Challenges in Receiving Care for Long COVID: A Qualitative Interview Study Among Primary Care Patients About Expectations and Experiences.

BACKGROUND: For many patients with post-COVID-19 condition (long COVID), primary care is the first point of interaction with the health care system. In principle, primary care is well situated to manage long COVID. Beyond expressions of disempowerment, however, the patient's perspective regarding the quality of long COVID care is lacking. Therefore, this study aimed to analyze the expectations and experiences of primary care patients seeking treatment for long COVID. METHODS: A phenomenological approach guided this analysis. Using purposive sampling, we conducted semistructured interviews with English-speaking, adult primary care patients describing symptoms of long COVID. We deidentified and transcribed the recorded interviews. Transcripts were analyzed using inductive qualitative content analysis. RESULTS: This article reports results from 19 interviews (53% female, mean age = 54 years). Patients expected their primary care practitioners (PCPs) to be knowledgeable about long COVID, attentive to their individual condition, and to engage in collaborative processes for treatment. Patients described 2 areas of experiences. First, interactions with clinicians were perceived as positive when clinicians were honest and validating, and negative when patients felt dismissed or discouraged. Second, patients described challenges navigating the fragmented US health care system when coordinating care, treatment and testing, and payment. CONCLUSION: Primary care patients' experiences seeking care for long COVID are incongruent with their expectations. Patients must overcome barriers at each level of the health care system and are frustrated by the constant challenges. PCPs and other health care professionals might increase congruence with expectations and experiences through listening, validating, and advocating for patients with long COVID.

Digital Intervention Promoting Physical Activity in People Newly Diagnosed with Parkinson's Disease: Feasibility and Acceptability of the Knowledge, Exercise-Efficacy and Participation (KEEP) Intervention.

Background: Exercise promotion interventions for people with Parkinson's disease (PD) are often offered on a face-to-face basis, follow a generic "one-size-fit-all" approach, and are not typically delivered at diagnosis. Considering PD's heterogenous nature, the existing evidence on the merits of exercise on symptom management and the expressed wishes of people living with PD for access to timely and tailored evidence-based information, there is a demand for interventions that are easily accessible, scalable and co-designed with people living with PD. Objective: Evaluate the feasibility and acceptability of a co-designed digital intervention promoting exercise and physical activity, in people newly diagnosed with PD. Methods: Thirty people living with PD for less than one year participated in an assessor-blinded randomized feasibility trial from June 2022 to April 2023. The intervention group received the 8-week Knowledge, Exercise Efficacy and Participation (KEEP) intervention comprising 6 interactive digital modules and 4 online live group discussions facilitated by a specialist physiotherapist. Assessments were performed at baseline, post intervention and at 6-month follow up. Results: Thirty participants were recruited to target with a 64% recruitment rate (30/47). All but one participant completed the 6-month follow-up assessment. There was high retention (97%), module completion (91%), and online discussion attendance (88%). Outcome measure collection was feasible, including accelerometer data with a daily average wear time of 23.9 hours (SD:0.295). Conclusions: The KEEP intervention was feasible and acceptable in people newly diagnosed with PD. A larger trial is needed to assess intervention efficacy and correlation between knowledge, self-efficacy, and activity levels.

Exercise and physical activity have been found beneficial in managing both motor and non-motor symptoms in people living with Parkinson's. But there aren't many programs available right after diagnosis that focus on exercise and explain why it's important for managing PD symptoms and how to exercise with PD. Most existing programs use a one-size-fit-all approach and don't give personalized information. In this study, researchers wanted to see if people who were recently diagnosed with PD would join a study promoting exercise through an online program. This program included educational information and live online group discussions with both people living with Parkinson's and a specialist physiotherapist. The program was developed together with people living with Parkinson's and healthcare professionals to ensure that it better suited the needs of people newly diagnosed with PD. Thirty people took part in the study. They were randomly put into two groups: one received the online program, while the other group continued with their usual care. Participants filled out questionnaires and wore a wrist accelerometer for seven days to track their physical activity levels. The researchers found that most participants stayed in the study (97%), completed the program modules (91%), and attended the live discussions (88%) and wore the accelerometers for 23.9 hours a day on average. Overall, the study showed that the program was doable and well-received. Participants said they had a better understanding on the benefits of exercise in PD. However, a larger study is needed to see if the program helps increase activity levels.

AAPM Task Group Report 299: Quality control in multi-energy computed tomography.

Multi-energy computed tomography (MECT) offers the opportunity for advanced visualization, detection, and quantification of select elements (e.g., iodine) or materials (e.g., fat) beyond the capability of standard single-energy computed tomography (CT). However, the use of MECT requires careful consideration as substantially different hardware and software approaches have been used by manufacturers, including different sets of user-selected or hidden parameters that affect the performance and radiation dose of MECT. Another important consideration when designing MECT protocols is appreciation of the specific tasks being performed; for instance, differentiating between two different materials or quantifying a specific element. For a given task, it is imperative to consider both the radiation dose and task-specific image quality requirements. Development of a quality control (QC) program is essential to ensure the accuracy and reproducibility of these MECT applications. Although standard QC procedures have been well established for conventional single-energy CT, the substantial differences between single-energy CT and MECT in terms of system implementations, imaging protocols, and clinical tasks warrant QC tests specific to MECT. This task group was therefore charged with developing a systematic QC program designed to meet the needs of MECT applications. In this report, we review the various MECT approaches that are commercially available, including information about hardware implementation, MECT image types, image reconstruction, and postprocessing techniques that are unique to MECT. We address the requirements for MECT phantoms, review representative commercial MECT phantoms, and offer guidance regarding homemade MECT phantoms. We discuss the development of MECT protocols, which must be designed carefully with proper consideration of MECT technology, imaging task, and radiation dose. We then outline specific recommended QC tests in terms of general image quality, radiation dose, differentiation and quantification tasks, and diagnostic and therapeutic applications.

Remote ischaemic preconditioning on gene expression and circulating proteins after subacute laparoscopic cholecystectomy: randomized clinical trial.

BACKGROUND: Surgical stress may lead to postsurgical hypercoagulability, endothelial dysfunction and systemic inflammation, which can impact on patient recovery. Remote ischaemic preconditioning is a procedure that activates the body's endogenous defences against ischaemia and reperfusion injury. Studies have suggested that remote ischaemic preconditioning has antithrombotic, antioxidative and anti-inflammatory effects. The hypothesis was that remote ischaemic preconditioning reduces surgery-induced systemic stress response. METHOD: During a 24-month period (2019-2021), adult patients undergoing subacute laparoscopic cholecystectomy due to acute cholecystitis were randomized to remote ischaemic preconditioning or control. Remote ischaemic preconditioning was performed less than 4 h before surgery on the upper arm. It consisted of four cycles of 5 min ischaemia and 5 min reperfusion. The gene expression of 750 genes involved in inflammatory processes, oxidative stress and endothelial function was investigated preoperatively and 2-4 h after surgery in both groups. In addition, changes in 20 inflammation- and vascular trauma-associated proteins were assessed preoperatively, 2-4 h after surgery and 24 h after surgery. RESULTS: A total of 60 patients were randomized. There were no statistically significant differences in gene expression 2-4 h after surgery between the groups (P > 0.05). Remote ischaemic preconditioning did not affect concentrations of circulating proteins up to 24 h after surgery (P > 0.05). CONCLUSION: The study did not demonstrate any effect of remote ischaemic preconditioning on expression levels of the chosen genes or in circulating immunological cytokines and vascular trauma-associated proteins up to 24 h after subacute laparoscopic cholecystectomy in patients with acute cholecystitis.

Impact of coding risk variant IFNGR2 on the B cell-intrinsic IFN-γ signaling pathway in multiple sclerosis.

B cells of people with multiple sclerosis (MS) are more responsive to IFN-γ, corresponding to their brain-homing potential. We studied how a coding single nucleotide polymorphism (SNP) in IFNGR2 (rs9808753) co-operates with Epstein-Barr virus (EBV) infection as MS risk factors to affect the IFN-γ signaling pathway in human B cells. In both cell lines and primary cells, EBV infection positively associated with IFN-γ receptor expression and STAT1 phosphorylation. The IFNGR2 risk SNP selectively promoted downstream signaling via STAT1, particularly in transitional B cells. Altogether, EBV and the IFNGR2 risk SNP independently amplify IFN-γ signaling, potentially driving B cells to enter the MS brain.

Comparing Medicare Fee-for-Service Beneficiaries with ESKD who Switched to Medicare Advantage versus Remained in Traditional Medicare.

ABSTRACT: Patients choosing Medicare Advantage vs. Medicare fee-for-service (FFS) differ with respect to race, socioeconomic status, and burden of disease. However, it is unclear whether these differences also occur among patients with kidney failure, who were newly allowed to switch to Medicare Advantage after the 21st Century Cares Act. We used data from the United States Renal Data System (USRDS) to examine differences in characteristics of dialysis patients and kidney transplant recipients who switched from FFS to Medicare Advantage compared with those who stayed with FFS in 2021, the first year such switching was allowed. We used unadjusted and adjusted logistic regression to compare odds of switching among demographic and geographic subgroups. Among 411,513 patients with FFS coverage in 2020, 10.1% switched to Medicare Advantage in 2021. Switchers constituted 12% of the dialysis population and 5% of the kidney transplant population. In the dialysis population, patients of Black race and Hispanic ethnicity were more likely to switch than patients of White race (adjusted OR 1.69, 95% Confidence Interval [CI] 1.64, 1.73 and OR 1.42, 95% CI 1.40, 1.47, respectively), as were patients with dual eligibility for Medicaid (adjusted OR 1.12, 95% CI 1.09, 1.15). Patients living in the South were also more likely to switch to Medicare Advantage than those living in the West (adjusted OR 1.48, 95% CI 1.43, 1.52). Similar differences were observed among kidney transplant recipients. Patients who switched from FFS to Medicare Advantage were disproportionately from historically marginalized groups, including Black, Hispanic, and low income individuals. They were also more likely to live in the South. These differences may threaten the generalizability of USRDS data that relies on FFS insurance claims and suggest that comparisons of outcomes between FFS and MA beneficiaries with kidney failure should be adjusted for key patient characteristics.

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.

To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS-driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer. We established that ERK controls a highly dynamic and complex phosphoproteome that converges on cyclin-dependent kinase regulation and RAS homolog guanosine triphosphatase function (RHO GTPase). Our findings establish the most comprehensive molecular portrait and mechanisms by which ERK drives KRAS-dependent pancreatic cancer growth.

Comparison of In-person Versus Online Comprehensive Pelvic Floor Rehabilitation Program Following Prostatectomy.

OBJECTIVE: To compare continence outcomes in post-prostatectomy patients undergoing supervised in-person versus online pelvic floor muscle training and pelvic floor education (iPMFT vs oPFMT/PFE). Despite the proven benefit of in-person PFMT for urinary incontinence (UI) following prostatectomy, numerous barriers impede access. We developed a comprehensive online program to deliver oPFMT/PFE. METHODS: We performed a retrospective review of patients receiving iPFMT versus oPFMT/PFE with minimum 12-month follow-up. Outcomes were assessed at 3 weeks, 3-, 6-, and 12 months following robotic-assisted laparoscopic prostatectomy using validated ICIQ-MLUTS and IIQ-7 questionnaires and additional items (daily pad use [PPD] and satisfaction). The primary study outcome was ICIQ-MLUTS SUI domain score (SDS). Secondary outcomes were PPD, PPD cure (0 PPD at 12 months), SUI cure (12-month SDS=baseline score), and QOL score (IIQ-7 Sum). RESULTS: Analysis included 41 men. Though men enrolled in oPFMT/PFE demonstrated lower SUI domain scores than iPFMT at most time points (3wk P <.01, 3 mo P = .04, 6 mo P = .15, 12 mo P = .04), the rate of improvement from 3 weeks to other time points was similar between groups (P = NS at all time points). SDS Cure was no different for oPFMT/PFE (75%, 15/20) compared to iPFMT (60%, 12/20, P = .3). PPD and IIQ-7 were also similar at all time points and demonstrated a similar rate of decrease over time through 12 months. CONCLUSION: Significant and similar improvements in UI and QOL are seen both in men completing iPFMT or oPFMT/PFE programs. Our novel online program provides another option to improve PFMT/PFE access in men undergoing RALP.

Effects of feeding α-amylase-expressed corn silage and grain on performance, enteric methane production, and carcass characteristics in beef steers.

An experiment was conducted to evaluate the effects of feeding Enogen feed corn (EFC) silage or EFC grain with different grain processing (dry-rolled corn vs. whole-shelled corn) in feedlot cattle diets. Total 68 Angus cross-bred steers were blocked by body weight and the treatments (diets) were randomly assigned to steers in each block: a basal diet with isoline corn silage and isoline dry-rolled corn grain (IIR); the basal diet with EFC silage and isoline dry-rolled corn grain (EIR); the basal diet with EFC silage and EFC dry-rolled grain (EER); and the basal diet with EFC silage and EFC whole-shelled grain (EEW). Isoline refers to the isogenic counterpart of Enogen corn silage or grain. Steers received the assigned treatment over 32 wk of the entire experiment (backgrounding and finishing) until harvested. Part of the steers (eight blocks) in each treatment were used to measure CH4 production (g/d) using the GreenFeed and CH4 production per unit of DMI. All data were analyzed using a mixed procedure of SAS in a randomized complete block design, considering diet as a fixed effect and block as a random effect. Steers fed the EIR diet increased (P = 0.03) DMI compared to IIR during the backgrounding phase. However, feeding EFC silage or grain did not affect body weight, average daily gain, and feed efficiency during backgrounding and finishing phases. Feeding EEW decreased (P ≤ 0.05) body weight, average daily gain, feed efficiency, and tended to decrease (P = 0.06) hot carcass weight compared to EER during the finishing phase. Methane production per unit of DMI decreased (P = 0.02) for steers fed EIR compared with steers fed IIR only during the backgrounding phase. Feeding EFC grain had no effect on CH4 production (g/d) in both phases. In conclusion, feeding EFC silage or grain did not improve the performance of beef steers during the backgrounding and finishing phases in the current experiment condition. Methane production per unit of DMI was reduced for steers fed EFC silage compared with isoline corn silage only during the backgrounding phase.

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors.

Cancer cells convert nutrients into energy differently compared to healthy cells. This difference in metabolism allows them to grow and divide more quickly and sometimes to migrate to different areas of the body. The environment around cancer cells ­ known as the tumor microenvironment ­ contains a variety of different cells and blood vessels, which are bathed in interstitial fluid. This microenvironment provides nutrients for the cancer cells to metabolize, and therefore influences how well a tumor grows and how it might respond to treatment. Recent advances with techniques such as mass spectrometry, which can measure the chemical composition of a substance, have allowed scientists to measure nutrient levels in the tumor microenvironments of mice. However, it has been more difficult to conduct such studies in humans, as well as to compare the tumor microenvironment to the healthy tissue the tumors arose from. Abbott, Ali, Reinfeld et al. aimed to fill this gap in knowledge by using mass spectrometry to measure the nutrient levels in the tumor microenvironment of 55 patients undergoing surgery to remove kidney tumors. Comparing the type and levels of nutrients in the tumor interstitial fluid, the neighboring healthy kidney and the blood showed that nutrients in the tumor and healthy kidney were more similar to each other than those in the blood. For example, both the tumor and healthy kidney interstitial fluids contained less glucose than the blood. However, the difference between nutrient composition in the tumor and healthy kidney interstitial fluids was insignificant, suggesting that the healthy kidney and its tumor share a similar environment. Taken together, the findings indicate that kidney cancer cells must adapt to the nutrients available in the kidney, rather than changing what nutrients are available in the tissue. Future studies will be required to investigate whether this finding also applies to other types of cancer. A better understanding of how cancer cells adapt to their environments may aid the development of drugs that aim to disrupt the metabolism of tumors.

Level of BPA contamination in resin composites determines BPA release.

OBJECTIVES: Resin composites may release bisphenol A (BPA) due to impurities present in the monomers. However, there is a lack of knowledge regarding the leaching characteristics of BPA from resin composites. Therefore, experimental resin composites were prepared with known amounts of BPA. The objective of this study was (1) to determine which amount of BPA initially present in the material leaches out in the short term and, (2) how this release is influenced by the resin composition. METHODS: BPA (0, 0.001, 0.01, or 0.1 wt%) was added to experimental resin composites containing 60 mol% BisGMA, BisEMA(3), or UDMA, respectively, as base monomer and 40 mol% TEGDMA as diluent monomer. Polymerized samples (n = 5) were immersed at 37 °C for 7 days in 1 mL of water, which was collected and refreshed daily. BPA release was quantified with UPLC-MS/MS after derivatization with pyridine-3-sulfonyl chloride. RESULTS: Between 0.47 to 0.67 mol% of the originally added BPA eluted from the resin composites after 7 days. Similar elution trends were observed irrespective of the base monomer. Two-way ANOVA showed a significant effect of the base monomer on BPA release, but the differences were small and not consistent. SIGNIFICANCE: The released amount of BPA was directly proportional to the quantity of BPA present in the resin composite as an impurity. BPA release was mainly diffusion-based, while polymer composition seemed to play a minor role. Our results underscore the importance for manufacturers only to use monomers of the highest purity in dental resin composites to avoid unnecessary BPA exposure in patients.

Exploring the influence of activity participation on the economic value of nature-based recreation in the Sierra Nevada.

A more comprehensive understanding of how recreational values and forest visitation rates vary across different activities enables forest managers to tailor conservation and management strategies to align with preferences among visitors, ensuring more effective allocation of budgetary resources. However, current research often focuses on only a few recreational activities, resulting in limited insights for forest managers. This study aims to expand the nature-based activities considered so that management can better serve the broader public. We conduct a travel cost analysis using a large survey-based dataset to estimate the value of nature-based recreation in national forests in the Sierra Nevada region and assess how these values differ across main activities. We categorize recreational activities into five broad groups (Passive, Active, Camping, Winter, and Other) to offer a comprehensive view of recreational preferences. A truncated negative binomial regression accounting for endogenous stratification is used to analyze the relationship between the number of trips to the forests, travel cost, activity categories, and socio-demographic variables. Our results suggest a mean consumer surplus (CS) of $65 per visit per person to national forests in the Sierra Nevada. Aggregated over annual per person visits, the total CS is approximately $313.3 million per year. Our findings reveal variations in CS across activity groups, with winter activities (e.g., skiing, snowboarding) and active activities (e.g., hiking, fishing) attracting the highest number of visits, and the highest total CS. Our results provide valuable insights for national forest managers, facilitating the strategic allocation of limited resources to recreational activities that maximize societal welfare.

Magnet-assisted endoscopic removal of ferromagnetic metallic gastric foreign bodies in 4 dogs.

OBJECTIVE: Describe presenting signs, diagnostic findings, and magnet-assisted endoscopic removal method of ferromagnetic gastric foreign bodies (FBs) in dogs. CLINICAL PRESENTATION: Four dogs presented with ingestion of sharp metallic FBs. The presence of gastric FBs was confirmed by abdominal radiography. RESULTS: In 3 cases, initial attempts at endoscopic removal were unsuccessful because of ingesta and fluid in the stomach. A magnet contained within a Roth net was introduced endoscopically. Magnet and attached objects were successfully removed from the stomach. In the fourth case, removal with a magnet was judged to be the most expedient method of removal because multiple metallic objects were present. CLINICAL RELEVANCE: An endoscopic technique was used for the removal of difficult-to-visualize or multiple metallic FBs. The use of this technique allows the removal of ferromagnetic gastric FBs without surgery or risk of complications associated with the passage of sharp material through the gastrointestinal (GI) tract.

Long-term outcomes of revision total hip arthroplasty with the Zimmer Modular Revision hip system.

Aims: There are limited long-term studies reporting on outcomes of the Zimmer Modular Revision (ZMR) stem, and concerns remain regarding failure. Our primary aim was to determine long-term survival free from all-cause revision and stem-related failure for this modular revision stem in revision total hip arthroplasty (THA). Secondary aims included evaluating radiological and functional outcomes. Methods: We retrospectively identified all patients in our institutional database who underwent revision THA using the ZMR system from January 2000 to December 2007. We included 106 patients (108 hips) with a mean follow-up of 14.5 years (2.3 to 22.3). Mean patient age was 69.2 years (37.0 to 89.4), and 51.9% were female (n = 55). Indications for index revision included aseptic loosening (73.1%), infection (16.7%), fracture (9.3%), and stem fracture (0.9%). Kaplan-Meier analysis was used to determine the all-cause and stem-related failure revision-free survival. At most recent follow-up, Oxford Hip Scores (OHS) were collected, and radiological stem stability was determined using the Engh classification. Results: A total of 17 hips (15.7%) underwent re-revision of any component. Indications for re-revision were stem failure (35.3%; n = 6), infection (29.4%; n = 5), instability (29.4%; n = 5), and acetabular aseptic loosening (5.9%; n = 1). The five- and 15-year all-cause survival was 89.7% (95% confidence interval (CI) 86.7 to 92.7) and 83.3% (95% CI 79.6 to 87.0), respectively. There were six re-revisions (5.6%) for stem failure; five for stem fracture and one for aseptic loosening. The five- and 15-year survival free from stem-related failure was 97.2% (95% CI 95.6 to 98.8) and 94.0% (95% CI 91.6 to 96.4), respectively. At final follow-up, the mean OHS was 36.9 (8.0 to 48.0) and 95.7% (n = 66) of surviving modular revision stems were well-fixed in available radiographs. Conclusion: Femoral revision with the ZMR offers satisfactory long-term all-cause revision-free survival, good survival free of stem-related failure, and favourable clinical outcomes. Stem fracture was the most common reason for stem-related failure and occurred both early and late. This highlights the importance of both early and long-term surveillance for stem-related failure.

FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

A cohort study of sodium-glucose cotransporter-2 inhibitors after acute kidney injury among Veterans with diabetic kidney disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a 110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not.

Diet and physical activity interventions to improve cardiovascular disease risk factors in liver transplant recipients: Systematic review and meta-analysis.

BACKGROUND AND AIMS: Cardiovascular disease, associated risk factors and obesity are prevalent after liver transplant and modifiable through lifestyle changes. Understanding what lifestyle interventions and their respective components are effective is essential for translation to clinical practice. We aimed to investigate the effects of diet and physical activity interventions on weight, body mass index and other cardiovascular disease risk factors in liver transplant recipients, and systematically describe the interventions. METHODS: We systematically searched Embase, MEDLINE, Psycho Info, CINAHL, Cochrane central register of controlled trials, PeDro, AMED, BNI, Web of Science, OpenGrey, ClinicalTrials.gov and the international clinical trials registry from inception to 31 May 2023. Search results were screened by two independent reviewers: randomised control trials with interventions that targeted diet and physical activity behaviours in liver transplant recipients were considered eligible. Two independent reviewers extracted and synthesised data for study, participant and intervention details and results. We used the Revised Cochrane Risk of Bias Tool for Randomised Trials to assess risk of bias for outcomes and the GRADE approach to rate the quality of the body of evidence. When two or more studies reported findings for an outcome, we pooled data using random-effects meta-analysis. RESULTS: Six studies were included, reporting three physical activity and three combined diet and physical activity interventions. Participants were 2 months-4 years post-transplant. Interventions lasted 12 weeks-10 months and were delivered remotely and/or in-person, most commonly delivered to individual participants by health care or sports professionals. Five studies described individual tailoring, e.g. exercise intensity. Adherence to interventions ranged from 51% to 94%. No studies reported fidelity. Intervention components were not consistently reported. In meta-analysis, diet and physical activity interventions did not significantly reduce weight or body mass index compared to control groups, however no studies targeted participants with obesity. Diet and physical activity interventions reduced percentage body fat and triglycerides compared to control groups but did not reduce total cholesterol or increase activity. The GRADE quality of evidence was low or very low. CONCLUSION: Diet and physical activity interventions reduced percentage body fat and triglycerides in liver transplant recipients. Further good quality research is needed to evaluate their effect on other cardiovascular disease risk factors, including weight and BMI. Interventions need to be better described and evaluated to improve evidence base and inform patient care.