an indication for immediate hematoma evacuation, there may be a subgroup of patients in whom surgery can be safely deferred. Further data are needed to assess the optimal timing and indications of surgical treatment in these patients.Trans-Eurasian cultural and genetic exchanges have significantly influenced the demographic dynamics of Eurasian populations. The Hexi Corridor, located along the southeastern edge of the Eurasian steppe, served as an important passage of the ancient Silk Road in Northwest China and intensified the transcontinental exchange and interaction between populations on the Central Plain and in Western Eurasia. Historical and archeological records indicate that the Western Eurasian cultural elements were largely brought into North China via this geographical corridor, but there is debate on the extent to which the spread of barley/wheat agriculture into North China and subsequent Bronze Age cultural and technological mixture/shifts were achieved by the movement of people or dissemination of ideas. Here, we presented higher-resolution genome-wide autosomal and uniparental Y/mtDNA SNP or STR data for 599 northwestern Han Chinese individuals and conducted 2 different comprehensive genetic studies among Neolithic-to-pres historic Trans-Eurasian communication was primarily maintained through population movement, not simply cultural diffusion. The observed population dynamics in northwestern Han Chinese not only support the North China origin hypothesis but also reflect the multiple sources of the genetic diversity observed in this population.
Since 2010, laparoscopic transanal total mesorectal excision (TaTME) has been increasingly used for low and very low rectal cancer. It is supposed to improve visibility and access to the dissection planes in the pelvis. This study reports on short- and long-term outcomes of the first 100 consecutive patients treated with TaTME in a certified German colorectal cancer center.

Data were derived from digital patient files and official cancer registry reports for patients with TaTME tumor surgery between July 2014 and January 2020. The primary outcome was the 3-year local recurrence rate and local recurrence-free survival (LRFS). Secondary endpoints included overall survival (OAS), disease-free survival (DFS), operation time, completeness of local tumor resection, lymph node resection, and postoperative complications. The Kaplan-Meier method was employed for the survival analyses; competing risks were considered in the time-to-event analysis.

During the observation period, the average annual operation time decreased from 272 to 178min. Complete local tumor resection was achieved in 97% of the procedures. Major postoperative complications (Clavien-Dindo 3-4) occurred in 11% of the cases. At a median follow-up time of 2.7years, three patients had suffered from a local recurrence. Considering competing risks, this corresponds to a 3-year cumulative incidence rate for local recurrence of 2.2% and a 3-year LRFS of 81.9%. 3-year OAS was 82.9%, and 3-year DFS was 75.7%.

TaTME is associated with favorable short and long-term outcomes. Since it is technically demanding, structured training programs and more research on the topic are indispensable.
TaTME is associated with favorable short and long-term outcomes. Since it is technically demanding, structured training programs and more research on the topic are indispensable.
In patients with benign and refractory esophageal strictures (BES), repeating initial dilations in short intervals could be recommended, but little data are available to validate this strategy. Our aim was to evaluate long-term results of a scheduled program of repeated and sustained esophageal dilations in patients with refractory strictures.

Patients with BES requiring five or more dilations were retrospectively included and divided in two groups for analysis a SCHEDULED group (SDG) where patients were systematically rescheduled for the 5 first dilations; ON-DEMAND group (ODG) where patients were dilated only in case of recurrence of the dysphagia. Comparison between SDG and ODG was done with a 11 matching analysis and etiology of stricture. Clinical success was defined as the absence of dysphagia for more than a year.

39 patients with refractory BES were included with post-operative stenosis in 51.2% and post-caustic injury 28.2%; 10 were in SDG and 29 in ODG. In overall analysis (39 patients), the follow-up was 64.
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