Spread-out Bragg peak measurements using a compact quality assurance range calorimeter at the Clatterbridge Cancer Centre.

OBJECTIVE: The superior dose conformity provided by proton therapy relative to conventional X-ray radiotherapy necessitates more rigorous Quality Assurance (QA) procedures to ensure optimal patient safety. Practically however, time-constraints prevent comprehensive measurements to be made of the proton range in water: a key parameter in ensuring accurate treatment delivery. APPROACH: A novel scintillator-based device for fast, accurate water-equivalent proton range QA measurements for ocular proton therapy is presented. Experiments were conducted using a compact detector prototype, the Quality Assurance Range Calorimeter (QuARC), at the Clatterbridge Cancer Centre (CCC) in Wirral, UK for the measurement of pristine and spread-out Bragg peaks (SOBPs). The QuARC uses a series of 14 optically-isolated 100 x 100 x 2.85 mm polystyrene scintillator sheets, read out by a series of photodiodes. The detector system is housed in a custom 3D-printed enclosure mounted directly to the nozzle and a numerical model was used to fit measured depth-light curves and correct for scintillator light quenching. MAIN RESULTS: Measurements of the pristine 60 MeV proton Bragg curve found the QuARC able to measure proton ranges accurate to 0.2 mm and reduced QA measurement times from several minutes down to a few seconds. A new framework of the quenching model was deployed to successfully fit depth-light curves of SOBPs with similar range accuracy. SIGNIFICANCE: The speed, range accuracy and simplicity of the QuARC make the device a promising candidate for ocular proton range QA. Further work to investigate the performance of SOBP fitting at higher energies/greater depths is warranted.

Magnetic resonance enterography findings 46 weeks after initiation of biological therapy predict long-term adverse outcomes in Crohn's disease.

BACKGROUND AND AIMS: Magnetic resonance enterography (MRE) depicts transmural changes in response to biological treatment for Crohn's disease (CD); however, the long-term prognostic significance of these findings is unknown. The primary objective of this study was to identify findings on MRE 46 weeks after initiating biological treatment that predict adverse long-term outcomes. METHODS: Patients with CD underwent MRE 46 weeks after initiating biological treatment and were prospectively followed for 2 years. A logistic regression analysis was performed to assess the prognostic value of different radiologic findings for various predefined adverse outcomes. RESULTS: Of the 89 patients included, 46 (51.7%) had ≥1 adverse outcome during follow-up: 40 (44.9%) had clinical recurrence; 18 (20.2%) required surgery, 8 (9%) endoscopic balloon dilation, 12 (13.5%) hospitalization and 7 (7.8%) required corticosteroids. In the multivariate analysis, persistence of severe lesions (MaRIA ≥11) in any intestinal segment was associated with an increased risk of surgery [OR 11.6 (1.5-92.4)], of surgery and/or endoscopic balloon dilation [OR 6.3 (1.3-30.2)], and of clinical relapse [OR 4.6 (1.6-13.9)]. Penetrating lesions were associated with surgery [OR 3.4 (1.2-9.9)]. Creeping fat with hospitalization [OR 5.1 (1.1-25.0)] and corticosteroids requirement [OR 16.0 (1.2-210.0)]. The presence of complications (stricturing and/or penetrating lesions) was associated with having ≥1 adverse outcome [OR 3.35 (1.3-8.5)]. CONCLUSION: MRE findings at week-46 after initiating biological therapy can predict long-term adverse outcomes in CD. Therapeutic intervention may be required in patients with persistence of severe inflammatory lesions, CD-associated complications, or creeping fat.

Psychological Discomfort in Patients Undergoing Coronary Artery Bypass Graft (CABG) in West Bank: A Cohort Study.

Background/Objetives: Cardiovascular disease (CVD) remains a significant contributor to global morbidity and mortality rates. Coronary artery bypass graft (CABG) surgery is a critical intervention for patients with coronary artery disease, yet it poses psychological challenges that can impact recovery. Methods: This prospective cohort study, conducted across six hospitals in the West Bank/Palestine, aimed to assess changes in depression, anxiety, and stress levels among CABG patients and identify associated factors. The Arabic version of the Depression Anxiety Stress Scales (DASS-21) was administered before (one week) and after surgery (two and three weeks). Results: Of the 200 participants, 116 were men (58%). High levels of depression, anxiety, and stress were observed both before and after surgery, with statistically significant reductions in all these variables after surgery (p < 0.001). Regarding demographic factors, age displayed a weak positive correlation with depression (r = 0.283; p < 0.001), anxiety (r = 0.221; p = 0.002), and stress (r = 0.251; p < 0.001). Sex showed a weak correlation with stress pre-surgery (r = -0.160; p = 0.024). Conclusions: Patient outcomes could be improved by early identification and the provision of efficient treatments such as psychosocial therapy both before and after surgery.

Pathogenic bacteria prevalence in cultured Nile tilapia in Southwest Mexico: A real-time PCR analysis.

The present study investigates molecular-based PCR techniques to estimate the prevalence of fish pathogens in southwest Mexico where recurrent mortality in the tilapia cultures has been observed. Sample of internal organs and lesions of Nile tilapia were taken and analysed in 2018, 2019, 2020 and 2022 to detect bacterial pathogens using PCR. No samples were taken in 2021 due to the COVID-19 pandemic. The real-time PCR conditions were optimized to allow a qualitative reliable detection of the bacteria from fixed fish tissue. A total of 599 pond- and cage-cultured tilapia from the southwestern Mexican Pacific (Guerrero, Oaxaca and Chiapas states) were analysed. In this tropical region, during 2018 and 2019 water temperatures of the tilapia cultures were generally with the optimal range to grow Nile tilapia, although extreme values were recorded on some farms. Most of the tilapia sampled were apparently healthy. No Francisella sp. was detected in any sample, and Staphylococcus sp. was the most prevalent (from 0% to 64%) bacteria from the three states over time. Low prevalence of Aeromonas sp. was found, from 0% to 4.3%, although the fish pathogen Aeromonas dhakensis was not detected. Sterptococcus iniae was only detected in Chiapas in 2019 at a low prevalence (1.4%), while the major tilapia pathogen S. agalactiae was detected at a high prevalence (from 0% to 59%) in the three Mexican states. This is the first detection of these pathogenic bacteria in rural farms using real-time PCR and constitutes a great risk for tilapia aquaculture in Mexico, as well as a potential dispersion of these pathogens to other aquaculture areas.

The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.

Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583.

A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

ADC Values for Detecting Bowel Inflammation and Biologic Therapy Response in Patients With Crohn Disease: A Post Hoc Prospective Trial Analysis.

BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10-6 mm2/s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC (p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC (p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.

Conocimientos, actitudes y prácticas sobre la enfermedad de Chagas en una zona endémica de Boyacá, Colombia

Introducción: Los instrumentos para la obtención de información sobre los conocimientos, actitudes y prácticas de diversas enfermedades son ampliamente utilizados, ya que permiten obtener información clara y detallada de cada uno de los aspectos a indagar. Objetivo: Determinar conocimientos, actitudes y prácticas de la enfermedad de Chagas en una zona endémica de Boyacá, Colombia. Metodología: Estudio transversal que consistió en aplicar un instrumento validado que abordaba datos sociodemográficos, factores epidemiológicos, conocimientos, actitudes y prácticas de la enfermedad de Chagas en un integrante mayor de edad de 341 familias de Miraflores, Boyacá. Se emplearon escalas, óptimo, bueno, regular y malo; para el análisis bivariado se determinó el nivel de conocimientos, actitudes y prácticas con escala favorable y desfavorable. Se determinaron diferencias significativas de factores de riesgo, conocimientos, actitudes y prácticas de la enfermedad entre el grupo de hombres y mujeres encuestados. Resultados: El 68,6 % de la población nació en Miraflores, con un 48 % de escolaridad primaria y pertenecientes a la zona rural en su mayoría (57,2 %); en las mujeres predomina la ocupación de ama de casa, mientras que en los hombres es más frecuente la agricultura. Se identificaron conocimientos (48,1 %) y actitudes (82,1 %) óptimas sobre la enfermedad de Chagas que minimizan el riesgo de contraer la infección por T. cruzi; paradójicamente, se encontraron malas prácticas (61,9 %) en el hogar que no previenen la enfermedad. Se observó relación entre el nivel de escolaridad bajo, sexo femenino, ser menor de 49 años, vivir en zona urbana y actividades del hogar y un conocimiento favorable acerca de la enfermedad de Chagas, aunque sin evidencia estadística. Conclusiones: Se hace necesario incorporar programas que garanticen el aprendizaje y la implementación de actitudes y prácticas favorables contra la enfermedad en habitantes de zonas endémicas.

Introduction: The use of measurement tools to obtain information about knowledge, attitudes and practices of various diseases are widely used, since they allow to collect clear and detailed information of every aspect needing examination. Objective: Determine knowledge, attitudes and practices regarding Chagas disease in an endemic zone in Boyaca, Colombia. Methods: Cross-sectional study that consisted of applying a validated instrument that addressed sociodemographic data, epidemiological factors, knowledge, attitudes and practices of the Chagas disease in an adult member of 341 families from Miraflores, Boyaca. The scale categories used were optimal, good, regular and bad; for the bivariate analysis, the level of knowledge, attitudes and practices was determined with a favorable and unfavorable scale. Significant differences in risk factors, knowledge, attitudes and practices of the disease were determined between the group of men and women surveyed. Results: Sixty-eight percent of the population were born in Miraflores, 48% had primary education and most belonged to the rural area (57.2%); in women the occupation of housewife predominated, in men agriculture was more frequent. Optimal knowledge (48.1%) and attitudes (82.1%) about the Chagas disease that minimize the risk of contracting T. cruzi infection were identified. Paradoxically, bad practices that did not prevent the disease were found at home (61,9%). significant regarding the low level of schooling, female gender, being under 49 years of age, living in an urban area and household activities, all of the above allows a favorable knowledge about Chagas disease, although without statistical evidence. Conclusion: It is necessary to incorporate programs that guarantee learning and implementation of favorable attitudes and practices against the disease in inhabitants of endemic areas.

Clinical and socio-demographic factors associated with dental extractions in a clinical sample.

The objective of the present study was to identify the reasons for dental extractions in patients seeking dental care in a university dental clinic in Mexico. This is a cross-sectional study that assessed 284 consecutive patients at the School of Dentistry, Autonomous University of the State of Mexico between August 2017 and November 2018. In total, 505 extractions were performed. The dependent variable was the reason for extraction: 0) dental caries and ensuing sequels (reference category); 1) periodontal disease and ensuing sequels; and 2) other reasons. Sociodemographic, socioeconomic, and clinical variables were included as independent variables. The analysis was done with multinomial logistic regression (Stata 14.0). Out of all extractions, 63.6% (n=321) were due to dental caries and ensuing sequels; 22.0% (n=111) were due to periodontal disease and ensuing sequels; 5.3% (n=27) endodontic failure; 5.1% (n=26) prosthetic indications; 1.6% (n=8) orthodontic indications; and the rest (2.4%) were due to other reasons. In the multivariate model extractions due to periodontal disease vs dental caries were associated with occasionally smoking tobacco (Odds Ratio, OR=3.90) or daily tobacco use (OR=3.19); the tooth to be extracted having been previously restored (OR=2.35); extracted anterior as opposed to posterior teeth (OR =2.63); and patients with multiple extractions (OR=2.68). In the case of extractions due to "other reasons", no variable was significant. Dental caries and periodontal disease were the main reasons for dental extraction in this sample. Several variables, mostly clinical, were associated with extractions for periodontal reasons.

MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting.

Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27Kip1 and p57Kip2, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS.

Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome.

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2- rs1080985, *4- rs3892097, *10 - rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03-0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28-0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.

Senescent and disease-associated microglia are modifiable features of aged brain white matter.

Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their selective vulnerability are not well defined. In naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampus-adjacent white matter. Through gold-standard gene expression and immunolabeling combined with high-dimensional spatial mapping, we identified microglial cell fates in aged white matter characterized by aberrant morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/Lgals3), B-cell lymphoma 2 (Bcl2), and cyclin dependent kinase inhibitors, including Cdkn2a/p16ink4a. Pharmacogenetic or pharmacological targeting of p16ink4a or BCL2 reduced white matter GAL3+ DAM abundance and rejuvenated microglial fimbria organization. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic intervention to promote homeostatic maintenance in the aged brain.

Full Pulpotomy as a Treatment for Irreversible Pulpitis in Permanent Teeth: A Systematic Review of the Literature Based on Case Reports.

The objective of this systematic review was to evaluate the current evidence of case reports where the treatment for permanent teeth with a diagnosis of irreversible pulpitis was a full pulpotomy. This study was carried out by two reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic electronic search was carried out in the PubMed, Google Scholar, and Scopus databases until the year 2022 to find articles in English where the treatment for irreversible pulpitis in permanent teeth was a full pulpotomy. Literature reviews, in vitro or animal studies, abstracts, and unpublished data were excluded. The intervention, control, and outcome parameters were selected following the "Population, Interventions, Control, and Outcome" (PICO) guidelines. A total of 636 articles were found, and 14 articles were selected to be included in this review. The selected articles describe cases of full pulpotomies in mature permanent teeth with a diagnosis of irreversible pulpitis with a total of 34 (100%) successful cases, where 18 were men and 16 were women, with an average age of 19.20 ± 10.59 years and an average follow-up of 35.82 ± 26.39 months, with 12 months being the minimum follow-up time. The material used most frequently for obturation of the full pulpotomy was mineral trioxide aggregate in 16 cases (47.06%). Within the limitations of this review, full pulpotomy presents a high success rate regardless of the tooth, age, or sex as a treatment for teeth diagnosed with irreversible pulpitis.

Equilibrio ocupacional en recursos de rehabilitación psicosocial durante el confinamiento por covid-19, estudio observacional prospectivo / Occupational balance in psychosocial rehabilitation resources during confinement by covid-19, prospective observational study

Objetivos: estudiar el impacto en el equilibrio ocupacional durante el primer cuatrimestre de la pandemia COVID-19 en España. Métodos: estudio observacional prospectivo en el que han participado 411 personas con diagnóstico de trastorno mental grave atendidas en dispositivos de rehabilitación psicosocial distribuidos por todo el territorio estatal. Se ha empleado el OBQ-E y la escala ACO, creada por las propias personas investigadoras. Resultados: el equilibrio ocupacional disminuye en la mayoría de las personas durante el periodo de confinamiento y vuelve a aumentar a un nivel similar al de la pre- pandemia según comienza la desescalada de medidas de confinamiento. Hay actividades como el uso de las nuevas tecnologías en las que se observa un incremento en la sensación de cambio ocupacional, que se mantiene tras el cierre del dispositivo. Conclusiones: el equilibrio ocupacional se ve alterado al modificar la rutina diaria y las condiciones del ambiente. Se puede observar una clara capacidad de resiliencia cuando las condiciones cambian y/o vuelven a la normalidad.(AU)

Objective: to study the impact on occupational balance during the first quarter of the COVID-19 pandemic in Spain. Methods: prospective observational study involving 411 persons with diagnosis of severe mental disorder treated in psychosocial rehabilitation devices distributed throughout the state territory. OBQ-E and the ACO scale, created by the researchers themselves, have been used. Results: n most of the participants their occupational balance drops during the confinement period and increases again to a level similar to that of the pre-pandemic as the de-escalation of confinement measures begins. There are activities such as the use of new technologies in which there is an increase in the feeling of occupational change, which continues after the closure of the device. Conclusions: the occupational balance is altered by modifying daily routine and environmental conditions. A clear resilience can be observed when conditions change and/or return to normal. (AU)

A Long Skip Connection for Enhanced Color Selectivity in CNN Architectures.

Some recent studies show that filters in convolutional neural networks (CNNs) have low color selectivity in datasets of natural scenes such as Imagenet. CNNs, bio-inspired by the visual cortex, are characterized by their hierarchical learning structure which appears to gradually transform the representation space. Inspired by the direct connection between the LGN and V4, which allows V4 to handle low-level information closer to the trichromatic input in addition to processed information that comes from V2/V3, we propose the addition of a long skip connection (LSC) between the first and last blocks of the feature extraction stage to allow deeper parts of the network to receive information from shallower layers. This type of connection improves classification accuracy by combining simple-visual and complex-abstract features to create more color-selective ones. We have applied this strategy to classic CNN architectures and quantitatively and qualitatively analyzed the improvement in accuracy while focusing on color selectivity. The results show that, in general, skip connections improve accuracy, but LSC improves it even more and enhances the color selectivity of the original CNN architectures. As a side result, we propose a new color representation procedure for organizing and filtering feature maps, making their visualization more manageable for qualitative color selectivity analysis.

Novel Therapeutics for Management of Lupus Nephritis: What Is Next?

Lupus nephritis is a severe, organ-threatening manifestation of systemic lupus erythematosus. The current standard of care in the treatment of lupus nephritis is limited to broad-spectrum immunosuppressants, which have significant concerns of short- and long-term toxicity. With traditional approaches, kidney survival and patient outcomes have remained suboptimal. Robust research in the therapeutics of lupus nephritis has resulted in development of many novel drugs targeting specific inflammatory response pathways. Some newer agents have shown a definitive signal of benefit when added to standard of care. With the advent of precision medicine in nephrology, lupus nephritis treatment may undergo a shift toward incorporating approaches using these newer drugs and individualizing care of our patients. This review highlights major advances in management of lupus nephritis over the last 25 years and explores the ongoing trials of emerging therapies in lupus nephritis.

Socioeconomic Inequalities in Alcohol and Tobacco Consumption: A National Ecological Study in Mexican Adolescents.

Alcohol and cigarettes are the psychoactive substances that adolescents use most frequently. When both addictions are combined, they carry the worst burden of disease globally. The objective of this study was to identify whether socioeconomic factors correlate with alcohol and tobacco consumption in Mexican adolescents aged 10 years or more and to establish the relationship in the consumption between the two substances. This ecological study utilized data describing alcohol and tobacco consumption among adolescents aged 10-16 years (n = 48,837 ≈ N = 11,621,100). Having ever consumed any alcohol-containing beverage constituted alcohol consumption. Smoking a cigarette within 30 days constituted cigarette consumption. For both variables, the state-level percentages reported in the survey were used. Diverse socioeconomic variables were collected from official sources. Data on the prevalence of tobacco use and alcohol consumption were entered into an Excel database estimated for each of the states of the Mexican Republic, as well as the socioeconomic variables. We performed the analysis using Stata 14. Consumption prevalence was 15.0% for alcohol and 4.2% for tobacco. Alcohol consumption was not correlated with any studied socioeconomic variable (p > 0.05). The prevalence of tobacco consumption among elementary school students correlated (p < 0.05) with the portion of the population living in private dwellings without sewage, drainage, or sanitation (r = 0.3853). The prevalence of tobacco consumption among middle-school adolescents correlated with the portion of the employed population that earned up to two minimum wages (r = 0.3960), the percentage in poverty by income 2008 (r = 0.4754) and 2010 (r = 0.4531), and the percentage in extreme poverty by income 2008 (r = 0.4612) and 2010 (r = 0.4291). Positive correlations were found between tobacco consumption and alcohol consumption among both elementary (r = 0.5762, p=0.0006) and middle-school children (r = 0.7016, p=0.0000). These results suggest that certain socioeconomic factors correlate with tobacco consumption but not alcohol consumption. A correlation between alcohol consumption and tobacco consumption was observed. The results can be used for developing interventions in adolescents.

Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.

Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.

Lip and Oral Cavity Cancer Incidence and Mortality Rates Associated with Smoking and Chewing Tobacco Use and the Human Development Index in 172 Countries Worldwide: An Ecological Study 2019-2020.

Tobacco use is associated with diseases worldwide, including cancer. This is one of the major public health problems globally, causing more than 19 million new cases in 2020. Lip and oral cavity cancer (LOCC) is neoplastic growth in the tongue, gums, and lips. The objective of this ecological study was to quantify the strength of the association between incidence and mortality of LOCC, with tobacco use and with the Human Development Index (HDI). Incidence and mortality data on LOCC were obtained for 172 countries in 2020, from the Global Cancer Observatory (GLOBOCAN). The prevalence of tobacco smoking and chewing was obtained from reports conducted in 2019. The inequality in human development was estimated using the HDI from the United Nations Development Program, Human Development Report (2019). Statistically significant correlations were observed between the incidence of LOCC and tobacco smoking and chewing prevalence, except for negative correlations between the prevalence of tobacco smoking LOCC mortality in women, just as in the case of the HDI. No statistically significant differences were found between the prevalence of tobacco chewing only and the incidence of LOCC overall and by sex. A higher LOCC incidence overall and by sex was associated with higher HDI. In conclusion, the present study found positive correlations for various HDI socioeconomic indicators and tobacco use with the incidence and mortality of LOCC, but also a few inverse correlations.

Effect of Heat Treatment on the Dry Sliding Wear Behavior of the Mg-3Zn-0.4Ca Alloy for Biodegradable Implants.

The wear behavior of the Mg-3wt.% Zn-0.4wt.% Ca (ZX30) alloy was tested using a pin-on-disc configuration with AZ31 alloy discs as counterparts under dry sliding conditions. The ZX30 alloy was tested in different states: as-cast, solution-treated, peak-aged, and over-aged. Wear rates and friction coefficients were measured at different loads and sliding speeds. Abrasion and oxidation were the main wear mechanisms found in all the conditions tested. Moreover, aluminum oxides were detected on the worn surfaces, which indicates the presence of an adhesive wear mechanism. The wear behavior of the studied ZX30 alloy showed a greater tendency towards oxidative wear than other Mg alloys, and the microstructure observed strongly affected the wear behavior.