Molecular Profiling of Axial Spondyloarthritis Patients Reveals an Association between Innate and Adaptive Cell Populations and Therapeutic Response to Tumor Necrosis Factor Inhibitors.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.

Impact of copy number variants in epilepsy plus neurodevelopment disorders.

INTRODUCTION: Epilepsy, a neurological disorder characterized by recurring unprovoked seizures due to excessive neuronal excitability, is primarily attributed to genetic factors, accounting for an estimated 70 % of cases. Array-comparative genomic hybridization (aCGH) is a crucial genetic test for detecting copy number variants (CNVs) associated with epilepsy. This study aimed to analyze a cohort of epilepsy patients with CNVs detected through aCGH to enhance our understanding of the genetic underpinnings of epilepsy. METHODS: A retrospective cross-sectional study was conducted using the aCGH database from the Genetics Department of the Faculty of Medicine of the University of Porto, encompassing 146 patients diagnosed with epilepsy, epileptic encephalopathy, or seizures. Clinical data were collected, and aCGH was performed following established guidelines. CNVs were classified based on ACMG standards, and patients were categorized into four groups according to their clinical phenotype. RESULTS: Among the 146 included patients, 94 (64 %) had at least one CNV, with 22 (15.1 %) classified as pathogenic or likely pathogenic. Chromosomes 1, 2, 16, and X were frequently implicated, with Xp22.33 being the most reported region (8 CNVs). The phenotype "Epilepsy and global developmental delay/intellectual disability" showed the highest prevalence of clinically relevant CNVs. Various CNVs were identified across different groups, suggesting potential roles in epilepsy. CONCLUSIONS: This study highlights the significance of aCGH in unraveling the genetic basis of epilepsy and tailoring treatment strategies. It contributes valuable insights to the expanding knowledge in the field, emphasizing the need for research to elucidate the diverse genetic causes of epilepsy.

Sex and body mass index impact on digit circumference for Leeds Dactylitis Index calculation.

OBJECTIVES: To estimate digit circumference and the impact of sex and body mass index (BMI) for the calculation of the Leeds Dactylitis Index (LDI) in psoriatic arthritis (PsA) patients with bilateral dactylitis. METHODS: Digit circumference of the hands and the foot were measured with a dactylometer and were studied according to sex and BMI (divided in 4 weight categories) in healthy Portuguese subjects, using Student's t-test and One-way ANOVA, respectively. The effect size of sex and BMI were calculated using Cohen's d test and Eta squared, respectively. Multiple linear regression was used to calculate the effect of sex and BMI, as well as their interaction, to create a formula to predict digit circumference. RESULTS: Fifty-nine participants (33 women, 26 men) with a mean BMI of 24.8 were included. Men's mean digit circumferences were statistically higher than those of women (p<0.001), with a large sex effect size in most of the digits. Differences in the mean circumference between the four BMI categories were statistically significant (p<0.05) for all digits, with a large BMI effect size. Sex and BMI were independent variables to predict mean digit circumference (p<0.001). A new tool (based on regression analysis) allowing to estimate the circumference of digits for males and females of different BMIs is presented. CONCLUSIONS: Our data allows the calculation of digit circumference for males and females of different BMIs in the Portuguese population; and shows that BMI influences digital circumference supporting BMI inclusion in LDI references tables.

18 Months of Treatment with Triheptanoin in 2 Patients with Long Chain Fatty Acid Oxidation Disorders.

INTRODUCTION: Long-chain fatty acid oxidation disorders (LC-FAOD) are inborn errors of metabolism, also identified in newborn screening in Portugal. They interfere with adequate energy utilization, namely by muscles, heart, and liver. Treatment aims to maintain patients in an anabolic state, with increased caloric intake, using carbohydrates and medium-chain fatty acids. Treatment with triheptanoin (THP), a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect that increases energy availability to the cell, has been advocated as an efficacious and safe therapy in LC-FAOD. METHODS: Retrospective revision of clinical records of 2 LC-FAOD patients comparing number, severity and admissions for rhabdomyolysis crises, maximum CK values and weight gain in a period of 18 months before and after treatment with THP. RESULTS/CASE REPORT: Patient 1 is a 12 year old male with VLCADD, with main manifestation being rhabdomyolysis crises. After he started THP we found a decrease in admissions (6 to 2), less rhabdomyolysis crises treated at home (5 to 3), and lower maximum CK values (72352 U/L to 13.000U/L). He had a large increase in weight - 13kg in 18 months. He was able to start pool exercises with no rhabdomyolysis associated. Patient 2 is an 8 year old male with LCAHDD, with main manifestations being rhabdomyolysis crises and retinopathy. After he started THP we found a decrease in admissions (4 to 1), no rhabdomyolysis crises treated at home, and lower maximum CK values (100.000U/L to 19848 U/L). He also increased his weight - 7kg in 18 months. He plays football in school and swims with no rhabdomyolysis associated. In both patients, no major side effects were observed. CONCLUSION: In our patients, we could observe a reduction in the number of admissions, and less severe rhabdomyolysis crises after THP use. The weight gain was significant. There were no major side effects. Despite regarding only two patients, our findings are in line with the latest literature on THP and LC-FAOD, reinforcing the utility of THP as one more tool in the treatment of these disorders with rhabdomyolysis as the main manifestation. The weight increase is an issue to be aware of and to address from the start of the treatment.

Neonatal Glycogen Storage Disease Type IA: A Rare Presentation.

Glucose homeostasis is essential for energy production and the central nervous system function, depending on glycogen metabolism. Glycogen storage diseases (GSD) are caused by enzymatic defects of the glycogen degradation and mainly involve the liver since the inhibition of hepatic glycogen breakdown results in its excessive storage and hepatomegaly. Other findings are hypoglycemia and hyperlactatemia and consequent neurological symptoms. GSD Type Ia is a severe disease with clinical manifestations usually occurring in the first months. Morbidity and mortality are high, when not treated. The patient was a male newborn, with nonconsanguineous couple, born by eutocic delivery and weight 3760 g. On Day 2, weight loss >10% and jaundice were noticed, and physical examination was as normal. The investigation showed low glucose that only respond to iv glucose, metabolic acidosis, hyperlactatemia and elevated liver enzymes. Considering his inherited metabolic disease, he was transferred to the Reference Center. Complementary tests showed hypertriglyceridemia and absence of ketone bodies. Abdominal US revealed a liver in the upper limit of normal. Most likely clinical diagnosis was GSD type Ia, confirmed by genetic test. He needed iv glucose, but then stabilized with formula without galactose, supplemented with dextrin every 2 hours. He is now 7 months old, has flash glucose self-monitoring system, maintaining frequent feedings, with sporadic hypoglycemia with normal physical development and no hepatomegaly. Hypoglycemia and early weight loss in newborns are red flags for metabolic diseases or other conditions. When accompanied by other metabolic findings, such as hyperlactatemia and metabolic acidosis, associated with short fasting periods, glycogen metabolism disorders must be considered. Patients with GSD Type Ia generally appear normal at birth and an early presentation is not frequent within the first hours after birth. Moreover, avoiding fasting and hypoglycemia are of vital importance for better cognitive outcome, global prognosis, and prevention of other metabolic abnormalities.

Theoretical-methodological essay on gender identity information validity in epidemiological surveillance of violence.

The inclusion of the "gender identity" field in the Brazilian violence surveillance system, although representing a step forward, still has limitations that may compromise epidemiological data validity. Existing response options for victims' identities do not adequately cover the diversity of this analysis category, resulting in classification biases. Additionally, the absence of options for cisgender identities reflects an approach that naturalizes these identities, while trans identities are considered deviant and subject to surveillance. To overcome these limitations, it is imperative to adopt a broader understanding of gender as a social and performative construction. This requires a reassessment of social structures and data collection instruments. In this context of discussion, this theoretical-methodological essay aims to reflect on gender identity measurement in the Reporting Diseases System interpersonal and self-inflicted violence surveillance system, taking as frameworks the theoretical conceptions about gender as a performative act and the foundations of validity in epidemiological investigations.

Cycling versus swapping strategies in psoriatic arthritis: results from the rheumatic diseases Portuguese register.

OBJECTIVE: To compare the 2-year retention rate between a second tumor necrosis factor alpha inhibitor (TNFi) and secukinumab (SEK) or ustekinumab (UST), in Psoriatic Arthritis (PsA) patients with previous inadequate response to their first TNFi. METHODS: Prospective longitudinal cohort study with a follow-up period of 2 years using the Nationwide Portuguese Reuma.pt database. Patients with a clinical diagnosis of PsA who also fulfill the CASPAR classification criteria, with previous treatment failure to a first-line TNFi and having started a second biotechnological drug (TNFi, SEK or UST) were included. The Cycling group was defined as switching from a first TNFi to a second TNFi, and the Swapping group as switching from a first TNFi to SEK or UST. Sociodemographic data, disease characteristics, disease activity scores and physical function at baseline and after 6, 12 and 24 months were recorded. Cox-proportional hazards regression was used to compare retention rates between Cycling and Swapping groups. To obtain a predictor model of 2-year discontinuation, a multivariable Cox regression model was performed. RESULTS: In total, 439 patients were included, 58% were female, with a mean age (standard deviation) of 49 (12) years. Globally, 75.6% initiated a second TNFi (Cycling group), and 24.4% started SEK/UST (Swapping group). The retention rates after 6, 12 and 24 months were 72%/66%/59% in the Cycling group; and 77%/66%/59% in the Swapping group. There were no significant differences in retention rates between both strategies (HR: 1.06, 95% CI 0.72-1.16). After 2 years of follow-up, 34.4% of patients discontinued their second biologic, mainly due to inefficacy (72.8%), with no differences found between groups. Baseline treatment with glucocorticoids was the only predictor of discontinuation after 2 years of follow-up (HR:1.668, 95% CI 1.154-2.409). CONCLUSIONS: After failure of a first TNF inhibitor, Cycling and Swapping strategies result in similar retention rates suggesting that both are acceptable in the management of patients with psoriatic arthritis.

Determinants of health-related quality of life and global functioning and health in axSpA, pSpA, and PsA: results from the ASAS-PerSpA study.

OBJECTIVES: We aim to identify determinants of health-related quality of life (HRQoL) and global functioning and health (GH) in axial spondyloarthritis (axSpA), peripheral spondyloarthritis (pSpA), and psoriatic arthritis (PsA). METHODS: ASAS-perSpA study data were analyzed. Models for the three patient groups were performed separately to explore factors associated with HRQoL and GH, assessed by EQ-5D and ASAS-HI, respectively. RESULTS: The analyses included 4185 patients: 2719 with axSpA, 433 with pSpA, and 1033 with PsA.In axSpA, disease activity (DA) (ß=-0.061), physical function (ß=-0.041), female sex (ß=-0.019), and fibromyalgia (ß=-0.068) were associated with worse HRQoL; age (ß = 0.001) and university education (ß = 0.014) with better HRQoL. In pSpA, DA (ß=-0.04) and physical function (ß=-0.054) were associated with worse HRQoL. In PsA, DA (ß=-0.045), physical function (ß=-0.053), axial disease (ß=-0.041), and female sex (ß=-0.028) were associated with worse HRQoL.In axSpA, DA (ß = 0.889), physical function (ß = 0.887), peripheral disease (ß = 0.564), female sex (ß = 0.812) and fibromyalgia (ß = 1.639) were associated with worse GH; age (ß=-0.013) and university education (ß=-0.274) with better GH. In pSpA, physical function (ß = 1.142), and female sex (ß = 1.060) were associated with worse GH; university education (ß=-0.611) with better GH. In PsA, DA (ß = 0.703), physical function (ß = 1.025), axial involvement (ß = 0.659), female sex (ß = 0.924), and fibromyalgia (ß = 1.387) were associated with worse GH; age (ß=-0.024) and university education (ß=-0.856) with better GH. CONCLUSIONS: DA and physical function are major HRQoL and GH determinants across spondyloarthritis types, and clinical characteristics and sociodemographic factors play an important role, highlighting the importance of a holistic approach for individual patients.

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era.

Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.

BRAT1 associates with INTS11/INTS9 heterodimer to regulate key neurodevelopmental genes.

Integrator is a multi-subunits protein complex involved in regulation of gene expression. Several Integrator subunits have been found to be mutated in human neurodevelopmental disorders, suggesting a key role for the complex in the development of nervous system. BRAT1 is similarly linked with neurodegenerative diseases and neurodevelopmental disorders such as rigidity and multifocal-seizure syndrome. Here, we show that INTS11 and INTS9 subunits of Integrator complex interact with BRAT1 and form a trimeric complex in human HEK293T cells as well as in pluripotent human embryonal carcinoma cell line (NT2). We find that BRAT1 depletion disrupts the differentiation of NT2 cells into astrocytes and neural cells. Loss of BRAT1 results in inability to activate many neuronal genes that are targets of REST, a neuronal silencer. We identified BRAT1 and INTS11 co-occupying the promoter region of these genes and pinpoint a role for BRAT1 in recruiting INTS11 to their promoters. Disease-causing mutations in BRAT1 diminish its association with INTS11/INTS9, linking the manifestation of disease phenotypes with a defect in transcriptional activation of key neuronal genes by BRAT1/INTS11/INTS9 complex. Highlights: Integrator subunits INTS9 and INTS11 tightly interact with BRAT1 Depletion of BRAT1 causes a dramatic delay in human neural differentiation BRAT1 and INTS11 module targets the promoters of neural marker genes and co-regulates their expression. The recruitment of INTS11 to these sites is BRAT1-dependent. Pathogenic E522K mutation in BRAT1 disrupts its interaction with INTS11/INTS9 heterodimer.

Detection of Abnormal Prion Protein by Immunohistochemistry.

Abnormal prion proteins (PrPSc) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs). These neurodegenerative diseases affect humans and several animal species and include scrapie, zoonotic bovine spongiform encephalopathy (BSE), chronic wasting disease of cervids (CWD), and the newly identified camel prion disease (CPD). Diagnosis of TSEs relies on immunodetection of PrPSc by application of both immunohistochemistry (IHC) and western immunoblot methods (WB) on encephalon tissues, namely, the brainstem (obex level). IHC is a widely used method that uses primary antibodies (monoclonal or polyclonal) against antigens of interest in cells of a tissue section. The antibody-antigen binding can be visualized by a color reaction that remains localized in the area of the tissue or cell where the antibody was targeted. As such, in prion diseases, as in other fields of research, the immunohistochemistry techniques are not solely used for diagnostic purposes but also in pathogenesis studies. Such studies involve detecting the PrPSc patterns and types from those previously described to identify the new prion strains. As BSE can infect humans, it is recommended that biosafety laboratory level-3 (BSL-3) facilities and/or practices are used to handle cattle, small ruminants, and cervid samples included in the TSE surveillance. Additionally, containment and prion-dedicated equipment are recommended, whenever possible, to limit contamination. The PrPSc IHC procedure consists of a formic acid epitope-demasking step also acting as a prion inactivation measure, as formalin-fixed and paraffin-embedded tissues used in this technique remain infectious. When interpreting the results, care must be taken to distinguish non-specific immunolabeling from target labeling. For this purpose, it is important to recognize artifacts of immunolabeling obtained in known TSE-negative control animals to differentiate those from specific PrPSc immunolabeling types, which can vary between TSE strains, host species, and prnp genotype, further described herein.

Copy number variations on chromosome 2: impact on human phenotype, a cross-sectional study.

Background: Copy number variations (CNVs) on chromosome 2 are associated with a variety of human diseases particularly neurodevelopmental disorders. Array comparative genomic hybridization (aCGH) constitutes an added value for the diagnosis of neurodevelopmental or neuropsychiatric diseases. This study aims to establish a genotype-phenotype correlation, reporting CNVs on the chromosome 2, contributing for a better characterization of the molecular significance of rare CNVs in this chromosome. Methods: To accomplish this, a cross-sectional study was performed using genetic information included in a database of the Department of Genetics of the Faculty of Medicine and clinical data from Hospital database. CNVs were classified as pathogenic, benign, variants of unknown significance, and likely pathogenic or likely benign, in accordance with the ACMG Standards and Guidelines. Results: A total of 2897 patients were studied using aCGH, 32 with CNVs on chromosome 2, 24 classified as likely pathogenic, and 8 as pathogenic. Genomic intervals with a higher incidence were one 2p25.3 and 2q13 regions. Conclusions: This study will help to establish new genotype-phenotype correlations, allowing update of databases and literature and the improvement of diagnosis and genetic counseling which could be an added value for prenatal genetic counseling.

In a community-based setting spondyloarthritis patients report higher levels of physical disability than chronic low back pain patients - results from EpiReuma.pt.

OBJECTIVES: Chronic low back pain (CLBP) is a common health problem and in most patients it is not possible to identify a specific cause (non-specific CLBP). Spondyloarthritis is a musculoskeletal disorder characterized by (often inflammatory) back pain and spinal stiffness. The impact of CLBP and spondyloarthritis on patients' physical function may be different. This study aims to compare physical disability in patients with spondyloarthritis and CLBP, in a population-based setting. Furthermore, we aim to identify modifiable risk factors for physical disability among these two populations. METHODS: Data from EpiReumaPt, a national health cohort with 10 661 individuals, conducted from September 2011 to December 2013, was used. Physical function was accessed by the Health Assessment Questionnaire Disability Index (HAQ-DI) and by the physical function dimension of the 36-Item Short Form Survey (SF-36). Univariable and multivariable linear regression analyses were used to assess the differences between groups. Factors associated with physical disability were explored for both diseases. RESULTS: We evaluated 92 patients with spondyloarthritis, 1376 patients with CLBP and 679 subjects without rheumatic and musculoskeletal diseases (RMDs). Spondyloarthritis and CLBP patients reported significantly higher levels of disability in HAQ-DI (ß=0.33; p < 0.001 and ß=0.20; p < 0.001, respectively) than subjects without RMDs. In comparison to CLBP patients, spondyloarthritis patients reported higher disability (ß=0.14; p=0.03). The physical domains of SF-36, bodily pain and general health, where more affected in spondyloarthritis patients than in CLBP patients (ß=-6.61; p=0.02 and ß=-5.94; p=0.001, respectively). Spondyloarthritis and CLBP patients had a worse physical summary score (PCS) than mental summary score (MCS), and only PCS was significantly worse in comparison to subjects without RMDs. Factors associated with physical disability in CLBP were low back pain intensity, older age, obesity, multimorbidity, and retirement. Similarly, in spondyloarthritis physical disability was associated with retirement and multimorbidity. Factors associated with lower disability were alcohol consumption and male gender in CLBP, and regular physical exercise was associated with lower disability in both disorders. CONCLUSIONS: In this nationwide cohort, spondyloarthritis and CLBP patients reported significant physical disability. Regular physical exercise was associated with lower disability in both diseases.

Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

The Integrator complex regulates microRNA abundance through RISC loading.

MicroRNA (miRNA) homeostasis is crucial for the posttranscriptional regulation of their target genes during development and in disease states. miRNAs are derived from primary transcripts and are processed from a hairpin precursor intermediary to a mature 22-nucleotide duplex RNA. Loading of the duplex into the Argonaute (AGO) protein family is pivotal to miRNA abundance and its posttranscriptional function. The Integrator complex plays a key role in protein coding and noncoding RNA maturation, RNA polymerase II pause-release, and premature transcriptional termination. Here, we report that loss of Integrator results in global destabilization of mature miRNAs. Enhanced ultraviolet cross-linking and immunoprecipitation of Integrator uncovered an association with duplex miRNAs before their loading onto AGOs. Tracing miRNA fate from biogenesis to stabilization by incorporating 4-thiouridine in nascent transcripts pinpointed a critical role for Integrator in miRNA assembly into AGOs.

Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia.

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.

Violence in the neighborhood and mental health of community health workers in a Brazilian metropolis.

Violence is a major social problem in Brazil, with severe repercussions on the health care sector. Primary health care professionals, especially community health workers (CHWs), are at high risk of violence at facilities and in the socially vulnerable area where they work. This study analyzed the relationships between adverse working conditions and dimensions of localized violence on the prevalence of common mental disorders (CMD) among CHWs in Fortaleza, a state capital in Northeastern Brazil. Information was collected with a self-report questionnaire containing items on sociodemographic data, work-related violence, psychoemotional signs and symptoms (Self-Reporting Questionnaire-20), mental health care, and absence from work due to general or mental health issues. Based on the responses of 1,437 CHWs, the prevalence of CMD (32.75%) was associated with perceived, witnessed, or suffered violence in the work area. In the hierarchical analysis, CMD were associated with age, sex, religious identity, years of experience as a CHW with the Family Health Strategy (FHS), work neighborhood, activities in the community, considering the lack of bonding with families as an obstacle, having suffered domestic violence, use of medication for emotional dysregulation, identifying the neighborhood as violent, considering violence a physical or mental health determinant, and identifying impunity as a cause of violence. Thus, the work and mental health of CHWs were significantly affected by violence dimensions. Our findings are relevant to the adoption of strategies to mitigate the effects of violence on the work and mental health of CHWs.

Health-related quality of life among spondyloarthritis and chronic low back pain patients: results from a nationwide population-based survey.

PURPOSE: Both spondyloarthritis and chronic low back pain (CLBP) significantly impact health-related quality of life (HRQoL). It is important to clarify whether these disorders have different impacts on the several domains of HRQoL as different mechanisms may necessitate different treatment interventions. Moreover, the factors associated with HRQoL can inform more targeted group interventions to promote HRQoL. METHODS: We used data from EpiReumaPt, a population-based survey conducted from September 2011 to December 2013. HRQoL was assessed with EuroQoL-5-Dimensions (EQ-5D). Spondyloarthritis was diagnosed by expert opinion (rheumatologist) and predefined criteria. CLBP was diagnosed if low back pain was present on the day of the interview and persisted for > 90 days. Univariable and multivariable linear regression analyses compared HRQoL among subjects with spondyloarthritis, CLBP, and no rheumatic diseases. Multivariable linear regression analyses evaluated HRQoL factors in spondyloarthritis and CLBP subjects. RESULTS: We included 92 spondyloarthritis patients, 1376 CLBP patients, and 679 subjects without rheumatic diseases. HRQoL was similarly affected in spondyloarthritis and CLBP (ß = - 0.03, 95% CI [- 0.08; 0.03]) in all EQ5D dimensions. A much lower HRQoL was found in spondyloarthritis and CLBP patients compared with subjects without rheumatic diseases (ß = - 0.14, 95% CI [- 0.19; - 0.10]; ß = - 0.12, 95% CI [- 0.14; - 0.09], respectively). In spondyloarthritis subjects, multimorbidity and active disease were associated with worse HRQoL (ß = - 0.18; 95% CI [- 0.24; 0.03]; ß = - 0.13; 95% CI [- 0.29; - 0.05], respectively), and regular physical exercise was associated with better HRQoL (ß = 0.18; 95% CI [0.10; 0.30]). In CLBP subjects, multimorbidity (ß = - 0.11; 95% CI [- 0.14; - 0.08]), obesity (ß = - 0.04; 95% CI [- 0.08; - 0.01]), and low back pain intensity (ß = - 0.02; 95% CI [- 0.03; - 0.02]) were associated with worse HRQoL, and regular physical exercise (ß = 0.08; 95% CI [0.05; 0.11]) was significantly associated with better HRQoL. CONCLUSION: Spondyloarthritis and CLBP subjects reported similar levels of impairment in the mental, physical, and social domains of HRQoL. Future health plans should address modifiable factors associated with HRQoL in these conditions to achieve better outcomes.