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Int J Cardiol Heart Vasc. 2024 Feb 9;51:101339. doi: 10.1016/j.ijcha.2024.101339. eCollection 2024 Apr.

ABSTRACT

BACKGROUND: Cardiac magnetic resonance imaging (CMR) based T1 mapping and extracellular volume fraction (ECV) are powerful tools for identifying myocardial fibrosis. This systematic review and meta-analysis aims to characterize the utility of native T1 mapping and ECV in patients with non-ischemic cardiomyopathy (NICM) and to clarify the prognostic significance of elevated values.

METHODS: A literature search was conducted for studies reporting on use of CMR-based native T1 mapping and ECV measurement in NICM patients and their association with major adverse cardiac events (MACE), ventricular arrhythmias (VAs), and left ventricular reverse remodeling (LVRR). Databases searched included: Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar. The search was not restricted to time or publication status.

RESULTS: Native T1 and ECV were significantly higher in NICM patients compared to controls (MD 78.80, 95 % CI 50.00, 107.59; p < 0.01; MD 5.86, 95 % CI 4.55, 7.16; p < 0.01). NICM patients who experienced MACE had higher native T1 and ECV (MD 52.87, 95 % CI 26.59, 79.15; p < 0.01; MD 6.03, 95 % CI 3.79, 8.26; p < 0.01). There was a non-statistically significant trend toward higher native T1 time in NICM patients who experienced VAs. NICM patients who were poor treatment responders had higher baseline native T1 and ECV (MD 40.58, 95 % CI 12.90, 68.25; p < 0.01; MD 3.29, 95 % CI 2.25, 4.33; p < 0.01).

CONCLUSIONS: CMR-based native T1 and ECV quantification may be useful tools for risk stratification of patients with NICM. They may provide additional diagnostic utility in combination with LGE, which poorly characterizes fibrosis in patients with diffuse myocardial involvement.

PMID:38371310 | PMC:PMC10873728 | DOI:10.1016/j.ijcha.2024.101339

Transpl Int. 2024 Feb 2;36:11792. doi: 10.3389/ti.2023.11792. eCollection 2023.

ABSTRACT

90% of the UK diabetic population are classified as T2DM. This study aims to compare outcomes after SPK transplant between recipients with T1DM or T2DM. Data on all UK SPK transplants from 2003-2019 were obtained from the NHSBT Registry (n = 2,236). Current SPK transplant selection criteria for T2DM requires insulin treatment and recipient BMI < 30 kg/m2. After exclusions (re-transplants/ambiguous type of diabetes) we had a cohort of n = 2,154. Graft (GS) and patient (PS) survival analyses were conducted using Kaplan-Meier plots and Cox-regression models. Complications were compared using chi-squared analyses. 95.6% of SPK transplants were performed in recipients with T1DM (n = 2,060). Univariate analysis showed comparable outcomes for pancreas GS at 1 year (p = 0.120), 3 years (p = 0.237), and 10 years (p = 0.196) and kidney GS at 1 year (p = 0.438), 3 years (p = 0.548), and 10 years (p = 0.947). PS was comparable at 1 year (p = 0.886) and 3 years (p = 0.237) and at 10 years (p = 0.161). Multi-variate analysis showed comparable outcomes in pancreas GS (p = 0.564, HR 1.221, 95% CI 0.619, 2.406) and PS(p = 0.556, HR 1.280, 95% CI 0.563, 2.911). Comparable rates of common complications were demonstrated. This is the largest series outside of the US evaluating outcomes after SPK transplants and shows similar outcomes between T1DM and T2DM recipients. It is hoped dissemination of this data will lead to increased referral rates and assessment of T2DM patients who could benefit from SPK transplantation.

PMID:38370534 | PMC:PMC10869449 | DOI:10.3389/ti.2023.11792

Br J Surg. 2024 Jan 31;111(2):znae020. doi: 10.1093/bjs/znae020.

NO ABSTRACT

PMID:38364060 | DOI:10.1093/bjs/znae020

JMIR Form Res. 2024 Feb 16;8:e44717. doi: 10.2196/44717.

ABSTRACT

BACKGROUND: Respiratory rate is a crucial indicator of disease severity yet is the most neglected vital sign. Subtle changes in respiratory rate may be the first sign of clinical deterioration in a variety of disease states. Current methods of respiratory rate monitoring are labor-intensive and sensitive to motion artifacts, which often leads to inaccurate readings or underreporting; therefore, new methods of respiratory monitoring are needed. The PulsON 440 (P440; TSDR Ultra Wideband Radios and Radars) radar module is a contactless sensor that uses an ultrawideband impulse radar to detect respiratory rate. It has previously demonstrated accuracy in a laboratory setting and may be a useful alternative for contactless respiratory monitoring in clinical settings; however, it has not yet been validated in a clinical setting.

OBJECTIVE: The goal of this study was to (1) compare the P440 radar module to gold standard manual respiratory rate monitoring and standard of care telemetry respiratory monitoring through transthoracic impedance plethysmography and (2) compare the P440 radar to gold standard measurements of respiratory rate in subgroups based on sex and disease state.

METHODS: This was a pilot study of adults aged 18 years or older being monitored in the emergency department. Participants were monitored with the P440 radar module for 2 hours and had gold standard (manual respiratory counting) and standard of care (telemetry) respiratory rates recorded at 15-minute intervals during that time. Respiratory rates between the P440, gold standard, and standard telemetry were compared using Bland-Altman plots and intraclass correlation coefficients.

RESULTS: A total of 14 participants were enrolled in the study. The P440 and gold standard Bland-Altman analysis showed a bias of -0.76 (-11.16 to 9.65) and an intraclass correlation coefficient of 0.38 (95% CI 0.06-0.60). The P440 and gold standard had the best agreement at normal physiologic respiratory rates. There was no change in agreement between the P440 and the gold standard when grouped by admitting diagnosis or sex.

CONCLUSIONS: Although the P440 did not have statistically significant agreement with gold standard respiratory rate monitoring, it did show a trend of increased agreement in the normal physiologic range, overestimating at low respiratory rates, and underestimating at high respiratory rates. This trend is important for adjusting future models to be able to accurately detect respiratory rates. Once validated, the contactless respiratory monitor provides a unique solution for monitoring patients in a variety of settings.

PMID:38363588 | DOI:10.2196/44717

Eur J Med Res. 2024 Feb 15;29(1):124. doi: 10.1186/s40001-024-01711-z.

ABSTRACT

Tumor progression and eradication have long piqued the scientific community's interest. Recent discoveries about the role of chemokines and cytokines in these processes have fueled renewed interest in related research. These roles are frequently viewed as contentious due to their ability to both suppress and promote cancer progression. As a result, this review critically appraised existing literature to discuss the unique roles of cytokines and chemokines in the tumor microenvironment, as well as the existing challenges and future opportunities for exploiting these roles to develop novel and targeted treatments. While these modulatory molecules play an important role in tumor suppression via enhanced cancer-cell identification by cytotoxic effector cells and directly recruiting immunological effector cells and stromal cells in the TME, we observed that they also promote tumor proliferation. Many cytokines, including GM-CSF, IL-7, IL-12, IL-15, IL-18, and IL-21, have entered clinical trials for people with advanced cancer, while the FDA has approved interferon-alpha and IL-2. Nonetheless, low efficacy and dose-limiting toxicity limit these agents' full potential. Conversely, Chemokines have tremendous potential for increasing cancer immune-cell penetration of the tumor microenvironment and promoting beneficial immunological interactions. When chemokines are combined with cytokines, they activate lymphocytes, producing IL-2, CD80, and IL-12, all of which have a strong anticancer effect. This phenomenon opens the door to the development of effective anticancer combination therapies, such as therapies that can reverse cancer escape, and chemotaxis of immunosuppressive cells like Tregs, MDSCs, and TAMs.

PMID:38360737 | DOI:10.1186/s40001-024-01711-z

Am J Transplant. 2024 Feb 13:S1600-6135(24)00134-5. doi: 10.1016/j.ajt.2024.02.008. Online ahead of print.

ABSTRACT

Time to arrest in donors after circulatory death is unpredictable and can vary. This leads to variable periods of warm ischaemic damage prior to pancreas transplantation. There is little evidence supporting procurement team stand-down times based on donor time to death (TTD). We examined what impact TTD had on pancreas graft outcomes following DCD SPK transplantation. Data were extracted from the UK transplant registry from 2014 to 2022. Predictors of graft loss were evaluated by a Cox proportional hazards model. Adjusted restricted cubic spline (RCS) models were generated to further delineate the relationship between TTD and outcome. Three-hundred-and-seventy-five DCD simultaneous kidney-pancreas transplant recipients were included. Increasing TTD was not associated with graft survival (aHR 0.98, 95% CI 0.68-1.41, P=0.901). Increasing asystolic time worsened graft survival (aHR 2.51, 95% CI 1.16-5.43, P=0.020). RCS modelling revealed a non-linear relationship was demonstrated between asystolic time and graft survival, and no relationship between TTD and graft survival. We found no evidence that TTD impacts on pancreas graft survival after DCD SPK transplantation, however increasing asystolic time was a significant predictor of graft loss. Procurement teams should attempt to minimise asystolic time to optimize pancreas graft survival rather than focus on the duration of TTD.

PMID:38360185 | DOI:10.1016/j.ajt.2024.02.008

EClinicalMedicine. 2024 Feb 7;69:102465. doi: 10.1016/j.eclinm.2024.102465. eCollection 2024 Mar.

ABSTRACT

BACKGROUND: Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of clinical and genomic data has restricted understanding of national LS ascertainment and outcomes, and precluded evaluation of NICE guidance on testing and management. To address this, via collaboration between researchers, the National Disease Registration Service (NDRS), NHS Genomic Medicine Service Alliances (GMSAs), and NHS Regional Clinical Genetics Services, a comprehensive registry of LS carriers in England has been established.

METHODS: For comprehensive ascertainment of retrospectively identified MMR pathogenic variant (PV) carriers (diagnosed prior to January 1, 2023), information was retrieved from all clinical genetics services across England, then restructured, amalgamated, and validated via a team of trained experts in NDRS. An online submission portal was established for prospective ascertainment from January 1, 2023. The resulting data, stored in a secure database in NDRS, were used to investigate the demographic and genetic characteristics of the cohort, censored at July 25, 2023. Cancer outcomes were investigated via linkage to the National Cancer Registration Dataset (NCRD).

FINDINGS: A total of 11,722 retrospective and 570 prospective data submissions were received, resulting in a comprehensive English National Lynch Syndrome Registry (ENLSR) comprising 9030 unique individuals. The most frequently identified pathogenic MMR genes were MSH2 and MLH1 at 37.2% (n = 3362) and 29.1% (n = 2624), respectively. 35.9% (n = 3239) of the ENLSR cohort received their LS diagnosis before their first cancer diagnosis (presumptive predictive germline test). Of these, 6.3% (n = 204) developed colorectal cancer, at a median age of initial diagnosis of 51 (IQR 40-62), compared to 73 years (IQR 64-80) in the general population (p < 0.0001).

INTERPRETATION: The ENLSR represents the first comprehensive national registry of PV carriers in England and one of the largest cohorts of MMR PV carriers worldwide. The establishment of a secure, centralised infrastructure and mechanism for routine registration of newly identified carriers ensures sustainability of the data resource.

FUNDING: This work was funded by the Wellcome Trust, Cancer Research UK and Bowel Cancer UK. The funder of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

PMID:38356732 | PMC:PMC10864212 | DOI:10.1016/j.eclinm.2024.102465

Nat Commun. 2024 Feb 13;15(1):1334. doi: 10.1038/s41467-024-45680-7.

ABSTRACT

G protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using 13C methyl methionine and 19F NMR, we investigate the agonist-bound active state of β1AR and its ternary complexes with different G proteins in solution. We find the receptor in the ternary complexes adopts very similar conformations. In contrast, the full agonist-bound receptor active state assumes a conformation differing from previously characterised activation intermediates or from β1AR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of β1AR for Gs results from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.

PMID:38351103 | PMC:PMC10864275 | DOI:10.1038/s41467-024-45680-7

Nat Commun. 2024 Feb 13;15(1):1334. doi: 10.1038/s41467-024-45680-7.

ABSTRACT

G protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using 13C methyl methionine and 19F NMR, we investigate the agonist-bound active state of β1AR and its ternary complexes with different G proteins in solution. We find the receptor in the ternary complexes adopts very similar conformations. In contrast, the full agonist-bound receptor active state assumes a conformation differing from previously characterised activation intermediates or from β1AR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of β1AR for Gs results from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.

PMID:38351103 | DOI:10.1038/s41467-024-45680-7

J Public Health Res. 2024 Feb 8;13(1):22799036241231544. doi: 10.1177/22799036241231544. eCollection 2024 Jan.

ABSTRACT

Terrorism has emerged as an increasingly pressing global issue, giving rise to escalating casualties and devastating implications for peace and security. The low- and middle-income countries (LMICs), already grappling with inadequate healthcare services and an estimated annual mortality toll ranging from 5.7 to 8.4 million, face further setbacks as terrorism exacerbates their prevailing healthcare deficiencies. Among the aspects of how terrorism affects healthcare in LMICs are high morbidity, mortality, and treatment wait times. The four principal areas of reverberation encompass amplified vulnerabilities in healthcare systems, financial shortfalls in LMIC healthcare systems, worsened personnel shortages in healthcare, and the devastating impact on healthcare facilities. In response to these challenges, international organizations and countries have played a pivotal role in mitigating the impact of terrorism on healthcare systems. Additionally, to improve healthcare in these regions, investing in infrastructure, supporting healthcare workers, and ensuring safety are paramount. Implementing mobile health interventions, traditional medicine, and mobile laboratories may enhance healthcare accessibility. Further, employing blockchain technology for data security and supply chain management may strengthen healthcare systems in these areas.

PMID:38343397 | PMC:PMC10854384 | DOI:10.1177/22799036241231544

Cancer Res Commun. 2024 Feb 9. doi: 10.1158/2767-9764.CRC-23-0244. Online ahead of print.

ABSTRACT

Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A *0201. We then validated the binding affinity and stability of the top predicted peptides through in-vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific cytotoxic T lymphocytes (CTLs) from healthy female donors. Lastly, using in-vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies.

PMID:38335301 | DOI:10.1158/2767-9764.CRC-23-0244

Front Cardiovasc Med. 2024 Jan 25;11:1284562. doi: 10.3389/fcvm.2024.1284562. eCollection 2024.

ABSTRACT

Dyslipidemia is a leading contributor to atherosclerotic cardiovascular disease (ASCVD). There has been a significant improvement in the treatment of dyslipidemia in the past 10 years with the development of new pharmacotherapies. The intent of this review is help enhance clinicians understanding of non-statin lipid lowering therapies in accordance with the 2022 American College of Cardiology Expert Consensus Clinical Decision Pathway on the Role of Non-statin Therapies for LDL-Cholesterol Lowering. We also present a single-center experience implementing a systematic inpatient protocol for lipid lowering therapy for secondary prevention of ASCVD.

PMID:38333418 | PMC:PMC10851935 | DOI:10.3389/fcvm.2024.1284562

Pain. 2024 Jan 29. doi: 10.1097/j.pain.0000000000003159. Online ahead of print.

ABSTRACT

Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn's disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Potential pronociceptive mediators were identified based on gene upregulation in IBD biopsy tissue and cognate receptor expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt , which encode the precursor to angiotensin II (Ang II), in samples from UC patients ( P = 3.2 × 10 -8 ). Consistent with the marked expression of the angiotensin AT 1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca 2+ in capsaicin-sensitive, voltage-gated sodium channel subtype Na V 1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT 1 receptor antagonist valsartan. Findings from our study identify AT 1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.

PMID:38293826 | DOI:10.1097/j.pain.0000000000003159

Pain. 2024 Jan 29. doi: 10.1097/j.pain.0000000000003159. Online ahead of print.

ABSTRACT

Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Putative pronociceptive mediators were identified based on analysis of differentially expressed genes in IBD biopsy tissue and single-cell gene expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt, which encode the precursor to angiotensin II (Ang II), in samples from UC patients (P = 3.2 × 10-8). Consistent with the marked expression of the angiotensin AT1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca2+ in capsaicin-sensitive, voltage-gated sodium channel subtype NaV1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT1 receptor antagonist valsartan. Findings from our study identify AT1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.

PMID:38293826 | DOI:10.1097/j.pain.0000000000003159

J Neurosci Res. 2024 Jan;102(1):e25261. doi: 10.1002/jnr.25261.

ABSTRACT

Membrane trafficking is a physiological process encompassing different pathways involved in transporting cellular products across cell membranes to specific cell locations via encapsulated vesicles. This process is required for cells to mature and function properly, allowing them to adapt to their surroundings. The retromer complex is a complex composed of nexin proteins and peptides that play a vital role in the endosomal pathway of membrane trafficking. In humans, any interference in normal membrane trafficking or retromer complex can cause profound changes such as those seen in neurodegenerative disorders such as Alzheimer's and Parkinson's. Several studies have explored the potential causative mechanisms in developing both disease processes; however, the role of retromer trafficking in their pathogenesis is becoming increasingly significant with promising therapeutic applications. This manuscript describes the processes involved in membrane transport and the roles of the retromer in the onset and progression of Alzheimer's and Parkinson's. Moreover, we will also explore how these aberrant mechanisms may serve as possible avenues for treatment development in both diseases and the prospect of its future application.

PMID:38284858 | DOI:10.1002/jnr.25261