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Reframing pain: the power of individual and societal factors to enhance pain treatment.
The effectiveness of analgesics can be increased if synergistic behavioural, psychological, and pharmacological interventions are provided within a supportive environment.
Self-Administration of Aspirin After Chest Pain for the Prevention of Premature Cardiovascular Mortality in the United States: A Population-Based Analysis.
BACKGROUND: Aspirin, an effective, low-cost pharmaceutical, can significantly reduce mortality if used promptly after acute myocardial infarction (AMI). However, many AMI survivors do not receive aspirin within a few hours of symptom onset. Our aim was to quantify the mortality benefit of self-administering aspirin at chest pain onset, considering the increased risk of bleeding and costs associated with widespread use. METHODS AND RESULTS: We developed a population simulation model to determine the impact of self-administering 325 mg aspirin within 4 hours of severe chest pain onset. We created a synthetic cohort of adults ≥ 40 years old experiencing severe chest pain using 2019 US population estimates, AMI incidence, and sensitivity/specificity of chest pain for AMI. The number of annual deaths delayed was estimated using evidence from a large, randomized trial. We also estimated the years of life saved (YOLS), costs, and cost per YOLS. Initiating aspirin within 4 hours of severe chest pain onset delayed 13 016 (95% CI, 11 643-14 574) deaths annually, after accounting for deaths due to bleeding (963; 926-1003). This translated to an estimated 166 309 YOLS (149391-185 505) at the cost of $643 235 (633 944-653 010) per year, leading to a cost-effectiveness ratio of $3.70 (3.32-4.12) per YOLS. CONCLUSIONS: For
Etiologically Based Functional Taxonomy of the Preterm Birth Syndrome.
Preterm birth (PTB) is a complex syndrome traditionally defined by a single parameter, namely, gestational age at birth (ie, ˂37 weeks). This approach has limitations for clinical usefulness and may explain the lack of progress in identifying cause-specific effective interventions. The authors offer a framework for a functional taxonomy of PTB based on (1) conceptual principles established a priori; (2) known etiologic factors; (3) specific, prospectively identified obstetric and neonatal clinical phenotypes; and (4) postnatal follow-up of growth and development up to 2 years of age. This taxonomy includes maternal, placental, and fetal conditions routinely recorded in data collection systems.
Does BCR/ABL1 positive Acute Myeloid Leukaemia Exist?
SummaryThe BCR/ABL1 fusion gene, usually carried by the Philadelphia chromosome (Ph) resulting from t(9;22)(q34;q11) or variants, is pathognomonic for chronic myeloid leukaemia (CML). It is also occasionally found in acute lymphoblastic leukaemia (ALL) mostly in adults and rarely in de novo acute myeloid leukaemia (AML). Array Comparative Genomic Hybridization (aCGH) was used to study six Ph(+)AML, three bi‐lineage and four Ph(+)ALL searching for specific genomic profiles. Surprisingly, loss of the IKZF1 and/or CDKN2A genes, the hallmark of Ph(+)ALL, were recurrent findings in Ph(+)AML and accompanied cryptic deletions within the immunoglobulin and T cell receptor genes. The latter two losses have been shown to be part of ‘hot spot’ genome imbalances associated with BCR/ABL1 positive pre‐B lymphoid phenotype in CML and Ph(+)ALL. We applied Significance Analysis of Microarrays (SAM) to data from the ‘hot spot’ regions to the Ph(+)AML and a further 40 BCR/ABL1(+) samples looking for differentiating features. After exclusion of the most dominant markers, SAM identified aberrations unique to de novo Ph(+)AML that involved relevant genes. While the biological and clinical significance of this specific genome signature remains to be uncovered, the unique loss within the immunoglobulin genes provides a simple test to enable the differentiation of clinically similar de novo Ph(+) AML and myeloid blast crisis of CML.
Antigen receptor gene rearrangements reflect on the heterogeneity of adult Acute Lymphoblastic Leukaemia (ALL) with implications of cell‐origin of ALL subgroups – a UKALLXII study
SummaryCytogenetic and molecular investigations of Acute Lymphoblastic Leukaemia (ALL) have identified the existence of distinct clinical subgroups. Molecular monitoring of clonal Immunoglobulin and T cell receptor (IG/TR) gene rearrangements has become an important tool in stratification of therapy of ALL. In order to determine whether certain features of the patient‐specific rearrangements could hold further prognostic clues or provide information on the cell of origin of ALL, a comprehensive analysis of structural and biological features (V gene usage, coding frame and mutational status and complementarity‐determining region ‐III length) of 473 IG/TR rearrangements identified in 229 adults with ALL was carried out. Distinct variable‐gene usage profiles were identified between ALL subgroups, particularly for patients positive for BCR‐ABL1 compared to MLL‐AFF1 positive leukaemias; suggesting that the former is derived from a more mature B progenitor. Interestingly, occurrence of TRGV1‐TRGV8 was prognostic for better event‐free survival (31% at 4 years with vs. 0% at 4 years without, P = 0·05). The heterogeneity in clinical outcome is suggested by the basic molecular processes of antigen receptor gene rearrangements as shown in this work.
Minimal residual disease is a significant predictor of treatment failure in non T‐lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993
SummaryThe predictive value of molecular minimal residual disease (MRD) monitoring using polymerase chain reaction amplification of clone‐specific immunoglobulin or T‐cell Receptor rearrangements was analysed in 161 patients with non T‐lineage Philadelphia‐negative acute lymphoblastic leukaemia (ALL) participating in the UK arm of the international ALL trial UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993. MRD positivity (≥10−4) in patients treated with chemotherapy alone was associated with significantly shorter relapse‐free survival (RFS) at several time‐points during the first year of therapy. MRD status best discriminated outcome after phase 2 induction, when the relative risk of relapse was 8·95 (2·85–28·09)‐fold higher in MRD‐positive (≥10−4) patients and the 5‐year RFS 15% [95% confidence interval (CI) 0–40%] compared to 71% (56–85%) in MRD‐negative (<10−4) patients (P = 0·0002) When MRD was detected prior to autologous stem cell transplantation (SCT), a significantly higher rate of treatment failure was observed [5‐year RFS 25% (CI 0–55%) vs. 77% (95% CI 54–100%) in MRD‐negative/<10−4, P = 0·01] whereas in recipients of allogeneic‐SCT in first complete remission, MRD positivity pre‐transplant did not adversely affect outcome. These data provide a rationale for introducing MRD‐based risk stratification in future studies for the delineation of those at significant risk of treatment failure in whom intensification of therapy should be evaluated.
Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology
The distinct nature of acute lymphoblastic leukemia (ALL) in adults, evidenced by inferior treatment outcome and different genetic landscape, mandates specific studies of disease-initiating mechanisms. In this study, we used NOD/LtSz-scid IL2Rγ nullc (NSG) mouse xenotransplantation approaches to elucidate leukemia-initiating cell (LIC) biology in primary adult precursor B (pre-B) ALL to optimize disease modeling. In contrast with xenografting studies of pediatric ALL, we found that modification of the NSG host environment using preconditioning total body irradiation (TBI) was indispensable for efficient engraftment of adult non-t(4;11) pre-B ALL, whereas t(4;11) pre-B ALL was successfully reconstituted without this adaptation. Furthermore, TBI-based xenotransplantation of non-t(4;11) pre-B ALL enabled detection of a high frequency of LICs (<1:6900) and permitted frank leukemic engraftment from a remission sample containing drugresistant minimal residual disease. Investigation of TBI-sensitive stromal-derived factor-1/chemokine receptor type 4 signaling revealed greater functional dependence of non-t(4;11) pre-B ALL on this niche-based interaction, providing a possible basis for the differential engraftment behavior. Thus, our studies establish the optimal conditions for experimental modeling of human adult pre-B ALL and demonstrate the critical protumorogenic role of microenvironment-derived SDF-1 in regulating adult pre-B LIC activity that may present a therapeutic opportunity. © 2014 by The American Society of Hematology.
Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1
Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10−3 and 36/67 (53%) and 53/67 (79%) at 10−4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.
Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1 (Leukemia, (2019), 33, 8, (1910-1922), 10.1038/s41375-019-0413-0)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Attenuated, oncolytic, but not wild-type measles virus infection has pleiotropic effects on human neutrophil function
We previously showed that neutrophils play a role in regression of human tumor xenografts in immunodeficient mice following oncolytic vaccine measles virus (MV-Vac) treatment. In this study, we sought, using normal human neutrophils, to identify potential neutrophil-mediated mechanisms for the attenuated MV-Vac induced effects seen in vivo, by comparison with those consequent on wild-type (WT-MV) infection. Both MV-Vac and WT-MV infected and replicated within neutrophils, despite lack of SLAM expression. In both cases, neutrophils survived longer ex vivo postinfection. Furthermore, MV-Vac (but not WT-MV) infection activated neutrophils and stimulated secretion of several specific antitumor cytokines (IL-8, TNF-α, MCP-1, and IFN-α) via induction of de novo RNA and protein synthesis. In addition, MV-Vac (but not WT-MV) infection caused TRAIL secretion in the absence of de novo synthesis by triggering release of prefabricated TRAIL, via a direct effect upon degranulation. The differences between the outcome of infection by MV-Vac and WT-MV were not entirely explained by differential infection and replication of the viruses within neutrophils. To our knowledge, this is the first demonstration of potential mechanisms of oncolytic activity of an attenuated MV as compared with its WT parent. Furthermore, our study suggests that neutrophils have an important role to play in the antitumor effects of oncolytic MV. Copyright © 2012 by The American Association of Immunologists, Inc.
Differential cytopathology and kinetics of measles oncolysis in two primary B-cell malignancies provides mechanistic insights
Clinical trials using vaccine measles virus (MV) as anticancer therapy are already underway. We compared the oncolytic potential of MV in two B-cell malignancies; adult acute lymphoblastic leukemia (ALL, an aggressive leukemia) and chronic lymphocytic leukemia (CLL, an indolent leukemia overexpressing Bcl-2) using patient-derived material. In vitro, distinct cytopathological effects were observed between MV-infected primary ALL and CLL cells, with large multinucleated syncytia forming in ALL cultures compared to minimal cell-to-cell fusion in infected CLL cells. Cell viability and immunoblotting studies confirmed rapid cell death in MV-infected ALL cultures and slower MV oncolysis of CLL cells. In cell lines, overexpression of Bcl-2 diminished MV-induced cell death providing a possible mechanism for the slower kinetic of MV oncolysis in CLL. In vivo, intratumoral MV treatment of established subcutaneous ALL xenografts had striking antitumor activity leading to complete resolution of all tumors. The antitumor activity of MV was also evident in disseminated ALL xenograft models. In summary, both ALL and CLL are targets for MV-mediated lysis albeit with different kinetics. The marked sensitivity of both primary ALL cells and ALL xenografts to MV oncolysis highlights the tremendous potential of MV as a novel replicating-virus therapy for adult ALL. © The American Society of Gene &Cell Therapy.
Detection of non-cardiac fetal abnormalities by ultrasound at 11-14 weeks: systematic review and meta-analysis.
OBJECTIVES: To assess diagnostic accuracy of 2D ultrasound at 11-14 weeks gestation as a screening test for individual fetal anomalies and identify screening factors impacting detection. METHODS: Systematic review and meta-analysis, developed and registered with PROSPERO (CRD42018111781). MEDLINE, EMBASE, Web of Science Core Collection and The Cochrane Library) were searched for studies evaluating the diagnostic accuracy of screening for 16 pre-specified, non-cardiac, congenital anomalies considered to be of interest to the early anomaly scan. We included prospective and retrospective studies from any healthcare setting and low risk, mixed risk and unselected populations. The reference standard was the detection of an anomaly on postnatal or post-mortem examination. Data were extracted to populate 2 x 2 tables and meta-analysis (random-effects model) undertaken to determine the diagnostic accuracy of screening for the pre-specified anomalies (individually and as a composite). Secondary analyses were performed to determine the impact of (1) imaging protocol (2) ultrasound modality (3) publication year and (4) index of sonographer suspicion at time of scan. Post-hoc secondary analysis was conducted to assess performance for studies from 2010. Risk of bias and quality assessment was undertaken for included studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). RESULTS: From 5684 citations, 202 papers were identified as eligible and reviewed, resulting in the inclusion of 526,322 fetuses (52 studies) of which 2,399 were affected by one or more of the 16 anomalies. Individual anomalies were not equally amenable to detection on first trimester ultrasound ranging from high (>80%) detection rates for severe conditions including acrania (98%), gastroschisis (96%) and exomphalos (95%) and holoprosencephaly (88%); they were lower for open spina bifida (69%), lower urinary tract obstruction (66%) lethal skeletal dysplasias (57%) and limb reduction defects (50%) and below 50% for facial clefts (43%), polydactyly (40%) and congenital diaphragmatic hernia (38). Conditions with low (<30%) detection rates included bilateral renal agenesis (25%), closed spina bifida (21%), isolated cleft lip only (14%) and talipes (11%). Specificity was >99% for all anomalies. Secondary analysis showed improvement of detection with publication year, and that the use of imaging protocols had a statistically significant impact on screening performance (p<0.0001). CONCLUSIONS: Accurate detection of congenital anomalies using first trimester ultrasound is feasible. In this study we have determined screening characteristics for individual anomalies and have shown that detection rates and false positive rates are dependent on the type of anomaly. The use of a standardised protocol allows diagnostic performance to be maximised, and this particularly enhances screening performance for the detection of spina bifida, facial clefts and limb reduction defects. Highlighting the types of anomalies amenable to diagnosis and determining favourable screening test factors can support the development of first-trimester anomaly screening programs. This article is protected by copyright. All rights reserved.
MicroRNA analysis of medium/large placenta extracellular vesicles in normal and preeclampsia pregnancies
BackgroundPreeclampsia (PE) is a hypertensive disorder of pregnancy, affecting 2%–8% of pregnancies worldwide, and is the leading cause of adverse maternal and fetal outcomes. The disease is characterized by oxidative and cellular stress and widespread endothelial dysfunction. While the precise mechanisms are not entirely understood, the pathogenesis of PE is closely linked to placental dysfunction and, to some extent, syncytiotrophoblast extracellular vesicle release (STB-EVs). These vesicles can be divided into the less well-studied medium/large EVs (220–1,000 nm) released in response to stress and small EVs (<220 nm) released as a component of intercellular communication. The previously described production of m/lSTB-EVs in response to cellular stress combined with the overwhelming occurrence of cellular and oxidative stress in PE prompted us to evaluate the microRNAome of PE m/lSTB-EVs. We hypothesized that the microRNAome profile of m/lSTB-EVs is different in PE compared to normal pregnancy (NP), which might permit the identification of potential circulating biomarkers not previously described in PE.Methods/study designWe performed small RNA sequencing on medium/large STB-EVs isolated from PE and NP placentae using dual-lobe ex vivo perfusion. The sequencing data was bioinformatically analyzed to identify differentially regulated microRNAs. Identified microRNAs were validated with quantitative PCR analysis. We completed our analysis by performing an in-silico prediction of STB-EV mechanistic pathways.ResultsWe identified significant differences between PE and NP in the STB-EVs micro ribonucleic acid (microRNA) profiles. We verified the differential expression of hsa-miR-193b-5p, hsa-miR-324-5p, hsa-miR-652-3p, hsa-miR-3196, hsa-miR-9-5p, hsa-miR-421, and hsa-miR-210-3p in the medium/large STB-EVs. We also confirmed the differential abundance of hsa-miR-9-5p in maternal serum extracellular vesicles (S EVs). In addition, we integrated the results of these microRNAs into the previously published messenger RNA (mRNA) data to better understand the relationship between these biomolecules.ConclusionsWe identified a differentially regulated micro-RNA, hsa-miR-9-5p, that may have biomarker potential and uncovered mechanistic pathways that may be important in the pathophysiology of PE.
Predicting risk of endometrial failure: a biomarker signature that identifies a novel disruption independent of endometrial timing in patients undergoing hormonal replacement cycles.
OBJECTIVE: To propose a new gene expression signature that identifies endometrial disruptions independent of endometrial luteal phase timing and predicts if patients are at risk of endometrial failure. DESIGN: Multicentric, prospective study. SETTING: Reproductive medicine research department in a public hospital affiliated with private fertility clinics and a reproductive genetics laboratory. PATIENTS: Caucasian women (n = 281; 39.4 ± 4.8 years old with a body mass index of 22.9 ± 3.5 kg/m2) undergoing hormone replacement therapy between July 2018 and July 2021. Endometrial samples from 217 patients met RNA quality criteria for signature discovery and analysis. INTERVENTION(S): Endometrial biopsies collected in the mid-secretory phase. MAIN OUTCOME MEASURE(S): Endometrial luteal phase timing-corrected expression of 404 genes and reproductive outcomes of the first single embryo transfer (SET) after biopsy collection to identify prognostic biomarkers of endometrial failure. RESULTS: Removal of endometrial timing variation from gene expression data allowed patients to be stratified into poor (n = 137) or good (n = 49) endometrial prognosis groups on the basis of their clinical and transcriptomic profiles. Significant differences were found between endometrial prognosis groups in terms of reproductive rates: pregnancy (44.6% vs. 79.6%), live birth (25.6% vs. 77.6%), clinical miscarriage (22.2% vs. 2.6%), and biochemical miscarriage (20.4% vs. 0%). The relative risk of endometrial failure for patients predicted as a poor endometrial prognosis was 3.3 times higher than those with a good prognosis. The differences in gene expression between both profiles were proposed as a biomarker, coined the endometrial failure risk (EFR) signature. Poor prognosis profiles were characterized by 59 upregulated and 63 downregulated genes mainly involved in regulation (17.0%), metabolism (8.4%), immune response, and inflammation (7.8%). This EFR signature had a median accuracy of 0.92 (min = 0.88, max = 0.94), median sensitivity of 0.96 (min = 0.91, max = 0.98), and median specificity of 0.84 (min = 0.77, max = 0.88), positioning itself as a promising biomarker for endometrial evaluation. CONCLUSION(S): The EFR signature revealed a novel endometrial disruption, independent of endometrial luteal phase timing, present in 73.7% of patients. This EFR signature stratified patients into 2 significantly distinct and clinically relevant prognosis profiles providing opportunities for personalized therapy. Nevertheless, further validations are needed before implementing this gene signature as an artificial intelligence (AI)-based tool to reduce the risk of patients experiencing endometrial failure.
Reducing stigma and improving access to care for people with mental health conditions in the community: protocol for a multi-site feasibility intervention study (Indigo-Local).
BACKGROUND: Stigma and discrimination towards people with mental health conditions by their communities are common worldwide. This can result in a range of negative outcomes for affected persons, including poor access to health care. However, evidence is still patchy from low- and middle-income countries (LMICs) on affordable, community-based interventions to reduce mental health-related stigma and to improve access to mental health care. METHODS: This study aims to conduct a feasibility (proof-of-principle) pilot study that involves developing, implementing and evaluating a community-based, multi-component, public awareness-raising intervention (titled Indigo-Local), designed to reduce stigma and discrimination and to increase referrals of people with mental health conditions for assessment and treatment. It is being piloted in five LMICs - China, Ethiopia, India, Nepal and Tunisia - and includes several key components: a stakeholder group workshop; a stepped training programme (using a 'Training of Trainers' approach) of community health workers (or similar cadres of workers) and service users that includes repeated supervision and booster sessions; awareness-raising activities in the community; and a media campaign. Social contact and service user involvement are instrumental to all components. The intervention is being evaluated through a mixed-methods pre-post study design that involves quantitative assessment of stigma outcomes measuring knowledge, attitudes and (discriminatory) behaviour; quantitative evaluation of mental health service utilization rates (where feasible in sites); qualitative exploration of the potential effectiveness and impact of the Indigo-Local intervention; a process evaluation; implementation evaluation; and an evaluation of implementation costs. DISCUSSION: The outcome of this study will be contextually adapted, evidence-based interventions to reduce mental health-related stigma in local communities in five LMICs to achieve improved access to healthcare. We will have replicable models of how to involve people with lived experience as an integral part of the intervention and will produce knowledge of how intervention content and implementation strategies vary across settings. The interventions and their delivery will be refined to be acceptable, feasible and ready for larger-scale implementation and evaluation. This study thereby has the potential to make an important contribution to the evidence base on what works to reduce mental health-related stigma and discrimination and improve access to health care.
Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).
STUDY QUESTION: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P