Association of Pulmonary Function Test Abnormalities and Quality-of-Life Measures after COVID-19 Infection.

BACKGROUND: Long-COVID is a multisystem disease that can lead to significant impairments in health-related quality of life (HRQoL). Following COVID-19 infection, abnormalities on pulmonary function tests (PFT) are common. The primary aim of this study is to evaluate for any correlation between PFT abnormalities and impairment in HRQoL scores following COVID-19 infection. METHODS: This is an analysis of a prospective cohort of patients in Louisville, KY who were infected with COVID-19. Data collected included demographics, past medical history, laboratory tests, PFTs, and several HRQoL questionnaires such as the EuroQol 5 Dimension HRQoL questionnaire (EQ-5D-5L), Generalized Anxiety Disorder 7 (GAD-7), Patient Health Questionnaire (PHQ-9), and Posttraumatic stress disorder checklist for DSM-5 (PCL-5). Descriptive statistics were performed, comparing PFTs (normal vs abnormal) and time since COVID-19 infection (3- vs 6- vs ≥ 12 months). RESULTS: There were no significant differences in FEV1, FVC, or the percentage of patients with abnormal PFTs over time after COVID-19 infection. Following COVID-19, patients with normal PFTs had worse impairment in mobility HRQoL scores and change in GAD-7 scores over time. There were no differences over time in any of the HRQoL scores among patients with abnormal PFTs. CONCLUSIONS: Among patients with an abnormal PFT, there was no temporal association with HRQoL scores as measured by EQ-5D-5L, GAD-7, PHQ-9, and PCL-5. Among patients with a normal PFT, mobility impairment and anxiety may be associated with COVID-19 infection. Following COVID-19 infection, impairment in HRQoL scores is not completely explained by the presence of abnormalities on spirometry.

Dementia is associated with worse procedural outcomes after mitral valve transcatheter edge-to-edge repair.

BACKGROUND: Patients with dementia are at increased risk for adverse events following valvular surgery. Outcomes after mitral transcatheter edge-to-edge repair (TEER) for mitral regurgitation in this vulnerable population are not well understood. METHODS: We queried the National Inpatient Sample database for all hospitalizations for mitral TEER between 2016 and 2019. Patients with a validated diagnosis code for dementia were identified by ICD-10 codes and compared to a matched cohort of non-dementia patients using multivariable regression analysis. The primary outcome was in-hospital mortality. Secondary outcomes were hospital length of stay, discharge to nursing facility, total hospital charges, and in-hospital adverse events. RESULTS: 24,550 hospitalizations for mitral TEER were identified, including 880 patients (3.6 %) with dementia. Dementia was associated with higher in-hospital mortality (OR 4.31, 95 % CI 2.65 to 6.99, p < 0.001), prolonged length of hospital stay (OR 1.33, 95 % CI 1.12 to 1.57, p 0.001), higher discharge rate to nursing facility (OR 2.71, 95 % CI 2.13-3.44, p < 0.001), and higher rate of in-hospital adverse events including delirium (OR 5.88, 95 % CI 4.06 to 8.52, p < 0.001) and acute stroke (OR 8.87, 95 % CI 5.01 to 15.70, p < 0.001). CONCLUSIONS: Dementia is associated with worse post-procedural outcomes after mitral TEER. Further investigation is needed to elucidate mechanisms of poor clinical outcomes and guide shared decision-making in this vulnerable population.

UHRF1 poly-auto-ubiquitination induced by the anti-cancer drug, thymoquinone, is involved in the DNA repair machinery recruitment.

DNA methylation is one of the most important epigenetic mark involved in many physiologic cellular processes and pathologies. During mitosis, the transmission of DNA methylation patterns from a mother to the daughter cells is ensured through the action of the Ubiquitin-like, containing PHD and RING domains, 1/DNA methyltransferase 1 (UHRF1/DNMT1) tandem. UHRF1 is involved in the silencing of many tumor suppressor genes (TSGs) via mechanisms that remain largely to be deciphered. The present study investigated the role and the regulation of UHRF1 poly-ubiquitination induced by thymoquinone, a natural anti-cancer drug, known to enhance or re-activate the expression of TSGs. We found that the auto-ubiquitination of UHRF1, induced by TQ, is mediated by reactive oxygen species, and occurs following DNA damage. We demonstrated that the poly-ubiquitinated form of UHRF1 is K63-linked and can still silence the tumor suppressor gene p16INK4A/CDKN2A. We further showed that TQ-induced auto-ubiquitination is mediated via the activity of Tip60. Since this latter is known as a nuclear receptor co-factor, we investigated if the glucocorticoid receptor (GR) might be involved in the regulation of UHRF1 ubiquitination. Activation of the GR, with dexamethasone, did not influence auto-ubiquitination of UHRF1. However, we could observe that TQ induced a K48-linked poly-ubiquitination of GR, probably involved in the proteosomal degradation pathway. Mass-spectrometry analysis of FLAG-HA-tagged UHRF1 identified UHRF1 partners involved in DNA repair and showed that TQ increased their association with UHRF1, suggesting that poly-ubiquitination of UHRF1 is involved in the DNA repair process. We propose that poly-ubiquitination of UHRF1 serves as a scaffold to recruit the DNA repair machinery at DNA damage sites.

Comparing the effect of sexual counseling based on BETTER and PLISSIT models on sexual assertiveness in women with breast cancer after mastectomy.

BACKGROUND: Sexual changes in breast cancer occur after diagnosis and treatment, including a mastectomy. Sexual assertiveness is an effective factor in sexual satisfaction, which means the ability to convey sexual feelings, beliefs, and thoughts. Given the limited studies on sexual assertiveness in breast cancer and different client participation, this study was conducted to compare the effect of sexual counseling based on two models of PLISSIT (Permission, Limited Information, Specific Suggestion, Intensive Therapy) and BETTER (Bring Up, Explain, Tell, Time, Education, Record) on sexual assertiveness in women after mastectomy. MATERIALS AND METHODS: This quasi-experimental intervention was conducted in 2021 in Mashhad, Iran. Seventy-eight mastectomized women with breast cancer were assigned to the BETTER (n = 39) and PLISSIT (n = 39) groups using permuted block randomization with a block size of 4 and an allocation ratio of 1:1. Both groups received four individual counseling sessions, one week apart. The research tools included a demographic information form and the Hulbert index of sexual assertiveness. Changes in the mean scores of sexual assertiveness between the two groups were evaluated before and four weeks after the intervention, and the mean changes were compared between the groups. Data analysis was conducted using the Kolmogorov-Smirnov test, independent t-test, paired t-test, and Chi-square tests using Statistical Package for the Social Sciences (SPSS) version 25 (P < 0.05). RESULTS: The results of the study showed that before the intervention, there was no significant difference in the score of sexual assertiveness in both groups (P = 0.253). The mean score of sexual assertiveness changes before and after the intervention in the BETTER group (8.07 ± 4.9) was significantly higher than in the PLISSIT group (5.58 ± 4.7) (P < 0.001). CONCLUSION: The results indicated that BETTER sexual counseling was more effective in increasing the sexual assertiveness of mastectomized women than PLISSIT counseling. Due to its simplicity and client-centeredness, this model can be used in breast cancer care programs.

Kinesin family member 12-related hepatopathy: A generally indolent disorder with elevated gamma-glutamyl-transferase activity.

Exome sequencing (ES) has identified biallelic kinesin family member 12 (KIF12) mutations as underlying neonatal cholestatic liver disease. We collected information on onset and progression of this entity. Among consecutively referred pediatric patients at our centers, diagnostic ES identified 4 patients with novel, biallelic KIF12 variants using the human GRCh38 reference sequence, as KIF12 remains incompletely annotated in the older reference sequence GRCh37. A review of these and of 21 reported patients with KIF12 variants found that presentation with elevated serum transaminase activity in the context of trivial respiratory infection, without clinical features of liver disease, was more common (n = 18) than manifest cholestatic disease progressing rapidly to liver transplantation (LT; n = 7). Onset of liver disease was at age <1 year in 15 patients; LT was more common in this group. Serum gamma-glutamyl transpeptidase activity (GGT) was elevated in all patients, and total bilirubin was elevated in 15 patients. Liver fibrosis or cirrhosis was present in 14 of 18 patients who were biopsied. The 16 different pathogenic variants and 11 different KIF12 genotypes found were not correlated with age of onset or progression to LT. Identification of biallelic pathogenic KIF12 variants distinguishes KIF12-related disease from other entities with elevated GGT.

Application of the integrated threat theory to conservation law enforcement.

Interactions between law enforcement agents in conservation (e.g., rangers) and illegal resource users (e.g., illegal hunters) can be violent and sometimes fatal, which negatively affects conservation efforts and people's well-being. Models from social psychology, such as integrated threat theory (ITT) (intergroup interactions shape intergroup emotions, prejudices and perceived threats leading to hostile attitudes or behaviors between groups), are useful in addressing such interactions. Conservation approaches relying mainly on law enforcement have never been investigated using this framework. Using a structured questionnaire, we collected data from 282 rangers in protected and unprotected areas (n = 50) in northern Iran. We applied Bayesian structural equation modeling in an assessment of rangers' affective attitudes (i.e., emotions or feelings that shape attitudes toward a person or object) toward illegal hunters in an ITT framework. Rangers' positive perceptions of illegal hunters were negatively associated with intergroup anxiety (emotional response to fear) and negative stereotypes about a hunter's personality, which mediated the relationship between negative contact and affective attitudes. This suggests that negative contact, such as verbal abuse, may lead rangers to perceive illegal hunters as arrogant or cruel, which likely forms a basis for perceived threats. Rangers' positive contact with illegal hunters, such as playing or working together, likely lowered their perceived realistic threats (i.e., fear of property damage). Perceived realistic threats of rangers were positively associated with negative contacts (e.g., physical harm). The associations we identified suggest that relationships based on positive interactions between rangers and illegal hunters can reduce fear and prejudice. Thus, we suggest that rangers and hunters be provided with safe spaces to have positive interactions, which may help lower tension and develop cooperative conservation mechanisms.

Aplicación de la teoría integrada de la amenaza a la implementación de las leyes de conservación Resumen Las interacciones entre los agentes de la ley de la conservación (p. ej.: guardabosques) y los usuarios ilegales de recursos (p. ej.: cazadores ilegales) pueden ser violentas y a veces fatales, lo que afecta negativamente los esfuerzos de conservación y el bienestar de las personas. Los modelos de la psicología social, como la teoría integrada de la amenaza (TIA) (una amenaza percibida que deriva en prejuicios entre los grupos), tienen un uso potencial para tratar estas interacciones. Nunca se ha usado este marco para investigar las estrategias de conservación que dependen principalmente de la implementación de la ley. Usamos un cuestionario estructurado para recolectar datos de 282 guardabosques en áreas protegidas y no protegidas (n = 50) en el norte de Irán. Aplicamos el modelo de ecuación estructural bayesiano a la evaluación de las actitudes afectivas que tienen los guardabosques (es decir, emociones o sentimientos que forjan la actitud hacia una persona o un objeto) hacia los cazadores ilegales en un marco de TIA. La percepción negativa que tienen los guardabosques de los cazadores ilegales estuvo asociada negativamente con ansiedad intergrupal (la respuesta emocional al miedo) y estereotipos negativos de la personalidad de los cazadores, las cuales mediaron la relación entre el contacto negativo y las actitudes afectivas. Esto sugiere que el contacto negativo, como el abuso verbal, puede causar que los guardabosques perciban a los cazadores ilegales como arrogantes o crueles, lo que probablemente forma una base para las amenazas percibidas. El contacto positivo entre los guardabosques y los cazadores ilegales, como jugar o trabajar juntos, probablemente disminuyó la percepción de las amenazas realistas (es decir, miedo al daño material). La percepción que tienen los guardabosques de las amenazas realistas estuvieron asociadas positivamente con los contactos negativos (p. ej.: daño físico). Las asociaciones que identificamos sugieren que las relaciones basadas en las interacciones positivas entre los guardabosques y los cazadores ilegales pueden reducir el miedo y los prejuicios. Por lo tanto, sugerimos que se les proporcionen espacios seguros a los guardabosques y a los cazadores ilegales para que puedan tener interacciones positivas, lo que podría ayudar a reducir tensiones y a desarrollar mecanismos cooperativos de conservación.

Biliary Disease in a Tertiary Care Hospital: A Review of Clinical and Radiological Burden.

Introduction Gallbladder disease accounts for a significant percentage of surgical admissions per year. A review of these cases was done to assess their hospital impact with an evaluation of the efficacy of radiological modalities in terms of evaluation, ideal use, and clinical application. Therefore, this study aims to review the demographics of the disease, the diagnostic yield of radiological modalities, and the overall outcome in regards to the hospital policies and medical services provided in hopes of achieving suitable clinical pathways, increasing the efficiency of gallbladder disease assessment, and limiting unwarranted investigations. Methods This is a single-center, retrospective study that included all the surgical emergency admissions from January 1st to December 31st 2018, in the Salmaniya Medical Complex, Kingdom of Bahrain. A total sample of 163 emergency admissions (cases) was selected from those aged 14 and older with documented biliary stones or biliary-related disease. A review of radiological modalities for diagnosis included plain radiographs (AXR, CXR), US abdomen, CT scans, and MRCP/MRI, which were then correlated with histopathological findings confirming the presence of gallstone disease. In addition to evaluating readmissions and emergency visits in terms of hospital burden. Results One hundred and sixty-three (10.44%) of 1,562 surgical admission cases in 2018 were diagnosed with biliary tree disease (76 males, 87 females). A total of 419 different radiological investigations were requested in 161 of the cases evaluated: 53.7% of plain radiographs (AXR, CXR), 33.2% of US abdomen, 11.9% of CT scan, and 1.2% of MRCP/MRI. Ultrasound showed a sensitivity of 48.72% and a specificity of 100%, while CT scan sensitivity was 57.14% and a specificity of 100% when it came to detecting gallstones and gallbladder-related disease. Plain radiographs add no direct benefit to diagnosing biliary disease.  Conclusion Gallbladder disease is very prevalent with a wide array of disease entities, requiring radiological assistance in diagnosis. Ultrasound is the ideal modality for the diagnosis of biliary disease due to its ease of use and availability; it has high sensitivity and specificity, and it can be complemented by other modalities such as CT scans and MRCP/MRI when it comes to assessing for complications. On the other hand, plain radiographs have no significant value in the detection of gallbladder-related disease, and their utilization should be limited to emergency cases with high clinical suspicion.

Identification and Characterization of HIRIP3 as a Histone H2A Chaperone.

HIRIP3 is a mammalian protein homologous to the yeast H2A.Z deposition chaperone Chz1. However, the structural basis underlying Chz's binding preference for H2A.Z over H2A, as well as the mechanism through which Chz1 modulates histone deposition or replacement, remains enigmatic. In this study, we aimed to characterize the function of HIRIP3 and to identify its interacting partners in HeLa cells. Our findings reveal that HIRIP3 is specifically associated in vivo with H2A-H2B dimers and CK2 kinase. While bacterially expressed HIRIP3 exhibited a similar binding affinity towards H2A and H2A.Z, the associated CK2 kinase showed a notable preference for H2A phosphorylation at serine 1. The recombinant HIRIP3 physically interacted with the H2A αC helix through an extended CHZ domain and played a crucial role in depositing the canonical core histones onto naked DNA. Our results demonstrate that mammalian HIRIP3 acts as an H2A histone chaperone, assisting in its selective phosphorylation by Ck2 kinase at serine 1 and facilitating its deposition onto chromatin.

Quality of life, mood disorders, and cognitive impairment in adults with ß-thalassemia.

Advances in understanding the disease process in ß-thalassemia supported development of various treatment strategies that resulted in improved survival. Improved survival, however, allowed multiple morbidities to manifest and cemented the need for frequent, lifelong treatment. This has directly impacted patients' health-related quality of life and opened the door for various psychiatric and cognitive disorders to potentially develop. In this review, we summarize available evidence on quality of life, depression and anxiety, suicidality, and cognitive impairment in adult patients with ß-thalassemia while sharing our personal insights from experience in treating patients with both transfusion-dependent and non-transfusion-dependent forms.

In praise of postgraduate career clinics: Translating health professionals' willingness to engagement.

AIM: To capture and retain healthcare staff in postgraduate courses relevant to individual career aspirations, service requirements and continuous practice development (CPD) within an English UK university. DESIGN: Two virtual career clinics for postgraduate practitioners to engage in CPD offers within the university. An online post-enrolment online survey to explore their experiences of engagement with the university. METHODS: Mixed: qualitative and quantitative methods. Engaging 10 participants attended the career clinics, and 42 participants with an online survey. RESULTS: The career clinics were well received by participants who mapped CPD requirements and individual career aspirations. The surveys exposed challenges with marketing and enrolment; however, these were mitigated with support. Four recommendations are presented within this paper applicable to the international postgraduate education of all health practitioners.

Natural Killer Cell Infiltration in Prostate Cancers Predict Improved Patient Outcomes.

BACKGROUND: Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline. METHODS: DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests, with corrections for multiple comparisons where appropriate. RESULTS: In both a pan-tumor and prostate cancer (PCa) -specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2-9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response. CONCLUSIONS: Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.

von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease.

ABSTRACT: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

Αlpha-thalassemia: A practical overview.

α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and ß globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.

Management of transfusion-dependent ß-thalassemia (TDT): Expert insights and practical overview from the Middle East.

ß-Thalassemia is one of the most common monogenetic diseases worldwide, with a particularly high prevalence in the Middle East region. As such, we have developed long-standing experience with disease management and devising solutions to address challenges attributed to resource limitations. The region has also participated in the majority of clinical trials and development programs of iron chelators and more novel ineffective erythropoiesis-targeted therapy. In this review, we provide a practical overview of management for patients with transfusion-dependent ß-thalassemia, primarily driven by such experiences, with the aim of transferring knowledge to colleagues in other regions facing similar challenges.

Insight into the mechanism of AML del(9q) progression: hnRNP K targets the myeloid master regulators CEBPA (C/EBPα) and SPI1 (PU.1).

Deletions on the long arm of chromosome 9 (del(9q)) are recurrent abnormalities in about 2 % of acute myeloid leukemia cases, which usually involve HNRNPK and are frequently associated with other known aberrations. Based on an Hnrnpk haploinsufficient mouse model, a recent study demonstrated a function of hnRNP K in pathogenesis of myeloid malignancies via the regulation of cellular proliferation and myeloid differentiation programs. Here, we provide evidence that reduced hnRNP K expression results in the dysregulated expression of C/EBPα and additional transcription factors. CyTOF analysis revealed monocytic skewing with increased levels of mature myeloid cells. To explore the role of hnRNP K during normal and pathological myeloid differentiation in humans, we characterized hnRNP K-interacting RNAs in human AML cell lines. Notably, RNA-sequencing revealed several mRNAs encoding key transcription factors involved in the regulation of myeloid differentiation as targets of hnRNP K. We showed that specific sequence motifs confer the interaction of SPI1 and CEBPA 5' and 3'UTRs with hnRNP K. The siRNA mediated reduction of hnRNP K in human AML cells resulted in an increase of PU.1 and C/EBPα that is most pronounced for the p30 isoform. The combinatorial treatment with the inducer of myeloid differentiation valproic acid resulted in increased C/EBPα expression and myeloid differentiation. Together, our results indicate that hnRNP K post-transcriptionally regulates the expression of myeloid master transcription factors. These novel findings can inaugurate novel options for targeted treatment of AML del(9q) by modulation of hnRNP K function.

A 28-Year-Old Woman With Nail Discoloration, Recurrent Bronchitis, and Left-Sided Facial Swelling.

CASE PRESENTATION: A 28-year-old woman with a history of congenital hip dysplasia was referred for evaluation of recurrent bronchitis. She had undergone left hip replacement with titanium implants 11 years prior to presentation. The patient reported frequent bouts of bronchitis, sinusitis, and left-sided nontender facial swelling that started after the hip replacement surgery. She also reported nail discoloration of her left first toenail 1 year after this procedure, and nail discoloration of her right first toenail 3 years after the procedure. She was treated for onychomycosis without improvement. Review of symptoms was positive for chronic dry cough and facial tenderness but was negative for dyspnea, wheezing, or chest tightness. She previously had been diagnosed with common variable immunodeficiency based on low immunoglobulin levels, and the condition was maintained with monthly IV immunoglobulins but without any improvement or change in the frequency of sinusitis, bronchitis, or facial swelling. She did not use tobacco, and her family history was unremarkable.

MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.

BACKGROUND: Inherited defects in the base-excision repair gene MBD4 predispose individuals to adenomatous polyposis and colorectal cancer, which is characterized by an accumulation of C > T transitions resulting from spontaneous deamination of 5'-methylcytosine. METHODS: Here, we have investigated the potential role of MBD4 in regulating DNA methylation levels using genome-wide transcriptome and methylome analyses. Additionally, we have elucidated its function through a series of in vitro experiments. RESULTS: Here we show that the protein MBD4 is required for DNA methylation maintenance and G/T mismatch repair. Transcriptome and methylome analyses reveal a genome-wide hypomethylation of promoters, gene bodies and repetitive elements in the absence of MBD4 in vivo. Methylation mark loss is accompanied by a broad transcriptional derepression phenotype affecting promoters and retroelements with low methylated CpG density. MBD4 in vivo forms a complex with the mismatch repair proteins (MMR), which exhibits high bi-functional glycosylase/AP-lyase endonuclease specific activity towards methylated DNA substrates containing a G/T mismatch. Experiments using recombinant proteins reveal that the association of MBD4 with the MMR protein MLH1 is required for this activity. CONCLUSIONS: Our data identify MBD4 as an enzyme specifically designed to repair deaminated 5-methylcytosines and underscores its critical role in safeguarding against methylation damage. Furthermore, it illustrates how MBD4 functions in normal and pathological conditions.

Automated detection, segmentation and measurement of major vessels and the trachea in CT pulmonary angiography.

Mediastinal structure measurements are important for the radiologist's review of computed tomography pulmonary angiography (CTPA) examinations. In the reporting process, radiologists make measurements of diameters, volumes, and organ densities for image quality assessment and risk stratification. However, manual measurement of these features is time consuming. Here, we sought to develop a time-saving automated algorithm that can accurately detect, segment and measure mediastinal structures in routine clinical CTPA examinations. In this study, 700 CTPA examinations collected and annotated. Of these, a training set of 180 examinations were used to develop a fully automated deterministic algorithm. On the test set of 520 examinations, two radiologists validated the detection and segmentation performance quantitatively, and ground truth was annotated to validate the measurement performance. External validation was performed in 47 CTPAs from two independent datasets. The system had 86-100% detection and segmentation accuracy in the different tasks. The automatic measurements correlated well to those of the radiologist (Pearson's r 0.68-0.99). Taken together, the fully automated algorithm accurately detected, segmented, and measured mediastinal structures in routine CTPA examinations having an adequate representation of common artifacts and medical conditions.

Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study.

CALYPSO (NCT02435212), a randomized, open-label, multicenter, phase 2 study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pre-treated patients aged 2 to 0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and dispersible tablets formulations, and was consistent with the general safety profile of deferasirox.

Perceptions of Obstetrics/Gynecology Surgeons on Non-medically Indicated Cesarean Sections: A Cross-Sectional Study.

BACKGROUND: Numerous factors can influence decisions regarding the type of delivery of human babies. There is an increasing demand for non-medically indicated cesarean sections (CS) (non-miCS) or CS on request (CSor). Therefore, this survey study aimed to identify the factors that may foster the decision of CS among obstetricians. METHODS: After the sample size calculation returned with 132 needed participants, confidence surveys were sent electronically or disseminated in paper form to nearly all obstetricians (around 200) in the province between mid-August 2021 and mid-February 2022. After signing the consent form, obstetricians were able to provide responses to the four sections of the questionnaire. Data from the copies of the paper were entered into Excel by a local data collector. The data analysis was done using Statistical Product and Service Solutions (SPSS) (IBM SPSS Statistics for Windows, Armonk, NY) and followed the following sequence: summary statistics were done first; then the groups (for and against non-miCS) were compared using analysis of variance (ANOVA); and, finally, regression models were conducted to determine the factors that may affect the favorability of doing non-miCS. RESULTS: A total of 104 obstetricians responded to the survey. Approximately 62.5% of them performed CSor for women who requested it. In addition, more than half (57.7%) agreed that all women had the right and autonomy to choose their mode of delivery. Most providers (65.4) agreed that fear of vaginal delivery (VD) and a bad experience with it are rational reasons for performing a CSor. Unfortunately, some obstetricians (18.3%) faced lawsuits when they refused to perform CSor. As for the factors that may influence the acceptance of obstetricians to non-miCS, it was found that obstetricians who are unsure or refuse to answer (OR=4.30, 95%-CI 1.25-16.29, p=0.025), along with people who do not always perform CSor (OR=4.33, 95%-CI 1.59-12.50, p=0.005) or even refuse it (3.54, 95%-CI 1.05-12.96, p=0.046), are more likely to agree that women have the right to request CSor. CONCLUSION: The surge in CSor rates was mostly correlated with an attempt to escape the fear of VD. However, given the wide discrepancies in obstetricians' opinions in this survey, we cannot draw firm conclusions about the reasons behind this phenomenon. It is also important to explore possible ways to address the problem, such as through litigation with providers who refuse to perform a CSor and through economic reform to protect women from money-grubbing obstetricians.