Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRß chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

A comparison of the outcomes of pulmonary versus extrapulmonary extensive-stage small cell carcinoma.

BACKGROUND: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1-0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features. AIMS: We conducted a retrospective cohort study comparing the outcomes of extensive-stage (ES) SCLC and EPSCC. METHODS: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and overall response rates (ORRs). RESULTS: Three hundred and eighty-four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5-1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58-1.46, P = 0.74) and ORR were 73% versus 68%. CONCLUSIONS: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics.

Exploring Changes in Myocyte Structure, Contractility, and Energetics From Mechanical Unloading in Patients With Heart Failure Undergoing Ventricular Assist Device Implantation: A Systematic Review and Meta-Analysis.

AIMS: Recent reports of myocardial recovery after mechanical unloading with left ventricular assist devices (LVADs) have challenged the prevailing notion that end-stage heart failure (HF) is irreversible. To improve our understanding of this phenomenon, we comprehensively analysed the structural, functional, and energetic changes in failing human cardiomyocytes after LVAD implantation. METHODS: Based on a prospectively registered protocol (PROSPERO-CRD42022380214), 30 eligible studies were identified from 940 records with a pooled population of 648 patients predominantly with non-ischaemic cardiomyopathy. RESULTS: LVAD led to a substantial regression in myocyte size similar to that of donor hearts (standardised mean difference, -1.29; p<0.001). The meta-regression analysis revealed that HF duration was a significant modifier on the changes in myocyte size. There were some suggestions of fibrosis reversal (-5.17%; p=0.009); however, this was insignificant after sensitivity analysis. Developed force did not improve in cardiac trabeculae (n=5 studies); however, non-physiological isometric contractions were tested. At the myocyte level (n=4 studies), contractile kinetics improved where the time-to-peak force reduced by 41.7%-50.7% and time to 50% relaxation fell by 47.4%-62.1% (p<0.05). Qualitatively, LVAD enhanced substrate utilisation and mitochondrial function (n=6 studies). Most studies were at a high risk of bias. CONCLUSION: The regression of maladaptive hypertrophy, partial fibrosis reversal, and normalisation in metabolic pathways after LVAD may be a testament to the heart's remarkable plasticity, even in the advanced stages of HF. However, inconsistencies exist in force-generating capabilities. Using more physiological force-length work-loop assays, addressing the high risks of bias and clinical heterogeneity are crucial to better understand the phenomenon of reverse remodelling.

Myocardial Fatigue at a Glance.

Expanding on the modern lexicon of heart failure (HF), the novel mechano-energetic concept of myocardial fatigue describes a transiently energy-depleted myocardium with impaired contractility and relaxation in the face of adverse haemodynamic load. It encompasses established concepts of ventricular-arterial decoupling, deranged cardiac energetics and impaired myocardial efficiency, offering an alternative explanation for functional causes of HF.

The Role of the Vasculature in Heart Failure.

The contribution of the vasculature in the development and progression of heart failure (HF) syndromes is poorly understood and often neglected. Incorporating both arterial and venous systems, the vasculature plays a significant role in the regulation of blood flow throughout the body in meeting its metabolic requirements. A deterioration or imbalance between the cardiac and vascular interaction can precipitate acute decompensated HF in both preserved and reduced ejection fraction phenotypes. This is characterised by the increasingly recognised concept of ventricular-arterial coupling: a well-balanced relationship between ventricular and vascular stiffness, which has major implications in HF. Often, the cause of decompensation is unknown, with international guidelines mainly centred on arrhythmia, infection, acute coronary syndrome and its mechanical complications as common causes of decompensation; the vascular component is often underrecognised. A better understanding of the vascular contribution in cardiovascular failure can improve risk stratification, earlier diagnosis and facilitate earlier optimal treatment. This review focuses on the role of the vasculature by integrating the concepts of ventricular-arterial coupling, arterial stiffness and venous return in a failing heart.

Disparities in nonmelanoma skin cancer in Hispanic/Latino patients based on Mohs micrographic surgery defect size: A multicenter retrospective study.

BACKGROUND: There is limited literature regarding potential disparities in nonmelanoma skin cancer for patients with skin of color. OBJECTIVE: Use the sizes of Mohs micrographic surgery defects to examine disparities in nonmelanoma skin cancer among Hispanic/Latino patients with a secondary aim to examine the effect of insurance type. METHODS: We conducted a multicenter retrospective study using data from 3 major institutions in Los Angeles County. A total of 3486 Mohs micrographic surgeries of basal cell, squamous cell, and basosquamous cell carcinomas were analyzed. RESULTS: Mohs micrographic surgery defect sizes were 17% larger among Hispanic/Latino patients compared with non-Hispanic White patients. More notably, when comparing defect sizes of squamous cell carcinomas to those of basal cell carcinomas, defects were 80% larger among Hispanic/Latino patients compared to non-Hispanic White patients who had 25% larger defect sizes. Compared to patients with Medicare, patients with health maintenance organization and Medicaid/health maintenance organization had 22% and 52% larger defect sizes, respectively, whereas patients with preferred provider organization, had 10% smaller defect sizes. LIMITATIONS: The data included were from a single county population. CONCLUSION: Disparities regarding nonmelanoma skin cancer exist between patients with skin of color and White patients. Patients and the medical community need to be cognizant that skin cancer can develop in patients regardless of their race and ethnicity.

Myocardial Fatigue: a Mechano-energetic Concept in Heart Failure.

PURPOSE OF REVIEW: This review combines existing mechano-energetic principles to provide a refreshing perspective in heart failure (HF) and examine if the phenomenon of myocardial fatigue can be rigorously tested in vitro with current technological advances as a bridge between pre-clinical science and clinical practice. RECENT FINDINGS: As a testament to the changing paradigm of HF pathophysiology, there has been a shift of focus from structural to functional causes, as reflected in its modern universal definition and redefined classification. Bolstered by recent landmark trials of sodium-glucose cotransport-2 inhibitors across the HF spectrum, there is a rekindled interest to revisit the basic physiological tenets of energetic efficiency, metabolic flexibility, and mechanical load on myocardial performance. Indeed, these principles are well established in the study of skeletal muscle fatigue. Since both striated muscles share similar sarcomeric building blocks, is it possible that myocardial fatigue can occur in the face of sustained adverse supra-physiological load as a functional cause of HF? Myocardial fatigue is a mechano-energetic concept that offers a novel functional mechanism in HF. It is supported by current studies on exercise-induced cardiac fatigue and reverse translational science such as from recent landmark trials on sodium glucose co-transporter 2 inhibitors in HF. We propose a novel framework of myocardial fatigue, injury, and damage that aligns with the contemporary notion of HF as a continuous spectrum, helps determine the chance and trajectory of myocardial recovery, and aims to unify the plethora of cellular and molecular mechanisms in HF.

Iatrogenic Decompensated Heart Failure.

PURPOSE OF REVIEW: To provide an overview of the potential iatrogenic causes of acute decompensated heart failure (AHF) and an evidence-based management strategy to address this. RECENT FINDINGS: As the heart failure (HF) population continues to age and become burdened with greater comorbidities and polypharmacy, patients become more susceptible to the iatrogenic precipitants of HF. The following clinical scenarios are familiar to clinicians, but the sequelae to AHF are often unanticipated: HF medications withdrawn during an intercurrent illness and not restarted, cardiotoxic therapy prescribed for cancer without timely and regular monitoring of left ventricular function, excessive intravenous fluids administered for sepsis or postoperatively, a blood transfusion volume not adjusted for body weight, iatrogenic anaemia that goes unnoticed or an inappropriate type of pacemaker implanted in a patient with underlying left ventricular systolic dysfunction. Iatrogenic decompensated HF is a phenomenon that is infrequently documented in the literature but increasingly confronted by clinicians of all specialties. It is associated with a high mortality and morbidity rate. By having greater awareness of these triggers, iatrogenic AHF should be one that is prevented rather than managed when it occurs.

Inferior Vena Cava Filter Evaluation and Management for the Diagnostic Radiologist: A Comprehensive Review Including Inferior Vena Cava Filter-Related Complications and PRESERVE Trial Filters.

Inferior vena cava filters are commonly encountered devices on diagnostic imaging that were highlighted in a 2010 Food and Drug Administration safety advisory regarding their complications from long-term implantation. The Predicting the Safety and Effectiveness of Inferior Vena Cava Filters (PRESERVE) trial is an ongoing after-market study investigating the safety and utility of commonly utilized filters in practice today. While most of these filters are safe, prompt recognition and management of any filter-associated complication is imperative to prevent or reduce the morbidity and mortality associated with them. This review is aimed at discussing the appropriate utilization and placement of inferior vena cava filters in addition to the recognition of filter-associated complications on cross-sectional imaging. An overview of the PRESRVE trial filters is also provided to understand each filter's propensity for specific complications.

Verrucous melanoma masquerading as a seborrheic keratosis.

Seborrheic keratosis is a benign condition that can mimic many different non-melanoma and melanoma neoplasms. There have been several case reports of underlying squamous cell carcinomas or intraepidermal carcinomas appearing within lesions that look analogous to seborrheic keratoses. We present a patient with a verrucous melanoma that could be mistaken for a benign skin tumor like an inflamed seborrheic keratosis. In our patient's case, her verrucous plaque was initially clinically suggestive of a benign seborrheic keratosis. However, given the patient's complaint of pain associated with the lesion, a biopsy was performed and revealed a verrucous-keratotic malignant melanoma, which was subsequently removed through surgical excision. It is important to remain vigilant of this diagnosis, as treatment for inflamed seborrheic keratosis often includes a trial of cryotherapy, which potentially could lead to a delayed diagnosis of an underlying malignant lesion.

Atypical cellular neurothekeoma: A potential diagnostic pitfall for benign and malignant spindle cell lesions in skin.

Cellular neurothekeomas (CNTs) are rare, benign cutaneous tumors that arise primarily on the head and neck, with a slight female predominance. CNTs with atypical features have been described, including those with an infiltrative growth pattern. Although CNTs with atypical features are benign, recognition of this entity can pose diagnostic challenges. Here, we report a case of CNT with an unusual clinical presentation on the left second digit, and with atypical histological features including an infiltrative growth pattern, which could have been mistaken for features of malignancy.

An unusual clinical presentation of myxoid dermatofibrosarcoma protuberans with a prominent vasculature: A potential pitfall in the diagnosis of myxoid soft tissue tumors.

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue tumor that arises primarily on the trunk and extremities but seldom on the scalp. Several variants of DFSP have been described, including myxoid DFSP. Although typical DFSP may have focally myxoid areas, myxoid DFSP, in which most of the stroma is myxoid, is rare and can pose diagnostic challenges. Here, we report a case of myxoid DFSP with an unusual clinical presentation that could have been mistaken for a lipoma. Additionally, the myxoid DFSP displayed prominent vasculature in a myxoid stroma, which could have been mistaken for a myxoid liposarcoma.

Pain catastrophizing mediates the relationship between trait happiness and depressive symptoms in individuals with current pain.

OBJECTIVE: There is an extensive relationship between chronic pain and depression; however, there is less research examining whether pain-specific factors, such as pain intensity, predict depression, above and beyond the role of normative factors, such as positive emotions. The current study characterized the independent contributions of pain intensity, pain catastrophizing, and a trait measure of happiness to self-rated depressive symptoms. METHODS: We recruited and enrolled 70 volunteers across 3 groups of participants: two groups of patients with current low back pain (one group on opioids and one group opioid-naïve), and individuals in a methadone maintenance treatment program. RESULTS: Of note, participants reporting concurrent opioid use reported significantly higher levels of depressive symptomatology, although study groups did not differ on any other clinical variables. In our path model, we failed to find direct relationships between pain (intensity or duration) and either trait happiness or depressive symptoms (p > .05). However, our analysis did reveal that individuals with chronic back pain who reported higher levels of trait happiness reported lower levels of depressive symptomatology; this effect was significantly mediated by lower levels of pain catastrophizing (standardized ab = -.144, p = .002). CONCLUSION: Our analysis suggests that trait happiness, while unrelated to ongoing pain, may predict a decreased vulnerability to depressive symptoms in individuals with chronic pain, which may operate via lower levels of pain catastrophizing.

Quantitative Aggregation of Microbiome Sequencing Data Provides Insights into the Associations between the Skin Microbiome and Psoriasis.

Although prior studies have reported distinct skin microbiome profiles associated with psoriasis, differences in methods and analyses limit generalizable conclusions. Individual studies have actually reported conflicting findings; for example, Propionibacterium and Staphylococcus have been significantly associated with both psoriatic lesions and healthy skin. Qualitative reviews have attempted to summarize this body of work, but there is great variability across the studies' findings and methods. To better unify these data, we created a meta-analysis of all publicly available datasets by utilizing a uniform bioinformatics pipeline and reference database to investigate associations of the skin microbiome in psoriasis. A total of 977 skin swab samples (341 lesional, 295 nonlesional, and 341 healthy) from 6 studies were analyzed. The aggregated analysis revealed a higher relative abundance of microorganisms, including Staphylococcus aureus and Corynebacterium simulans, among others, from patients with psoriasis than those from healthy swab samples; in addition, Cutibacterium acnes, Lawsonella unclassified, and S warneri were significantly higher in healthy samples. Furthermore, comparison of functional pathways predicted from 16S gene markers showed that L-ornithine biosynthesis and L-histidine biosynthesis were lower in psoriatic lesions than in healthy controls. Taken together, this meta-analysis allows for a more generalizable association between the skin microbiome and psoriasis.

Poly(U) polymerase activity in Caenorhabditis elegans regulates abundance and tailing of sRNA and mRNA.

Terminal nucleotidyl transferases add nucleotides to the 3' end of RNA to modify their stability and function. In Caenorhabditis elegans, the terminal uridyltransferases/poly(U) polymerases PUP-1 (aka CID-1, CDE-1), PUP-2, and PUP-3 affect germline identity, survival, and development. Here, we identify small RNA (sRNA) and mRNA targets of these PUPs and of a fourth predicted poly(U) polymerase, F43E2.1/PUP-4. Using genetic and RNA sequencing approaches, we identify RNA targets of each PUP and the U-tail frequency and length of those targets. At the whole organism level, PUP-1 is responsible for most sRNA U-tailing, and other PUPs contribute to modifying discrete subsets of sRNAs. Moreover, expression of PUP-2, PUP-3, and especially PUP-4 limit uridylation on some sRNAs. The relationship between uridylation status and sRNA abundance suggests that U-tailing can have a negative or positive effect on abundance depending on context. sRNAs modified by PUP activity primarily target mRNAs that are ubiquitously expressed or most highly expressed in the germline. mRNA data obtained with a Nanopore-based method reveal that addition of U-tails to non-adenylated mRNA is substantially reduced in the absence of PUP-3. Overall, this work identifies PUP RNA targets, defines the effect of uridylation loss on RNA abundance, and reveals the complexity of PUP regulation in C. elegans development.

Giant Klebsiella pneumoniae pyogenic liver abscess in the left liver lobe presenting with dyspepsia and vaginal discharge.

Pyogenic liver abscess (PLA) commonly occurs in the right liver lobe, causing the typical symptoms of fever and right upper quadrant pain. Less than one-third of cases occur in the left lobe. We describe an unusual presentation of a giant left-sided PLA that was compressing the stomach and surrounding venous vasculature, causing the respective symptoms of gastro-oesophageal reflux and vaginal discharge from secondary pelvic congestion syndrome. CT revealed a solitary 14 cm×10 cm×10 cm multiloculated lesion, replacing most of the left liver lobe. It was successfully treated with intravenous antibiotics and percutaneous drainage, resulting in complete resolution at 1-year follow-up. This case explores the predisposing risk factor of diabetes in PLA and its association with Klebsiella pneumoniae, which was the offending pathogen in our patient. We also discuss the phenomenon of secondary pelvic venous congestion syndrome and compare similar cases of left-sided PLA, highlighting the different modes of presentation and treatment options.

Real-world evaluation of glucose-lowering therapies and the use of weight-adjusted variable rate intravenous insulin infusion in the management of hyperglycaemia in patients with acute coronary syndrome (REGULATE-ACS).

INTRODUCTION: Admission hyperglycaemia in acute coronary syndromes (ACS) is a strong independent predictor of adverse clinical outcomes post-ACS. We examined the safety, efficacy, and feasibility of a modified, weight-adjusted variable rate intravenous insulin infusion (VRIII) and evaluated current practice of prescribing novel cardio-protective glucose-lowering therapies in patients presenting with acute hyperglycaemia across the ACS spectrum. METHODS: REGULATE-ACS was an observational single-centre study of consecutive patients admitted with acute hyperglycaemia post-ACS between 2020 and 2021. Following updated local guidance on a modified VRIII, we evaluated its safety and efficacy in glycaemic control, cardio-metabolic complications including hypoglycaemia (blood glucose <3 mmol/L) and 30-day mortality. We also determined the prescription of glucose-lowering therapies pre-discharge. RESULTS: Out of 107 patients, mean age was 64.9 ± 12.2 years, 82% had known diabetes, and 15% newly diagnosed diabetes. 86.9% (n = 93) had an admission glucose ≥11 mmol/L. In patients treated with VRIII (n = 63/93, 67.7%), glucose improved from 17.5 to 9.0 mmol/L (IQR 7.1-12.1), which was 3 mmol/L lower (p = 0.03) than in patients not treated with VRIII (n = 30/93, 32.3%) where median glucose reduced from 12.6 to 12 mmol/L (IQR 8.6-13.9). No significant hypoglycaemia, arrhythmia or worsening pulmonary oedema associated with VRIII was found. Novel glucose-lowering therapies were initiated in 20/71 (28.2%) and 3/15 (20.0%) of patients with prior and newly diagnosed diabetes, respectively. CONCLUSION: This real-world analysis provides further support of efficacy, safety, and feasibility of a modified, weight-adjusted VRIII in managing acute hyperglycaemia in ACS. Despite established cardio-protective benefits of novel glucose-lowering therapies, <1/3 of eligible patients received such agents pre-discharge, demanding further research and awareness.

Profiling the Biomechanical Responses to Workload on the Human Myocyte to Explore the Concept of Myocardial Fatigue and Reversibility: Rationale and Design of the POWER Heart Failure Study.

It remains unclear why some patients develop heart failure without evidence of structural damage. One theory relates to impaired myocardial energetics and ventricular-arterial decoupling as the heart works against adverse mechanical load. In this original study, we propose the novel concept of myocardial fatigue to capture this phenomenon and aim to investigate this using human cardiomyocytes subjected to a modern work-loop contractility model that closely mimics in vivo cardiac cycles. This proof-of-concept study (NCT04899635) will use human myocardial tissue samples from patients undergoing cardiac surgery to develop a reproducible protocol to isolate robust calcium-tolerant cardiomyocytes. Thereafter, work-loop contractility experiments will be performed over a range of preload, afterload and cycle frequency as a function of time to elicit any reversible reduction in contractile performance (i.e. fatigue). This will provide novel insight into mechanisms behind heart failure and myocardial recovery and serve as a valuable research platform in translational cardiovascular research.

Rising arterial stiffness with accumulating comorbidities associates with heart failure with preserved ejection fraction.

AIMS: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular-vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. METHODS AND RESULTS: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near-normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = -0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e') on echocardiography (r = -0.307, P = 0.014). CONCLUSIONS: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at-risk intermediate phenotypes (e.g. pre-HFpEF) before overt HFpEF occurs.