Prognostic significance of lymphocytic foci composition in minor salivary gland biopsies for severe disease flare and severity in Sjögren's syndrome: a 3-year follow-up cohort study.

Introduction: This was an ambispective cohort study evaluating the prognostic significance of lymphocytic foci and its lymphoid composition in minor salivary gland biopsy (MSGB) for short-term disease flare and severity in Sjögren's syndrome (SS). Methods: The inclusion criteria comprised individuals meeting the ACR/EULAR 2016 criteria who underwent MSGB with an infiltration of more than 50 lymphocytes and received clinical diagnosis between September 2017 and December 2018. Patients with inadequate biopsy samples were excluded. The number of lymphocytic foci and their lymphoid composition in MSGB were assessed using immunofluorescence staining. Major organ damage and improvements in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) were measured. Statistical analyses, including Cox and linear regressions, were conducted. Results: A total of 78 patients with at least one lymphocytic focus were included in the study. The presence of higher T-cell counts in lymphocytic foci in MSGB was associated with severe disease flare, and a logarithmic transformation of T-cell count indicated increased risk (HR 1.96, 95% CI 0.91-4.21). Improvements in the ESSDAI were associated with higher total lymphocyte count and T- and B-cell numbers in the lymphoid composition of the lymphocytic foci. Seropositive patients exhibited higher T CD4+ cell numbers. Correlation analysis showed negative associations between age and lymphocytic foci and the T-cell count. Positive correlations were observed between antinuclear antibody (ANA) titers and total lymphocyte numbers. Discussion: Patients with a higher number of T cells in the lymphocytic infiltrates of lymphocytic foci may have a two-fold risk of severe disease flare. The number of B cells and T CD4+ cells in the lymphocytic infiltrates of lymphocytic foci showed a weak but positive relation with the ESSDAI improvement during follow-up. Age and seropositivity appeared to influence the lymphoid composition of the lymphocytic foci.

Exploring the influence of baseline rheumatoid factor levels on TNF inhibitor retention rate in patients with rheumatoid arthritis: a multicentre and retrospective study.

OBJECTIVE: To assess whether the retention rate of certolizumab pegol (CZP) was longer than that of other tumour necrosis factor inhibitors (TNFi) based on baseline rheumatoid factor (RF) levels. METHODS: Longitudinal, retrospective and multicentre study including patients with RA who were treated with any TNFi (monoclonal antibodies (mAB), etanercept (ETA) or CZP). Log-rank test and Cox regressions were conducted to evaluate the retention rate in the three groups according to the level of RF, with the third quartile of the baseline levels used as cut-off: <200 (

Impact of IL6R genetic variants on treatment efficacy and toxicity response to sarilumab in rheumatoid arthritis.

BACKGROUND: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes. METHODS: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores. RESULTS: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity. CONCLUSIONS: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Multifunctional Nanomaterials for Biofortification and Protection of Tomato Plants.

Calcium phosphate nanoparticles were doped with zinc ions to produce multifunctional nanomaterials for efficient agronomic fortification and protection of plants. The resulting round-shaped nanoparticles (nanoZn) were composed of 20.3 wt % Ca, 14.8 wt % P, and 13.4 wt % Zn and showed a pH-controlled solubility. NanoZn were stable in aqueous solutions at neutral pH but dissolved in citric acid at pH 4.5 (i.e., the pH inside tomato fruits), producing a pH-responsive delivery of the essential nutrients Ca, P, and Zn. In fact, the foliar application of nanoZn on tomato plants provided tomatoes with the highest Zn, Ca, and P contents (causing, respectively, a 65, 65, and 15% increase with respect to a conventional treatment with ZnSO4) and the highest yields. Additionally, nanoZn (100 ppm of Zn) inhibited in vitro the growth of Pseudomonas syringae (Ps), the main cause of bacterial speck, and significantly reduced Ps incidence and mortality in tomato seeds, previously inoculated with the pathogen. Therefore, nanoZn present dual agricultural applicability, enriching crops with nutrients with important metabolic functions in humans and simultaneously protecting the plants against important bacterial-based diseases, with considerable negative impact in crop production.

Development and validation of the COVID-19 Hospitalized Patient Deterioration Index.

OBJECTIVES: To develop a COVID-19-specific deterioration index for hospitalized patients: the COVID Hospitalized Patient Deterioration Index (COVID-HDI). This index builds on the proprietary Epic Deterioration Index, which was not developed for predicting respiratory deterioration events among patients with COVID-19. STUDY DESIGN: A retrospective observational cohort was used to develop and validate the COVID-HDI model to predict respiratory deterioration or death among hospitalized patients with COVID-19. Deterioration events were defined as death or requiring high-flow oxygen, bilevel positive airway pressure, mechanical ventilation, or intensive-level care within 72 hours of run time. The sample included hospitalized patients with COVID-19 diagnoses or positive tests at Kaiser Permanente Southern California between May 3, 2020, and October 17, 2020. METHODS: Machine learning models and 118 candidate predictors were used to generate benchmark performance. Logit regression with least absolute shrinkage and selection operator and physician input were used to finalize the model. Split-sample cross-validation was used to train and test the model. RESULTS: The area under the receiver operating curve was 0.83. COVID-HDI identifies patients at low risk (negative predictive value [NPV] > 98.5%) and borderline low risk (NPV > 95%) of an event. Of all patients, 74% were identified as being at low or borderline low risk at some point during their hospitalization and could be considered for discharge with or without home monitoring. A high-risk group with a positive predictive value of 51% included 12% of patients. Model performance remained high in a recent cohort of patients. CONCLUSIONS: COVID-HDI is a parsimonious, well-calibrated, and accurate model that may support clinical decision-making around discharge and escalation of care.

Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

COVID-19: Overview of rheumatology fellows.

SARS-COV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs. We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19.

COVID-19: La visión del residente de reumatología / COVID-19: Overview of Rheumatology Fellows

La infección por SARS-CoV-2 se ha extendido por todo el mundo desde diciembre de 2019, en Wuhan, China. La pandemia ha demostrado ampliamente la resistencia de los sistemas de salud mundiales, convirtiéndose en la mayor emergencia sanitaria desde la Segunda Guerra Mundial. No existe un enfoque terapéutico único para el tratamiento de COVID-19 y el trastorno inmunitario asociado. La falta de ensayos clínicos aleatorizados (ECA) ha llevado a diferentes países a enfrentar la enfermedad con base en series de casos, o a partir de resultados de estudios observacionales con fármacos fuera de ficha técnica.Los reumatólogos en general, y específicamente los residentes, hemos vivido en primera línea la pandemia, modificando nuestras actividades y alterando nuestro itinerario formativo. Hemos atendido pacientes, hemos aprendido el manejo y gracias a nuestra experiencia previa en fármacos para la artritis o la arteritis de células gigantes, hemos utilizado estos fármacos para tratar la COVID-19.(AU)

SARS-CoV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs.We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19.(AU)

Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias.

Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive, given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic KOs, we report here that - whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild MCPH during development - lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs). Our mouse model of MCPH8 suggests that loss of CEP135 results in centriole duplication defects, TP53 activation, and cell death of NPs. Trp53 ablation in a Cep135-deficient background prevents cell death but not MCPH, and it leads to subcortical heterotopias, a malformation seen in MCPH8 patients. These results suggest that MCPH in some MCPH patients can arise from the lack of adaptation to centriole defects in NPs and may lead to architectural defects if chromosomally unstable cells are not eliminated during brain development.

COVID-19: Overview of Rheumatology Fellows. / COVID-19: La visión del residente de reumatología.

SARS-CoV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs. We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19.

COVID-19: la visión del residente de reumatología / COVID-19: overview of rheumatology fellowss

La infección por SARS-CoV-2 se ha extendido por todo el mundo desde diciembre de 2019, en Wuhan, China. La pandemia ha demostrado ampliamente la resistencia de los sistemas de salud mundiales, convirtiéndose en la mayor emergencia sanitaria desde la Segunda Guerra Mundial. No existe un enfoque terapéutico único para el tratamiento de COVID-19 y el trastorno inmunitario asociado. La falta de ensayos clínicos aleatorizados (ECA) ha llevado a diferentes países a enfrentar la enfermedad con base en series de casos, o a partir de resultados de estudios observacionales con fármacos fuera de ficha técnica. Los reumatólogos en general, y específicamente los residentes, hemos vivido en primera línea la pandemia, modificando nuestras actividades y alterando nuestro itinerario formativo. Hemos atendido pacientes, hemos aprendido el manejo y gracias a nuestra experiencia previa en fármacos para la artritis o la arteritis de células gigantes, hemos utilizado estos fármacos para tratar la COVID-19

SARS-CoV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs. We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19

Case Report: Pulmonary Papillomatosis in a Patient Presenting with Cough and Hemoptysis.

A previously healthy patient was seen in the Emergency Department for evaluation of a one-month history of cough and one-day history of hemoptysis. A computed tomography scan of the thorax found a mass on the right lower pulmonary lobe and a mass on the left upper lobe. A biopsy specimen of the right lobe lung mass, obtained during bronchoscopy, demonstrated papilloma. This case report, from a pulmonologist's perspective, includes a comprehensive review of the patient's clinical presentation and outcome, as well as a discussion of recurrent respiratory papillomatosis.