Publications by authors named "David Simon"

282 Publications

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

JAMA 2021 09;326(10):926-939

University of Cincinnati, Cincinnati, Ohio.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.

Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.

Design, Participants, And Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.

Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.

Main Outcomes And Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.

Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).

Conclusions And Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.
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http://dx.doi.org/10.1001/jama.2021.10207DOI Listing
September 2021

Diagnostic and Prognostic Value of Lung Ultrasound B-Lines in Acute Heart Failure With Concomitant Pneumonia.

Front Cardiovasc Med 2021 19;8:693912. Epub 2021 Aug 19.

Institute of Clinical Physiology, National Research Council, Pisa, Italy.

To evaluate the potential confounding effect of concomitant pneumonia (PNM) on lung ultrasound (LUS) B-lines in acute heart failure (AHF). We enrolled 86 AHF patients with (31 pts, AHF/PNM) and without (55 pts, AHF) concomitant PNM. LUS B-lines were evaluated using a combined antero-lateral (AL) and posterior (POST) approach at admission (T0), after 24 h from T0 (T1), after 48 h from T0 (T2) and before discharge (T3). B-lines score was calculated at each time point on AL and POST chest, dividing the number of B-lines by the number of explorable scanning sites. The decongestion rate (DR) was calculated as the difference between the absolute B-lines number at discharge and admission, divided by the number of days of hospitalization. Patients were followed-up and hospital readmission for AHF was considered as adverse outcome. At admission, AHF/PNM patients showed no difference in AL B-lines score compared with AHF patients [AHF/PNM: 2.00 (IQR: 1.44-2.94) vs. AHF: 1.65 (IQR: 0.50-2.66), = 0.072], whereas POST B-lines score was higher [AHF/PNM: 3.76 (IQR: 2.70-4.77) vs. AHF = 2.44 (IQR: 1.20-3.60), < 0.0001]. At discharge, AL B-lines score [HR: 1.907 (1.097-3.313), = 0.022] and not POST B-lines score was found to predict adverse events (AHF rehospitalization) after a median follow-up of 96 days (IQR: 30-265) in the overall population. Assessing AL B-lines alone is adequate for diagnosis, pulmonary congestion (PC) monitoring and prognostic stratification in AHF patients, despite concomitant PNM.
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http://dx.doi.org/10.3389/fcvm.2021.693912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416771PMC
August 2021

Accuracy and usability of a diagnostic decision support system in the diagnosis of three representative rheumatic diseases: a randomized controlled trial among medical students.

Arthritis Res Ther 2021 Sep 6;23(1):233. Epub 2021 Sep 6.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.

Background: An increasing number of diagnostic decision support systems (DDSS) exist to support patients and physicians in establishing the correct diagnosis as early as possible. However, little evidence exists that supports the effectiveness of these DDSS. The objectives were to compare the diagnostic accuracy of medical students, with and without the use of a DDSS, and the diagnostic accuracy of the DDSS system itself, regarding the typical rheumatic diseases and to analyze the user experience.

Methods: A total of 102 medical students were openly recruited from a university hospital and randomized (unblinded) to a control group (CG) and an intervention group (IG) that used a DDSS (Ada - Your Health Guide) to create an ordered diagnostic hypotheses list for three rheumatic case vignettes. Diagnostic accuracy, measured as the presence of the correct diagnosis first or at all on the hypothesis list, was the main outcome measure and evaluated for CG, IG, and DDSS.

Results: The correct diagnosis was ranked first (or was present at all) in CG, IG, and DDSS in 37% (40%), 47% (55%), and 29% (43%) for the first case; 87% (94%), 84% (100%), and 51% (98%) in the second case; and 35% (59%), 20% (51%), and 4% (51%) in the third case, respectively. No significant benefit of using the DDDS could be observed. In a substantial number of situations, the mean probabilities reported by the DDSS for incorrect diagnoses were actually higher than for correct diagnoses, and students accepted false DDSS diagnostic suggestions. DDSS symptom entry greatly varied and was often incomplete or false. No significant correlation between the number of symptoms extracted and diagnostic accuracy was seen. It took on average 7 min longer to solve a case using the DDSS. In IG, 61% of students compared to 90% in CG stated that they could imagine using the DDSS in their future clinical work life.

Conclusions: The diagnostic accuracy of medical students was superior to the DDSS, and its usage did not significantly improve students' diagnostic accuracy. DDSS usage was time-consuming and may be misleading due to prompting wrong diagnoses and probabilities.

Trial Registration: DRKS.de, DRKS00024433 . Retrospectively registered on February 5, 2021.
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http://dx.doi.org/10.1186/s13075-021-02616-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420018PMC
September 2021

COVID-19 and immune-mediated inflammatory diseases: effect of disease and treatment on COVID-19 outcomes and vaccine responses.

Lancet Rheumatol 2021 Aug 27. Epub 2021 Aug 27.

Department of Internal Medicine 3, Friedrich-Alexander University Erlangen-Nuermberg, Erlangen, Germany.

At the beginning of the COVID-19 pandemic, patients with immune-mediated inflammatory diseases were considered to be at high risk for SARS-CoV-2 infection and the development of severe COVID-19. Data collected over the past year, however, suggest that a diagnosis of inflammatory arthritis, psoriasis, or inflammatory bowel diseases does not increase risk for SARS-CoV-2 infection or severe COVID-19 compared with people without these diseases. Furthermore, substantial data suggest that certain medications frequently used in patients with immune-mediated inflammatory diseases, in particular cytokine inhibitors, might even lower the risk for severe COVID-19. Conversely, glucocorticoids and potentially B-cell-depleting treatments seem to worsen COVID-19 outcomes. Additionally, the first data on SARS-CoV-2 vaccination in patients with these diseases suggest that tolerability of vaccination in patients with immune-mediated inflammatory diseases is good, although the immune response to vaccination can be somewhat reduced in this patient group, particularly those taking methotrexate or CD20-targeted treatment.
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http://dx.doi.org/10.1016/S2665-9913(21)00247-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397302PMC
August 2021

Digital Approaches for a Reliable Early Diagnosis of Psoriatic Arthritis.

Front Med (Lausanne) 2021 11;8:718922. Epub 2021 Aug 11.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

Psoriatic arthritis (PsA) is a chronic inflammatory disease that develops in up to 30% of patients with psoriasis. In the vast majority of cases, cutaneous symptoms precede musculoskeletal complaints. Progression from psoriasis to PsA is characterized by subclinical synovio-entheseal inflammation and often non-specific musculoskeletal symptoms that are frequently unreported or overlooked. With the development of increasingly effective therapies and a broad drug armamentarium, prevention of arthritis development through careful clinical monitoring has become priority. Identifying high-risk psoriasis patients before PsA onset would ensure early diagnosis, increased treatment efficacy, and ultimately better outcomes; ideally, PsA development could even be averted. However, the current model of care for PsA offers only limited possibilities of early intervention. This is attributable to the large pool of patients to be monitored and the limited resources of the health care system in comparison. The use of digital technologies for health (eHealth) could help close this gap in care by enabling faster, more targeted and more streamlined access to rheumatological care for patients with psoriasis. eHealth solutions particularly include telemedicine, mobile technologies, and symptom checkers. Telemedicine enables rheumatological visits and consultations at a distance while mobile technologies can improve monitoring by allowing patients to self-report symptoms and disease-related parameters continuously. Symptom checkers have the potential to direct patients to medical attention at an earlier point of their disease and therefore minimizing diagnostic delay. Overall, these interventions could lead to earlier diagnoses of arthritis, improved monitoring, and better disease control while simultaneously increasing the capacity of referral centers.
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http://dx.doi.org/10.3389/fmed.2021.718922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385754PMC
August 2021

Perturbations in cardiac metabolism in a human model of acute myocardial ischaemia.

Metabolomics 2021 Aug 23;17(9):76. Epub 2021 Aug 23.

School of Chemistry and Manchester Centre for Integrative Systems Biology, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK.

Introduction: Acute myocardial ischaemia and the transition from reversible to irreversible myocardial injury are associated with abnormal metabolic patterns. Advances in metabolomics have extended our capabilities to define these metabolic perturbations on a metabolome-wide scale.

Objectives: This study was designed to identify cardiac metabolic changes in serum during the first 5 min following early myocardial ischaemia in humans, applying an untargeted metabolomics approach.

Methods: Peripheral venous samples were collected from 46 patients in a discovery study (DS) and a validation study (VS) (25 for DS, 21 for VS). Coronary sinus venous samples were collected from 7 patients (4 for DS, 3 for VS). Acute myocardial ischaemia was induced by transient coronary occlusion during percutaneous coronary intervention (PCI). Plasma samples were collected at baseline (prior to PCI) and at 1 and 5 min post-coronary occlusion. Samples were analyzed by Ultra Performance Liquid Chromatography-Mass Spectrometry in an untargeted metabolomics approach.

Results: The study observed changes in the circulating levels of metabolites at 1 and 5 min following transient coronary ischaemia. Both DS and VS identified 54 and 55 metabolites as significant (P < 0.05) when compared to baseline levels, respectively. Fatty acid beta-oxidation and anaerobic respiration, lysoglycerophospholipids, arachidonic acid, docosahexaenoic acid, tryptophan metabolism and sphingosine-1-phosphate were identified as mechanistically important.

Conclusion: Using an untargeted metabolomics approach, the study identified important cardiac metabolic changes in peripheral and coronary sinus plasma, in a human model of controlled acute myocardial ischaemia. Distinct classes of metabolites were shown to be involved in the rapid cardiac response to ischemia and provide insights into diagnostic and interventional targets.
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http://dx.doi.org/10.1007/s11306-021-01827-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382649PMC
August 2021

Quality of a Supporting Mobile App for Rheumatic Patients: Patient-Based Assessment Using the User Version of the Mobile Application Scale (uMARS).

Front Med (Lausanne) 2021 22;8:715345. Epub 2021 Jul 22.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

Mobile applications promise to improve current health care. However, current mobile app quality ratings are mostly physician-based. The aim of this study was (1) to assess the quality of the self-management app Rheuma Auszeit using the validated uMARS (User Version of the Mobile App Rating Scale) app quality assessment tool and (2) to evaluate the association between uMARS scores and patients' characteristics. Consecutive patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis were seen at the rheumatology clinic at university hospital Erlangen, Germany. They were asked to test Rheuma Auszeit, evaluate its quality using uMARS and complete a paper-based survey evaluating the individual preferences, attitudes and ehealth literacy. The association between uMARS scores and patients' characteristics was further explored. Between December 2018 and January 2019, a total of 126 patients evaluated Rheuma Auszeit using uMARS and filled out the paper-based survey. The median uMARS score was 3.9, IQR 0.7. Functionality was the domain with the highest rating (median 4.8, IQR 0.8), followed by aesthetics (median 4.0, IQR 0.7), information (median 3.5, IQR 0.8), and engagement (median 3.2, IQR 1.0). Subjective quality was average (median 3.0, IQR 1.0). The lowest scoring individual item was customization with a median of 2.5/5. Lower functionality scores were reported among older female rheumatic patients ( < 0.004). Older male rheumatic patients reported a higher subjective quality score ( < 0.024). Perceived disease activity and disease duration did not significantly correlate with any uMARS subdomain scores. eHealth literacy significantly correlated with functionality uMARS subdomain ratings (Rho = 0.18; < 0.042). Preferred time of app usage significantly correlated with engagement (Rho = 0.20; < 0.024), functionality (Rho = 0.19; < 0.029), total uMARS score (Rho = 0.21; < 0.017) and subjective quality score (Rho = 0.21; < 0.017). The vast majority of rheumatic patients would consider recommending Rheuma Auszeit to other patients (117/126; 92.9%). Rheuma Auszeit was well-accepted by German patients suffering from rheumatoid arthritis, psoriatic arthritis and ankylosing spondyloarthritis. Lacking customization could lead to low app compliance and should be improved. Lower functionality scores among older female rheumatic patients highlight the need for patient education. The study underlines the potential and feasibility of therapeutic complementary digital solutions in rheumatology.
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http://dx.doi.org/10.3389/fmed.2021.715345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339429PMC
July 2021

Gestational diabetes is associated with postpartum hemorrhage in Indigenous Australian women in the PANDORA study: A prospective cohort.

Int J Gynaecol Obstet 2021 Jul 30. Epub 2021 Jul 30.

Wellbeing and Preventable Chronic Disease Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.

Objective: To assess associations of hyperglycemia in pregnancy with the risk of postpartum hemorrhage (PPH) in a prospective cohort of Indigenous and non-Indigenous women, compared with normoglycemia.

Methods: Data were from 1102 (48% Indigenous) women of the Pregnancy And Neonatal Diabetes Outcomes in Remote Australia (PANDORA) Study. Age-adjusted associations of gestational diabetes mellitus (GDM) or pre-existing type 2 diabetes mellitus (T2DM), obstetric and demographic covariables with PPH (blood loss ≥500 ml) were assessed using logistic regression. Multivariable-adjusted models included Indigenous ethnicity, diabetes type and their interaction.

Results: A higher proportion of Indigenous women developed PPH than non-Indigenous women (32% versus 22%; P < 0.001). Compared with non-Indigenous women with normoglycemia, risks of PPH for Indigenous women with GDM or T2DM were higher (odds ratio [OR] 1.83, 95% confidence intervals [CI] 1.11-3.02, and OR 1.72, 95% CI 0.99-3.00 after age adjustment, OR 1.84, 95% CI 1.06-3.19, and OR 1.33, 95% CI 0.70-2.54 after adjustment for school education and delivery mode, and OR 1.62, 95% CI 0.95-2.77, and OR 0.99, 95% CI 0.53-1.86 after adjustment for birth weight). Importantly, Indigenous women without hyperglycemia in pregnancy were not at increased risk of PPH.

Conclusion: The significantly higher rates of PPH experienced by Indigenous women compared with non-Indigenous women may be explained by a greater effect of GDM among Indigenous women that was only partly accounted for by birth weight.
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http://dx.doi.org/10.1002/ijgo.13846DOI Listing
July 2021

Invader removal triggers competitive release in a threatened avian predator.

Proc Natl Acad Sci U S A 2021 Aug;118(31)

Department of Fisheries and Wildlife, Oregon State University, Corvallis, OR 97331.

Changes in the distribution and abundance of invasive species can have far-reaching ecological consequences. Programs to control invaders are common but gauging the effectiveness of such programs using carefully controlled, large-scale field experiments is rare, especially at higher trophic levels. Experimental manipulations coupled with long-term demographic monitoring can reveal the mechanistic underpinnings of interspecific competition among apex predators and suggest mitigation options for invasive species. We used a large-scale before-after control-impact removal experiment to investigate the effects of an invasive competitor, the barred owl (), on the population dynamics of an iconic old-forest native species, the northern spotted owl (). Removal of barred owls had a strong, positive effect on survival of sympatric spotted owls and a weaker but positive effect on spotted owl dispersal and recruitment. After removals, the estimated mean annual rate of population change for spotted owls stabilized in areas with removals (0.2% decline per year), but continued to decline sharply in areas without removals (12.1% decline per year). The results demonstrated that the most substantial changes in population dynamics of northern spotted owls over the past two decades were associated with the invasion, population expansion, and subsequent removal of barred owls. Our study provides experimental evidence of the demographic consequences of competitive release, where a threatened avian predator was freed from restrictions imposed on its population dynamics with the removal of a competitively dominant invasive species.
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http://dx.doi.org/10.1073/pnas.2102859118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346899PMC
August 2021

"We are only looking at the tip of the iceberg in infertility": perspectives of health providers about fertility issues and management among Aboriginal and Torres Strait Islander people.

BMC Health Serv Res 2021 Jul 17;21(1):704. Epub 2021 Jul 17.

Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, VIC, Melbourne, Australia.

Introduction: Aboriginal and Torres Strait Islander women and men are disproportionately affected by a range of risk factors for infertility. However, remarkably little is known about the prevalence of infertility in this group, or how Aboriginal and Torres Strait Islander people access fertility treatments including assisted reproductive technology (ART). This qualitative study aims to explore health care provider (HCP) perspectives on the health burden of infertility among Aboriginal and Torres Strait Islander people, as well as factors that may affect access to infertility treatment for this group.

Method: Semi-structured interviews were conducted with HCPs (8 doctors; 3 nurses and 1 Aboriginal Health Practitioner) working in fertility care in the Northern Territory, Australia. Transcribed interviews were analysed using an iterative thematic approach using the NVivo-9 software package.

Results: Providers perceive infertility as an underestimated health issue in this patient population, reporting a high prevalence of infertility-related risk factors but fewer clinical encounters of diagnosis and treatment. Perceived barriers to accessing fertility care included cultural differences such as the shame and stigma associated with reproductive health and the separation of men's business and women's business; service-related barriers such as limited timely and affordable access to specialist health services and; a lack of culturally responsive and appropriate fertility services. Providers had mixed opinions on their role in ameliorating inequities of access, and hence a range of strategies to address barriers were suggested. These included a greater patient education, ongoing patient support and providing a culturally safe environment.

Conclusion: The current study adds to the understanding of how Aboriginal and Torres Strait Islander people access fertility treatments. There is a need for further research to quantify infertility in Aboriginal and Torres Strait Islander people, investigate community perceptions towards infertility and identify community-driven priorities to improve access to fertility care for this population.
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http://dx.doi.org/10.1186/s12913-021-06714-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285865PMC
July 2021

Virtual teaching for medical students during SARS-CoV-2 pandemic.

Clin Exp Rheumatol 2021 Jul 7. Epub 2021 Jul 7.

Department of Internal Medicine 3, Rheumatology and Immunology, and German Center Immune Therapy, University Hospital Erlangen, Germany.

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July 2021

Performance of a Handheld Ultrasound Device to Assess Articular and Periarticular Pathologies in Patients with Inflammatory Arthritis.

Diagnostics (Basel) 2021 Jun 22;11(7). Epub 2021 Jun 22.

Department of Internal Medicine 3, Friedrich-Alexander University (FAU) Erlangen-Nuremberg and Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.

The purpose of this study was to assess the accuracy and performance of a new handheld ultrasound (HHUS) machine in comparison to a conventional cart-based sonographic machine in patients with inflammatory arthritis (IA). IA patients with at least one tender and swollen joint count were enrolled. US was performed on the clinically affected joints using a cart-based sonographic device (Samsung HS40) and a HHUS device (Butterfly iQ). One blinded reader scored all images for the presence of erosions, bony enlargement, synovial hypertrophy, joint effusion, bursitis, tenosynovitis, and enthesitis. Synovitis was graded (B mode and power Doppler (PD)) by the 4-level EULAR-OMERACT scale. To avoid bias by the blinded reader, we included 67 joints of two healthy volunteers in the evaluation. We calculated the overall concordance and the concordance by type of joint and pathological finding. We also measured the time required for the US examination per joint with both devices. Thirty-two patients (20 with RA, 10 with PsA, and one each with gout and SLE-associated arthritis) were included, and 186 joints were examined. The overall raw concordance in B mode was 97% (κappa 0.90, 95% CI (0.89, 0.94)). In B mode, no significant differences were found in relation to type of joint or pathological finding examined. The PD mode of the HHUS device did not detect any PD signal, whereas the cart-based device detected a PD signal in 61 joints (33%). The portable device did not offer any time savings compared to the cart-based device (47.0 versus 46.3 s). The HHUS device was accurate in the assessment of structural damage and inflammation in patients with IA, but only in the B mode. Significant improvements are still needed for HHUS to reliably demonstrate blood flow detection in PD mode.
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http://dx.doi.org/10.3390/diagnostics11071139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305786PMC
June 2021

Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration.

Dev Cell 2021 Jul 30;56(13):1900-1916.e5. Epub 2021 Jun 30.

Laboratory of Stem Cell Biology and Regenerative Medicine, Department of Biology, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address:

Stem cells (SCs) play a key role in homeostasis and repair. While many studies have focused on SC self-renewal and differentiation, little is known regarding the molecular mechanism regulating SC elimination and compensation upon loss. Here, we report that Caspase-9 deletion in hair follicle SCs (HFSCs) attenuates the apoptotic cascade, resulting in significant temporal delays. Surprisingly, Casp9-deficient HFSCs accumulate high levels of cleaved caspase-3 and are improperly cleared due to an essential caspase-3/caspase-9 feedforward loop. These SCs are retained in an apoptotic-engaged state, serving as mitogenic signaling centers by continuously releasing Wnt3 and instructing proliferation. Investigating the underlying mechanism, we reveal a caspase-3/Dusp8/p38 module responsible for Wnt3 induction, which operates in both normal and Casp9-deleted HFSCs. Notably, Casp9-deleted mice display accelerated wound repair and de novo hair follicle regeneration. Taken together, we demonstrate that apoptotic cells represent a dynamic SC niche, from which emanating signals drive SC proliferation and tissue regeneration.
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http://dx.doi.org/10.1016/j.devcel.2021.06.008DOI Listing
July 2021

Brief Report: Humoral and cellular immune responses to SARS-CoV-2 infection and vaccination in B cell depleted autoimmune patients.

Arthritis Rheumatol 2021 Jul 1. Epub 2021 Jul 1.

Department of Internal Medicine 3, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

Objective: B cell depletion is an established therapeutic principle in a wide range of autoimmune disease. However, B cells are also critical for inducing protective immunity after infection and vaccination. We therefore assessed humoral and cellular immune responses after infection with or vaccination against severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) in B cell depleted patients and B cell competent healthy controls.

Methods: Antibody (ELISA) and T cell (IFNγ ELISPOT) responses against the SARS-CoV-2 spike S1 and nucleocapsid proteins were assessed in a limited number of infected (N=6) and vaccinated (N=8) B cell depleted autoimmune patients as well as infected (N=30) and vaccinated (N=30) healthy controls.

Results: As expected, B and T cell responses to the nucleocapsid were observed only after infection, while respective responses to spike S1 were found both after infection and vaccination. A SARS-CoV-2 antibody response was observed in all vaccinated controls (30/30, 100%) but in none (0/8) of the vaccinated B-cell-depleted patients. In contrast, after SARS-CoV-2 infection, both B-cell-depleted patients (spike S: 5/6, 83%; nucleocapsid 3/6, 50%) and healthy controls (spike S: 28/30, 94%; nucleocapsid 28/30, 93%) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated B cell depleted subjects and in the controls.

Conclusion: These data show that B cell depletion completely blocks humoral but not T cell SARS-CoV-2 vaccination response. Furthermore, limited humoral immune responses are found in B cell depleted patients after SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/art.41914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427106PMC
July 2021

Correspondence on 'Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort'.

Ann Rheum Dis 2021 Oct 29;80(10):e161. Epub 2021 Jun 29.

Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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http://dx.doi.org/10.1136/annrheumdis-2021-220898DOI Listing
October 2021

Biomechanical stress in the context of competitive sports training triggers enthesitis.

Arthritis Res Ther 2021 06 21;23(1):172. Epub 2021 Jun 21.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany.

Objective: To evaluate the influence of mechanical stress on the development of immediate enthesitis.

Methods: The BEAT study is an interventional study that assessed entheses in competitive badminton players before and immediately after a 60-min intensive training session. Power Doppler (PD) signal and Gray scale (GS) changes were assessed in the insertion sites of both Achilles tendon, patellar tendons, and lateral humeral epicondyles and quantified using a validated scoring system.

Results: Thirty-two badminton players were included. One hundred ninety-two entheseal sites were examined twice. The respective empirical total scores for PD examination were 0.1 (0.3) before and 0.5 (0.9) after training. Mean total GS scores were 2.9 (2.5) and 3.1 (2.5) before and after training, respectively. The mean total PD score difference of 0.4 between pre- and post-training was significant (p = 0.0014), whereas no significant difference for the mean total GS score was observed. Overall, seven participants (22%) showed an increased empirical total PD score. A mixed effects model showed a significant increase of PD scores after training, with a mean increase per site of 0.06 (95% CI 0.01 to 0.12, p = 0.017).

Conclusions: Mechanical stress leads to rapid inflammatory responses in the entheseal structures of humans. These data support the concept of mechanoinflammation in diseases associated with enthesitis.
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http://dx.doi.org/10.1186/s13075-021-02530-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215784PMC
June 2021

Relations Between the McGurk Effect, Social and Communication Skill, and Autistic Features in Children with and without Autism.

J Autism Dev Disord 2021 Jun 8. Epub 2021 Jun 8.

Frist Center for Autism & Innovation, Vanderbilt University, Nashville, TN, USA.

Children with autism show alterations in multisensory integration that have been theoretically and empirically linked with the core and related features of autism. It is unclear, however, to what extent multisensory integration maps onto features of autism within children with and without autism. This study, thus, evaluates relations between audiovisual integration and core and related autism features across children with and without autism. Thirty-six children reported perceptions of the McGurk illusion during a psychophysical task. Parents reported on participants' autistic features. Increased report of illusory percepts tended to covary with reduced autistic features and greater communication skill. Some relations, though, were moderated by group. This work suggests that associations between multisensory integration and higher-order skills are present, but in some instances vary according to diagnostic group.
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http://dx.doi.org/10.1007/s10803-021-05074-wDOI Listing
June 2021

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.

Ann Rheum Dis 2021 10 25;80(10):1339-1344. Epub 2021 May 25.

Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA

Objective: To investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.

Methods: Established patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response.

Results: Although healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination.

Conclusions: In two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.
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http://dx.doi.org/10.1136/annrheumdis-2021-220597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219484PMC
October 2021

Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease.

medRxiv 2021 May 12. Epub 2021 May 12.

Objective: To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.

Methods: Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response.

Results: Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination.

Conclusions: In two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.

Key Messages: The impact of COVID-19 has been felt across the globe and new hope has arisen with the approval of mRNA vaccines against the SARS-CoV-2. Studies have shown immunogenicity and efficacy rates of over 90% in the immunocompetent adult population. However, there is a lack of knowledge surrounding the response of patients with immune-mediated inflammatory diseases (IMIDs) who may also be on immunomodulatory medications.Patients with IMID have been shown to have attenuated immune responses to seasonal influenza vaccination. This study looks at the humoral and cellular immune response to two doses of BNT162b2 mRNA COVID-19 Vaccine in participants with IMID (on immunomodulators) compared with healthy controls.Individuals with IMID on methotrexate demonstrate up to a 62% reduced rate of adequate immunogenicity to the BNT162b2 mRNA vaccination. Those on anti-cytokine or non-methotrexate oral medications demonstrate similar levels of immunogenicity as healthy controls (greater than 90%).Similarly, vaccination did not induce an activated CD8+ T cell response in participants on background methotrexate, unlike healthy controls and patients with IMID not receiving methotrexate. These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.
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http://dx.doi.org/10.1101/2021.05.11.21256917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132259PMC
May 2021

A New Approach to the Development of Disease-Modifying Therapies for PD.

Authors:
David K Simon

Mov Disord 2021 05;36(5):1281

Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1002/mds.28589DOI Listing
May 2021

A Virtual Reality-Based App to Educate Health Care Professionals and Medical Students About Inflammatory Arthritis: Feasibility Study.

JMIR Serious Games 2021 May 11;9(2):e23835. Epub 2021 May 11.

Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany.

Background: Inflammatory arthritides (IA) such as rheumatoid arthritis or psoriatic arthritis are disorders that can be difficult to comprehend for health professionals and students in terms of the heterogeneity of clinical symptoms and pathologies. New didactic approaches using innovative technologies such as virtual reality (VR) apps could be helpful to demonstrate disease manifestations as well as joint pathologies in a more comprehensive manner. However, the potential of using a VR education concept in IA has not yet been evaluated.

Objective: We evaluated the feasibility of a VR app to educate health care professionals and medical students about IA.

Methods: We developed a VR app using data from IA patients as well as 2D and 3D-visualized pathological joints from X-ray and computed tomography-generated images. This VR app (Rheumality) allows the user to interact with representative arthritic joint and bone pathologies of patients with IA. In a consensus meeting, an online questionnaire was designed to collect basic demographic data (age, sex); profession of the participants; and their feedback on the general impression, knowledge gain, and potential areas of application of the VR app. The VR app was subsequently tested and evaluated by health care professionals (physicians, researchers, and other professionals) and medical students at predefined events (two annual rheumatology conferences and academic teaching seminars at two sites in Germany). To explore associations between categorical variables, the χ or Fisher test was used as appropriate. Two-sided P values ≤.05 were regarded as significant.

Results: A total of 125 individuals participated in this study. Among them, 56% of the participants identified as female, 43% identified as male, and 1% identified as nonbinary; 59% of the participants were 18-30 years of age, 18% were 31-40 years old, 10% were 41-50 years old, 8% were 51-60 years old, and 5% were 61-70 years old. The participants (N=125) rated the VR app as excellent, with a mean rating of 9.0 (SD 1.2) out of 10, and many participants would recommend use of the app, with a mean recommendation score of 3.2 (SD 1.1) out of 4. A large majority (120/125, 96.0%) stated that the presentation of pathological bone formation improves understanding of the disease. We did not find any association between participant characteristics and evaluation of the VR experience or recommendation scores.

Conclusions: The data show that IA-targeting innovative teaching approaches based on VR technology are feasible.
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http://dx.doi.org/10.2196/23835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150404PMC
May 2021

The applicability of the Eating Disorder Inventory in pregnancy.

Eat Weight Disord 2021 May 7. Epub 2021 May 7.

Institute of Behavioural Sciences, Semmelweis University, Budapest, Hungary.

Purpose: The aim of our study was validating Eating Disorder Inventory (EDI) among pregnant women, who are vulnerable to eating disorders (EDs).

Methods: In 2012-2013, 1146 women (aged 18-47 years) completed a questionnaire including EDI during the first 3 days after delivery. We checked factorial validity of three diagnostic subscales of EDI with confirmative factor analysis and internal validity by Cronbach's alpha and item-total correlation. We also tested discriminative validity by comparing average of the three subscale of EDI in case of ED and non-ED groups.

Results: When applying the EDI to pregnant women, it seems necessary to exclude five items on three diagnostic subscales: on the Drive for Thinness subscale, 4 items remain (out of 7); on the Bulimia subscale, 6 items remain (out of 7); the Body Dissatisfaction subscale decreases from 9 to 8 items. Cronbach's alpha and item-total correlation values meet the requirements defined by Garner et al. The internal consistency of the EDI has proved to be appropriate, indicating that it is a reliable screening tool.

Conclusions: Thinking, attitudes, and behaviors connected to eating, along with the relation to altering body weight change during pregnancy. Vomiting usually accompanies pregnancy; body weight gain within wide limits is also regarded as normal during pregnancy. These behaviors and changes are not feasible to use for measuring ED symptoms. These aspects cannot be neglected when screening eating disorders in pregnant women.

Level Of Evidence: Level IV evidence obtained from multiple time series with or without an intervention.
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http://dx.doi.org/10.1007/s40519-021-01197-2DOI Listing
May 2021

Deep learning methods allow fully automated segmentation of metacarpal bones to quantify volumetric bone mineral density.

Sci Rep 2021 May 6;11(1):9697. Epub 2021 May 6.

Pattern Recognition Lab-Computer Science, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Arthritis patients develop hand bone loss, which leads to destruction and functional impairment of the affected joints. High resolution peripheral quantitative computed tomography (HR-pQCT) allows the quantification of volumetric bone mineral density (vBMD) and bone microstructure in vivo with an isotropic voxel size of 82 micrometres. However, image-processing to obtain bone characteristics is a time-consuming process as it requires semi-automatic segmentation of the bone. In this work, a fully automatic vBMD measurement pipeline for the metacarpal (MC) bone using deep learning methods is introduced. Based on a dataset of HR-pQCT volumes with MC measurements for 541 patients with arthritis, a segmentation network is trained. The best network achieves an intersection over union as high as 0.94 and a Dice similarity coefficient of 0.97 while taking only 33 s to process a whole patient yielding a speedup between 2.5 and 4.0 for the whole workflow. Strong correlation between the vBMD measurements of the expert and of the automatic pipeline are achieved for the average bone density with 0.999 (Pearson) and 0.996 (Spearman's rank) with [Formula: see text] for all correlations. A qualitative assessment of the network predictions and the manual annotations yields a 65.9% probability that the expert favors the network predictions. Further, the steps to integrate the pipeline into the clinical workflow are shown. In order to make these workflow improvements available to others, we openly share the code of this work.
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http://dx.doi.org/10.1038/s41598-021-89111-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102473PMC
May 2021

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.

Ann Rheum Dis 2021 10 6;80(10):1312-1316. Epub 2021 May 6.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

Objectives: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs).

Methods: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded.

Results: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID.

Conclusions: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.
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http://dx.doi.org/10.1136/annrheumdis-2021-220461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103562PMC
October 2021

A good gut feeling on Sarm1-mediated axon degeneration.

Protein Cell 2021 Aug 26;12(8):596-598. Epub 2021 Apr 26.

Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.

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http://dx.doi.org/10.1007/s13238-021-00842-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310545PMC
August 2021

Accuracy, patient-perceived usability, and acceptance of two symptom checkers (Ada and Rheport) in rheumatology: interim results from a randomized controlled crossover trial.

Arthritis Res Ther 2021 04 13;23(1):112. Epub 2021 Apr 13.

RheumaDatenRhePort (rhadar), Planegg, Germany.

Background: Timely diagnosis and treatment are essential in the effective management of inflammatory rheumatic diseases (IRDs). Symptom checkers (SCs) promise to accelerate diagnosis, reduce misdiagnoses, and guide patients more effectively through the health care system. Although SCs are increasingly used, there exists little supporting evidence.

Objective: To assess the diagnostic accuracy, patient-perceived usability, and acceptance of two SCs: (1) Ada and (2) Rheport.

Methods: Patients newly presenting to a German secondary rheumatology outpatient clinic were randomly assigned in a 1:1 ratio to complete Ada or Rheport and consecutively the respective other SCs in a prospective non-blinded controlled randomized crossover trial. The primary outcome was the accuracy of the SCs regarding the diagnosis of an IRD compared to the physicians' diagnosis as the gold standard. The secondary outcomes were patient-perceived usability, acceptance, and time to complete the SC.

Results: In this interim analysis, the first 164 patients who completed the study were analyzed. 32.9% (54/164) of the study subjects were diagnosed with an IRD. Rheport showed a sensitivity of 53.7% and a specificity of 51.8% for IRDs. Ada's top 1 (D1) and top 5 disease suggestions (D5) showed a sensitivity of 42.6% and 53.7% and a specificity of 63.6% and 54.5% concerning IRDs, respectively. The correct diagnosis of the IRD patients was within the Ada D1 and D5 suggestions in 16.7% (9/54) and 25.9% (14/54), respectively. The median System Usability Scale (SUS) score of Ada and Rheport was 75.0/100 and 77.5/100, respectively. The median completion time for both Ada and Rheport was 7.0 and 8.5 min, respectively. Sixty-four percent and 67.1% would recommend using Ada and Rheport to friends and other patients, respectively.

Conclusions: While SCs are well accepted among patients, their diagnostic accuracy is limited to date.

Trial Registration: DRKS.de, DRKS00017642 . Registered on 23 July 2019.
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http://dx.doi.org/10.1186/s13075-021-02498-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042673PMC
April 2021

An anterograde pathway for sensory axon degeneration gated by a cytoplasmic action of the transcriptional regulator P53.

Dev Cell 2021 04;56(7):976-984.e3

Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Axon remodeling through sprouting and pruning contributes to the refinement of developing neural circuits. A prominent example is the pruning of developing sensory axons deprived of neurotrophic support, which is mediated by a caspase-dependent (apoptotic) degeneration process. Distal sensory axons possess a latent apoptotic pathway, but a cell body-derived signal that travels anterogradely down the axon is required for pathway activation. The signaling mechanisms that underlie this anterograde process are poorly understood. Here, we show that the tumor suppressor P53 is required for anterograde signaling. Interestingly loss of P53 blocks axonal but not somatic (i.e., cell body) caspase activation. Unexpectedly, P53 does not appear to have an acute transcriptional role in this process and instead appears to act in the cytoplasm to directly activate the mitochondrial apoptotic pathway in axons. Our data support the operation of a cytoplasmic role for P53 in the anterograde death of developing sensory axons.
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http://dx.doi.org/10.1016/j.devcel.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034543PMC
April 2021

Gender differential in low psychological health and low subjective well-being among older adults in India: With special focus on childless older adults.

PLoS One 2021 8;16(3):e0247943. Epub 2021 Mar 8.

Paris 1 Pantheon-Sorbonne University, Paris, France.

Background: Gender and health are two factors that shape the quality of life in old age. Previous available literature established an associaton between various demographic and socio-economic factors with the health and well-being of older adults in India; however, the influence of childless aged is neglected. Therefore, the study examined the gender differential in psychological health and subjective well-being among older adults, focusing on childless older adults.

Methodology: This study utilized data from Building a Knowledge Base on Population Aging in India (BKPAI). Psychological health and subjective well-being were examined for 9541 older adults aged 60 years & above. Descriptive statistics and bivariate analysis were used to find the preliminary results. Further, multivariate analysis has been done to fulfill the objective of the study.

Results: Around one-fifth (21.2%) of the men reported low psychological health, whereas around one-fourth (25.5%) of the women reported low psychological health. Further, around 24 per cent of men and 29 per cent of women reported low subjective well-being. Results found that low psychological well-being (OR = 1.87, C.I. = 1.16-3.01), as well as low subjective well-being (OR = 1.78, C.I. = 1.15-2.76), was higher in childless older women than in childless older men. Higher education, community involvement, good self-rated health, richest wealth quintile, and residing in urban areas significantly decrease the odds of low subjective well-being and low psychological well-being among older adults.

Conclusion: There is a need to improve older adults' psychological health and subjective well-being through expanded welfare provisions, especially for childless older adults. Moreover, there is an immediate requirement to cater to the needs of poor and uneducated older adults.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247943PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939372PMC
March 2021

Advanced machine learning for predicting individual risk of flares in rheumatoid arthritis patients tapering biologic drugs.

Arthritis Res Ther 2021 02 27;23(1):67. Epub 2021 Feb 27.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany.

Background: Biological disease-modifying anti-rheumatic drugs (bDMARDs) can be tapered in some rheumatoid arthritis (RA) patients in sustained remission. The purpose of this study was to assess the feasibility of building a model to estimate the individual flare probability in RA patients tapering bDMARDs using machine learning methods.

Methods: Longitudinal clinical data of RA patients on bDMARDs from a randomized controlled trial of treatment withdrawal (RETRO) were used to build a predictive model to estimate the probability of a flare. Four basic machine learning models were trained, and their predictions were additionally combined to train an ensemble learning method, a stacking meta-classifier model to predict the individual flare probability within 14 weeks after each visit. Prediction performance was estimated using nested cross-validation as the area under the receiver operating curve (AUROC). Predictor importance was estimated using the permutation importance approach.

Results: Data of 135 visits from 41 patients were included. A model selection approach based on nested cross-validation was implemented to find the most suitable modeling formalism for the flare prediction task as well as the optimal model hyper-parameters. Moreover, an approach based on stacking different classifiers was successfully applied to create a powerful and flexible prediction model with the final measured AUROC of 0.81 (95%CI 0.73-0.89). The percent dose change of bDMARDs, clinical disease activity (DAS-28 ESR), disease duration, and inflammatory markers were the most important predictors of a flare.

Conclusion: Machine learning methods were deemed feasible to predict flares after tapering bDMARDs in RA patients in sustained remission.
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http://dx.doi.org/10.1186/s13075-021-02439-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913400PMC
February 2021
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