tbuckley/cabot-search huggingface dataset:
Culturally tailored therapeutic interventions for people affected by dementia: a systematic review and new conceptual model
Authors: Tiffeny James, Naaheed Mukadam, Andrew Sommerlad, Stefanny Guerra Ceballos, Gill Livingston
Journal: The Lancet Healthy Longevity (2021)

Most people with dementia live in low and middle-income countries (LMICs) and there is an increased dementia prevalence in some minority ethnic groups in high-income countries. However, most interventions are devised for majority populations in high-income countries. We systematically searched 11 electronic databases for culturally tailored interventions for people with dementia and their family carers in LMICs and minority ethnic groups, without limit on language or date. 23 of 22 221 studies fulfilled inclusion criteria. Interventions adapted peripheral intervention components by, for example, translation and reducing the stigma of psychological therapy by emphasising physical illness and learning. Core therapeutic components were not changed. We found evidence-based, multicomponent interventions adapted for Latinx carers were acceptable, feasible, and effective in the USA and Columbia. Interventions developed for carers in India were effective there but not in other LMICs. Culturally adapted cognitive stimulation therapy was acceptable and effective for people with dementia in sub-Saharan Africa. We propose a new conceptual model from our findings to aid implementation of culturally appropriate treatments for people affected by dementia in LMICs and minority ethnic groups. Evidence-based interventions need cultural adaptation for different settings with therapeutic components retained. If they are acceptable, feasible, and remain effective then full effectiveness trials are unnecessary.
Modulation of the RANK/RANKL/OPG system and FOXP3+ regulatory T cells in the tumor microenvironment of noninvasive bladder cancer after intravesical oncotherad immunotherapy associated with platelet-rich plasma.
Authors: Bianca Ribeiro de Souza Sasaki, Ianny Brum Reis, Gabriela Oliveira, Nelson Duran, Wagner José Fávaro
Journal: Journal of Clinical Oncology (2021)

462 Background: The activity of the receptor activator of nuclear factor-kβ RANK/RANKL in cancer cells has been correlated with tumor progression and poor prognosis in solid tumors including bladder cancer. Regulatory T cells (Tregs), often identified by FOXP3 biomarker, suppress the anti-tumor response and allow immune tolerance through suppression of T cells. Immunomodulator OncoTherad is an inorganic phosphate nanocomplex associated with glycosidic protein, developed by the University of Campinas/Brazil, with antitumor effects. Previous reports have demonstrated immune activation and antitumor effects of Platelet Rich Plasma (PRP). We evaluated the effects of OncoTherad associated with PRP in the RANK/RANKL system and Tregs in a mouse model of non-muscle invasive bladder cancer (NMIBC). Methods: C57BL/6J mice were assigned to groups (n = 42): Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 consecutive weeks after induction. Results: After NMIBC induction, all animals in the Cancer group showed flat carcinoma in situ (pTis) and both percentages of RANK, RANKL, OPG, and FOXP3 positive cells and the intensity of immunoreaction for these antigens were significantly higher in comparison with healthy animals. In addition to ensuring this NMIBC model, these results indicated the involvement of RANK/RANKL in urothelial carcinogenesis and the presence of Tregs in a suppressed immune tumor microenvironment. Mice treated with PRP only showed a 28.6% rate of tumor progression inhibition (TPI) and exhibited papillary urothelial carcinoma (pTa) and pTis. In this group, the intensity of the RANKL and FOXP3 immunoreaction was weaker when compared to the Cancer group. Thus, PRP showed immunomodulatory effects, reducing Tregs that are sources of RANKL. Oncotherad immunotherapy led to an TPI of 85.7%, and benign flat hyperplasia was the most frequent diagnosis. Oncotherad reduced the total RANK and RANKL immunoreactivities and decreased the intensity of RANKL immunostaining in comparison to the Cancer. In the OncoTherad+PRP 10 mg/ml or 20 mg/ml group, TPI was 71.4%, with a predominance of non-malignant lesions such as flat hyperplasia, low-grade intraurothelial neoplasia, and reactive atypia. Treatments with Oncotherad and Oncotherad plus PRP decreased the percentage of FOXP3+ cells and reduced the intensity of FOXP3 immunoreaction compared to the Cancer and PRP groups. Conclusions: The tumor inhibition obtained with Oncotherad plus PRP was related to the alteration of the immune profile of the tumor microenvironment by decreasing RANK/RANKL expression and Tregs, resulting in an effective immune response against the tumor.
Letter by Loomba et al Regarding Article, “Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic”
Authors: Rohit S. Loomba, Enrique G. Villarreal, Saul Flores
Journal: Circulation (2021)

We read with great interest the article by Belhadjer and colleagues 1 regarding multisystem inflammatory syndrome in children (MIS-C) that has been associated with pandemic coronavirus disease 2019 .They describe the incidence of acute cardiac decompensation in these children and the response to intravenous immunoglobulin.The inflammatory state being noted in children in relation to COVID-19 is likely Kawasaki disease (KD) with macrophage activation syndrome (MAS).The authors discuss the similarities and differences in what they refer to as MIS-C with the following differences noted: median age greater in their cohort and left ventricular dysfunction more prevalent with MIS-C.However, are these differences truly enough to coin a new clinical entity? 1 Certainly, KD has been described in older children, particularly in its atypical form.Some rare cases have even been described in adults. 2 Left ventricular dysfunction is said to be more prevalent with MIS-C as well, but perhaps this is because of the greater inflammation seen in COVID-19 and the resulting KD.The reconciliation here seems to be MAS, a condition in which macrophages are inappropriately activated, leading to a self-propagating cycle of increasing inflammation.KD has been demonstrated to be associated with MAS, although less frequently than juvenile idiopathic arthritis.In the setting of KD-induced MAS, there is evidence of a hyperinflammatory condition demonstrated by high levels of serum ferritin, a high C-reactive protein, a high procalcitonin, and elevated interleukin levels, among other findings.The incidence of cardiac dysfunction and mortality is higher in these patients when compared with children with KD without MAS. 3D has been associated with viral illnesses, including previous pandemic viruses. 4dditionally, KD has been associated with MAS, a hyperinflammatory state that is highly similar to what is being described here as MIS-C.So why do the authors feel this should be treated as a new clinical entity?Trying to make this a new clinical entity could just lead to delay in diagnosis and management of this condition.This possibility has already been noted, anecdotally, by experiences shared on electronic listservs.Prompt intravenous immunoglobulin treatment seems to be beneficial, as do steroids, just as with KD-induced MAS.Similar presentation and response to treatment would seem to indicate that this is KD with MAS.Referring to it as such may prevent delays in clinical recognition and management.
Clinical trial transparency in the Americas: the need to coordinate regulatory spheres
Journal: BMJ (2018)

Notwithstanding widespread support for clinical trials data transparency, its implementation faces significant challenges. Transparency of pharmaceutical data has been hampered by some industry resistance, by the qualification of such data as commercially confidential information, and by inconsistencies in overlapping regulatory spheres. This article discusses key developments related to registering pharmaceutical clinical trials and sharing data submitted to drug regulatory agencies in the Americas. Then, reports from three countries (Argentina, Brazil, Canada) are discussed to show what transparency measures they have implemented and what challenges remain. These short case studies shed light on various initiatives, positive outcomes, and persistent challenges — even in countries with relatively advanced research, pharmaceutical product production, and regulatory sectors. They further highlight how different jurisdictions address the tension between public-health-oriented transparency initiatives and the tendency to treat data as commercial goods. Finally, the paper suggests that research ethics review could play a role in moving forward with data transparency, but it puts forward that research ethics governance ought to be developed more coherently in order to ensure the public accountability of the governance system.
Fiona Caldicott: president of the Royal College of Psychiatrists and the first national data guardian, whose legacy includes the Caldicott principles and Caldicott guardians
Authors: Penny Warren
Journal: BMJ (2021)

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Photo: Lucy Caldicott

In November 2018 the Royal College of Psychiatrists honoured Fiona Caldicott with a lifetime achievement award. She was the college’s first female dean in 1990 and its first female president in 1993. She led many public bodies, and her name is enshrined in data protection: today patients’ confidential information is protected by the Caldicott principles, which are upheld by Caldicott guardians. Her skills in psychiatric medicine equipped her perfectly for this work. Her colleague Michael Sharpe said, “Fiona was a psychotherapist first and foremost. In all the organisations she participated in, she used her skills of listening, reflecting, and helping groups reach a conclusion.”

Fiona Soesan was born in Troon, Ayrshire, on 12 January 1941. Her parents, Joseph and Elizabeth, had moved there when Joseph (who later became a barrister) was working in munitions. In 1944 the family moved to Ilford in east London, and her sister, Judith, was born in 1946. Fiona won a local authority scholarship to the City of London School for Girls and rose to be head girl. …
Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B
Authors: Edward J. Gane, Hyung Joon Kim, Kumar Visvanathan, Yoon Jun Kim, Anh‐Hoa Nguyen, Jeffrey J. Wallin, Diana Y. Chen, Circe McDonald, Priyanka Arora, Susanna K. Tan, Anuj Gaggar, Stuart K. Roberts, Young‐Suk Lim
Journal: Hepatology (2021)

Background and Aims In patients with chronic hepatitis B (CHB) infection, activation of toll‐like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll‐like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. Approach and Results In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half‐life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose‐dependent increases in serum cytokines, including IL‐12p40 and IL‐1RA, which are important for the expansion and activity of multiple T‐ cell subsets and innate immunity. Conclusion Selgantolimod was safe and well‐tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
Clinical Course of Pregnancy and Long-Term Follow-Up After Delivery in Hypertrophic Cardiomyopathy
Authors: Maria Beatrice Musumeci, Paolo Spirito, Maria Rosa Conte, Rosa Lillo, Emmanuela Devoto, Pietro Francia, Domitilla Russo, Massimo Volpe, Luca Boni, Camillo Autore
Journal: Journal of the American College of Cardiology (2021)
Functional requirement for RGD and PKD domains of GPNMB in breast cancer metastasis
Authors: April Rose, Caterina Russo, Matthew Annis, Peter Siegel
Journal: Cancer Research (2008)

3681  The morbidity and mortality associated with breast cancer results primarily from the spread of cancer cells from the breast to secondary organs. Currently, there are very few available therapies that effectively target breast cancer metastases. Identification and characterization of the functional mediators of metastasis is critical to the development of targeted anti-metastatic therapies.  	We have recently identified GPNMB (Osteoactivin, DC-HIL, HGFIN) as a novel mediator of breast cancer metastasis to bone. Here, we show the GPNMB protein is detectable in a subset of human breast cancer cell lines, but undetectable in normal breast epithelial cells. Furthermore, GPNMB is highly expressed in in vivo selected, aggressively lung-metastatic breast cancer cells, and ectopic expression of this gene in 66cl4 mammary carcinoma cells is sufficient to promote primary tumor growth and spontaneous lung metastases in vivo. These results argue that GPNMB may function as a more general regulator of breast cancer metastasis. To further investigate the relevance of GPNMB expression in human breast cancer, we have analyzed the gene expression profiles from 3 independent datasets comprising 99, 118, and 295 human breast tumors. Kaplan-Meier analysis reveals significant correlations in each dataset, between increased GPNMB expression and shorter metastasis-free and overall survival times.  An increasing body of literature is emerging, linking high levels of GPNMB expression with progression of diverse cancer types. Indeed, a GPNMB-targeted, cytotoxin conjugated antibody (CR011 vc-MMAE) is currently being investigated in Phase I clinical trials as a therapy for patients with Stage III/IV melanoma. Despite these observations, very little known about the metastasis-promoting functions of this protein. To further our understanding of GPNMB-dependent pro-metastatic effects, we have generated mutations that disrupt specific domains within the protein. GPNMB is a type I transmembrane glycoprotein with an extracellular integrin recognition motif (RGD), a putative ligand binding domain (PKD), a single transmembrane domain and a short cytoplasmic tail. Our data show that GPNMB enhances the invasive capacity of breast cancer cells in a PKD-dependent manner and promotes adhesion to endothelium in an RGD dependent manner. Due to its role in promoting endothelial adhesion and invasion, we are currently developing a model to monitor GPNMB-dependent extravasation of breast cancer cells in vivo.  Together, these results offer mechanistic insight into the metastogenic roles of GPNMB, a molecule that is highly expressed in aggressive human breast cancers. Moreover, this data provides further rationale toward the pursuit of GPNMB-targeted therapies for breast cancer.
Glycemic Control and Use of High-risk Antihyperglycemic Agents Among Nursing Home Residents With Diabetes in Ontario, Canada
Authors: Iliana C. Lega, Michael A. Campitelli, Jeremy Matlow, Yingbo Na, Nathan M. Stall, Paula A. Rochon, Lorraine L. Lipscombe
Journal: JAMA Internal Medicine (2021)

This cohort study examines levels of glycemic control among nursing home residents with diabetes and compares rates of intensive glycemic control with high-risk antihyperglycemic agents across levels of cognitive impairment.
“Alongside-balloon-dilation” as a novel endoscopic bailout involving external cutting of an entrapped biliary self-expandable metal stent delivery system
Authors: Vincent Zimmer
Journal: Endoscopy (2021)

Placement of a biliary fully covered self-expandable metal stent (FCSEMS) as the mainstay treatment in pancreatic cancer is usually straightforward once guidewire passage has been achieved. However, entrapment of the deployed stent, mostly by diameter mismatch between the olive-shaped tip of the stent applicator system in cases of high-grade and tight strictures, may complicate the procedure [1]. In such situations it is prudent to pause a while and let the stent expand further or, as is my routine practice, to gently push forward the outer delivery catheter sheath, until full contact with the olive tip is re-established, followed by cautious withdrawal of the device without dislodging the stent. Among the very few rescue techniques in the literature, nasal re-outing of the system with later extraction and utilization of a dedicated low-profile angioplasty balloon has been reported. Here, another technique designated “alongside-balloon-dilation” is pioneered [2] [3].
MRI-guided fusion biopsy of the prostate resection bed among post-radical prostatectomy patients with rising PSA.
Authors: Cheyenne Williams, Nabila Khondakar, Michael Daneshvar, Luke P. O'Connor, Jillian Egan, Nitin Yerram, Alexis Rompre-Brodeur, Jeunice Owens-Walton, Maria Merino, Peter L. Choyke, Bradford Wood, Baris Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2021)

208 Background: Following treatment of prostate cancer with radical prostatectomy (RP), biochemical recurrence (BCR) can be detected with elevated PSA. This may be attributed to either cancer recurrence or retained benign prostatic gland tissue. Options for detecting malignancy after RP currently entail diagnostic imaging and biopsy with transrectal ultrasound (TRUS). TRUS alone has limited accuracy in detecting recurrence in the prostate bed. MRI fusion-guided biopsy (Fbx) may be a more accurate method of detecting post-RP local recurrence. We hypothesize that Fbx for diagnosing benign versus malignant recurrence in the prostate bed is feasible and produces clinically meaningful results. Methods: Our institutional database was queried for patients who received RP and demonstrated BCR between February 2015 and July 2020. All patients with evidence of prostate bed recurrence on mpMRI were included in this analysis. Cancer detection via mpMRI-guided fusion biopsy using the UroNav platform was evaluated and patient variables including final Gleason Grade group (GG), margin involvement, PSA at BCR, and prostate bed lesion size were analyzed with univariate logistic regression. Results: 40 patients (median age = 68) with BCR underwent post-RP mpMRI. 25/40 (62.5%) patients had MRI-visible lesions, and among those, 17/25 (68%) patients underwent Fbx of the prostate bed. 15/17 (88.2%) Fbxs detected prostate tissue (either benign or cancer), 11/17 (64.7%) contained cancer, and 4/17 (23.5%) contained benign prostate glands. Median cores per biopsy was 4 (IQR 4-6). Among the 83 cores obtained, 57 (68.6%) cores contained prostate gland tissue and 26 (31.3%) contained fibromuscular tissue. Of those 57 with gland tissue, 33 (57.9%) cores contained cancer, and 24 (42.1%) contained benign prostate tissue. Among patients with benign biopsies, none had further evidence of metastasis at median follow-up of 13.5 months after Fbx and 182 months after RP. On final RP pathology, 4 patients had GG1 disease, 4 had GG2, 4 had GG3, 2 had GG4, and 3 had GG5. 6/17 (35%) patients had positive RP margins. Median prostate bed lesion size was 1.3 cm (IQR 0.9-1.5). Prostate bed lesion size (cm) was the only variable significantly associated with cancer on Fbx (OR = 2.20, 95% CI:1.29-3.76, p = 0.011). Conclusions: mpMRI-Fbx is a feasible method for reliably targeting prostate bed lesions. With this technique, we found improved accuracy for biopsy-proven recurrence in the prostate bed. This technique will help direct treatment planning of salvage therapies among patients with detectable PSA post-RP. [Table: see text]
A Pragmatic, Randomized Clinical Trial of Gestational Diabetes Screening
Authors: Teresa A. Hillier, Kathryn L. Pedula, Keith K. Ogasawara, Kimberly K. Vesco, Caryn E.S. Oshiro, Suzanne L. Lubarsky, Jan Van Marter
Journal: New England Journal of Medicine (2021)

Gestational diabetes mellitus is common and is associated with an increased risk of adverse maternal and perinatal outcomes. Although experts recommend universal screening for gestational diabetes, consensus is lacking about which of two recommended screening approaches should be used.
DTFLOW: Inference and Visualization of Single-Cell Pseudotime Trajectory Using Diffusion Propagation
Authors: Jiangyong Wei, Tianshou Zhou, Xinan Zhang, Tianhai Tian
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract One of the major challenges in single-cell data analysis is the determination of cellular developmental trajectories using single-cell data. Although substantial studies have been conducted in recent years, more effective methods are still strongly needed to infer the developmental processes accurately. This work devises a new method, named DTFLOW, for determining the pseudo-temporal trajectories with multiple branches. DTFLOW consists of two major steps: a new method called Bhattacharyya kernel feature decomposition (BKFD) to reduce the data dimensions, and a novel approach named Reverse Searching on k-nearest neighbor graph (RSKG) to identify the multi-branching processes of cellular differentiation. In BKFD, we first establish a stationary distribution for each cell to represent the transition of cellular developmental states based on the random walk with restart algorithm, and then propose a new distance metric for calculating pseudotime of single cells by introducing the Bhattacharyya kernel matrix. The effectiveness of DTFLOW is rigorously examined by using four single-cell datasets. We compare the efficiency of DTFLOW with the published state-of-the-art methods. Simulation results suggest that DTFLOW has superior accuracy and strong robustness properties for constructing pseudotime trajectories. The Python source code of DTFLOW can be freely accessed at https://github.com/statway/DTFLOW.