tbuckley/cabot-search huggingface dataset:
Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome
Authors: Martina Parrini, Shovan Naskar, Micol Alberti, Ilaria Colombi, Giovanni Morelli, Anna Rocchi, Marina Nanni, Federica Piccardi, Severine Charles, Giuseppe Ronzitti, Federico Mingozzi, Andrea Contestabile, Laura Cancedda
Journal: Molecular Therapy (2021)

A common feature of diverse brain disorders is the alteration of GABA-mediated inhibition because of aberrant, intracellular chloride homeostasis induced by changes in the expression and/or function of chloride transporters. Notably, pharmacological inhibition of the chloride importer NKCC1 is able to rescue brain-related core deficits in animal models of these pathologies and in some human clinical studies. Here, we show that reducing NKCC1 expression by RNA interference in the Ts65Dn mouse model of Down syndrome (DS) restores intracellular chloride concentration, efficacy of gamma-aminobutyric acid (GABA)-mediated inhibition, and neuronal network dynamics in vitro and ex vivo. Importantly, adeno-associated virus (AAV)-mediated, neuron-specific NKCC1 knockdown in vivo rescues cognitive deficits in diverse behavioral tasks in Ts65Dn animals. Our results highlight a mechanistic link between NKCC1 expression and behavioral abnormalities in DS mice and establish a molecular target for new therapeutic approaches, including gene therapy, to treat brain disorders characterized by neuronal chloride imbalance. A common feature of diverse brain disorders is the alteration of GABA-mediated inhibition because of aberrant, intracellular chloride homeostasis induced by changes in the expression and/or function of chloride transporters. Notably, pharmacological inhibition of the chloride importer NKCC1 is able to rescue brain-related core deficits in animal models of these pathologies and in some human clinical studies. Here, we show that reducing NKCC1 expression by RNA interference in the Ts65Dn mouse model of Down syndrome (DS) restores intracellular chloride concentration, efficacy of gamma-aminobutyric acid (GABA)-mediated inhibition, and neuronal network dynamics in vitro and ex vivo. Importantly, adeno-associated virus (AAV)-mediated, neuron-specific NKCC1 knockdown in vivo rescues cognitive deficits in diverse behavioral tasks in Ts65Dn animals. Our results highlight a mechanistic link between NKCC1 expression and behavioral abnormalities in DS mice and establish a molecular target for new therapeutic approaches, including gene therapy, to treat brain disorders characterized by neuronal chloride imbalance.
POS1216 SYMPTOM RATES, ATTITUDES AND MEDICATION ADHERENCE OF RHEUMATIC AND MUSCULOSKELETAL DISEASE PATIENTS DURING THE SARS-CoV2 PANDEMIC
Authors: K. Murray, S. Quinn, M. Turk, A. O’rourke, E. Molloy, L. O’neill, A. B. Mongey, U. Fearon, D. Veale
Journal: Annals of the Rheumatic Diseases (2021)

Background: SARS-CoV2 has caused over two million deaths globally. The relationship between rheumatic and musculoskeletal disease (RMDs), immunosuppressive medications and COVID-19 is unclear. Objectives: This study explores the rates of COVID-19 symptoms and positive tests, DMARD adherence and attitudes to virtual clinics. amongst RMD patients. Methods: An online population survey was disseminated via the Arthritis Ireland website and social media channels. Results: There were 1381 respondents with RMD, 74.8% were on immunosuppressive medication. COVID-19 symptoms were reported by 3.7% of respondents of which 0.46% tested positive, no different from the general population at that timepoint. The frequency of COVID-19 symptoms was higher for respondents with spondyloarthropathy [odds ratio (OR) 2.06, 95% CI: 1.14, 3.70] and lower in those on immunosuppressive medication (OR 0.48, 95% CI: 0.27, 0.88), and those compliant with health authority (HSE) guidance (OR 0.47, 95% CI: 0.25, 0.89). Adherence to RMD medications was reported in 84.1%, with 57.1% using health authority guidelines for information on medication use. Importantly, adherence rates were higher amongst those who cited guidelines (89.3% vs 79.9%, P &lt;0.001), and conversely lower in those with COVID-19 symptoms (64.0% vs 85.1%, P =0.009). Finally, the use of virtual clinics was supported by 70.4% of respondents. Conclusion: The rate of COVID-19 positivity in RMD patients was similar to the general population. COVID-19 symptoms were lower amongst respondents on immunosuppressive medication and those adherent to medication guidelines. Respondents were supportive of HSE advice and virtual rheumatology clinics. Disclosure of Interests: Kieran Murray Grant/research support from: Bresnihan Molloy and Newman fellowships, Sean Quinn: None declared, Matthew Turk: None declared, Anna O’Rourke: None declared, Eamonn Molloy: None declared, Lorraine O’Neill: None declared, Anne Barbara Mongey: None declared, Ursula Fearon: None declared, Douglas Veale: None declared.
POS1417 DO SOCIAL FACTORS IMPACT ON BIOLOGICS COSTS IN RHEUMATOID ARTHRITIS? RESULTS FROM THE MOROCCAN RBSMR REGISTRY
Authors: S. Farih, H. Rkain, S. Fellous, S. Ahid, R. Abouqal, T. Latifa, I. Hmamouchi, L. Achemlal, I. El Bouchti, A. EL Maghraoui, I. Ghozlani, H. Hassikou, T. Harzy, I. Linda, O. Mkinsi, R. Niamane, R. Bahiri, F. Allali
Journal: Annals of the Rheumatic Diseases (2021)

Background: Objectives: The aim of this study was to estimate the annual direct cost of biologics in rheumatoid arthritis and to evaluate the impact of social factors on biological use and costs. Methods: Patients in the Moroccan register of biologicals (RBSMR) with available 1-year data were included. Variables related to socio-economic status, disease and biological were collected. Direct costs included prices of biologics, costs of infusions, and subcutaneous injections. Biological use and costs were compared based on social factors. Results: Our study included 197 patients (female sex of 86.8%, mean age of 52.3 ± 11 years). Patients were on one of the following therapies: Rituximab (n=132), Tocilizumab (n=37) or TNF-blockers (n=28). 44.2% of included patients have the RAMED medical assistance (health insurance scheme for the economically underprivileged). Illiteracy was noted in 45.7% of cases. Median one-year direct costs per patient were €1,665 [€1,472 - €9,879]. There was no statistically significant difference in costs between men and women (p&gt;0.05), between illiterate and literate (p&gt;0.05). There was a statistically significant difference in costs between patients with the RAMED medical assistance scheme and other health insurances (p&lt;0.01). Conclusion: This study showed that Moroccan RA patients had equal access to biologics regardless of their gender or level of education. Indeed, the insurance system influence the costs of biologics. Accessibility of those expensive treatments in a developing country seems be explained by efforts of the Moroccan ministry of health who has allocated a substantial budget for biologic DMARDs for patients with RAMED in the tertiary structures in our country. Disclosure of Interests: None declared
AB0615 ASSESSMENT OF THE IMPACT OF OBESITY ON BONE LOSS
Authors: M. Yasmine, S. Mariem, S. Miladi, A. Fazaa, E. Frigui, L. Souebni, K. Ouenniche, S. Kassab, S. Chekili, K. Ben Abdelghani, A. Laatar
Journal: Annals of the Rheumatic Diseases (2021)

Background: Most of the available evidence supports a lower risk of vertebral fracture in obese adults. This belief was partially suggested by the positive correlation between bone mineral density (BMD) and body mass index (BMI). Objectives: We aimed to assess the association of BMI with BMD and to explore their relation with age and gender. Methods: This is a cross-sectional study including Tunisian patients referred for an assessment of BMD through dual-energy X-ray absorptiometry (DXA). BMD was measured using standard methods over the lumbar spine L1-L4, the total proximal femur. The results were expressed as T-scores according to the World Health Organization definition. Patients were sub-grouped according to age (≤50 and &gt;50 years). Association between BMD and age as well as BMI was also assessed (G1: obese patients and G2: non-obese patients). The level of significance was fixed for p&lt;0.05 Results: The study included 100 patients with a female predominance (sex ratio =10.1). The mean age for women was 61.9 ±13 [18-83] years and the mean age for men was 59.7± 7.5 [47-72] years. The mean body mass index was 29.1± 5 kg/m 2 [15-45] for women and 27.6 ±3.6 Kg/m 2 [22.8-32.9] for men. Forty percent of all patients were obese with a mean BMI of 32.9 kg/m 2 ± 4.3. Osteopenia was diagnosed in half of the men (55.5%) and most of the women (70%). Twenty-nine percent of patients suffered from osteoporosis. BMD of the spine was similar between men and women (p=0.53). Men had higher BMD of the hip than women (p=0,038). The mainstream of the subjects &gt;50 years had more vertebral fractures, suffered more from osteoporosis and had a higher BMI than those &lt; 50 years (95% % vs 5%; p=0.04), (92.3% vs 77 %; p=0.03) and (82.5% vs 17.5%; p=0.05) respectively. There was no correlation between BMD of the spine and higher BMI (0.94 in G1 vs 0.98 in G2, p=0.3). Similarly, there was no correlation between BMD of the hip and higher BMI (0.9 in G1 vs 0.84 in G2, p=0.2). Moreover, Obese patients had less a vertebral fracture but with no statistically significant correlation (21% in G1 vs 25% in G2; p=0.2). Conclusion: Our study showed that obesity was frequent among Tunisian patients but was not associated with a higher BMD. Older age was directly associated with a lower BMD and higher risk for vertebral fracture. Disclosure of Interests: None declared.
Exosome-based delivery of super-repressor IκBα ameliorates kidney ischemia-reperfusion injury
Authors: Seonghun Kim, Sul A Lee, Heakyung Yoon, Myung Yoon Kim, Jae-Kwang Yoo, So-Hee Ahn, Cheol Hyoung Park, Jimin Park, Bo Young Nam, Jung Tak Park, Seung Hyeok Han, Shin-Wook Kang, Nam Hee Kim, Hyun Sil Kim, Dawool Han, Jong In Yook, Chulhee Choi, Tae-Hyun Yoo
Journal: Kidney International (2021)
A locus coeruleus to dentate gyrus noradrenergic circuit modulates aversive contextual processing
Authors: Dong-oh Seo, Eric T. Zhang, Sean C. Piantadosi, David J. Marcus, Laura E. Motard, Bryce K. Kan, Adrian M. Gomez, Tammy K. Nguyen, Li Xia, Michael R. Bruchas
Journal: Neuron (2021)
Factors associated with HIV infection among children in Larkana District, Pakistan: a matched case-control study
Authors: Fatima Mir, Apsara Ali Nathwani, Victoria Simms, Syed Hani Abidi, Amna Rehana Siddiqui, Aneeta Hotwani, Sikander Ali Memon, Saqib Ali Shaikh, Jamila Soomro, Sharaf Ali Shah, Baseer Achakzai, Sofia Furqan, Quaid Saeed, Palwasha Khan, Helen A Weiss, Syed Faisal Mahmood, Rashida Abbas Ferrand
Journal: The Lancet HIV (2021)
In patients hospitalized with COVID-19, adding azithromycin to usual care did not reduce 28-d mortality
Authors: Simon O’Connor
Journal: Annals of Internal Medicine (2021)

Source CitationRECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397:605-12. https://pubmed.ncbi.nlm.nih.gov/33545096/AbstractClinical Impact RatingsHospitalists: Infectious Disease: Critical Care: Pulmonology:
AB0793 CONTRIBUTION OF INVESTIGATIONS FOR THE QUEST OF PRIMITIVE CANCER IN FRONT OF BONE METASTASIS
Authors: S. Boussaid, S. Rekik, S. Mechergui, S. Jemmali, E. Cheour, H. Sahli, M. Elleuch
Journal: Annals of the Rheumatic Diseases (2021)

Background: Bone metastases (OM) or secondary cancers bones are bony locations of tumor cells, away from a primary malignant tumor. The Bone metastases are the most common metastases. They can be revealing in 20 to 30% cases or complicate the course of a known cancer. The bone metastases are a pejorative prognostic factor. Objectives: The aim of this study was to identify the Contribution of diagnostic methods for the quest of primitive cancer in presence of bone metastasis. Methods: We conduct a retrospective study of 35 files of patients who were hospitalized in the rheumatology department. All patients underwent a questionnaire and a clinical examination. Additional radiological assessment, bone biopsies, biopsies of other sites, bone scintigraphy and tumor markers were carried out on a case-by-case basis. Results: Thirty-five cases (25 men and 10 women) were analysed. The average age was 61 years [45-85]. Seven patients had a known history of neoplasia. One or more bone biopsies were performed in 8 cases. The vertebrae were the most biopsied bone site (6 cases). The bone biopsies were in favour of carcinoma (3 cases), adenocarcinoma (2 cases), squamous cell carcinoma (1 case) and inconclusive (2 cases). Non bony biopsies (2 pulmonary, 2 prostatic, 1 mammary) concluded to an adenocarcinoma (3 cases) and a carcinoma (2 cases). Bone scintigraphy was carried out in 7 cases and showed in all cases diffuse or localized hyperfixation. The localized value of tumor markers appeared relatively low except for Prostate Specific Antigen (PSA). Other metastatic localisations were identified: hepatic (6 cases) and pulmonary (1 case). The primary cancer identified was pulmonary for 11 patients, prostatic for 7, gynaecological for 4 and digestive for 3. One patient had Otorhinolaryngological cancer and another had bone cancer. Bone biopsy allowed the diagnosis in 6 cases (17%). The primary cancer was discovered by a biopsy of other non-bone sites in 5 cases (14%). Neoplastic antecedents and clinical context were considered sufficient in 16 cases (45%). Primary cancer remained undetermined in 8 cases (22%). Conclusion: Bone biopsy, as well as non-bone biopsy, remains an essential tool in the etiological diagnosis of bone metastases. They are very contributive in the same proportions. PSA is a major diagnostic asset in the search for primary cancer. Disclosure of Interests: None declared
POS1078 CURRENT REGISTRIES IN PSA DO NOT WELL REFLECT THE PROFILES OF PATIENTS WITH PsA BECAUSE THEY ORIGINATE IN SIMILAR COUNTRIES: A SYSTEMATIC LITERATURE REVIEW OF 27 REGISTRIES, OR 16183 PATIENTS
Authors: G. S. Moysidou, K. Aouad, A. Rakotozafiarison, B. Fautrel, L. Gossec
Journal: Annals of the Rheumatic Diseases (2021)

Background: Psoriatic arthritis (PsA) is a multidimensional inflammatory disease with a great geographic variability and a global average prevalence estimated at 133 every 100,000 subjects according to a recent systematic review and meta-analysis (1). Registries and cohorts reflect more closely real-world data than randomized controlled trials (RCTS) and may indicate ongoing interest of each country on PsA. Objectives: The purpose of this study is to assess how recent registries and PsA related cohorts reflect its worldwide prevalence. Methods: A systematic literature review was performed in Pubmed Medline (PROSPEROCRD42020175745) to identify all articles reporting on either registries or longitudinal cohorts in PsA, published between 2010 and March 2020. Registries centered on drugs or not PsA-specific, trials and long term extension studies were excluded. The data collection comprised registries’ and cohorts’ originating countries, patient characteristics and the clinical outcome measures reported. Statistics were descriptive. Results: Of 673 articles, 73 were relevant for analysis, corresponding to 27 registries or PsA specific cohorts, with the participation of 30 countries. The overall number of patients was 16,183 with a mean of 599 per study. Overall, 50.1% were men, weighted mean age was 50,6 years and weighted mean disease duration was 6.9 years. Most of the registries were based in Europe (67%) or North America (26%) whereas Africa was underrepresented (Figure 1). USA was the most represented country participating in 6 registries. Mean age and mean disease duration were shorter in international registries (Table 1). Caspar diagnostic criteria were the most frequently used, mainly in the national registries (86,4%), whereas the use of diagnostic criteria was more heterogenous in the international registries. Conclusion: Recent registries and PsA specific cohorts do not cover the worldwide spectrum of the disease. References: [1]Scotti L, Franchi M, Marchesoni A, Corrao G. Prevalence and incidence of psoriatic arthritis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2018 Aug;48(1):28-34 Table 1. Description of 27 ongoing PsA registries or PsA cohorts, comparing nationwide and international registries NATIONWIDE REGISTRIES (N=22) INTERNATIONAL REGISTRIES (N=5) WOMEN (%) 49,4 50,8 MEAN AGE, WEIGTHED (YEARS) 52,32 48,09 MEAN DISEASE DURATION, WEIGHTED (YEARS) 8,59 5,86 CASPAR DIAGNOSTIC CRITERIA (%) 86,4 40 Figure 1. Geographical distribution of PsA registries Disclosure of Interests: None declared.
RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic
Authors: Mark Griffiths, Susanna Meade, Charlotte Summers, Daniel Francis McAuley, Alastair Proudfoot, Marta Montero Baladia, Paul M Dark, Kate Diomede, Simon J Finney, Lui G Forni, Chris Meadows, Ian A Naldrett, Brijesh Patel, Gavin D Perkins, Mark A Samaan, Laurence Sharifi, Ganesh Suntharalingam, Nicholas T Tarmey, Harriet F Young, Matt P Wise, Peter M Irving
Journal: Thorax (2021)

COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template.An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again.Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease.The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.
Ensuring fair distribution of COVID-19 vaccines: is an intellectual waiver the answer?
Authors: Talha Khan Burki
Journal: The Lancet Respiratory Medicine (2021)

On May 5, 2021, the US Government announced that it was in favour of waiving intellectual property protections for the COVID-19 vaccines. "This is a global health crisis, and the extraordinary circumstances of the COVID-19 pandemic call for extraordinary measures", stated US Trade Representative, Katherine Tai. "The administration believes strongly in intellectual property protections, but in service of ending this pandemic, supports the waiver of those protections for COVID-19 vaccines." Tai added that the USA would pursue such a waiver at the World Trade Organisation (WTO).
Myeloid Resistance is not Futile: Biomarkers of Immunotherapy in Bladder Cancer
Authors: Charles G. Drake
Journal: Clinical Cancer Research (2021)

Abstract The majority of patients with urothelial cancer do not respond to immune checkpoint blockade directed at the PD-(L)1 axis. Recently, robust profiling data were used to derive predictive biomarker signatures for both protumorigenic immunity and adaptive antitumor immunity; combining these has greater predictive power than either alone. Clinically, these results suggest that myeloid cells may be primary drivers of nonresponsiveness in urothelial cancer. See related article by Wang et al., p. 4287
AB0620 MODIFICATION OF THE DECISION OF THE ANTI-OSTEOPOROSIS TREATMENT AFTER PERFORMING THE VFA
Authors: H. Tantaoui, K. Nassar, S. Janani
Journal: Annals of the Rheumatic Diseases (2021)

Background: Spinal fractures are the most common of all osteoporotic fractures. Its diagnosis is essential, because the discovery of a vertebral fracture testifies the gravity of osteoporosis and modifies the therapeutic intervention threshold by justifying a specific anti-osteoporosis treatment. The evolution of densitometers now makes it possible to take a true X-ray image using software called “Vertebral Fracture Assessment” or VFA. Objectives: To assess the impact of VFA results on therapeutic decision-making after measuring bone mineral density. Methods: We conducted a retrospective and descriptive study in the rheumatology department. We included all patient followed at the consultation for bone pathologies, in whom a measurement of bone mineral density and a supplementation of VFA were performed. Clinical data, BMD, VFA and the therapeutic decision by anti-osteoporosis treatment before and after VFA were collected. Results: Sixty-one patients were included. The mean age was 62.8 years [38 - 85 years]. Sex ratio (female / male) was 19.3. At BMD level, patients with osteoporosis and osteopenia were 49% and 51% respectively. VFA objectified at least one spinal fracture in 64% of patients. Prior to VFA, anti-osteoporosis therapy was indicated to 49% of patients, based on clinical data and BMD. After performing VFA, the prescription of anti-osteoporosis therapy was indicated to 80% of patients. Conclusion: Patients who had no indication for osteoporosis treatment based on BMD data, VFA was able to modify their therapeutic treatment by detecting vertebral fractures in patients who had back pain. Disclosure of Interests: None declared.
Incidental Detection of Sinonasal Inverted Papilloma With 68Ga-FAPI PET/CT in a Patient With Esophageal Cancer
Authors: Huipan Liu, Xiao Yang, Lin Liu, Lei Lei, Yue Chen
Journal: Clinical Nuclear Medicine (2021)

Abstract A 68-year-old man with newly diagnosed esophageal cancer was included in a clinical trial of 68 Ga-FAPI PET/CT study in tumors (ChiCTR2100044131). Increased tracer uptake was noted in esophageal cancer. In addition, sinonasal inverted papilloma also revealed increased FAPI activity.
PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial
Authors: Stefanie Kreissl, Helen Goergen, Ina Buehnen, Carsten Kobe, Alden Moccia, Richard Greil, Dennis A Eichenauer, Josée M Zijlstra, Jana Markova, Julia Meissner, Michaela Feuring-Buske, Martin Soekler, Hans-Joachim Beck, Wolfgang Willenbacher, Wolf-Dieter Ludwig, Thomas Pabst, Max S Topp, Felicitas Hitz, Martin Bentz, Ulrich Bernd Keller, Dagmar Kühnhardt, Helmut Ostermann, Bernd Hertenstein, Walter Aulitzky, Georg Maschmeyer, Tom Vieler, Hans Eich, Christian Baues, Harald Stein, Michael Fuchs, Volker Diehl, Markus Dietlein, Andreas Engert, Peter Borchmann
Journal: The Lancet Haematology (2021)
Ribosomal protein S26 serves as a checkpoint of T-cell survival and homeostasis in a p53-dependent manner
Authors: Chaojia Chen, Jiali Peng, Shuaiya Ma, Yuming Ding, Tao Huang, Shigang Zhao, Lifen Gao, Xiaohong Liang, Chunyang Li, Chunhong Ma
Journal: Cellular and Molecular Immunology (2021)