tbuckley/cabot-search huggingface dataset:
Africa's need for more COVID-19 clinical trials
Authors: Munyaradzi Makoni
Journal: The Lancet (2021)

Africa's need for more COVID-19 clinical trialsFew treatments and vaccines are being tested in Africa, leaving a lack of data for the COVID-19 response.Munyaradzi Makoni reports from Cape Town, South Africa.Experts are calling for more clinical trials of vaccines and therapies for COVID-19 to be done in Africa to ensure effective treatment and prevention for the continent.The pandemic has spurred unprecedented efforts in research and development globally, but, of the more than 3000 trials of interventions for COVID-19 that are underway, only 145 are taking place in Africa.Only 2% of clinical trials took place in Africa before COVID-19, yet drugs now offered were mostly tested on non-Africans, says Bernhards Ogutu, chief research officer with the Kenya Medical Research Institute.As a result, there is concern over the lack of information on the efficacy of new drugs and vaccines in African populations.Bartholomew Dicky Akanmori, regional adviser for vaccine research and regulation, WHO Regional Office for Africa, says that more studies are needed to assess the long-term safety and duration of protection of different COVID-19 vaccines in different population groups."It is difficult to generalise clinical findings for an entire continent", he said."We have a huge population of 1•2 billion people, larger than North America and Europe combined", said Jenniffer Mabuka-Maroa, from the African Academy of Sciences."And this population also happens to be very genetically diverse and under unique environmental exposures that influence our body responses to drugs and vaccines."While there may be few clinical trials in Africa, WHO Africa says COVID-19 vaccines undergo rigorous testing in clinical trials to prove that they meet internationally agreed standards for safety and efficacy.Some African countries also have high rates of comorbidities, such as HIV and tuberculosis, for which COVID-19 vaccines need to be tested for efficacy
Targeted mutagenesis in mouse cells and embryos using an enhanced prime editor
Authors: Soo-Ji Park, Tae Yeong Jeong, Seung Kyun Shin, Da Eun Yoon, Soo-Yeon Lim, Sol Pin Kim, Jungmin Choi, Hyunji Lee, Jeong-Im Hong, Jinhee Ahn, Je Kyung Seong, Kyoungmi Kim
Journal: Genome biology (2021)

Prime editors, novel genome-editing tools consisting of a CRISPR-Cas9 nickase and an engineered reverse transcriptase, can induce targeted mutagenesis. Nevertheless, much effort is required to optimize and improve the efficiency of prime-editing. Herein, we introduce two strategies to improve the editing efficiency using proximal dead sgRNA and chromatin-modulating peptides. We used enhanced prime-editing to generate Igf2 mutant mice with editing frequencies of up to 47% and observed germline transmission, no off-target effects, and a dwarf phenotype. This improved prime-editing method can be efficiently applied to cell research and to generate mouse models.
Signatures and Specificity of Tissue-Resident Lymphocytes Identified in Human Renal Peritumor and Tumor Tissue
Authors: Theresa Dornieden, Arne Sattler, Anna Pascual-Reguant, Annkathrin Helena Ruhm, Lion Gabriel Thiel, Yasmin Samira Bergmann, Linda Marie Laura Thole, Ralf Köhler, Anja Andrea Kühl, Anja Erika Hauser, Sengül Boral, Frank Friedersdorff, Katja Kotsch
Journal: Journal of the American Society of Nephrology (2021)

Tissue-resident memory T (TRM) cells are known to be important for the first line of defense in mucosa-associated tissues. However, the composition, localization, effector function, and specificity of TRM cells in the human kidney and their relevance for renal pathology have not been investigated.Lymphocytes derived from blood, renal peritumor samples, and tumor samples were phenotypically and functionally assessed by applying flow cytometry and highly advanced histology (multi-epitope ligand cartography) methods.CD69+CD103+CD8+ TRM cells in kidneys display an inflammatory profile reflected by enhanced IL-2, IL-17, and TNFα production, and their frequencies correlate with increasing age and kidney function. We further identified mucosa-associated invariant T and CD56dim and CD56bright natural killer cells likewise expressing CD69 and CD103, the latter significantly enriched in renal tumor tissues. CD8+ TRM cell frequencies were not elevated in kidney tumor tissue, but they coexpressed PD-1 and TOX and produced granzyme B. Tumor-derived CD8+ TRM cells from patients with metastases were functionally impaired. Both CD69+CD103-CD4+ and CD69+CD103-CD8+ TRM cells form distinct clusters in tumor tissues in proximity to antigen-presenting cells. Finally, EBV, CMV, BKV, and influenza antigen-specific CD8+ T cells were enriched in the effector memory T cell population in the kidney.Our data provide an extensive overview of TRM cells' phenotypes and functions in the human kidney for the first time, pointing toward their potential relevance in kidney transplantation and kidney disease.
Hypertranscription and replication stress in cancer
Authors: Akhil Bowry, Richard D.W. Kelly, Eva Petermann
Journal: Trends in cancer (2021)

Replication stress results from obstacles to replication fork progression, including ongoing transcription, which can cause transcription-replication conflicts. Oncogenic signaling can promote global increases in transcription activity, also termed hypertranscription. Despite the widely accepted importance of oncogene-induced hypertranscription, its study remains neglected compared with other causes of replication stress and genomic instability in cancer. A growing number of recent studies are reporting that oncogenes, such as RAS, and targeted cancer treatments, such as bromodomain and extraterminal motif (BET) bromodomain inhibitors, increase global transcription, leading to R-loop accumulation, transcription-replication conflicts, and the activation of replication stress responses. Here we discuss our mechanistic understanding of hypertranscription-induced replication stress and the resulting cellular responses, in the context of oncogenes and targeted cancer therapies.
AB0728 OSTEOGENESIS IMPERFECTA: ABOUT 12 CASES
Authors: O. Jomaa, J. Mahbouba, S. Zrour, I. Bejia, M. Touzi, N. Bergaoui
Journal: Annals of the Rheumatic Diseases (2021)

Background: Osteogenesis imperfecta (OI), is a rare hereditary disease characterized by bone fragility and low bone mass. The clinical presenatation is various with varying severity skeletal signs and inconstant extra-skeletal signs. Type 1 is the most common form (60% of cases). Objectives: Our objective is to describe the various clinical features observed over a period of 15 years. Methods: This is a retrospective descriptive study including 12 patients followed for OI, hospitalized in the Rheumatology Department at Fattouma Bourguiba Hospital Monastir TUNISIA between 2006 and 2019. Files were collected and analyzed. Results: They are 9 boys and 3 girls with an average age of 14.9 ± 8.6 years. Consanguinity was reported in 25% of cases. The reason leading to consultation was, recurrent fractures (75%), blue sclera (16.7), and bone deformity (8.3%). The number of previous fractures was on average of 5, all of which were caused by a low energy trauma. Similar family cases were noted in 41.6%. The mean age of the first fracture was 4.41 ± 3.2 years. The most frequent fracture sites were respectively: femur (7/12), leg (6/12), tibia (3/12), humerus (4/12), ankle (2/12), and forearm (2/12). A deformity was noted in 58.3% of the cases: lumbar kyphosis (2), exaggerated dorsal kyphosis (2), femurs in parenthesis (2), and an anarchic deformity of 2 lower limbs (1). Imperfect dentinogenesis was found in 8.3% of cases, while ENT examination revealed conductive and sensorineural hearing loss in 2 patients each. The main radiological abnormalities were diffuse bone demineralization (9 patients), cortical thinning (5 patients), vertebral compression (3 patients), and fracture (2 patients). The bone densitometry showed a mean Z score of 3.49±1.4 in the lumbar spine. The average serum calcium level was 2.38±1.15, alkaline phosphatases were elevated in all cases with an average of 756±624.9. The vitamin D level was deficient in all cases with an average of 22.75±5.3. All patients received in addition to the vitamin-calcium supplementation, pamidronate intravenously at a dose of 9mg/kg/year with a mean number of 6 cures. The main side effects observed during the infusion were abdominal pain, polyarthralgia and asthenia (1 patient), chest pain (1 patient) and fever and chills (1 patient). The control bone densitometry showed a mean Z score of 1.81±1.2 in the lumbar spine. Conclusion: Despite advances in the OI diagnosis and treatment, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice. References: [1] https://doi.org/10.1097/med.0000000000000367 Disclosure of Interests: None declared
Aberrant Hedgehog Signaling in Myelodysplastic Syndrome Accelerates Leukemic Transformation Via Smoothened-Dependent and Smoothened-Independent Gli1 Activation
Authors: Bonnie W Lau, Kyounghee Huh, Rafael Madero-Marroquin, Federico De Marchi, Yiting Lim, Francisco Lobo, Luigi Marchionni, Peter D. Aplan, William Matsui, Lukasz P. Gondek
Journal: Blood (2017)
Expanding sports and exercise medicine research in Cameroon: current challenges and defining what is needed
Authors: Douryang Maurice
Journal: British Journal of Sports Medicine (2021)

Sports and exercise medicine (SEM) clinicians embrace evidence-based practice as a means to improve quality of care, ultimately improving the overall health of the community. However, implementation and dissemination of research evidence to SEM practice encounters many barriers in different settings. SEM is well established in many developed countries,1–3 but in some African countries such as Cameroon, SEM research is ‘embryonic’ and its expansion faces many difficulties. This editorial highlights contextual challenges to conducting research and developing the field in Cameroon and recommends pathways for improvement.

The relative absence of formal training programmes in SEM represents a major challenge to the expansion of SEM research in Cameroon. Contemporary curricula represent the starting point for the development of any field and guide health research.3 4 In Cameroon, the SEM curricula are not available in most existing medical schools. The University of Yaounde I offers a 2-year master’s degree in sports medicine, and a few other universities and institutes offer only a 3–5-year curriculum in general physiotherapy and/or rehabilitation with both research and sports medicine as elective teaching modules. Thus, knowledge and awareness of SEM as a clinical specialty and the methods and priorities …
131I Ablation of an Entire Thyroid Gland in Locally Invasive Differentiated Thyroid Cancer Without Surgery
Authors: Grace Yung, Nicholas Forwood, Robert Russo, Kirtan Ganda, Robert Mansberg
Journal: Clinical Nuclear Medicine (2021)

Abstract A 79-year-old man with locally metastatic papillary thyroid cancer to left-sided cervical lymph nodes was referred for radioiodine therapy. He was considered unfit for thyroidectomy due to extensive local involvement and severe interstitial lung disease requiring continuous oxygen. The patient was treated with low doses of radioiodine (approximately 30 mCi) every 6 months with corticosteroid cover for 3 years with good effect. Sequential 131 I scanning and serum thyroglobulin levels confirmed virtual complete ablation of the thyroid gland. The patient remained well on thyroid hormone replacement.
The Need for Critical Examination of Disparities in Immunotherapy and Targeted Therapy Use Among Patients With Cancer
Authors: Sepideh Ashrafzadeh, Maryam M. Asgari, Alan C. Geller
Journal: JAMA Oncology (2021)

This Viewpoint examines factors that may be associated with disparities in the use of immunotherapies and targeted therapies across different patient groups and proposes strategies to decrease disparities in cancer care.
AB0007 STAT4 RS7574865 G/T POLYMORPHISM AS MARKER OF PREDISPOSITION TO SYSTEMIC LUPUS ERYTHEMATOSUS WITH JUVENILE ONSET
Authors: M. Kaleda, M. Krylov, I. Nikishina
Journal: Annals of the Rheumatic Diseases (2021)

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a significant genetic predisposition. Recent studies have identified STAT4 (signal transducers and transcription activators 4) as a susceptibility gene for SLE. Objectives: To investigate the hypothesis of the association of STAT4 rs7574865 G/T polymorphism with the predisposition to SLE in children and its relationship with some of SLE manifestations. Methods: The case-control pilot study included 143 children (39 with SLE and 103 healthy unrelated volunteers as a control group). Diagnosis of SLE was based on 2012 SLICC criteria. STAT4 rs7574865 G/T polymorphism was investigated using allele-specific real-time polymerase chain reaction (RT-PCR). Results: The group of pts with SLE consisted of 29 girls and 10 boys, with an average age of 11.8±3.7 years (from 3 to 17 years) and an average disease duration of 4.1±2.4 years. 79.5% pts had acute cutaneous lupus at the onset, 46.1% - nonscarring alopecia, 71.8% - arthritis, 23.1% - oral and nasal ulcers, 23.1% - serositis, 43.6% - renal involvement, 35.9% –neuropsychiatric disorders. Leucopenia/lymphopenia was found in 71.8% of pts, thrombocytopenia – in 23,1%. ANA were detected in 100% pts, anti-dsDNA – in 79.5%, anti-Sm – in 31.6%, antiphospholipid antibodies - in 7,3%, hypocomplementemia – in 61.5%, positive direct Coombs test – in 35.9 %. Macrophage activation syndrome at the onset was documented in 15.4 % of pts. The distribution of rs7574865 genotypes in the control group showed no significant deviations from the Hardy-Weinberg equilibrium. The distribution of genotype frequencies among pts had statistically significant differences compared to the control (χ2=12.95, p=0.0015): GG-30.8% and 63.1% (p=0.001), GT-56.4% and 33.0% (p=0.018), TT-12.8% and 3.9% (p=0.114), GT+TT - 69.2% and 36.9% (p=0.0005). The frequency of the mutant STAT 4 allele T (polymorphism), was significantly higher in the SLE group than in the control group (41% and 20.4%, respectively; p=0.0007). We identified an association of the T allele with some clinical, laboratory, and immunological disorders in SLE: arthritis (OR 3.9, p=0.0002), acute cutaneous lupus (OR 2.47, p=0.003), nonscarring alopecia (OR 3.12, p=0.002), renal involvement (OR 2.42, p=0.022), leucopenia (OR 2.72, p=0.003), thrombocytopenia (OR 4.88, p=0.002), anti-dsDNA (OR 2.82, p=0.0006), hypocomplementemia (OR 2.34, p=0.012), positive direct Coombs test (OR 3.38, p=0.002). Conclusion: Our pilot study confirmed that the STAT4 rs7574865 G/T polymorphism was associated with the risk of SLE in children and some of SLE manifestations. Disclosure of Interests: None declared
POS0769 VALIDATION OF THE SIMPLE INDEX FOR DISEASE ACTIVITY OF SYSTEMIC LUPUS ERYTHEMATOSUS IN CHINESE PATIENTS
Authors: C. C. Mok, L. Y. Ho, K. L. Chan, J. Meenakshi
Journal: Annals of the Rheumatic Diseases (2021)

Objectives: To validate the SIMPLE index for systemic lupus erythematosus (SLE) disease activity assessment in Chinese patients. Methods: Adult patients (age ≥18 years) who fulfilled the 2013 SLICC criteria for SLE and were followed in the Rheumatology clinics of Tuen Mun Hospital, Hong Kong were recruited in a cross-sectional study. Participants were invited to complete the SIMPLE questionnaire before seeing doctors on the same day. The two laboratory results were supplemented by research nurses. Physicians, who were blinded to the SIMPLE results, were asked to complete disease activity assessment by the SELENA-SLEDAI and physicians’ global assessment (PGA) after consultation. Correlation was made between the SIMPLE score and the SLEDAI/PGA scores by Spearman’s rank correlation test. Receiver operating characteristic (ROC) analysis was performed to find the best cut-off SIMPLE score that predicted a clinical SLEDAI score of 1-6 (mild SLE activity) and ≥7 (moderate/severe activity). Results: 364 SLE patients were studied (94% women; age 45.4±13.4 years; disease duration 13.2±8.0 years). The proportion of patients having a history of neuropsychiatric and renal disease that required immunosuppressive therapies was 9.3% and 56%, respectively. At the time of questionnaire completion, 69 (19%) patients had SLEDAI ≥6 and 192 (53%) had SLEDAI 1-5. The mean SLEDAI was 3.04±2.85 and PGA score was 0.62±0.55. A total of 161 (44%) had SDI score ≥1. The mean SIMPLE index was 26.0±12.9. SIMPLE index correlated significantly with SLEDAI (ρ=0.76; p&lt;0.001) and PGA score (ρ=0.48; p&lt;0.001). ROC analysis showed that a SIMPLE index of &gt;27 points best predicted a clinical SLEDAI score of 1-6 (area under the curve [AUC] 0.78[0.73-0.84]; sensitivity 0.75; specificity 0.71), and &gt;36.8 points best predicted a clinical SLEDAI score of ≥7 (AUC 0.87[0.69-1.00]; sensitivity 0.88, specificity 0.85). Conclusion: SIMPLE shows a good correlation with SELENA-SLEDAI and PGA. It is a simple tool that enables patients to self-report disease activity and communicate with the health care team more efficiently. Disclosure of Interests: None declared
Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
Authors: Mirco Friedrich, Roman Sankowski, Lukas Bunse, Michael Kilian, Edward Green, Carina Ramallo Guevara, Stefan Pusch, Gernot Poschet, Khwab Sanghvi, Markus Hahn, Theresa Bunse, Philipp Münch, Hagen M. Gegner, Jana K. Sonner, Anna von Landenberg, Frederik Cichon, Katrin Aslan, Tim Trobisch, Lucas Schirmer, Denis Abu-Sammour, Tobias Kessler, Miriam Ratliff, Daniel Schrimpf, Felix Sahm, Carsten Hopf, Dieter H. Heiland, Oliver Schnell, Jürgen Beck, Chotima Böttcher, Camila Fernandez-Zapata, Josef Priller, Sabine Heiland, Ilona Gutcher, Francisco J. Quintana, Andreas von Deimling, Wolfgang Wick, Marco Prinz, Michael Platten
Journal: Nature Cancer (2021)

Abstract The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.
Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial
Authors: Pradeesh Sivapalan, Charlotte Suppli Ulrik, Therese Sophie Lapperre, Rasmus Dahlin Bojesen, Josefin Eklöf, Andrea Browatzki, Jon Torgny Wilcke, Vibeke Gottlieb, Kjell Erik Julius Håkansson, Casper Tidemandsen, Oliver Tupper, Howraman Meteran, Christina Bergsøe, Eva Brøndum, Uffe Bødtger, Daniel Bech Rasmussen, Sidse Graff Jensen, Lars Pedersen, Alexander Jordan, Helene Priemé, Christian Søborg, Ida E. Steffensen, Dorthe Høgsberg, Tobias Wirenfeldt Klausen, Martin Steen Frydland, Peter Lange, Asger Sverrild, Muhzda Ghanizada, Filip K. Knop, Tor Biering-Sørensen, Jens D. Lundgren, Jens-Ulrik Stæhr Jensen
Journal: European Respiratory Journal (2021)

Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having
Cost-effectiveness of Dapagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction
Authors: Justin T. Parizo, Jeremy D. Goldhaber-Fiebert, Joshua A. Salomon, Kiran K. Khush, John A. Spertus, Paul A. Heidenreich, Alexander T. Sandhu
Journal: JAMA Cardiology (2021)

<h3>Importance</h3> In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, dapagliflozin was shown to reduce cardiovascular mortality and hospitalizations due to heart failure while improving patient-reported health status. However, the cost-effectiveness of adding dapagliflozin therapy to standard of care (SOC) is unknown. <h3>Objective</h3> To estimate the cost-effectiveness of dapagliflozin therapy among patients with chronic heart failure with reduced ejection fraction (HFrEF). <h3>Design, Setting, and Participants</h3> This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, and utilities from the DAPA-HF trial and other published literature. Costs were derived from published sources. Patients with HFrEF included subgroups based on diabetes status and health status impairment due to heart failure. We compiled parameters from the literature including DAPA-HF, on which our model is based, and many other sources from December 2019 to February 27, 2021. We performed our analysis in February 2021. <h3>Exposures</h3> Dapagliflozin or SOC. <h3>Main Outcomes and Measures</h3> Hospitalizations for heart failure, life-years, quality-adjusted life-years (QALYs), costs, and the cost per QALY gained (incremental cost-effectiveness ratio). <h3>Results</h3> In the model, dapagliflozin therapy yielded a mean of 0.78 additional life-years and 0.46 additional QALYs compared with SOC at an incremental cost of $38 212, resulting in a cost per QALY gained of $83 650. The cost per QALY was similar for patients with or without diabetes and for patients with mild or moderate impairment of health status due to heart failure. The cost-effectiveness was most sensitive to estimates of the effect on mortality and duration of therapy effectiveness. If the cost of dapagliflozin decreased from $474 to $270 (43% decline), the cost per QALY gained would drop below $50 000. <h3>Conclusions and Relevance</h3> These findings suggest that dapagliflozin provides intermediate value compared with SOC, based on American College of Cardiology/American Heart Association benchmarks. Additional data regarding the magnitude of mortality reduction would improve the precision of cost-effectiveness estimates.