tbuckley/cabot-search huggingface dataset:
CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease
Authors: Khurrum Shahzad, Sameen Fatima, Moh’d Mohanad Al-Dabet, Ihsan Gadi, Hamzah Khawaja, Saira Ambreen, Ahmed Elwakiel, Nora Klöting, Matthias Blüher, Peter P. Nawroth, Peter R. Mertens, Sven Michel, Frank Jaschinski, Richard Klar, Berend Isermann
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement The endoplasmic reticulum (ER) stress response and the maladaptive and cell-death–promoting transcription factor C/EBP homologous protein (CHOP) have been linked with diabetic kidney disease (DKD). Specific therapies targeting maladaptive ER stress signaling are lacking. We show that an antisense oligonucleotide (ASO)–based approach reducing CHOP expression ameliorates DKD in mice, providing renal protection on top of ACE inhibition. CHOP inhibition improves both glomerular and tubular damage. ASO-based therapies are a potentially new approach to target maladaptive ER stress signaling and improve DKD. Background Maladaptive endoplasmic reticulum stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell-death–promoting transcription factor C/EBP homologous protein (CHOP). Here, we determined whether locked nucleic acid (LNA)–modified antisense oligonucleotides (ASOs) targeting CHOP ameliorate experimental DKD. Methods We determined the efficacy of CHOP-ASO in the early and late stages of experimental DKD (in 8- or 16-week-old db/db mice, respectively) alone or with an angiotensin-converting enzyme inhibitor (ACEi), after an in vivo dose-escalation study. We used renal functional parameters and morphologic analyses to assess the effect of CHOP-ASO and renal gene-expression profiling to identify differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. Results CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at the early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. CHOP-ASO affected a significantly larger number of genes and disease pathways, including reduced sodium-glucose transport protein 2 (Slc5a2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented death of human kidney cells in vitro . Conclusions The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi, particularly at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.
Risk of a permanent work-related disability pension after incident venous thromboembolism in Denmark: A population-based cohort study
Authors: Helle Jørgensen, Erzsébet Horváth-Puhó, Kristina Laugesen, Sigrid Brækkan, John-Bjarne Hansen, Henrik Toft Sørensen
Journal: PLoS Medicine (2021)

Long-term complications of venous thromboembolism (VTE) hamper physical function and impair quality of life; still, it remains unclear whether VTE is associated with risk of permanent work-related disability. We aimed to assess the association between VTE and the risk of receiving a permanent work-related disability pension and to assess whether this association was explained by comorbidities such as cancer and arterial cardiovascular disease.A Danish nationwide population-based cohort study consisting of 43,769 individuals aged 25 to 66 years with incident VTE during 1995 to 2016 and 218,845 birth year-, sex-, and calendar year-matched individuals from the general population, among whom 45.9% (N = 120,540) were women, was established using Danish national registries. The cohorts were followed throughout 2016, with permanent work-related disability pension as the outcome. Hazard ratios (HRs) with 95% confidence intervals (CIs) for disability pension were computed and stratified by sex and age groups (25 to 34, 35 to 44, 45 to 54, and 55 to 66 years of age) and adjusted for comorbidities and socioeconomic variables. Permanent work-related disability pensions were granted to 4,415 individuals with VTE and 9,237 comparison cohort members (incidence rates = 17.8 and 6.2 per 1,000 person-years, respectively). VTE was associated with a 3-fold (HR 3.0, 95% CI: 2.8 to 3.1) higher risk of receiving a disability pension. Adjustments for socioeconomic status and comorbidities such as cancer and cardiovascular diseases reduced the estimate (HR 2.3, 95% CI: 2.2 to 2.4). The risk of disability pension receipt was slightly higher in men than in women (HR 2.5, 95% CI: 2.3 to 2.6 versus HR 2.1, 95% CI: 2.0 to 2.3). As this study is based on medical and administrative registers, information on post-VTE care, individual health behavior, and workplace factors linked to disability pension in the general population are lacking. Furthermore, as disability pension schemes vary, our results might not be directly generalizable to other countries or time periods.In this study, incident VTE was associated with increased risk of subsequent permanent work-related disability, and this association was still observed after accounting for comorbidities such as cancer and cardiovascular diseases. Our results emphasize the social consequences of VTE and may help occupational and healthcare professionals to identify vulnerable individuals at risk of permanent exclusion from the labor market after a VTE event.
When biology meets behaviour: can medication adherence mask the contribution of pharmacogenetic effects in asthma?
Authors: Job F.M. van Boven, Boudewijn J.H. Dierick, Omar S. Usmani
Journal: European Respiratory Journal (2021)

<b>Medication adherence and inhaler technique may confound, in both a positive and a negative manner, outcomes of pharmacogenetic asthma studies. The importance of understanding patient behaviour when interpreting their biology should be emphasised.</b>https://bit.ly/3tQdh1p
RBC distribution width predicts thrombosis risk in polycythemia vera
Authors: Dan Liu, Bing Li, Zefeng Xu, Peihong Zhang, Tiejun Qin, Shiqiang Qu, Lijuan Pan, Xiujuan Sun, Zhongxun Shi, Huijun Huang, Huijun Wang, Robert Peter Gale, Zhijian Xiao
Journal: Leukemia (2021)
Sex work, gender transition, family rejection and depressive symptoms among transgender women in India
Authors: Ankur Srivastava, Jordan P. Davis, Prachi Patel, Elkan E. Daniel, Shama Karkal, Eric Rice
Journal: International Journal of Transgender Health (2021)

Background: Transgender women in India face unique stressors associated with minority experiences, such as experiences of gender transition and participation in sex work. However, the relationship between sex work, transition and mental health outcomes is understudied in this population. Aims: This article aims to examine the association between gender transition status, sex work, family rejection and depressive symptoms among transgender women in India. Methods: Data comes from a cross-sectional epidemiological study with transgender women from three states of India; Karnataka, Maharashtra and Tamil Nadu (N = 1366). Multivariate regressions were used to examine the association between sex work status and gender transition and how gender transition, and sex work are associated with depressive symptoms. Results: 70% of the sample reported being in sex work and over 82% endorsed taking some form of gender transition service. Those who reported being in sex work were significantly more likely to have undergone breast augmentation, hormonal therapy and gender affirming surgery. Those who reported ever being married were less likely to report gender affirming surgery and were more likely to report hormonal therapy. Additionally, being in sex work, undergoing transition, leaving home because of sexual orientation, and being married were significantly associated with depressive symptoms. Discussion: Community-led organizations and other service agencies must incorporate intersectional experiences and identities, including sex work and gender transition, in their programs to further social and health justice for transgender women in India. Policy and programmatic implications are discussed. Supplemental data for this article is available online at https://doi.org/10.1080/26895269.2021.1939220.
Foot orthoses versus hip exercises and the effect of greater foot mobility in the management of patellofemoral pain: PhD Academy Award
Authors: Mark Matthews
Journal: British Journal of Sports Medicine (2021)

I investigated if we could optimise who should receive foot orthoses in the management of people who have patellofemoral pain. I did this by investigating if a patient’s presenting characteristic—foot mobility—helps to determine who benefits most from foot orthoses, compared with hip exercises, in a large multicentre randomised clinical trial in Australia and Denmark.

I was driven by clinical curiosity. Patellofemoral pain is considered a multifactorial condition with underlying biomechanical, neuromuscular and/or psychological contributors. International consensus1 and clinical guidelines2 recommend exercise therapy targeting the hip muscles and/or the knee and a distal consideration of foot orthoses. The recommendation of proximal and distal approaches presents two clinical quandaries. First, which individual’s presenting characteristic(s) may help guide clinicians which end of the lower limb to prioritise (ie, foot orthoses or hip exercises) and second, which of these treatments …
Applications of medicinal chemistry for drug discovery against <i>Acanthamoeba</i> infections
Authors: Usman Ahmed, Ayaz Anwar, Seng‐Kai Ong, Areeba Anwar, Naveed Ahmed Khan
Journal: Medicinal Research Reviews (2021)

Abstract Acanthamoeba is a genus of free‐living amoebae, pervasively found in the environment. Most of its pathogenic species are the causative agent of sight‐threatening Acanthamoeba keratitis and fatal granulomatous amoebic encephalitis. Despite the advancements in the field of chemotherapy, treating Acanthamoeba infections is still challenging due to incomplete knowledge of the complicated pathophysiology. In case of infection, the treatment regimen for the patients is often ineffective due to delayed diagnosis, poor specificity, and side‐effects. Besides the resistance of Acanthamoeba cysts to most of the drugs, the recurrence of infection further complicates the recovery. Thus, it is necessary to develop an effective treatment which can eradicate these rare, but serious infections. Based on various computational and in vitro studies, it has been established that the synthetic scaffolds such as heterocyclic compounds may act as potential drug leads for the development of antiamoebic drugs. In this review, we report different classes of synthetic compounds especially heterocyclic compounds which have shown promising results against Acanthamoeba . Moreover, the antiamoebic activities of synthetic compounds with their possible mode of actions against Acanthamoeba , have been summarized and discussed in this review.
A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction
Authors: Jinhui Gao, Keiran A. Logan, Heather Nesbitt, Bridgeen Callan, Thomas McKaig, Mark Taylor, Mark Love, Anthony P. McHale, Darren M. Griffith, John F. Callan
Journal: Journal of Controlled Release (2021)
Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis
Authors: Olivier Tabone, Raman Verma, Akul Singhania, Probir Chakravarty, William J. Branchett, Christine M. Graham, Jo Lee, Tran Trang, Frederic Reynier, Philippe Leissner, Karine Kaiser, Marc Rodrigue, Gerrit Woltmann, Pranabashis Haldar, Anne O’Garra
Journal: The Journal of Experimental Medicine (2021)

Blood transcriptomics have revealed major characteristics of the immune response in active TB, but the signature early after infection is unknown. In a unique clinically and temporally well-defined cohort of household contacts of active TB patients that progressed to TB, we define minimal changes in gene expression in incipient TB increasing in subclinical and clinical TB. While increasing with time, changes in gene expression were highest at 30 d before diagnosis, with heterogeneity in the response in household TB contacts and in a published cohort of TB progressors as they progressed to TB, at a bulk cohort level and in individual progressors. Blood signatures from patients before and during anti-TB treatment robustly monitored the treatment response distinguishing early and late responders. Blood transcriptomics thus reveal the evolution and resolution of the immune response in TB, which may help in clinical management of the disease.
Endoscopic extraction of a gastric submucosal foreign body after precise location with endoscopic ultrasound combined with endoscopic submucosal dissection
Authors: Yuqing Mao, Bin Hu, Xiaoyuan Gong, Shengzheng Luo, Youchen Xia, Chenghong Fu, Baiwen Li
Journal: Endoscopy (2021)

A 34-year-old woman was referred to the emergency department of our hospital with persistent epigastric pain for 2 days. Abdominal computed tomography (CT) scanning showed an 18-mm high density shadow in the gastric antrum, consistent with suspected penetration of the gastric wall ([Fig. 1]). Gastroscopy however showed no obvious foreign body ([Fig. 2]). The patient was still suffering from abdominal pain. We speculated that a foreign body might have completely imbedded into the submucosa or even the gastric serosal layer, which would make it more difficult to detect. We therefore proceeded to endoscopic ultrasound (EUS) and found a cordlike hyperechoic shadow in the submucosa of the gastric antrum ([Fig. 3 a]). Because there was a risk of perforation if the foreign body was not removed in a timely fashion, a special endoscopic operation was immediately arranged for the patient.
Multifaceted roles of a bioengineered nanoreactor in repressing radiation-induced lung injury
Authors: Tao Liu, Qunfang Yang, Haiping Zheng, Honglin Jia, Yufeng He, Xuan Zhang, Junfeng Zheng, Yue Xi, Haigang Zhang, Renshan Sun, Xiaohong Chen, Wenjun Shan
Journal: Biomaterials (2021)
Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors
Authors: Ying Zhang, Tao Wang, Xiaojun Zhang, Winnie Deuther-Conrad, Hualong Fu, Mengchao Cui, Jinming Zhang, Peter Brust, Yiyun Huang, Hongmei Jia
Journal: Acta Pharmaceutica Sinica B (2021)

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ2) receptor ligands. Two ligands with high σ2 receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand [18F]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective σ2 receptor ligand CM398 led to significant reductions in both brain uptake (29%-54%) and brain-to-blood ratio (60%-88%) of the radioligand in a dose-dependent manner, indicating high and saturable specific binding of [18F]9 to σ2 receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [18F]9 in the brain that is consistent with the distribution pattern of σ2 receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [18F]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [18F]9 as the first highly specific and promising imaging agent for σ2 receptors in the brain.
Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study
Authors: Martin Hutchings, Rogier Mous, Michael Roost Clausen, Peter Johnson, Kim M Linton, Martine E D Chamuleau, David John Lewis, Anna Sureda Balari, David Cunningham, Roberto S Oliveri, Brian Elliott, Dena DeMarco, Ada Azaryan, Christopher Chiu, Tommy Li, Kuo-mei Chen, Tahamtan Ahmadi, Pieternella J Lugtenburg
Journal: The Lancet (2021)
Texas’s new abortion law is an attack on medical practice and women’s rights, say doctors
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

Texas law Senate Bill 8 (SB 8) went into effect on 1 September, effectively banning abortions in the state. In a midnight ruling on 1 September, the US Supreme Court refused to block it despite appeals from reproductive rights organisations, civil rights organisations, and clinics.

Abortion until fetal viability has been constitutionally protected since the 1973 Supreme Court Roe v Wade decision. The court has allowed states to require restrictions such as waiting periods, counselling, and ultrasounds.

The Texas law bans abortions after six weeks of pregnancy if fetal cardiac activity is detected. That is before many women know they are pregnant. There is no exception for rape or incest, although abortion in medical emergencies is permitted if documented in writing.

The ruling was immediately condemned by President Joe Biden, Vice President Kamala Harris, and medical organisations, who described it a direct attack on medical practice and women’s rights.

The Supreme Court 5-4 decision reflected its …
Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators
Authors: Maarten Fornerod, Jing Ma, Sanne Noort, Yu Liu, Michael P. Walsh, Lei Shi, Stephanie Nance, Yanling Liu, Yuanyuan Wang, Guangchun Song, Tamara Lamprecht, John Easton, Heather L. Mulder, Donald Yergeau, Jacquelyn Myers, Jennifer L. Kamens, Esther A. Obeng, Martina Pigazzi, Marie Jarosova, Charikleia Kelaidi, Sophia Polychronopoulou, Jatinder K. Lamba, Sharyn D. Baker, Jeffrey E. Rubnitz, Dirk Reinhardt, Marry M. van den Heuvel-Eibrink, Franco Locatelli, Henrik Hasle, Jeffery M. Klco, James R. Downing, Jinghui Zhang, Stanley Pounds, C. Michel Zwaan, Tanja A. Gruber
Journal: Blood Cancer Discovery (2021)

Abstract Genomic characterization of pediatric patients with acute myeloid leukemia (AML) has led to the discovery of somatic mutations with prognostic implications. Although gene-expression profiling can differentiate subsets of pediatric AML, its clinical utility in risk stratification remains limited. Here, we evaluate gene expression, pathogenic somatic mutations, and outcome in a cohort of 435 pediatric patients with a spectrum of pediatric myeloid-related acute leukemias for biological subtype discovery. This analysis revealed 63 patients with varying immunophenotypes that span a T-lineage and myeloid continuum designated as acute myeloid/T-lymphoblastic leukemia (AMTL). Within AMTL, two patient subgroups distinguished by FLT3-ITD and PRC2 mutations have different outcomes, demonstrating the impact of mutational composition on survival. Across the cohort, variability in outcomes of patients within isomutational subsets is influenced by transcriptional identity and the presence of a stem cell–like gene-expression signature. Integration of gene expression and somatic mutations leads to improved risk stratification. Significance: Immunophenotype and somatic mutations play a significant role in treatment approach and risk stratification of acute leukemia. We conducted an integrated genomic analysis of pediatric myeloid malignancies and found that a combination of genetic and transcriptional readouts was superior to immunophenotype and genomic mutations in identifying biological subtypes and predicting outcomes. This article is highlighted in the In This Issue feature, p. 549
Abstract 15999: Impact and Cost-Effectiveness of Long-Term Intermittent Photoplethysmography Monitoring in Stroke Patients
Authors: Tine Proesmans, Lien Desteghe, Dana Berti, Dieter Nuyens, Dries De Cock, Veerle Soufflet, Pieter Vandervoort, Valerie Storms, Paul Dendale, Johan Vijgen
Journal: Circulation (2018)

Introduction: Conventional monitoring strategies are not sufficiently sensitive to detect underlying atrial fibrillation in stroke patients. Although it is understood that prolonged monitoring can ...
Magnetic resonance elastography plus Fibrosis‐4 versus FibroScan–aspartate aminotransferase in detection of candidates for pharmacological treatment of NASH‐related fibrosis
Authors: Nobuharu Tamaki, Kento Imajo, Suzanne Sharpton, Jinho Jung, Nobuyoshi Kawamura, Masato Yoneda, Mark A. Valasek, Cynthia Behling, Claude B. Sirlin, Atsushi Nakajima, Rohit Loomba
Journal: Hepatology (2021)

Patients with NAFLD with significant hepatic fibrosis (Stage ≥ 2) are at increased risk of liver-related morbidity and are candidates for pharmacologic therapies. In this study, we compared the diagnostic accuracy of MEFIB (the combination of magnetic resonance elastography [MRE] and Fibrosis-4 [FIB-4]) and FAST (FibroScan-aspartate aminotransferase; combined liver stiffness measurement by vibration-controlled transient elastography, controlled attenuation parameter, and aspartate aminotransferase) for detecting significant fibrosis.This prospective cohort study included 234 consecutive patients with NAFLD who underwent liver biopsy, MRE, and FibroScan at the University of California San Diego (UCSD cohort) and an independent cohort (N = 314) from Yokohama City University, Japan. The primary outcome was diagnostic accuracy for significant fibrosis (Stage ≥ 2). The proportions of significant fibrosis in the UCSD and Yokohama cohorts were 29.5% and 66.2%, respectively. Area under the receiver operating characteristic curve (95% CI) of MEFIB (0.860 [0.81-0.91]) was significantly higher than that of FAST (0.757 [0.69-0.82]) in the UCSD cohort (p = 0.005), with consistent results in the Yokohama cohort (AUROC, 0.899 [MEFIB] versus 0.724 [FAST]; p < 0.001). When used as the rule-in criteria (MEFIB, MRE ≥ 3.3 kPa and FIB-4 ≥ 1.6; FAST ≥ 0.67), the positive predictive value for significant fibrosis was 91.2%-96.0% for MEFIB and 74.2%-89.2% for FAST. When used as the rule-out criteria (MEFIB, MRE < 3.3 kPa and FIB-4 < 1.6; FAST ≤ 0.35), the negative predictive value for significant fibrosis was 85.6%-92.8% for MEFIB and 57.8%-88.3% for FAST.MEFIB has higher diagnostic accuracy than FAST for significant fibrosis in NAFLD, and our results support the utility of a two-step strategy for detecting significant fibrosis in NAFLD.
European Association of Urology Guidelines on Non–muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ)
Authors: Marko Babjuk, Maximilian Burger, Otakar Capoun, Daniel Cohen, Eva M. Compérat, José L. Dominguez Escrig, Paolo Gontero, Fredrik Liedberg, Alexandra Masson-Lecomte, A. Hugh Mostafid, Joan Palou, Bas W.G. van Rhijn, Morgan Rouprêt, Shahrokh F. Shariat, Thomas Seisen, Viktor Soukup, Richard J. Sylvester
Journal: European Urology (2021)
David Michael Roberts
Authors: Rhys Watkins
Journal: BMJ (2021)

David Michael Roberts (“Mike”) died after a long illness bravely fought, at the age of 62. He was a warm, loving husband, father, stepfather, brother, and son.

He was born in St Asaph and brought up in Buckley in north Wales. He attended senior school at Elfed High School, Buckley, where he was head boy and from which he became the first to attend university.

He studied medicine at Bristol University and subsequently continued …