CREST-UK: Real-world effectiveness, safety and outpatient delivery of CPX-351 for first-line treatment of newly diagnosed therapy-related AML and AML with myelodysplasia-related changes in the UK.

Favourable outcomes with CPX-351 versus conventional 7 + 3 were demonstrated in the pivotal phase III trial in adults aged 60-75 years with newly diagnosed, highrisk/secondary acute myeloid leukaemia (AML). As a complement to the clinical trial and to address important data gaps, the CPX-351 Real-World Effectiveness and SafeTy (CREST-UK; NCT05169307) study evaluated the use of CPX-351 in routine clinical practice in the UK, in 147 patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Best response of complete remission or complete remission with incomplete platelet or neutrophil recovery was achieved by 53% of evaluable patients. Kaplan-Meier median overall survival (OS) was 12.8 months (95% confidence interval 9.2-15.3). Fifty (34%) patients proceeded to haematopoietic cell transplantation (HCT); median OS landmarked from the HCT date was not reached. There were no new safety concerns with CPX-351 identified in CREST-UK. Patients treated with CPX-351 in the outpatient setting spent an average of 24.4, 16.7, 28.2, and 27.7 fewer days on the ward compared with inpatients during first induction, second induction, first consolidation, and second consolidation, respectively. The results from CREST-UK provide valuable insights into the effectiveness, safety, and outpatient delivery of CPX-351 in routine clinical practice in the UK.

Reduced protein-coding transcript diversity in severe dengue emphasises the role of alternative splicing.

Dengue fever, a neglected tropical arboviral disease, has emerged as a global health concern in the past decade. Necessitating a nuanced comprehension of the intricate dynamics of host-virus interactions influencing disease severity, we analysed transcriptomic patterns using bulk RNA-seq from 112 age- and gender-matched NS1 antigen-confirmed hospital-admitted dengue patients with varying severity. Severe cases exhibited reduced platelet count, increased lymphocytosis, and neutropenia, indicating a dysregulated immune response. Using bulk RNA-seq, our analysis revealed a minimal overlap between the differentially expressed gene and transcript isoform, with a distinct expression pattern across the disease severity. Severe patients showed enrichment in retained intron and nonsense-mediated decay transcript biotypes, suggesting altered splicing efficiency. Furthermore, an up-regulated programmed cell death, a haemolytic response, and an impaired interferon and antiviral response at the transcript level were observed. We also identified the potential involvement of the RBM39 gene among others in the innate immune response during dengue viral pathogenesis, warranting further investigation. These findings provide valuable insights into potential therapeutic targets, underscoring the importance of exploring transcriptomic landscapes between different disease sub-phenotypes in infectious diseases.

RNA editing in host lncRNAs as potential modulator in SARS-CoV-2 variants-host immune response dynamics.

Both host and viral RNA editing plays a crucial role in host's response to infection, yet our understanding of host RNA editing remains limited. In this study of in-house generated RNA sequencing (RNA-seq) data of 211 hospitalized COVID-19 patients with PreVOC, Delta, and Omicron variants, we observed a significant differential editing frequency and patterns in long non-coding RNAs (lncRNAs), with Delta group displaying lower RNA editing compared to PreVOC/Omicron patients. Notably, multiple transcripts of UGDH-AS1 and NEAT1 exhibited high editing frequencies. Expression of ADAR1/APOBEC3A/APOBEC3G and differential abundance of repeats were possible modulators of differential editing across patient groups. We observed a shift in crucial infection-related pathways wherein the pathways were downregulated in Delta compared to PreVOC and Omicron. Our genomics-based evidence suggests that lncRNA editing influences stability, miRNA binding, and expression of both lncRNA and target genes. Overall, the study highlights the role of lncRNAs and how editing within host lncRNAs modulates the disease severity.

Chronic Kidney Disease Diets for Kidney Failure Prevention: Insights from the IL-11 Paradigm.

Nearly every fifth adult in the United States and many older adults worldwide are affected by chronic kidney disease (CKD), which can progress to kidney failure requiring invasive kidney replacement therapy. In this review, we briefly examine the pathophysiology of CKD and discuss emerging mechanisms involving the physiological resolution of kidney injury by transforming growth factor beta 1 (TGFß1) and interleukin-11 (IL-11), as well as the pathological consequences of IL-11 overproduction, which misguides repair processes, ultimately culminating in CKD. Taking these mechanisms into account, we offer an overview of the efficacy of plant-dominant dietary patterns in preventing and managing CKD, while also addressing their limitations in terms of restoring kidney function or preventing kidney failure. In conclusion, this paper outlines novel regeneration strategies aimed at developing a reno-regenerative diet to inhibit IL-11 and promote repair mechanisms in kidneys affected by CKD.

Cell-specific housekeeping role of lncRNAs in COVID-19-infected and recovered patients.

A plethora of studies have demonstrated the roles of lncRNAs in modulating disease severity and outcomes during infection. However, the spatio-temporal expression of these lncRNAs is poorly understood. In this study, we used single-cell RNA-seq to understand the spatio-temporal expression dynamics of lncRNAs across healthy, SARS-CoV-2-infected, and recovered individuals and their functional role in modulating the disease and recovery. We identified 203 differentially expressed lncRNAs, including cell type-specific ones like MALAT1, NEAT1, ZFAS1, SNHG7, SNHG8, and SNHG25 modulating immune function in classical monocyte, NK T, proliferating NK, plasmablast, naive, and activated B/T cells. Interestingly, we found invariant lncRNAs (no significant change in expression across conditions) regulating essential housekeeping functions (for example, HOTAIR, NRAV, SNHG27, SNHG28, and UCA1) in infected and recovered individuals. Despite similar repeat element abundance, variant lncRNAs displayed higher Alu content, suggesting increased interactions with proximal and distal genes, crucial for immune response modulation. The comparable repeat abundance but distinct expression levels of variant and invariant lncRNAs highlight the significance of investigating the regulatory mechanisms of invariant lncRNAs. Overall, this study offers new insights into the spatio-temporal expression patterns and functional roles of lncRNAs in SARS-CoV-2-infected and recovered individuals while highlighting the importance of invariant lncRNAs in the disease context.

Dynamics of Whole Transcriptome Analysis (WTA) and Surface markers expression (AbSeq) in Immune Cells of COVID-19 Patients and Recovered captured through Single Cell Genomics.

Introduction: Single-cell multi-omics studies, such as multidimensional transcriptomics (whole transcriptomic analysis, WTA), and surface marker analysis (antibody sequencing, AbSeq), have turned out to be valuable techniques that offer inaccessible possibilities for single-cell profiling of mRNA, lncRNA, and proteins. Methods: We used this technique to understand the dynamics of mRNA and protein-level differences in healthy, COVID-19-infected and recovered individuals using peripheral blood mononuclear cells (PBMCs). Our results demonstrate that compared to mRNA expression, protein abundance is a better indicator of the disease state. Results: We demonstrate that compared to mRNA expression, protein abundance is a better indicator of the disease state. We observed high levels of cell identity and regulatory markers, CD3E, CD4, CD8A, CD5, CD7, GITR, and KLRB1 in healthy individuals, whereas markers related to cell activation, CD38, CD28, CD69, CD62L, CD14, and CD16 elevated in the SARS-CoV-2 infected patients at both WTA and AbSeq levels. Curiously, in recovered individuals, there was a high expression of cytokine and chemokine receptors (CCR5, CCR7, CCR4, CXCR3, and PTGRD2). We also observed variations in the expression of markers within cell populations under different states. Discussion: Furthermore, our study emphasizes the significance of employing an oligo-based method (AbSeq) that can help in diagnosis, prognosis, and protection from disease/s by identifying cell surface markers that are unique to different cell types or states. It also allows simultaneous study of a vast array of markers, surpassing the constraints of techniques like FACS to query the vast repertoire of proteins.

Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With NPM1 and FLT3 Mutations.

PURPOSE: To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. PATIENTS AND METHODS: One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). RESULTS: There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. CONCLUSION: Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.

Recent Advances in the Biology and CD123-Directed Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases.

A randomised evaluation of low-dose cytosine arabinoside plus lenalidomide versus single-agent low-dose cytosine arabinoside in older patients with acute myeloid leukaemia: Results from the LI-1 trial.

Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI-1 trial, we evaluated lenalidomide (LEN) in combination with low-dose cytosine arabinoside (LDAC) in patients aged >60 years unfit for intensive therapy and compared this to LDAC alone. Two hundred and two patients, randomised 1:1, were evaluable. Overall response rate (CR + CRi) was higher for LDAC + LEN versus LDAC (26% and 13.7% respectively p = 0.031). However, there was no difference in overall survival between the arms (14% and 11.5% at 2 years for LDAC + LEN and LDAC respectively). The addition of LEN was associated with increased toxicity and supportive care requirements.

Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.

ABSTRACT: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.

Geri-Mobile Health: Feasibility of a VA Mental Health Mobile Apps Coaching Program for Older Veterans.

OBJECTIVES: This program evaluation examined the feasibility, acceptability, and preliminary effects of an individualized coaching program to help older Veterans use VA mental health mobile apps to address mental health and well-being goals. METHODS: The program delivers individual technical and clinical support to facilitate the use of mobile devices and VA apps. Participants completed assessments of mobile device proficiency, app use frequency, app comfort, quality of life, and mental health symptoms (completed by a subset, n = 11) pre- and post-participation. RESULTS: Of 24 enrollees, 17 completed the program and received an average of 7.58 (SD = 2.87) sessions including the initial assessment. Mobile device proficiency (t (16) = -3.80, p = .002) and number of days/week apps were used (t (16) = -2.34, p = .032) increased significantly from pre- to post-participation. Depressive and anxiety scores decreased significantly (t (10) = 3.16, p = .010; t (10) = 3.29, p = .008) among the subset completing those measures. Overall satisfaction was high; 100% reported they would recommend the program. CONCLUSIONS: Findings suggest the program is feasible, highly acceptable, and increases mobile device proficiency and use of apps. CLINICAL IMPLICATIONS: Coaching programs can equip older adults with the skills to use mental health apps.

Dementia "e"-consults for Behavioral and Psychological Symptoms of Dementia: Improving access to specialty dementia care for rural Veterans.

OBJECTIVES: This paper characterizes a telephone-based e-consult program designed to assess and treat behavioral and psychological symptoms of dementia (BPSD) for older rural Veterans. METHODS: E-consults required geriatricians to conduct chart review and telephone calls to caregivers to determine behavior triggers, prior management attempts, and medications. Pharmacologic and non-pharmacological recommendations were provided with follow-up calls as needed. RESULTS: Evaluation of 364 Veterans (M age = 80.8, 32% in rural/distal clinics) showed 97% (n = 355) of E-consult interventions included caregiver dementia education to prepare them for managing disease progression and provide non-pharmacological strategies for BPSD. Ninety-four percent (n = 244) of Veterans received medication guidance. A total of 37,504 travel miles was saved, with an average of 108 miles for each Veteran. CONCLUSIONS: Findings support continued implementation of telephone and other virtual modalities of assessing and treating BPSD for older Veterans, thereby increasing access to dementia specialists, especially for rural older adults and their caregivers. A limitation to e-consults is the time needed to provide services compared to the maximum workload credit allowed. CLINICAL IMPLICATIONS: Virtual care improves access to Geriatric specialists and semi-urgent care that otherwise is not available. E-consults are effective in providing primary care providers guidance for diagnosis and management of dementia.

Suppressed transcript diversity and immune response in COVID-19 ICU patients: a longitudinal study.

Understanding the dynamic changes in gene expression during Acute Respiratory Distress Syndrome (ARDS) progression in post-acute infection patients is crucial for unraveling the underlying mechanisms. Study investigates the longitudinal changes in gene/transcript expression patterns in hospital-admitted severe COVID-19 patients with ARDS post-acute SARS-CoV-2 infection. Blood samples were collected at three time points and patients were stratified into severe and mild ARDS, based on their oxygenation saturation (SpO2/FiO2) kinetics over 7 d. Decline in transcript diversity was observed over time, particularly in patients with higher severity, indicating dysregulated transcriptional landscape. Comparing gene/transcript-level analyses highlighted a rather limited overlap. With disease progression, a transition towards an inflammatory state was evident. Strong association was found between antibody response and disease severity, characterized by decreased antibody response and activated B cell population in severe cases. Bayesian network analysis identified various factors associated with disease progression and severity, viz. humoral response, TLR signaling, inflammatory response, interferon response, and effector T cell abundance. The findings highlight dynamic gene/transcript expression changes during ARDS progression, impact on tissue oxygenation and elucidate disease pathogenesis.

Spatial mapping of posture-dependent resistance to passive displacement of the hypertonic arm post-stroke.

BACKGROUND: Muscles in the post-stroke arm commonly demonstrate abnormal reflexes that result in increased position- and velocity-dependent resistance to movement. We sought to develop a reliable way to quantify mechanical consequences of abnormal neuromuscular mechanisms throughout the reachable workspace in the hemiparetic arm post-stroke. METHODS: Survivors of hemiparetic stroke (HS) and neurologically intact (NI) control subjects were instructed to relax as a robotic device repositioned the hand of their hemiparetic arm between several testing locations that sampled the arm's passive range of motion. During transitions, the robot induced motions at either the shoulder or elbow joint at three speeds: very slow (6°/s), medium (30°/s), and fast (90°/s). The robot held the hand at the testing location for at least 20 s after each transition. We recorded and analyzed hand force and electromyographic activations from selected muscles spanning the shoulder and elbow joints during and after transitions. RESULTS: Hand forces and electromyographic activations were invariantly small at all speeds and all sample times in NI control subjects but varied systematically by transport speed during and shortly after movement in the HS subjects. Velocity-dependent resistance to stretch diminished within 2 s after movement ceased in the hemiparetic arms. Hand forces and EMGs changed very little from 2 s after the movement ended onward, exhibiting dependence on limb posture but no systematic dependence on movement speed or direction. Although each HS subject displayed a unique field of hand forces and EMG responses across the workspace after movement ceased, the magnitude of steady-state hand forces was generally greater near the outer boundaries of the workspace than in the center of the workspace for the HS group but not the NI group. CONCLUSIONS: In the HS group, electromyographic activations exhibited abnormalities consistent with stroke-related decreases in the stretch reflex thresholds. These observations were consistent across repeated testing days. We expect that the approach described here will enable future studies to elucidate stroke's impact on the interaction between the neural mechanisms mediating control of upper extremity posture and movement during goal-directed actions such as reaching and pointing with the arm and hand.

Single-cell RNA-Seq reveals intracellular microbial diversity within immune cells during SARS-CoV-2 infection and recovery.

Intracellular microorganisms, like viruses, bacteria, and fungi, pose challenges in detection due to their non-culturable forms. Transcriptomic analysis at cellular level enables exploration of distributions and the impact of these microorganisms on host cells, a domain that remains underexplored because of methodological limitations. Single-cell technology shows promise in addressing this by capturing polyadenine-tailed transcripts, because recent studies confirmed polyadenylation in microbial transcriptomes. We utilized single-cell RNA-seq from PBMCs to probe intracellular microbes in healthy, SARS-CoV-2-positive, and recovered individuals. Among 76 bacterial species detected, 16 showed significant abundance differences. Buchnera aphidicola, Streptomyces clavuligerus, and Ehrlichia canis emerged significantly in memory-B, Naïve-T, and Treg cells. Staphylococcus aureus, Mycoplasma mycoides, Leptospira interrogans, and others displayed elevated levels in SARS-CoV-2-positive patients, suggesting possible disease association. This highlights the strength of single-cell technology in revealing potential microorganism's cell-specific functions. Further research is essential for functional understanding of their cell-specific abundance across physiological states.

Comprehensive immunophenotyping of solid tumor-infiltrating immune cells reveals the expression characteristics of LAG-3 and its ligands.

Background: Immune cell expression profiling from patient samples is critical for the successful development of immuno-oncology agents and is useful to understand mechanism-of-action, to identify exploratory biomarkers predictive of response, and to guide treatment selection and combination therapy strategies. LAG-3 is an inhibitory immune checkpoint that can suppress antitumor T-cell responses and targeting LAG-3, in combination with PD-1, is a rational approach to enhance antitumor immunity that has recently demonstrated clinical success. Here, we sought to identify human immune cell subsets that express LAG-3 and its ligands, to characterize the marker expression profile of these subsets, and to investigate the potential relationship between LAG-3 expressing subsets and clinical outcomes to immuno-oncology therapies. Methods: Comprehensive high-parameter immunophenotyping was performed using mass and flow cytometry of tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs) from two independent cohorts of samples from patients with various solid tumor types. Profiling of circulating immune cells by single cell RNA-seq was conducted on samples from a clinical trial cohort of melanoma patients treated with immunotherapy. Results: LAG-3 was most highly expressed by subsets of tumor-infiltrating CD8 T central memory (TCM) and effector memory (TEM) cells and was frequently co-expressed with PD-1. We determined that these PD-1+ LAG-3+ CD8 memory T cells exhibited a unique marker profile, with greater expression of activation (CD69, HLA-DR), inhibitory (TIM-3, TIGIT, CTLA-4) and stimulatory (4-1BB, ICOS) markers compared to cells that expressed only PD-1 or LAG-3, or that were negative for both checkpoints. In contrast to tumors, LAG-3 expression was more limited in circulating immune cells from healthy donors and solid tumor patients. Additionally, we found abundant expression of the LAG-3 ligands MHC-II and galectin-3 in diverse immune cell types, whereas FGL1 and LSECtin were minimally expressed by immune cells in the tumor microenvironment (TME). Lastly, we found an inverse relationship between baseline and on-treatment levels of circulating LAG3 transcript-expressing CD8 memory T cells and response to combination PD-1 and CTLA-4 blockade in a clinical trial cohort of melanoma patients profiled by scRNAseq. Conclusions: These results provide insights into the nature of LAG-3- and ligand-expressing immune cells within the TME, and suggest a biological basis for informing mechanistic hypotheses, treatment selection strategies, and combination immunotherapy approaches to support continued development of dual PD-1 and LAG-3 blockade.

Dysregulated metal ion homeostasis underscores non-canonical function of CD8+ T cell during COVID-19.

Introduction: Several efforts have been made to describe the complexity of T cell heterogeneity during the COVID-19 disease; however, there remain gaps in our understanding in terms of the granularity within. Methods: For this attempt, we performed a single-cell transcriptomic analysis of 33 individuals (4 healthy, 16 COVID-19 positive patients, and 13 COVID-19 recovered individuals). Results: We found CD8+ T cell-biased lymphopenia in COVID-19 patients compared to healthy and recovered individuals. We also found an optimal Th1/Th2 ratio, indicating an effective immune response during COVID-19. Expansion of activated CD4+ T and NK T was detected in the COVID-19-positive individuals. Surprisingly, we found cellular and metal ion homeostasis pathways enriched in the COVID-19-positive individuals compared to the healthy and recovered in the CD8+ T cell populations (CD8+ TCM and CD8+ TEM) as well as activated CD4+ T cells. Discussion: In summary, the COVID-19-positive individuals exhibit a dynamic T cell mediated response. This response may have a possible association with the dysregulation of non-canonical pathways, including housekeeping functions in addition to the conventional antiviral immune response mediated by the T cell subpopulation. These findings considerably extend our insights into the heterogeneity of T cell response during and post-SARS-CoV-2 infection.

Benchmarking of the Cervical Cancer Care Cascade and Survival Outcomes After Radiation Treatment in a Low- and Middle-Income Country Setting.

PURPOSE: Timely radiation treatment (RT) is critical in cervical cancer treatment, but patients in low- and middle-income countries (LMICs) in sub-Saharan Africa often face barriers that delay care. Time to care was benchmarked in a multidisciplinary team (MDT) setting in Botswana. METHODS: Time intervals between steps in care were recorded for 230 patients reviewed at MDT between January 2016 and July 2018. Associations between RT delay and overall survival (OS) were evaluated using Kaplan-Meier curves and multivariable Cox proportional hazards models. RESULTS: For patients who received RT (n = 187; 81.3%), the median biopsy to pathology reporting interval was 25 (IQR, 19-36) days and was 57 (IQR, 28-68) days for patients who did not (P = .003). Intervals in care did not differ between patients who did and did not receive RT. Among treated patients, the uppermost quartile interval from pathology reporting to RT initiation was ≥111 days and that from RT simulation to initiation was ≥12 days. Among patients receiving a RT dose of ≥65 Gy (n = 100), the delay from RT simulation to initiation of >12 days was associated with worse median OS (2.0 v 4.6 years; P = .048); this association trended toward, although did not meet, statistical significance on multivariable analysis (hazard ratio, 2.35; 95% CI, 0.95 to 5.85; P = .07). CONCLUSION: The MDT-coordinated care model allows for systematic benchmarking of the patient treatment cascade. Barriers to timely treatment exist for this cohort in Botswana, and RT delay may be associated with OS of patients receiving curative treatment. Interventions to accelerate the timing of the radiation oncology care cascade may improve clinical outcomes in this LMIC setting.

Metagenomic signatures reveal the key role of phloretin in amelioration of gut dysbiosis attributed to metabolic dysfunction-associated fatty liver disease by time-dependent modulation of gut microbiome.

The importance of gut-liver axis in the pathophysiology of metabolic dysfunction-associated fatty liver disease (MAFLD) is being investigated more closely in recent times. However, the inevitable changes in gut microbiota during progression of the disease merits closer look. The present work intends to assess the time-dependent gut dysbiosis in MAFLD, its implications in disease progression and role of plant-derived prebiotics in its attenuation. Male C57BL/6J mice were given western diet (WD) for up to 16 weeks and phloretin was administered orally. The fecal samples of mice were collected every fourth week for 16 weeks. The animals were sacrificed at the end of the study and biochemical and histological analyses were performed. Further, 16S rRNA amplicon sequencing analysis was performed to investigate longitudinal modification of gut microbiome at different time points. Findings of our study corroborate that phloretin alleviated the metabolic changes and mitigated circulating inflammatory cytokines levels. Phloretin treatment resists WD induced changes in microbial diversity of mice and decreased endotoxin content. Prolonged exposure of WD changed dynamics of gut microbiota abundance and distribution. Increased abundance of pathogenic taxa like Desulfovibrionaceae, Peptostreptococcus, Clostridium, and Terrisporobacter was noted. Phloretin treatment not only reversed this dysbiosis but also modulated taxonomic signatures of beneficial microbes like Ruminococcus, Lactobacillus, and Alloprevotella. Therefore, the potential of phloretin to restore gut eubiosis could be utilized as an intervention strategy for the prevention of MAFLD and related metabolic disorders.