Expanding PFAS Identification with Transformation Product Libraries: Nontargeted Analysis Reveals Biotransformation Products in Mice.

Per- and polyfluoroalkyl substances (PFAS) are widely used persistent synthetic chemicals that have been linked to adverse health effects. While the behavior of PFAS has been evaluated in the environment, our understanding of reaction products in mammalian systems is limited. This study identified biological PFAS transformation products and generated mass spectral libraries to facilitate an automated search and identification.

Improving event prediction using general practitioner clinical judgement in a digital risk stratification model: a pilot study.

Background: Numerous tools based on electronic health record (EHR) data that predict risk of unscheduled care and mortality exist. These are often criticised due to lack of external validation, potential for low predictive ability and the use of thresholds that can lead to large numbers being escalated for assessment that would not have an adverse outcome leading to unsuccessful active case management. Evidence supports the importance of clinical judgement in risk prediction particularly when ruling out disease.

A real-world comparison of commercial use axicabtagene ciloleucel and lisocabtagene maraleucel in large B-cell lymphoma.

Lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) are anti-CD19 CAR-T therapies approved for relapsed and refractory large B cell lymphoma (R/R LBCL); however there is currently no published data on liso-cel outside of clinical trials, nor any data comparing these therapies. In this retrospective analysis, we reviewed patients receiving liso-cel or axi-cel at a single institution in the third-line setting. From June 2021 - September 2022, 50 patients received axi-cel and 37 liso-cel.

Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

Purpose: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established.

Methods: We performed an international multicenter retrospective study of patients with RT who received CAR-T.

The molecular map of CLL and Richter's syndrome.

Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution. A selection of CLL driver genes have been functionally interrogated to yield novel insights into the biology of CLL.

Social needs screening in primary care: A tool in the fight for health equity?

Progress on addressing health inequalities is slow and in many places around the world the gap between the privileged and the disadvantaged is widening. This is driven largely by an unfair and unequal distribution of the social determinants of health. While upstream policy and agenda commitment is needed to improve social determinants of health at a population level, healthcare also has a role.

DLBCL arising from indolent lymphomas: How are they different?

Transformation to diffuse large B-cell lymphoma (DLBCL) is a recognized, but unpredictable, clinical inflection point in the natural history of indolent lymphomas. Large retrospective studies highlight a wide variability in the incidence of transformation across the indolent lymphomas and the adverse outcomes associated with transformed lymphomas. Opportunities to dissect the biology of transformed indolent lymphomas have arisen with evolving technologies and unique tissue collections enabling a growing appreciation, particularly, of their genetic basis, how they relate to the preceding indolent lymphomas and the comparative biology with de novo DLBCL.

Impact of Sickle Cell Awareness Day on online health information seeking in Africa using Google Trends.

The United Nations Council Assembly recognized sickle cell disease (SCD) as a global public health problem due to its increasing burden, particularly in sub-Saharan Africa. To raise awareness, a resolution was adopted, designating June 19th as SCD awareness day. However, the impact of this awareness day on online health information seeking behaviour (OHISB) in African countries is not well understood, especially in Nigeria, Ghana and Uganda where SCD prevalence is high.

Applying sequence analysis to uncover 'real-world' clinical pathways from routinely collected data: a systematic review.

Objectives: This systematic review aims to elucidate the methodological practices and reporting standards associated with sequence analysis (SA) for the identification of clinical pathways in real-world scenarios, using routinely collected data.

Study Design And Setting: We conducted a methodological systematic review, searching five medical and health databases: MEDLINE, PsycINFO, CINAHL, EMBASE and Web of Science. The search encompassed articles from the inception of these databases up to February 28, 2023.

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma.

Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL.

ZNF683 marks a CD8 T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome.

Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyze single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 patients with RS. Response is associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells.

Integration of social determinants of health information within the primary care electronic health record: a systematic review of patient perspectives and experiences.

Background: Social determinants of health (SDOH) are the non-medical factors that impact health. Although geographical measures of deprivation are used, individual measures of social risk could identify those most at risk and generate more personalised care and targeted referrals to community resources. We know SDOH are important to health care, but it is not yet known whether their collection via the electronic health record (EHR) is acceptable and useful from the patient perspective.

Digital health and inpatient palliative care: a cohort-controlled study.

Objectives: End of life has unacceptable levels of hospital admission and death. We aimed to determine the association of a novel digital specific system (Proactive Risk-Based and Data-Driven Assessment of Patients at the End of Life, PRADA) to modify such events.

Methods: A cohort-controlled study of those discharged alive, who died within 90 days of discharge, comparing PRADA (n=114) with standard care (n=3730).

GP assessment of unmet need in a complex multimorbid population using a data-driven and clinical triage system: a prospective cohort study.

Background: Patients with unmet healthcare needs are more likely to access unscheduled care. Identifying these patients through data-driven and clinical risk stratification for active case management in primary care can help address patient need and reduce demand on acute services.

Aim: To determine how a proactive digital healthcare system can be used to undertake comprehensive needs analysis of patients at risk of unplanned admission and mortality.

Novel perfluoroalkyl substances (PFAS) discovered in whole blood using automated non-targeted analysis of dried blood spots.

A small subset of per- and polyfluoroalkyl substances (PFAS) are routinely screened in human blood. These compounds generally explain <50 % of the total PFAS in human blood. The percentage of known PFAS in human blood has been decreasing as replacement PFAS and more complex PFAS chemistries are introduced to the market.

Richter syndrome: novel insights into the biology of transformation.

Although the genetic landscape of chronic lymphocytic leukemia (CLL) has been broadly profiled by large-scale sequencing studies performed over the past decade, the molecular basis of the transformation of CLL into aggressive lymphoma, or Richter syndrome (RS), has remained incompletely characterized. Recent advances in computational methods of clonal deconvolution, as well as extensive sample collection efforts in this rapidly progressive malignancy, have now enabled comprehensive analysis of paired CLL and RS samples and have led to multiple new studies investigating the genetic, transcriptomic, and epigenetic origins of RS. In parallel, new genetically engineered and xenograft mouse models have provided the opportunity for gleaning fresh biological and mechanistic insights into RS development and stepwise evolution from antecedent CLL.

Interim Positron Emission Tomography During Frontline Chemoimmunotherapy for Follicular Lymphoma.

While most patients with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of patients will experience early progression, which is associated with poor subsequent outcomes. Novel biomarkers are needed to identify high-risk patients earlier. We hypothesized that interim positron emission tomography (PET) would predict progression-free survival (PFS) in this population.

Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes.

In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities.

Unlabelled: Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e.

Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples.

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL.

Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing.