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Debi Bhattacharya,1 Tracey J Brown,2 Allan B Clark,2 Alexandra L Dima,3 Claire Easthall,4 Natalie Taylor,5 Zhicheng Li6 1School of Healthcare, University of Leicester, Leicester, Leics, UK; 2Norwich Medical School, University of East Anglia, Norwich, Norf, UK; 3Research and Development Unit, Institut deRecerca Sant Joan de Déu, Sant Boi deLlobregat, BCN, Spain; 4School of Healthcare, University of Leeds, Leeds, West Yorks, UK; 5School of Population Health, University of New South Wales, Sydney, NSW, Australia; 6Susan Wakil School of Nursing and Midwifery, The University of Sydney, Sydney, NSW, AustraliaCorrespondence: Debi Bhattacharya, School of Healthcare, College of Life Sciences, University of Leicester, University Road, Leicester, LE1 7RH, UK, Tel +44116 252 2833, Email d.bhattacharya@leicester.ac.ukPurpose: To validate the Identification of Medication Adherence Barriers Questionnaire (IMAB-Q) as a tool to guide practitioners to identify patients who require support to take their medicines as prescribed, their key barriers to adherence and select relevant behaviour change techniques.Patients and Methods: Adults prescribed medication for cardiovascular disease prevention were recruited from nine community pharmacies in England. Participants completed the IMAB-Q comprising 30 items representing potential barriers to adherence developed from our previous mixed methods study (scoping review and focus groups) underpinned by the Theoretical Domains Framework. Participants also self-reported their adherence on a visual analogue scale (VAS) ranging from perfect adherence (100) to non-adherence (1). A subgroup of 30 participants completed the IMAB-Q twice to investigate test-retest reliability using weighted Kappa. Mokken scaling was used to investigate IMAB-Q structure. Spearman correlation was used to investigate IMAB-Q criterion validity compared to the VAS score.Results: From 1407 invitations, 608 valid responses were received. Respondents had a mean (SD) age of 70.12 (9.9) years and were prescribed a median (IQ) 4 (3, 6) medicines. Worry about unwanted effects (n = 212, 34.5%) and negative emotions evoked by medicine taking (n = 99, 16.1%) were most frequently reported. Mokken scaling did not organise related IMAB-Q items according to the TDF domains (scalability coefficient H = 0.3 to 0.6). Lower VAS self-reported adherence correlated with greater IMAB-Q reported barriers (rho = − 0.14, p = 0.001). Test-retest reliability of IMAB-Q items ranged from kappa co-efficient 0.9 to 0.3 (p < 0.05).Conclusion: The IMAB-Q is valid and reliable for identifying people not adhering and their barriers to adherence. Each IMAB-Q item is linked to a TDF domain which in turn is linked to relevant behaviour change techniques. The IMAB-Q can therefore guide patients and practitioners to select strategies tailored to a patient’s identified barriers.Keywords: theoretical domains framework, psychometrics, questionnaire, behaviour change, determinant, compliance

Ewelina Wilkos,2 Timothy JB Brown,3 Ksenia Slawinska,1 Katarzyna A Kucharska2,3 1Department of Neurology, 2Department of Neuroses, Personality and Eating Disorders Institute of Psychiatry and Neurology, Warsaw, Poland; 3Department of Medical Education, Hull York Medical School, Hull, UK Background: The essential role of the thalamus in neurocognitive processes has been well documented. In contrast, relatively little is known about its involvement in social cognitive processes such as recognition of emotion, mentalizing, or empathy. The aim of the study: This study was designed to compare the performance of eight patients (five males, three females, mean age ± SD: 63.7±7.9 years) at early stage of unilateral thalamic lesions and eleven healthy controls (six males, five females, 49.6±12.2 years) in neurocognitive tests (CogState Battery: Groton Maze Learning Test, GML; Groton Maze Learning Test-Delayed Recall, GML-DR; Detection Task, DT; Identification Task, IT; One Card Learning Task, OCLT; One Back Task, OBT; Two Back Task, TBT; Set-Shifting Task, S-ST) and other well-known tests (Benton Visual Retention Test, BVRT; California Verbal Learning Test, CVLT; The Rey-Osterrieth Complex Figure Test, ROCF; Trail Making Test, TMT part A and B; Color – Word Stroop Task, CWST; Verbal Fluency Test, VFT), and social cognitive tasks (The Penn Emotion Recognition Test, ER40; Penn Emotion Discrimination Task, EmoDiff40; The Penn Emotional Acuity Test, PEAT40; Reading the Mind in the Eyes Test, revised version II; Toronto Alexithymia Scale, TAS-20). Methods: Thalamic-damaged subjects were included if they experienced a single-episode ischemic stroke localized in right or left thalamus. The patients were examined at 3 weeks after the stroke onset. All were right handed. In addition, the following clinical scales were used: the Mini-Mental State Examination (MMSE), Spielberger State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI II). An inclusion criteria was a minimum score of 23/30 in MMSE. Results: Compared with the healthy controls, patients revealed significantly lower scores in CVLT, GML-DR, and VFT. Furthermore, compared to healthy controls, patients showed significantly delayed recognition of “happiness” in EmoDiff40 and significantly worse performance on Reading the Mind in the Eyes Test, revised version II. Neuropsychological assessment demonstrated some statistically significant deficits in learning and remembering both verbal and visual material, long-term information storing, problem solving, and executive functions such as verbal fluency. Conclusion: Patients at early stage of unilateral thalamic stroke showed both neurocognitive and social cognitive deficits. Further research is needed to increase understanding about diagnosis, early treatment, and prognosis of patients with thalamic lesions. Keywords: social cognitive deficits, neurocognitive deficits, thalamic stroke, posterior, inferolateral, paramedian

Background: Fast and reliable detection of Mycobacterium tuberculosis complex (MTBC) and drug resistance is crucial in establishing effective treatment and enforcing timely public health measures. Methods: The authors analysed the performance of a national U.K. molecular diagnostic service over a decade, based on the use of a line probe assay (Innolipa, LiPA) compared with conventional liquid and solid cultures with rapid molecular identification and culture-based drug resistance testing. Findings: Data were available for 7836 consecutive patient samples using LiPA and the reference microbiological technique (conventional liquid and solid cultures with rapid molecular identification and culture-based drug resistance testing). For all sputum specimens (n=3382) the sensitivity, specificity, positive predictive value, negative predictive value and accuracy for MTBC detection were 93.4%, 85.6%, 92.7%, 86.9% and 90.7%; the equivalent values for smear-positive sputum specimens (n=2606) were 94.7%, 80.9%, 93.9%, 83.3% and 91.3%. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for detection of rifampicin resistance in all sputum samples (n=1667) were 92.1%, 99.3%, 89.4%, 99.5% and 98.9%, respectively; the equivalent values for smear-positive sputum specimens (n=1477) were 93.3%, 99.3%, 87.5%, 99.6% and 99%. Between January 2006 and December 2008, LiPA saved 25.3 and 32.2 days for TB diagnosis and rifampicin resistance of smear-positive samples, respectively. Interpretation: A molecular diagnostic service, using a non-automated line probe assay approach, provides a rapid and reliable national service for diagnosing MTBC and rifampicin resistance. [ABSTRACT FROM AUTHOR]

BACKGROUND: Evidence is needed for the best long-term diet for weight loss, and improvement in cardiac risk and disease in obese adults. METHODS: We systematically reviewed randomized controlled trials (RCTs) in any language. We searched 13 databases and handsearched journals. Trials lasted 1 year or more. One investigator extracted the data and a second checked data extraction. Trial quality was assessed. RESULTS: Low fat diets (LFDs) produced significant weight losses up to 36 months (-3.55 kg; 95% CI, -4.54 to -2.55 kg). Blood pressure, lipids and fasting plasma glucose improved with these diets after 12 months. Four studies found that LFDs may prevent type 2 diabetes and reduce antihypertensive medication for up to 3 years. A very low calorie diet (VLCD, < 4.2 MJ day(-1)) was associated with the most weight loss after 12 months (-13.40 kg; 95% CI, -18.43 to -8.37 kg) in one small study with beneficial effects on asthma. There was no evidence that low carbohydrate protein sparing modified fasts (PSMFs) were associated with greater long-term weight loss than low calorie diets (LCDs, 4.2-6.7 MJ day(-1)) or VLCDs. PSMFs were, however, associated with greater lowering of fasting plasma glucose and HbA1c than LCDs. CONCLUSIONS: Little evidence supports the use of diets other than LFDs for weight reduction. With the increasing prevalence of morbid obesity, long-term follow-up in RCTs is needed to evaluate the effect of LCDs, VLCDs and PSMFs more fully. [ABSTRACT FROM AUTHOR]

BACKGROUND: Evidence is needed for the effectiveness of interventions given with reducing diets for obese adults: drug therapy, exercise, or behaviour therapy. METHODS: We systematically reviewed randomized controlled trials in any language. We searched 13 databases and handsearched journals. Trials lasted 1 year or more. One investigator extracted data and a second checked data extraction. Trial quality was assessed. RESULTS: Adding orlistat to diet was associated with weight change for up to 24 months (-3.26 kg, 95% CI, -4.15 to -2.37 kg), and statistically significant beneficial changes were found for total and LDL cholesterol, blood pressure and glycaemic control. Adding sibutramine to diet was associated with a 12 month weight change of -4.18 kg (95% CI, -5.14 to -3.21 kg), and statistically significant beneficial effects on high density lipoprotein cholesterol (HDL) and triglycerides (TGs), but an increase in diastolic blood pressure. Adding exercise to diet, or to diet and behaviour therapy, was associated with improved weight loss for up to 36 months and improvements in HDL, TGs and blood pressure. Adding behaviour therapy to diet, or to diet and sibutramine together, was associated with improved weight loss for up to 18 months. Adding drugs, exercise or behaviour therapy to dietary advice was each associated with similar weight change. CONCLUSIONS: Adding orlistat, sibutramine, exercise, or behaviour modification to dietary advice can improve long-term weight loss. [ABSTRACT FROM AUTHOR]

Background: The invasive potential of cancer cells is usually assessed in vitro using Matrigel as a surrogate basement membrane. Yet cancer cell interaction with collagen I matrices is critical, particularly for the peritoneal metastatic route undertaken by several cancer types including ovarian. Matrix metalloprotease (MMP) activity is important to enable cells to overcome the barrier constraints imposed by basement membranes and stromal matrices in vivo. Our objective was to compare matrices reconstituted from collagen I and Matrigel as representative barriers for ovarian cancer cell invasion.Methods: The requirement of MMP activity for ovarian cancer cell penetration of Matrigel and collagen matrices was assessed in 2D transwell and 3D spheroid culture systems.Results: The broad range MMP inhibitor GM6001 completely prevented cell perforation of polymerised collagen I-coated transwell membranes. In contrast, GM6001 decreased ES-2 cell penetration of Matrigel by only approximately 30% and had no effect on HEY cell Matrigel penetration. In 3D culture, ovarian cancer cells grown as spheroids also migrated into surrounding Matrigel matrices despite MMP blockade. In contrast, MMP activity was required for invasion into 3D matrices of collagen I reconstituted from acid-soluble rat-tail collagen I, but not from pepsin-extracted collagen I (Vitrogen/Purecol), which lacks telopeptide regions.Conclusion: Matrigel does not form representative barriers to ovarian cancer cells in either 2D or 3D culture systems. Our findings support the use of collagen I rather than Matrigel as a matrix barrier for invasion studies to better approximate critical interactions and events associated with peritoneal metastasis. [ABSTRACT FROM AUTHOR]

In Photosystem II electrons from water splitting pass through a primary quinone electron acceptor (Q A ) to the secondary plastoquinone (Q B ). The D2 protein forms the Q A -binding site and the D1 protein forms the Q B -binding site. A non-heme iron sits between Q A and Q B resulting in a quinone-Fe-acceptor complex that must be activated before assembly of the oxygen-evolving complex can occur. An extended loop (residues 223-266) between the fourth (helix D) and fifth (helix E) helices of the D1 protein activates forward electron transfer via a conformational change that stabilizes a bidentate bicarbonate ligand to the non-heme iron while simultaneously stabilizing the binding of Q B . We show that positioning of D1:Phe265 to provide a hydrogen bond to the distal oxygen of Q B is required for forward electron transfer. In addition, mutations targeting D1:Phe265, resulted in a 50 mV decrease in the Q B /Q B - midpoint potential., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A 2-year professional master of health science program at the University of Toronto provides a unique integrated educational program to train allied health science personnel to practice as physician extenders and health care professionals in two high-demand clinical laboratory disciplines, Pathologists' Assistant (PA) and Clinical Embryologist (CE). This report describes an integrated graduate program developed and delivered in a research-intensive laboratory medicine department. The core courses in fundamental biomedical science and in general medical laboratory function and operations formed the foundation on which the requisite clinical skills required to practice as a PA or CE were subsequently delivered as comprehensive CE and PA specialty courses and practicums. Students acquired research skills through courses that teach research methods, critical analysis of research articles, and biostatistics for clinical research scientists. A capstone research project provided students the opportunity to design a research project relevant to the CE or PA fields, perform and analyze the findings, and present the project as an oral abstract and a written scientific article. Students learn to face the clinical challenges by focusing on critical analysis of evidence-based professional practice. The PA field received a 5-year accreditation. CE and PA students presented their clinical research at national and international meetings, with some receiving awards, and published scientific articles. All graduates found meaningful employment in their respective fields, and initial employer response has been favorable., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Heritable mutations in BRCA1 associate with increased risk of high-grade serous tubo-ovarian cancer. Nongenetic risk factors associated with this cancer, which arises from fallopian tube epithelial (FTE) cells, suggests a role for repetitive ovulation wherein FTE cells are exposed to inflammatory signaling molecules within follicular fluid. We previously reported increased NFκB and EGFR signaling in BRCA1-deficient primary FTE cells, with follicular fluid exposure further increasing abundance of interferon-stimulated gene (ISG) transcripts, including the ubiquitin-like protein ISG15 and other ISGylation pathway members. Both NFκB and type I interferon signaling are upregulated by stimulation of cGAS-STING or MDA5 and RIGI pattern recognition receptors. Since some pattern recognition receptors and their signal transduction pathway members are ISGylated, we tested the impact of ISG15 and ISGylation on interferon regulatory factor 3 (IRF3) and NFκB signaling through cGAS-STING or RIGI and MDA5 activation. Expression of ISG15 or UBA7, the E1-like ISG15-activating enzyme, in immortalized FTE cells was disrupted by CRISPR gene editing. Activation of IRF3 by RIGI or MDA5 but not cGAS-STING was attenuated by loss of either ISG15 or UBA7 and this was reflected by a similar effect on NFκB activation and downstream targets. Loss of ISGylation decreased levels of both MDA5 and RIGI, with knockdown of RIGI but not MDA5, decreasing IRF3 and NFκB activation in parental cells. These finding indicate that ISGylation enhances the ability of dsRNA to activate cytokine release and proinflammatory signaling. Further work to explore ISGylation as a target for prevention of high-grade serous tubo-ovarian cancer in BRCA1 mutation carriers is warranted., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite several therapeutic advancements, the proportion of patients with advanced biliary tract cancers (BTC) surviving 5 years from diagnosis remains dismal. The increasing recognition of targetable genetic alterations in BTCs has ushered in a new era in the treatment of these patients. Newer therapeutic agents targeting mutations such as isocitrate dehydrogenase (IDH), fibroblastic growth factor receptor (FGFR), human epidermal growth factor receptor (HER), and so on have established a new standard of care for treatment upon progression on frontline therapy in patients with disease harboring these mutations., Areas Covered: The current review aims to concisely summarize progress with various targeted therapy options for BTC. We also briefly discuss future directions in clinical and translational research for the adoption of a personalized approach for the treatment of unresectable or advanced BTC., Expert Opinion: Several new agents continue to emerge as feasible treatment options for patients with advanced BTC harboring targetable mutations. There is a growing need to identify mechanisms to conquer primary and acquired resistance to these agents. The identification of potential biomarkers that predict response to targeted therapy may be helpful in adopting a more tailored approach. All patients receiving treatment for advanced BTC should undergo tissue genomic profiling at diagnosis.

Purpose: Systemic therapy with atezolizumab and bevacizumab can extend life for patients with advanced hepatocellular carcinoma (HCC). However, there is substantial variability in response to therapy and overall survival. Although current prognostic models have been validated in HCC, they primarily consider covariates that may be reflective of the severity of the underlying liver disease of patients with HCC. We developed and internally validated a classification and regression tree (CART) to identify patient characteristics associated with risks of early mortality, at or before 6 months from treatment initiation., Methods: This retrospective cohort study used the nationwide Flatiron Health electronic health record-derived deidentified database and included patients with a diagnosis of HCC after January 1, 2020, who received initial systemic therapy with atezolizumab and bevacizumab. CART was developed from available baseline clinical and demographic information to predict mortality within 6 months from treatment initiation. Model characteristics were compared to the albumin-bilirubin (ALBI) model and was further validated against a contemporary validation cohort of patients after a data update., Results: A total of 293 patients were analyzed. The CART identified seven cohorts of patients from baseline demographic and laboratory characteristics. The model had an area under the receiver operating curve (AUROC) of 0.739 (95% CI, 0.683 to 0.794) for predicting 6-month mortality. This model was internally valid and performed more favorably than the ALBI model, which had an AUROC of 0.608 (95% CI, 0.557 to 0.660). The model applied to the contemporary validation cohort (n = 111) had an AUROC of 0.666 (95% CI, 0.506 to 0.826)., Conclusion: Using CART, we identified unique cohorts of patients with HCC treated with atezolizumab and bevacizumab with distinct risks of early mortality. This approach outperformed the ALBI model and used clinical and laboratory characteristics that are readily available to oncologists caring for these patients.

Background: Colon cancers are categorized into mismatch repair deficient/microsatellite unstable (MSI-H) and mismatch repair proficient/microsatellite stable (MSS) cancers. This study aims to compare the disease characteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups., Methods: MSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Cancer Database. We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages. Within MSI-H and MSS groups, we conducted a landmark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival., Results: Of the 542,368 patients that met inclusion criteria, 120,751 (22%) had mismatch repair results available-out of these 96,928 (80%) had MSS colon cancers while 23,823 (19.7%) had MSI-H cancers. MSI-H disease had a bimodal age distribution (<40 years = 22%; ≥75 years = 26%) and was frequent among females (22%) and non-Hispanic Whites (20%). Among those < 65 years, 15% of low-risk stage 2 MSI-H patients and 40% of high-risk stage 2 MSI-H patients received adjuvant chemotherapy. More than two-thirds of stage 3 patients <65 years received adjuvant chemotherapy in both groups. After conducting propensity-score matching for age, gender, and co-morbidities, we found that adjuvant chemotherapy use had a trend towards lower overall survival (OS) in low-risk stage 2 MSI-H (HR = 1.8 [95% CI, 0.8-4.02]) and high-risk stage 2 MSI-H (HR = 1.42 [95% CI, 0.96-2.12]) groups. Adjuvant chemotherapy significantly improved OS in stage 3 colon cancer patients irrespective of microsatellite status or risk category of disease., Conclusions: MSI-H colon cancer had bimodal age distribution. Among stage 2 MSI-H patients <65 years, a notable proportion received adjuvant chemotherapy. Among MSI-H stage 2 patients, adjuvant chemotherapy use was associated with lower survival while it significantly improved survival for stage 3 patients, irrespective of MSI status., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Chinese National Cancer Center. Published by Elsevier B.V.)

Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas-entrapping material containing CO in a pre-clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo , mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4 weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Brown, Rutland, Choi, Tse, Peffers, Mongan, Arkill, Ritchie, Clarke, Ratan, Allegrucci, Grabowska and James.)

Background: The National Health Service Type 2 Diabetes Path to Remission programme in England (known as the NHS Low Calorie Diet programme when piloted) was established to support people living with excess weight and Type 2 Diabetes to lose weight and improve their glycaemic control. A mixed method evaluation was commissioned to provide an enhanced understanding of the long-term cost effectiveness of the pilot programme, its implementation, equity and transferability across broad and diverse populations. This study provided key insights on implementation and equity from the service providers' perspective., Methods: Thirteen focus groups were conducted with commercial providers of the programme, during the initial pilot rollout. Participants were purposively sampled across all provider organisations and staff roles involved in implementing and delivering the programme. Normalisation Process Theory (NPT) was used to design the topic schedule, with the addition of topics on equity and person-centredness. Data were thematically analysed using NPT constructs with additional inductively created codes. Codes were summarised, and analytical themes generated., Results: The programme was found to fulfil the requirements for normalisation from the providers' perspective. However, barriers were identified in engaging GP practices and receiving sufficient referrals, as well as supporting service users through challenges to remain compliant. There was variation in communication and training between provider sites. Areas for learning and improvement included adapting systems and processes and closing the gap where needs of service users are not fully met., Conclusions: The evaluation of the pilot programme demonstrated that it was workable when supported by effective primary care engagement, comprehensive training, and effective internal and external communication. However, limitations were identified in relation to programme specifications e.g. eligibility criteria, service specification and local commissioning decisions e.g. pattern of roll out, incentivisation of general practice. A person-centred approach to care is fundamental and should include cultural adaptation(s), and the assessment and signposting to additional support and services where required., (© 2024. The Author(s).)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α 1 -adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation., Competing Interests: Declaration of interests D.J.D. has consulted for Altimmune, Amgen, Kallyope, Merck, Novo Nordisk, Pfizer Inc., and Sanofi Inc. Mt. Sinai Hospital receives operating grant support from Amgen, Novo Nordisk, and Pfizer Inc. for studies in the Drucker lab. R.J.S. has consulted for Novo Nordisk, Scohia, CinRx, Fractyl, Structure Therapeutics, Congruenc Therapeutics, Calibrate, and Rewind and receives operating grant support from Novo Nordisk, Astra Zeneca, Fractyl, and Eli Lilly Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hematopoietic stem cells (HSCs) are supported by the bone marrow microenvironment to maintain normal production of blood cells. The niche may be considered an "ecosystem" that support the function of HSCs and other supportive cells. Alterations in the bone marrow niche are commonly observed in hematologic malignancies. Here, we review recent insights into the location and the molecular and cellular components of the bone marrow niche. Moreover, we discuss how the niche interacts with HSCs to drive the pathogenesis of hematopoietic malignancies. Overall, a better understanding of the influences on the HSC niche may drive therapeutic development targeting defective and aberrant hematopoiesis.

Purpose: PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized., Experimental Design: We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease., Results: Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib., Conclusions: Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005., (©2023 American Association for Cancer Research.)