tbuckley/cabot-search huggingface dataset:
Sex differences and the role of education in cognitive ageing: analysis of two UK-based prospective cohort studies
Authors: Mikaela Bloomberg, Aline Dugravot, Julien Dumurgier, Mika Kivimaki, Aurore Fayosse, Andrew Steptoe, Annie Britton, Archana Singh-Manoux, Séverine Sabia
Journal: The Lancet Public Health (2021)

BackgroundPrevious studies have shown an excess risk of Alzheimer's disease and related dementias among women. Education is thought to have a causal association with dementia onset. We aimed to investigate the role of education in influencing sex differences in cognitive ageing.MethodsWe analysed data from two prospective cohort studies in the UK; the English Longitudinal Study of Ageing (ELSA) and the Whitehall II study, to assess sex differences in cognitive performance and cognitive decline by birth cohort (birth year 1930–38, 1939–45, or 1946–55), before and after adjustment for education, and by high and low education level. Memory was assessed using immediate recall, for which data were available from all waves of the ELSA (2002–14) and Whitehall II (1997–2015) studies. Fluency was assessed using a semantic fluency test based on an animal naming task, with data available from all waves of the Whitehall II study and waves one to five (2002–10) and wave seven (2014) of the ELSA study. Cognitive scores were standardised separately in each study based on the mean and SD of the corresponding test among participants aged 50–59 years with secondary education.Findings15 924 participants were included from the two studies. In pooled analyses, women had better memory scores than men in all birth cohorts, irrespective of adjustment for education (eg, at age 60 years, birth cohort 1930–38, mean difference between sexes [male scores minus female scores] –0·25 SDs [95% CI –0·32 to –0·19] after adjustment for education), and in both education level groups. Memory decline was faster in men than in women (at age 60 years, birth cohort 1946–55, mean difference in 13-year change –0·15 SDs [–0·20 to –0·09]; after adjustment for education –0·14 SDs [–0·20 to –0·08]). Men had better fluency scores than women in earlier birth cohorts and in the low education group (at age 60 years, birth cohort 1930–38, mean difference 0·20 SDs [95% CI 0·05 to 0·36]); but women had better fluency scores than men in later birth cohorts and in the high education group (at age 60 years, birth cohort 1946–55, mean difference –0·17 SDs [–0·24 to –0·10]). No sex differences were observed for fluency decline.InterpretationOur findings suggest that decreasing disparities between sexes in education, due to secular increases in educational opportunities, could attenuate sex differences in dementia risk and cognitive decline in the future.FundingNational Institute on Aging, National Institutes of Health; UK Medical Research Council; British Heart Foundation; and National Institute for Health Research.
Current progress and limitations of AAV mediated delivery of protein therapeutic genes and the importance of developing quantitative pharmacokinetic/pharmacodynamic (PK/PD) models
Authors: Ekram Ahmed Chowdhury, Guy Meno-Tetang, Hsueh Yuan Chang, Shengjia Wu, Hsien Wei Huang, Tanguy Jamier, Jayanth Chandran, Dhaval K. Shah
Journal: Advanced Drug Delivery Reviews (2021)
Treatment response and clinical outcomes of well-differentiated high-grade neuroendocrine tumors to 177Lu-DOTATATE.
Authors: Kelley Lauren Coffman, Lisa Bodei, Tiffany Le, Ye Choi, Joanne F. Chou, Marinela Capanu, Mark Dunphy, Josef J. Fox, Ravinder K Grewal, Ryan Reddy, Christopher Riedl, Heiko Schöder, Diane Lauren Reidy, Nitya Prabhakar Raj
Journal: Journal of Clinical Oncology (2021)

368 Background: 177 Lu-DOTATATE is an approved therapy for somatostatin receptor (sstr) positive gastroenteropancreatic neuroendocrine tumors (NETs). There are little data available on response and outcomes for well differentiated (WD) high grade (HG) NETs treated with 177 Lu-DOTATATE. Methods: Pts with WD HGNETs treated with 177 Lu-DOTATATE at MSK from 2018-2020 were identified. Demographics, response to treatment, and progression-free survival (PFS) were determined. In pts with archival tumor tissue, next-generation sequencing (NGS) was performed through an institutional platform (MSK-IMPACT). Results: 19 pts were identified (mean age 54, 63% female). Site of tumor origin included: pancreas (14/19, 74%), small bowel (2/19, 10.5%), rectal (2/19, 10.5%), lung (1/19, 5%). Average tumor Ki-67 was 34.8 (range 22-56). All tumors were sstr avid on pre-treatment Ga68-DOTATATE PET/CT; none of the patients had sstr negative lesions detected. Median number of prior treatments (systemic and/or liver-directed) was 4 (range 2-7). All pts had progressive disease prior to initiation of 177 Lu-DOTATATE. 13 pts (68%) completed all four treatment cycles; treatment was incomplete in 6 pts due to treatment-related toxicities (n = 3) and clinical progression (n = 3). Best response by radiographic report was available in 16 patients (84%):10/16 (63%) with partial response, 1/16 (6%) with stable disease, 5/16 (31%) with disease progression. One pt with stable disease as best response received two additional cycles of 177 Lu-DOTATATE at progression. Median PFS (from date of first treatment with 177 Lu-DOTATATE until progression/death) was 11.1 months (95% CI 10.6 to NA). Five pts (26%) experienced dose modifying toxicity with 177 Lu-DOTATATE. The most common treatment-related toxicities were thrombocytopenia (9 pts, 47%; G3/4 in 1 pt, 5%), anemia (7 pts, 37%; G3/4 in 2 pts, 10.5%), leukopenia (6 pts, 32%; G3/4 in 0 pts), and AST/ALT elevation (4 pts, 21%; G3/4 in 0 pts). NGS results were available in the tumor tissue of 13 pts (68%). The most commonly observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations were identified. Conclusions: We observed a meaningful disease control rate of 69% during treatment of WD HGNETs with 177 Lu-DOTATATE. In this heavily pre-treated population, more than half of pts received all four treatment cycles with treatment-related toxicities largely bone-marrow related, as expected, based on historical data. As would be expected in sstr avid tumors, the vast majority had alterations in chromatin remodeling genes (MEN1, DAXX) consistent with WD NETs, with no RB1 alterations identified.
American Industry and the U.S. Cardiovascular Clinical Research Enterprise: An Appropriate Analogy?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Robert M. Califf, Robert A. Harrington
Journal: Journal of the American College of Cardiology (2011)
Rethinking immune checkpoint blockade: ‘Beyond the T cell’
Authors: Xiuting Liu, Graham D Hogg, David G DeNardo
Journal: Journal for ImmunoTherapy of Cancer (2021)

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.
Tumor microenvironments self-activated nanoscale metal-organic frameworks for ferroptosis based cancer chemodynamic/photothermal/chemo therapy
Authors: Yu Liang, Li Zhang, Chao Peng, Shiyu Zhang, Siwen Chen, Xin Qian, Wanxian Luo, Qing Dan, Yongyan Ren, Yingjia Li, Bingxia Zhao
Journal: Acta Pharmaceutica Sinica B (2021)

Ferroptosis, as a newly discovered cell death form, has become an attractive target for precision cancer therapy. Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione (GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). However, the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported. Herein, novel tumor microenvironments (TME)-activated metal-organic frameworks involving Fe & Cu ions bridged by disulfide bonds with PEGylation (FCSP MOFs) were developed, which would be degraded specifically under the redox TME, simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction, therefore causing ferroptosis. More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs. The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy. Better tumor therapeutic efficiency could be achieved by doxorubicin (DOX) loading since it can not only cause apoptosis, but also indirectly produce H2O2 to amplify Fenton reaction. Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.
AB0018 Intervetebral disc herniation: involvement of metalloproteinases
Authors: L Grange, P Gaudin, JJ Favre, M Peoc’h, R Juvin, X Phelip, JP Chirossel, F Morel
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Disc degeneration and physiopathology of disc herniation involves enzymatic processes mainly matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase-1 (TIMP-1) and cytokines (IL-1b, TNF-a). <h3>Objectives</h3> This study focuses on metalloproteinases secretion and expression by disc chondrocytes isolated from herniated and not herniated zone. <h3>Methods</h3> Eleven discs after discectomy are enzymatically digested, chondrocytes from both zones, herniated and not herniated, are cultured in alginate beads for 10 days in classical conditions. Analysis of MMP-2,-3,-7,-9,-13 and TIMP-1 by ELISA, zymography, RT-PCR and nested PCR are conducted with an immunochemical study on tissu fragments. <h3>Results</h3> - proteic level: (ELISA, zymography): ?presence of elevated levels of MMP-3, TIMP-1 in the non herniated part ?absence of MMP-13, MMP-9, pro MMP-7 in both parts -Transcriptional level (RT, PCR, nested PCR): ?expression of MMP-2, -3, TIMP-1 in both zones, weak expression of MMP-9 by nested PCR without difference between the two zones. ?absence or weak expression of MMP-13, -7. <h3>Conclusion</h3> There is an heterogeneous expression of MMP -2, -3, -9 and TIMP-1 by disc herniated and non herniated chrondocytes. The matrix metalloproteinases are probably involved early in the disc degeneration, the herniation could be the final result of matrix/cells interactions. The secretion of TIMP-1 and MMP-3 in the herniated zone may be related discal fibrosis included into the disc cicatrization. <h3>References</h3> Goupille P, Malcom I, Jayson V, Valat JP, Freemont AJ. Matrix metalloproteinases: the clue to Intervertébral disc degeneration? Spine 1998;23:1612–26 Matsui Y, Maeda M, Nakagami W, Iwata H. Theinvolvement ofmatrixmetalloproteinases in inflammation in lumbar disc herniation. Spine 1998;23:863–9 Crean JKG, Roberts S, Jaffray DC, Eisenstein SM, Duance VC. Matrix metalloproteinases in the human intervertebral disc. Role in disc degeneration and scoliosis. Spine 1997;22: 2877–84 Haro H, Crawford HC, Fingleton B, et al. Matrisian. Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc résorption. J Clin Invest. 2000;105(2):133–41 Poiraudeau S, Monteiro I, Anract P, Blanchard O, Revel M, Corvol MT. Phenotic characteristic of rabbit inter vertebral disccells. Spine 1999;24:837–44
Characterization of ascites- and tumor-infiltrating γδ T cells reveals distinct repertoires and a beneficial role in ovarian cancer
Authors: Emelie Foord, Lucas C. M. Arruda, Ahmed Gaballa, Charlotte Klynning, Michael Uhlin
Journal: Science Translational Medicine (2021)

γδ T cells are clonotypically distinct in ascites and tumors of patients with ovarian cancer and their functionality correlates with clinical outcome.
Data and Policy to Guide Opening Schools Safely to Limit the Spread of SARS-CoV-2 Infection
Authors: Margaret A. Honein, Lisa C. Barrios, John T. Brooks
Journal: JAMA (2021)

This Viewpoint from the CDC summarizes global data about SARS-CoV-2 outbreaks at K-12 schools and emphasizes implementation of community- and school-based policies shown to diminish spread of infection that would allow safer resumption of in-person education in the 2021/22 school year.
OP0102 GENE SCREENING OF PRIMARY IMMUNODEFICIENCY DISEASES IN PATIENTS WITH JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: J. LI, W. Wang, C. Y. Wang, J. Y. Pan, H. Song
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic lupus erythematosus (SLE) is one of the most common auto-immune diseases in childhood. Primary immunodeficiency disease (PID) patients may present or combine with autoimmune diseases. Objectives: This study aimed to perform gene sequencing via high-throughput sequencing technology in a series of Chinese pediatric SLE patients, and investigate the concomitant situation of PIDs and SLE. Gene sequencing results may help clarify the pathogenesis of SLE. Methods: This was a retrospective case series of SLE children who referred to the Peking Union Medical College Hospital between 01/2016 and 09/2019. Genetic tests were performed in patients who met the inclusion criteria. We then collected demographic, clinical, and treatment information of all involved patients. Descriptive statistics were used. Results: Seventy-one patients were finally included (eighteen boys and fifty-three girls). The median age at the time of disease onset was 9.5 (range, 3-15) years. It is notable that five patients experienced their first attack before the age of five. Twenty-seven patients showed a persistent increase in ESR during treatment, while thirteen cases presented with repeated CMV infection, thirty-four cases with persistent low complement levels, seven with basal ganglia calcification showed in skull CT or MRI, four with special type of rash (i.e., frostbite-like rash, discoid erythema, reticular erythema), two with obvious hepatosplenomegaly, and one case with type I diabetes. Gene sequencing results showed that about ten patients combine with primary immunodeficiency disease, including Aicardi-Goutières Syndrome (AGS) (n=4), Spondyloenchondro-dysplasia with immune dysregulation (SPENCDI) (n=1), STING-associated vasculopathy with onset in infancy (SAVI) (n=1), lysinuric protein intolerance (LPI) (n=1), Ras-associated autoimmune leukoproliferative disorder (RALD) (n=2). Conclusion: SLE patients who present atypical or refractory manifestations should attach importance to the existence of primary immunodeficiency disease. Genetic tests are recommended for patients with early-onset SLE, especially those with recurrent frostbite-like rash or persistent CMV infection since childhood. References: [1]T Tarr, B Dérfalvi, N Győri, et al. Similarities and differences between pediatric and adult patients with systemic lupus erythematosus[J]. Lupus. 2015, 24: 796–803. [2]Gupta S, Louis A G. Tolerance and Autoimmunity in Primary Immunodeficiency Disease: a Comprehensive Review[J]. Clinical Reviews in Allergy &amp; Immunology, 2013, 45(2):162-169. Disclosure of Interests: None declared
INNOVA: Interval or neoadjuvant chemotherapy in rectal cancer—A phase II randomized study comparing interval versus neoadjuvant chemotherapy in magnetic resonance imaging-defined high-risk rectal cancer.
Authors: Ramakrishnan Ayloor Seshadri, Trivadi S. Ganesan, Manikandan Dhanushkodi, Arunkumar M N, Shirley Sundersingh
Journal: Journal of Clinical Oncology (2021)

91 Background: Total neoadjuvant treatment is a promising option in rectal cancer. We aim to compare neoadjuvant versus interval chemotherapy in high risk rectal cancer to identify the optimal sequencing of treatment. Methods: Using a Simon two-stage design, newly diagnosed MRI defined high risk rectal cancer patients were randomly assigned in a 1:1 ratio to receive three 21 day cycles of chemotherapy with Capecitabine 1000 mg/m2 and Oxaliplatin 130 mg/m2 either before (Arm A-neoadjuvant) or after (Arm B-interval) chemoradiation followed by surgery. Primary end point was the pathological complete response (pCR) following surgery. A heirarchial model was used to assess the primary and secondary end points (toxicity and compliance) and compare the two regimens. (Clinical Trial Registry of India No. CTRI/2015/01/005385). Results: In this single centre study conducted between November 2015 and February 2020, 42 patients were randomised in the first stage. A pCR was seen in 4 patients in Arm A and 6 in Arm B. Hence another 52 patients were randomised in the second stage of which an additional 3 and 2 patients had a pCR leading to an overall pCR of 7 and 8 patients (15.5% vs 17% and 18.4% vs 19.5% in the intent-to-treat and per-protocol populations in Arm A and B respectively. This exceeded the minimum predetermined number of 5 pCR needed to qualify for further evaluation for each arm. Grade ≥3 toxicity was observed in 2.2% of 132 cycles and 4.6% of 129 cycles of chemotherapy delivered in 45 and 43 patients in Arm A and B respectively while 11/43 (25.5%) and 10/47 (21.2%) patients experienced grade ≥3 toxicity during chemoradiation. Treatment break of &gt; 7 days was seen in 23.2% and 29.7% of patients in Arm A and B respectively while 93.3% in Arm A and 100% of patients in Arm B completed all 3 planned cycles of pre-operative chemotherapy. A non-significant trend towards greater pathological downstaging was seen in Arm B than in Arm A (ypT1-2 39% vs 26.3%; p = 0.1 and ypN0 68.3% vs 57.9%; p = 0.5 respectively). Conclusions: In this phase two study, both neoadjuvant and interval chemotherapy emerged eligible for further evaluation against the standard of care in a future phase III study. Although we could not pick one winner based on pCR, toxicity or compliance, the greater downstaging observed with interval chemotherapy suggests it could play a greater role in an organ preservation approach. Clinical trial information:CTRI/2015/01/005385, UTN no: U111111650578.
Delivery of Health Services to Migrant and Seasonal Farmworkers
Authors: Thomas A. Arcury, Sara A. Quandt
Journal: Annual Review of Public Health (2006)

Farmworkers are low-paid, uninsured employees in an extremely hazardous industry, and they provide an essential service for U.S. society. This review evaluates the delivery of health services to farmworkers. It describes the farmworker population in the United States, noting characteristics (e.g., migratory and immigration status) that limit their access to and utilization of health services. It describes the health services needs of this population, including occupational health, mental health, oral health, and chronic disease treatment. Cultural, structural, legal, financial, and geographic barriers to health services utilization are described. Existing research on health services utilization among farmworkers is discussed. Programs that have been developed to address the barriers to health services utilization among farmworkers are reviewed. Finally, research needed to improve knowledge of farmworker health services utilization is suggested. These research needs include formal evaluations of existing programs and basic research to characterize the health services utilization patterns of farmworkers.
AB0097 Extra pyramidal syndrome as a manifestation of temporal arteritis
Authors: DG Michas, A Papadopoulos, E Sarra, M Deutsch, S Lionaki, P Kotsakis
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Temporal arteritis as a form of vasculitis can sometimes manifest itself be with neurological complications. Cases with symptoms of extra pyramidal system are rarely reported in bibliography. A case of a patient with temporal arteritis who presented lethargic syndrome followed by Parkinson disease is reported. <h3>Objectives</h3> Case report.A woman 80 years old was firstly admitted to our hospital with enlarged neck lymph nodes and fever. A lymph node biopsy indicated TBC. She was supplied with anti TBC treatment and significantly improved. Two months later she was admitted again with symptoms of rigour, neck stiffness and lethargy. Subarachnoid haemorrhage or meningitis was suspected. Brain CT scan and lumbar puncture were negative. She was supplied with corticosteroid treatment in large doses and the next day all the symptoms disappeared. On leaving hospital she was advised to continue the corticosteroids and gradually stop them. A month later and 10 days after finishing her therapy, she was again admitted with high fever, headache and extrapyramidal syndrome with hand and tongue tremor, stiffness of the musculature, hypokinesia and immobile facial expression. Physical examination indicated painful bilateral temporal arteries. Left temporal artery biopsy indicated giant cell arteritis. She was treated again with corticosteroids only and the signs and symptoms of temporal arteritis and extapyramidal syndrome disappeared. Patient is examined energy six months and her health has continuously been good. <h3>Methods</h3> <h3>Results</h3> <h3>Conclusion</h3> Temporal arteritis in rare forms of the disease is likely to manifest itself with parkinsonian syndrome. Corticosteroidal treatment is enough to improve the disease without supplement any special antiparkinsonian treatment.
Esophageal variceal treatment using a novel Doppler probe method
Authors: Yasutoshi Shiratori, Takaaki Yoshimoto, Kazuki Yamamoto
Journal: Endoscopy (2021)

Esophageal variceal recurrence after endoscopic treatment is a frequent event [1] [2] [3] [4]. Some studies have reported that endoscopic treatment assisted by endoscopic ultrasonography (EUS) that can evaluate variceal size and hemodynamics is effective in preventing variceal recurrence [3] [4]. Additionally, color Doppler evaluation by EUS is less invasive and enables endoscopists to identify the varices to be treated [4]. However, the Doppler-EUS method has issues related to its use: it is time-consuming, it is complicated to use convex transducers, and it requires scope replacement for additional treatment. The latest method, Doppler probe ultrasonography, uses a through-the-scope Doppler probe (Compumedics, DWL, Singen, Germany) ([Fig. 1 a]) that can evaluate the direction, waveform (that helps distinguish between arteries and veins), and the amount of blood flow ([Fig. 1 b, c]) [5]. Moreover, Doppler probe ultrasonography is simple, noninvasive, and requires no scope replacement for additional treatment. The procedure involves 1) identification of more risky varices, 2) detection of penetrating varices, 3) assisting appropriate hemostasis, and 4) evaluation after hemostatic treatment. Here we demonstrate two variceal treatments using this novel approach ([Video 1]).