Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities.

Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen-binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.

Cysteine Oxidation in Human Galectin-1 Occurs Sequentially via a Folded Intermediate to a Fully Oxidized Unfolded Form.

Galectins are multifunctional effectors in cellular homeostasis and dysregulation. Oxidation of human galectin-1 (Gal-1) with its six sulfhydryls produces a disulfide-bridged oxidized form that lacks normal lectin activity yet gains new glycan-independent functionality. Nevertheless, the mechanistic details as to how Gal-1 oxidation occurs remain unclear. Here, we used 15N and 13C HSQC NMR spectroscopy to gain structural insight into the CuSO4-mediated path of Gal-1 oxidation and identified a minimum two-stage conversion process. During the first phase, disulfide bridges form slowly between C16-C88 and/or C42-C66 to produce a partially oxidized, conformationally flexible intermediate that retains the ability to bind lactose. Site-directed mutagenesis of C16 to S16 impedes the onset of this overall slow process. During the second phase, increased motional dynamics of the intermediate enable the relatively distant C2 and C130 residues to form the third and final disulfide bond, leading to an unfolded state and consequent dimer dissociation. This fully oxidized end state loses the ability to bind lactose, as shown by the hemagglutination assay. Consistent with this model, we observed that the Gal-1 C2S mutant maintains intermediate-state structural features with a free sulfhydryl group at C130. Incubation with dithiothreitol reduces all disulfide bonds and allows the lectin to revert to its native state. Thus, the sequential, non-random formation of three disulfide bridges in Gal-1 in an oxidative environment acts as a molecular switch for fundamental changes to its functionality. These data inspire detailed bioactivity analysis of the structurally defined oxidized intermediate in, e.g., acute and chronic inflammation.

FOUND Trial: randomised controlled trial study protocol for case finding of obstructive sleep apnoea in primary care using a novel device.

INTRODUCTION: Obstructive sleep apnoea (OSA) is a common, but underdiagnosed, sleep disorder. If untreated, it leads to poor health outcomes, including Alzheimer's disease, cancer, cardiovascular disease and all-cause mortality. Our aim is to determine the feasibility and cost-effectiveness of moving the testing for OSA into general practice and how general practitioner (GP)-based screening affects overall detection rates. METHODS AND ANALYSIS: Randomised controlled trial of case finding of OSA in general practice using a novel Medicines and Healthcare products Regulatory Agency-registered device (AcuPebble SA100) compared with usual care with internal feasibility phase. A diverse sample of general practices (approximately 40) from across the West Midlands Clinical Research Network will identify participants from their records. Eligible participants will be aged 50-70 years with body mass index >30 kg/m2 and diabetes (type 1 or 2) and/or hypertension (office blood pressure >145/90 mm Hg or on treatment). They will exclude individuals with known OSA or chronic obstructive pulmonary disease, or those they deem unable to take part. After eligibility screening, consent and baseline assessment, participants will be randomised to either the intervention or control group. Participants in the intervention arm will receive by post the AcuPebble sleep test kit. Those in the control arm will continue with usual care. Follow-up questionnaires will be completed at 6 months. The study is powered (90%) to detect a 5% difference and will require 606 patients in each arm (713 will be recruited to each arm to allow for attrition). Due to the nature of the intervention, participants and GPs will not be blinded to the allocation. OUTCOMES: Primary: Detection rate of moderate-to-severe OSA in the intervention group versus control group. Secondary: Time to diagnosis and time to treatment for intervention versus control group for mild, moderate and severe OSA; cost-effectiveness analysis comparing the different testing pathways. ETHICS AND DISSEMINATION: The trial started on 1 November 2022. Ethical approval was granted from the South Central Oxford A Research Ethics Committee on 9 June 2023 (23/SC/0188) (protocol amendment version 1.3; update with amendment and approval to renumber to V2.0 on 29 August 2023). Patient recruitment began on 7 January 2024; initial planned end date will be on 31 April 2025.Results will be uploaded to the ISRCTN register within 12 months of the end of the trial date, presented at conferences, submitted to peer-reviewed journals and distributed via our patient and public involvement networks.The University of Warwick will act as the trial sponsor. The trial will be conducted in accordance with the Sponsor and Primary Care Clinical Trials Unit standard operating procedures. TRIAL REGISTRATION NUMBER: ISRCTN 16982033.

Pre-Frailty and Frailty in Hospitalized Older Adults: A Comparison Study in People with and without a History of Cancer in an Acute Medical Unit.

A prospective observational study was conducted in a cohort of older adults ≥65 years (n = 329), admitted to the acute medical unit (AMU) of a tertiary hospital, to describe and compare characteristics including frailty status and clinical outcomes. Multivariable models compared older adults with and without a history of cancer to determine characteristics associated with frailty and pre-frailty. An adjusted Poisson regression model was used to compare the length of hospital stay (LOS) between the two groups. About one-fifth (22%) of the cohort had a history of cancer. The most common cancer types were prostate (n = 20), breast (n = 13), lung (n = 8) and gastrointestinal (n = 8). There was no difference in the prevalence of pre-frailty/frailty among patients with or without a history of cancer (58% vs. 57%, p > 0.05). Pre-frailty/frailty was associated with polypharmacy (OR 8.26, 95% CI: 1.74 to 39.2) and malnutrition (OR 8.91, 95% CI: 2.15 to 36.9) in patients with a history of cancer. Adjusted analysis revealed that the risk of having a longer LOS was 24% higher in older adults with a history of cancer than those without (IRR 1.24, 95% CI 1.10 to 1.41, p < 0.001). Clinicians in the AMU should be aware that older adults with a history of cancer have a higher risk of a longer LOS compared to those without.

Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial.

The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.

A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells.

BAX and BAK are pro-apoptotic members of the BCL2 family that are required to permeabilize the mitochondrial outer membrane. The proteins can adopt a non-activated monomeric conformation, or an activated conformation in which the exposed BH3 domain facilitates binding either to a prosurvival protein or to another activated BAK or BAX protein to promote pore formation. Certain cancer cells are proposed to have high levels of activated BAK sequestered by MCL1 or BCLXL, thus priming these cells to undergo apoptosis in response to BH3 mimetic compounds that target MCL1 or BCLXL. Here we report the first antibody, 14G6, that is specific for the non-activated BAK conformer. A crystal structure of 14G6 Fab bound to BAK revealed a binding site encompassing both the α1 helix and α5-α6 hinge regions of BAK, two sites involved in the unfolding of BAK during its activation. In mitochondrial experiments, 14G6 inhibited BAK unfolding triggered by three diverse BAK activators, supporting crucial roles for both α1 dissociation and separation of the core (α2-α5) and latch (α6-α9) regions in BAK activation. 14G6 bound the majority of BAK in several leukaemia cell lines, and binding decreased following treatment with BH3 mimetics, indicating only minor levels of constitutively activated BAK in those cells. In summary, 14G6 provides a new means of assessing BAK status in response to anti-cancer treatments.

Iatrogenic Cerebrospinal Fluid Breast Augmentation: Rare Complication of Ventriculoperitoneal Shunts and Management Strategies.

BACKGROUND: Ventriculoperitoneal shunt is one of the most common neurosurgical procedures in the treatment of hydrocephalus. There are reports of migration of the distal catheter to the breast pocket where cerebrospinal fluid then collects and can develop into a pseudocyst. There exist case reports in the literature of patients with prior breast augmentation who present with distal catheter migration from the peritoneal space into the breast tissue. We present a case series of 3 patients with preexisting breast augmentation who returned with unilateral breast enlargement after ventriculoperitoneal shunt. In all 3 patients, the distal catheter migrated out of the peritoneal space and was found to be coiled around the breast prosthesis. Additionally, we offer recommendations for managing these complications and a review of the literature. METHODS: We performed a systematic review without meta-analysis of studies involving management of shunt migration in the setting of preexisting breast implants. We present a case series of 3 patients whom we treated with breast cerebrospinal pseudocyst after migration of the distal catheter into the breast tissue. RESULTS: A total of 17 studies, dating from 2002 to 2022, met our inclusion and exclusion criteria and were selected for full review. Catheter migration occurred between 2 weeks and 9 months of initial shunt placement. All patients presented with unilateral breast enlargement and cerebrospinal fluid pseudocyst formation. All patients underwent revision shunt surgery. Surgical treatment strategies used included reimplantation of the distal catheter into the pleural space or ipsilateral or contralateral peritoneal space or complete removal of the entire shunt system. CONCLUSIONS: Breast-related ventriculoperitoneal shunt complication is a rare entity that is increasingly seen as more patients receive breast augmentation. Breast-related shunt complications most commonly present with cerebrospinal fluid pseudocyst formation in the breast. It is important for neurosurgeons to be aware of an underlying breast implant before placing a ventriculoperitoneal shunt. For patients who have migration of the distal catheter into the breast, a protocol for managing these situations should be followed to ensure no shunt infection and avoidance of future catheter migration complications with subsequent shunt revisions.

Sequence differences between BAX and BAK core domains manifest as differences in their interactions with lipids.

The B-cell lymphoma 2 (BCL2) family members, BCL2-associated protein X (BAX) and BCL2 homologous antagonist killer (BAK), are required for programmed cell death via the mitochondrial pathway. When cells are stressed, damaged or redundant, the balance of power between the BCL2 family of proteins shifts towards BAX and BAK, allowing their transition from an inactive, monomeric state to a membrane-active oligomeric form that releases cytochrome c from the mitochondrial intermembrane space. That oligomeric state has an essential intermediate, a symmetric homodimer of BAX or BAK. Here we describe crystal structures of dimers of the core domain of BAX, comprising its helices α2-α5. These structures provide an atomic resolution description of the interactions that drive BAX homo-dimerisation and insights into potential interaction between core domain dimers and membrane lipids. The previously identified BAK lipid-interacting sites are not conserved with BAX and are likely to determine the differences between them in their interactions with lipids. We also describe structures of heterodimers of BAK/BAX core domains, yielding further insight into the differences in lipid binding between BAX and BAK.

Seizure outcomes following single-fraction versus hypofractionated radiosurgery for brain metastases: a single-center experience.

OBJECTIVE: Although seizures are a relatively common phenomenon in the setting of brain metastases (BMs), there are no discrete recommendations regarding the use of antiepileptic drugs (AEDs) in this population, either in general or in the context of treatment. The authors' aim was to better understand the underlying pathological factors as well as the therapeutic techniques that may lead to seizures following the radiosurgical treatment of BMs with the goal of guiding appropriate AED prophylaxis. METHODS: Adult patients with BMs diagnosed from 2013 to 2020 at a single academic institution and treated with radiation therapy were included in this study. The authors evaluated factors associated with the incidence of seizures throughout the disease course, with a focus on seizures in the 90-day period following stereotactic radiosurgery (SRS). RESULTS: Four hundred forty-four patients with newly diagnosed BMs were identified, 10% of whom had seizures at the time of presentation and 28% of whom had a seizure at any point during the study period. Tumor histology was significantly associated with initial seizure risk. AED use was highly variable. In the 90-day post-SRS period, the summed total planning target volume (PTV) was independently predictive of post-SRS seizures, regardless of the fractionation scheme (single fraction vs hypofractionated) and other clinical factors. The number of supratentorial BMs was not predictive of post-SRS seizures. CONCLUSIONS: PTV is a superior predictor of post-SRS seizures relative to the number of supratentorial BMs, as it serves as a volumetric proxy for intracranial disease burden. A larger PTV, alongside tumor histology and prior seizure history, should be considered in the decision-making process for AED use following radiosurgery.

Validation of Anti-Adeno Associated Virus Serotype rh10 (AAVrh.10) Total and Neutralizing Antibody Immunogenicity Assays.

Immunogenicity assessment of Adeno-Associated Virus (AAV) vectors is a critical part of gene therapy drug development. Whether the assays are used for inclusion/exclusion criteria or to monitor the safety and efficacy of the gene therapy, they are critical bioanalytical assessments. While total anti-AAV assays are perceived as easier to develop and implement than neutralizing anti-AAV assays, the gene therapy field is still nascent, and it is not yet clear which of the assays should be implemented at what stage of drug development. Recently AAVrh.10 has gained interest for use in gene therapies targeting cardiac, neurological, and other diseases due to its enhanced transduction efficiency. There is limited information on anti-AAVrh.10 antibodies and their clinical impact; thus, the information presented herein documents the validation of both a total antibody assay (TAb) and a neutralizing antibody (NAb) assay for anti-AAVrh.10 antibodies. In this manuscript, the validation was performed in accordance with the 2019 FDA immunogenicity guidance with additional evaluations to comply with CLIA where applicable. The AAVrh.10 TAb and NAb assays were compared in terms of sensitivity, drug tolerance, and precision, along with a concordance analysis using the same individual serum samples. This comparison gave insight into the utility of each format as a screening assay for inclusion into clinical studies.

"There could be something going wrong and I wouldn't even know": a qualitative study of perceptions of people with cancer about cardiovascular disease (CVD) risk and its management.

PURPOSE: Despite being at higher risk, many people with cancer do not receive adequate cardiovascular disease (CVD) risk assessment or management. The purpose of this research was to examine people with cancer's perceptions, experiences and needs regarding CVD risk factor awareness, assessment and management. METHODS: We conducted 15 individual interviews to examine people with cancer's perspectives regarding CVD care in cancer. Reflexive thematic analysis was utilised to collect and organise data into themes and to synthesise findings. RESULTS: Fifteen people (6 males) diagnosed with diverse cancer types participated. Majority participants were not or only somewhat aware of CVD risk in cancer, but all expressed it was an important issue. A diverse range of priorities and needs for CVD care was discussed, including some participants' prioritisation of dealing with cancer and preferred amount, type and manner of information provision and support. Websites and brochures were identified as potential solutions for optimising CVD care. CONCLUSIONS: Codesign methodology should be used to engage patients in the development of flexible, tailored resources to increase awareness of CVD risk and strategies for its management. IMPLICATIONS FOR CANCER SURVIVORS: Perceptions of people with cancer regarding CVD care can inform new interventions that reduce the impact of CVD in cancer.

Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen.

Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRASG12V peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions.

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.

Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.

BACKGROUND AND OBJECTIVE: Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment. METHODS: A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed. RESULTS: Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady­state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady­state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile. CONCLUSIONS: From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.

Reducing the impact of cardiovascular disease in older people with cancer: a qualitative study of healthcare providers.

PURPOSE: Cancer survivors are at greater risk of cardiovascular disease (CVD) than cancer-free controls. Despite evidence-based guidelines recommending CVD risk factor assessment, surveillance and risk-reduction, many people with cancer do not receive adequate CVD care. To address potential barriers and enablers of care, we examined healthcare professionals' (HCPs) perceptions and experiences of CVD risk assessment and management in people with cancer. METHODS: We conducted one focus group and 12 individual interviews to examine HCPs' perceptions and experiences of CVD care in care. We used reflexive thematic analysis to collect and analyse the qualitative data to construct and understand themes. RESULTS: Twenty-one HCPs participated (8 oncologists, 5 nurses, 3 general practitioners, 2 dietitians, 1 cardiologist, 1 haematologist and 1 physiotherapist). Majority of HCPs were aware of CVD risk in cancer but were concerned they could not deliver CVD care alone due to system-level barriers including lack of time and training. HCPs also perceived patient-level barriers including socioeconomic disadvantage and fatalistic outlook. Despite barriers, HCPs suggested diverse solutions for improving CVD care in cancer including new models-of-care, clinical pathways, risk assessment/management tools and education. CONCLUSIONS: The diversity of perceived barriers and suggested solutions identified by HCPs suggests the need for a multilevel approach tailored to context. Future research involving people with cancer is needed to co-design acceptable interventions. IMPLICATIONS FOR CANCER SURVIVORS: Improved understanding of HCP's perceptions can inform the development of new interventions to deliver CVD care to people with cancer to reduce morbidity and mortality.

Low muscle mass determined by psoas muscle area does not correlate with dual-energy x-ray absorptiometry or total lumbar muscle mass scores: A prospective cohort study of patients undergoing vascular surgery.

Background/Objective: Low muscle mass and sarcopenia have been explored as risk factors for poor outcomes following vascular surgery. The findings have been variable. The use of a diverse range of techniques to identify low muscle mass is a confounder in establishing the true relationship between low muscle mass, sarcopenia and outcomes. Our aim was to establish if different scoring methods identified the same patients as sarcopenic. We also explored which method best predicted outcomes. Method: 70 patients undergoing vascular surgery were prospectively assessed for sarcopenia using dual-energy x-ray absorptiometry (DEXA) scan, grip strength and gait speed. These patients underwent abdominal CT imaging as routine care. The muscle mass of each patient was determined using DEXA and by both psoas muscle and total skeletal muscle area on CT, normalised for patient height (PMI and CT-SMI, respectively). Low muscle mass was defined by published age- and sex-specific cut-offs. Grip strength data was combined with muscle mass to define sarcopenic patients. One- and 3-year mortality and time to readmission was recorded. Conclusion and Results: 10-22% of patients had low muscle mass and 4-10% of patients were sarcopenic, depending on the method employed. PMI did not correlate with DEXA or CT-SMI for low muscle mass, but CT-SMI correlated with DEXA (p = 0.0007). For sarcopenia, CT-SMI and DEXA scoring correlated (p = 0.002); PMI correlated with CT-SMI (p = 0.0006) but not DEXA. Low muscle mass by PMI predicted 1-year mortality (p = 0.02, X2 = 5.34, Effect size = 1.04) but the applicability of this finding is limited by the diverse pathologies explored. No other method predicted 1- or 3-year mortality or readmissions in this heterogenous cohort. The psoas area did not correlate with muscle mass defined by DEXA or total lumbar skeletal muscle area. Low psoas muscle index may be an independent marker of poor outcome, unrelated to generalised sarcopenia, and this warrants investigation in specific pathologies. A lower total number of patients were sarcopenic than had been expected, emphasising the need to use population-based pre-defined cut-offs.

The ability of the Global Leadership Initiative on Malnutrition (GLIM) to diagnose protein-energy malnutrition in patients requiring vascular surgery: a validation study.

Identifying nutritional deficits and implementing appropriate interventions in patients requiring vascular surgery is challenging due to the paucity of appropriate screening and assessment tools in this group. This retrospective study aimed to determine the validity of the Global Leadership Initiative on Malnutrition (GLIM) in identifying protein-energy malnutrition (PEM) in inpatients admitted to a vascular surgery unit, using the PG-SGA as the comparator. Diagnostic accuracy and consistency were determined between the GLIM and the Patient-Generated Subjective Global Assessment (PG-SGA) global rating. The GLIM determination was made retrospectively using the relevant parameters collected at baseline in the original study. Two hundred and twenty-four (70·1 % male) participants were included. The prevalence of PEM was 28·6 % on GLIM and 17 % via the PG-SGA. Compared with the PG-SGA, the GLIM achieved sensitivity of 73·7 % and specificity of 80·6 %; however positive predictive value was 43·7 % indicating that the GLIM over-diagnosed malnutrition compared with the PG-SGA. Kappa reached 0·427 indicating moderate diagnostic consistency. Due to the absence of an ideal instrument and the complexity of malnutrition often seen in this group which extends beyond PEM to significant micronutrient deficiencies, further work is required to determine the most appropriate instrument in this patient group, and how micronutrient status can also be included in the overall assessment given the critical role of micronutrients in this group.

Effect of anti-inflammatory diets on inflammation markers in adult human populations: a systematic review of randomized controlled trials.

CONTEXT: Chronic inflammation, characterized by prolonged elevated inflammation markers, is linked to several chronic conditions. Diet can influence the levels of inflammation markers in the body. OBJECTIVE: The aim of this systematic review was to assess the effects of anti-inflammatory diets on 14 different inflammation markers in adults. DATA SOURCES: This systematic review conducted searches using Medline, PubMed, EMCare, Cochrane, and CINAHL, to locate randomized controlled trials (RCTs). DATA EXTRACTION: Two researchers independently screened 1537 RCTs that measured changes in inflammation markers after prescription of an intervention diet. DATA ANALYSIS: In total, 20 RCTs were included and assessed qualitatively. The results demonstrated that a Mediterranean diet can bring about statistically significant and clinically meaningful between-group differences in interleukins -1α, -1ß, -4, -5, -6, -7, -8, -10, and -18, interferon γ, tumor necrosis factor α, C-reactive protein, and high-sensitivity C-reactive protein, as compared with a control diet. CONCLUSIONS: There may be a link between diet, inflammation markers, and disease outcomes in various adult populations. However, further research using consistent RCT protocols is required to determine correlations between diet, specific inflammation markers, and clinically relevant outcomes.

Physical activity interventions in older people with cancer: A review of systematic reviews.

INTRODUCTION: Whilst there has been a wealth of research on benefits of physical activity (PA) in people with cancer, with three published reviews of reviews, no review of reviews has focused on older adults (65 years or older) who may have unique biological characteristics and barriers. We summarised PA effectiveness from reviews where majority of study participants were 65 years or older. METHODS: Six databases were searched for systematic reviews of randomised controlled studies (RCTs)/quasi-RCTs examining any type of PA in reviews where majority of study participants were aged 65 years or older. Two reviewers conducted the search and analysis according to PRISMA and JBI guidelines. RESULTS: Fifteen reviews involving 76 different primary studies (5404 participants) were included. The majority (3827; 71%) had prostate cancer. PA was associated with benefits across multiple physical outcomes (muscle mass, functional performance, strength), improved fatigue and health service outcomes. In contrast to younger adults, there was no improvement in anxiety and mixed findings for quality of life and depression. CONCLUSION: PA is associated with multiple benefits in older adults with cancer, with some differences compared to younger individuals which may reflect biological or behavioural determinants. Future research should focus on mechanisms underlying PA effectiveness and underrepresented populations.

Paraganglioma masquerading as a primary liver lesion: A rare entity discovered during surgery.

A 54-year-old woman with controlled hypertension presented with abdominal pain and weight loss. Imaging revealed a 6.6 cm liver lesion. During resection, she became severely hypertensive and diagnosis was paraganglioma. Hepatic paragangliomas are exceedingly rare but must be considered in the differential of abdominal mass even without typical clinical symptoms.