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Preclinical and clinical studies on the administration of bone marrow-derived cells to restore perfusion show conflicting results. We conducted a systematic review and meta-analysis on preclinical studies to assess the efficacy of bone marrow-derived cells in the hind limb ischemia model and identify possible determinants of therapeutic efficacy. In vivo animal studies were identified using a systematic search in PubMed and EMBASE on 10 January 2022. 85 studies were included for systematic review and meta-analysis. Study characteristics and outcome data on relative perfusion were extracted. The pooled mean difference was estimated using a random effects model. Risk of bias was assessed for all included studies. We found a significant increase in perfusion in the affected limb after administration of bone marrow-derived cells compared to that in the control groups. However, there was a high heterogeneity between studies, which could not be explained. There was a high degree of incomplete reporting across studies. We therefore conclude that the current quality of preclinical research is insufficient (low certainty level as per GRADE assessment) to identify specific factors that might improve human clinical trials., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Context: Each year the European Association of Urology (EAU) produce a document based on the most recent evidence on the diagnosis, therapy, and follow-up of testicular cancer (TC)., Objective: To represent a summarised version of the EAU guidelines on TC for 2023 with a focus on key changes in the 2023 update., Evidence Acquisition: A multidisciplinary panel of TC experts, comprising urologists, medical and radiation oncologists, and pathologists, reviewed the results from a structured literature search to compile the guidelines document. Each recommendation in the guidelines was assigned a strength rating., Evidence Synthesis: For the 2023 EAU guidelines on TC, a review and restructure were undertaken. The key changes incorporated in the 2023 update include: new supporting text regarding venous thromboembolism prophylaxis in males with metastatic germ cell tumours receiving chemotherapy; quality of life after treatment; an update of the histological classifications and inclusion of the World Health Organization 2022 pathological classification; inclusion of the revalidation of the 1997 International Germ Cell Cancer Collaborative Group prognostic risk factors; and a new section covering oncology treatment protocols., Conclusions: The 2023 version of the EAU guidelines on TC include the highest available scientific evidence to standardise the management of TC. Better stratification and optimisation of treatment modalities will continue to improve the high survival rates for patients with TC., Patient Summary: This article presents a summary of the European Association of Urology guidelines on testicular cancer published in 2023 and includes the latest recommendations for management of this disease. The guidelines are a valuable resource that may help patients in understanding treatment recommendations., (Copyright © 2023. Published by Elsevier B.V.)

Cellular immune responses are of pivotal importance to understand SARS-CoV-2 pathogenicity. Using an enzyme-linked immunosorbent spot (ELISpot) interferon-γ release assay with wild-type spike, membrane and nucleocapsid peptide pools, we longitudinally characterized functional SARS-CoV-2 specific T-cell responses in a cohort of patients with mild, moderate and severe COVID-19. All patients were included before emergence of the Omicron (B.1.1.529) variant. Our most important finding was an impaired development of early IFN-γ-secreting virus-specific T-cells in severe patients compared to patients with moderate disease, indicating that absence of virus-specific cellular responses in the acute phase may act as a prognostic factor for severe disease. Remarkably, in addition to reactivity against the spike protein, a substantial proportion of the SARS-CoV-2 specific T-cell response was directed against the conserved membrane protein. This may be relevant for diagnostics and vaccine design, especially considering new variants with heavily mutated spike proteins. Our data further strengthen the hypothesis that dysregulated adaptive immunity plays a central role in COVID-19 immunopathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rümke, Smit, Bossink, Limonard, Muilwijk, Haas, Reusken, van der Wal, Thio, van Os, Gremmels, Beekman, Nijhuis, Wensing, Heron and Thijsen.)

Circadian rhythms influence the recruitment of immune cells and the onset of inflammation, which is pivotal in the response to ischemic cardiac injury after a myocardial infarction (MI). The hyperacute immune response that occurs within the first few hours after a MI has not yet been elucidated. Therefore, we characterized the immune response and myocardial damage 3 hours after a MI occurs over a full twenty-four-hour period to investigate the role of the circadian rhythms in this response. MI was induced at Zeitgeber Time (ZT) 2, 8, 14, and 20 by permanent ligation of the left anterior descending coronary artery. Three hours after surgery, animals were terminated and blood and hearts collected to assess the immunological status and cardiac damage. Blood leukocyte numbers varied throughout the day, peaking during the rest-phase (ZT2 and 8). Extravasation of leukocytes was more pronounced during the active-phase (ZT14 and 20) and was associated with greater chemokine release to the blood and expression of adhesion molecules in the heart. Damage to the heart, measured by Troponin-I plasma levels, was elevated during this time frame. Clock gene oscillations remained intact in both MI-induced and sham-operated mice hearts, which could explain the circadian influence of the hyperacute inflammatory response after a MI. These findings are in line with the clinical observation that patients who experience a MI early in the morning (i.e., early active phase) have worse clinical outcomes. This study provides further insight on the immune response occurring shortly after an MI, which may contribute to the development of novel and optimization of current therapeutic approaches., Competing Interests: LvL reports consultancy fees to UMCU from Abbott, Medtronic, Vifor, Novartis, and research materials from Roche and Sopachem (all outside of the current work). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kilgallen, van den Akker, Feyen, Crnko, Snijders Blok, Gremmels, du Pré, Reijers, Doevendans, de Jager, Sluijter, Sampaio-Pinto and van Laake.)

Effective treatments for chronic limb-threatening ischemia are lacking. (Pre)clinical studies on administration of bone marrow (BM) mononuclear cells (MNCs) and BM-derived mesenchymal stromal cells (MSCs) have shown variable results and no studies have directly compared administration of human BM MNCs and BM MSCs in in vivo models. We studied the effect of intramuscular administration of human BM-derived MNCs and MSCs on limb perfusion in the murine hindlimb ischemia (HLI) model. Human BM MNCs and MSCs were obtained from healthy consenting donors. Both cell types were cryopreserved before use. Twenty-four hours after induction of HLI, nude NMRI mice were randomized to receive intramuscular administration of human BM MNCs ( n  = 13), or BM MSCs ( n  = 14), or vehicle control ( n  = 19) in various doses. Limb perfusion was measured using laser Doppler imaging on day 0, 1, 4, 7, 10, and 14. Intramuscular injection of human BM MNCs did not improve limb perfusion as compared with vehicle over the 2 weeks after cell administration ( P  = 0.88, mean relative perfusion for vehicle 0.56 ± 0.04 and 0.53 ± 0.04 for BM MNCs at day 14). Administration of human BM MSCs significantly improved limb perfusion as compared with both BM MNCs and vehicle ( P  ≤ 0.001, mean relative perfusion at day 14 0.79 ± 0.06). Our data suggest that BM MNCs are less suitable than BM MSCs for cell-based therapy that aims to restore perfusion.

Background: Antigen-based point-of-care tests for identification of SARS-CoV-2 may markedly enhance effectiveness of population-based controlling strategies. Previous studies have demonstrated >70% sensitivity and high specificity compared with reverse transcriptase real-time PCR (RT-PCR) in symptomatic individuals, but test performance for asymptomatic individuals is unknown., Methods: Test performance of the Panbio COVID-19 Ag Rapid Test (Abbott) was compared with RT-PCR in a longitudinal cohort study of asymptomatic football players and staff members of professional football clubs. Based on timing of symptoms and prior and subsequent test results, positive RT-PCR tests were categorised as presymptomatic, early or late infection, or persistent RNA shedding., Findings: 2425 tests were performed in 824 individuals, of which 52 (6.3%) were SARS-CoV-2 positive based on RT-PCR. There were 2406 paired sets from asymptomatic subjects for analysis. Sixteen Panbio tests were inconclusive, for which sensitivity analyses were performed (considering results as either positive or negative or being excluded). Sensitivity of Panbio for screening of asymptomatic individuals ranged from 80.0% (61.4-92.3) to 86.67% (69.2-96.2) and specificity from 99.53% (95% CI 99.2 to 99.8) to 100% (95% CI 99.8 to 100). Sensitivity of Panbio to detect subjects with presymptomatic/early infection (n=42) ranged from 81.82% (95% CI 67.3 to 91.8) to 90.91% (95% CI 78.3 to 97.5) with specificity always above 99%., Interpretation: The Panbio COVID-19 Ag rapid test identifies 81%-90% of presymptomatic and early asymptomatic SARS-CoV-2 infections with high specificity. This test may therefore be adopted in testing strategies such as targeted screening of specific populations where prevalence is low., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Cell therapy has been studied in many different research domains. Cellular replacement of damaged solid tissues is at an early stage of development, with much still to be understood. Systematic reviews and meta-analyses are widely used to aggregate data and find important patterns of results within research domains.We set out to find common biological denominators affecting efficacy in preclinical cell therapy studies for renal, neurological and cardiac disease., Methods: We used datasets of five previously published meta-analyses investigating cell therapy in preclinical models of chronic kidney disease, spinal cord injury, stroke and ischaemic heart disease. We transformed primary outcomes to ratios of means to permit direct comparison across disease areas. Prespecified variables of interest were species, immunosuppression, cell type, cell origin, dose, delivery and timing of the cell therapy., Results: The five datasets from 506 publications yielded data from 13 638 animals. Animal size affects therapeutic efficacy in an inverse manner. Cell type influenced efficacy in multiple datasets differently, with no clear trend for specific cell types being superior. Immunosuppression showed a negative effect in spinal cord injury and a positive effect in cardiac ischaemic models. There was a dose-dependent relationship across the different models. Pretreatment seems to be superior compared with administration after the onset of disease., Conclusions: Preclinical cell therapy studies are affected by multiple variables, including species, immunosuppression, dose and treatment timing. These data are important when designing preclinical studies before commencing clinical trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Monitoring renal function is a vital part of kidney research involving rats. The laborious measurement of glomerular filtration rate (GFR) with administration of exogenous filtration markers does not easily allow serial measurements. Using an in-house database of inulin clearances, we developed and validated a plasma creatinine- and plasma urea-based equation to estimate GFR in a large cohort of male rats [development cohort n = 325, R 2  = 0.816, percentage of predictions that fell within 30% of the true value (P30) = 76%] that had high accuracy in the validation cohort ( n = 116 rats, R 2  = 0.935, P30 = 79%). The equation was less accurate in rats with nonsteady-state creatinine, in which the equation should therefore not be used. In conclusion, applying this equation facilitates easy and repeatable estimates of GFR in rats. NEW & NOTEWORTHY This is the first equation, that we know of, which estimates glomerular filtration rate in rats based on a single measurement of body weight, plasma creatinine, and plasma urea.

Background: RT-qPCR is the reference test for identification of active SARS-CoV-2 infection, but is associated with diagnostic delay. Antigen detection assays can generate results within 20 min and outside of laboratory settings. Yet, their diagnostic test performance in real life settings has not been determined., Methods: The diagnostic value of the Panbio™ COVID-19 Ag Rapid Test (Abbott), was determined in  comparison to RT-qPCR (Seegene Allplex) in community-dwelling mildly symptomatic subjects in a medium (Utrecht, the Netherlands) and high endemic area (Aruba), using two concurrently obtained nasopharyngeal swabs.Findings: 1367 and 208 subjects were enrolled in Utrecht and Aruba, respectively. SARS-CoV-2 prevalence, based on RT-qPCR, was 10.2% ( n  = 139) and 30.3% ( n  = 63) in Utrecht and Aruba respectively. Specificity of the Panbio™ COVID-19 Ag Rapid Test was 100% (95%CI: 99.7-100%) in both settings. Test sensitivity was 72.6% (95%CI: 64.5-79.9%) in the Netherlands and 81.0% (95% CI: 69.0-89.8%) in Aruba. Probability of false negative results was associated with RT-qPCR Ct-values, but not with duration of symptoms. Restricting RT-qPCR test positivity to Ct-values <32 yielded test sensitivities of 95.2% (95%CI: 89.3-98.5%) in Utrecht and 98.0% (95%CI: 89.2-99.95%) in Aruba., Interpretation: In community-dwelling subjects with mild respiratory symptoms the Panbio™ COVID-19 Ag Rapid Test had 100% specificity, and a sensitivity above 95% for nasopharyngeal samples when using Ct-values <32 cycles as cut-off for RT-qPCR test positivity. Considering short turnaround times, user friendliness, low costs and opportunities for decentralized testing, this test can improve our efforts to control transmission of SARS-CoV-2., Competing Interests: Dr. Wensing reports grants from ViiV Healthcare, Gilead, grants from Janssen, Gilead, Merck, grants from Janssen, Gilead, Merck, ViiV Healthcare, grants from ARK diagnostics, outside the submitted work. All other authors report no conflict., (© 2020 Published by Elsevier Ltd.)

Objective: Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity, and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI., Research Design and Methods: We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography-tandem mass spectrometry at baseline in 160 patients (64.8 ± 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes ( n = 86, comprising n = 53 deaths and n = 49 amputations [first event counted]) over the 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. Associations are reported per 1 SD plasma marker., Results: Higher plasma MGO levels were associated with more adverse outcomes (relative risk 1.44; 95% CI 1.11-1.86) and amputations separately (1.55; 1.13-2.21). We observed a similar but weaker trend for mortality (1.28; 0.93-1.77). The MGO-derived AGE N ε -(carboxyethyl)lysine was also associated with more adverse outcomes (1.46; 1.00-2.15) and amputations (1.71; 1.04-2.79). d-Lactate was not associated with adverse incident outcomes. Higher plasma MGO levels were also associated with more inflammation and white blood cells and fewer progenitor cells., Conclusions: Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI., (© 2020 by the American Diabetes Association.)

Objective: Chronic limb-threatening ischemia (CLTI) is associated with high morbidity and mortality rates. More than 50% of all CLTI patients die within 5 years after presentation. Patient-specific survival prediction is critical for informing treatment strategies, even for those without a clear option for revascularization. We validated a survival prediction model, developed in a revascularized Vascular Quality Initiative (VQI) cohort, in a Western European no-option CLTI cohort., Methods: The VQI survival prediction model was applied to the validation cohort (N = 150) to compare estimated mortality and observed mortality at 2 years after baseline. Performance of the VQI model was tested by evaluating discrimination using the receiver operating characteristic area under the curve and calibration using the Hosmer-Lemeshow goodness-of-fit test., Results: The 2-year survival rate was 79% in the validation cohort compared with 83% in the VQI cohort. Baseline characteristics were significantly different for 13 of 17 variables. The C statistic was 0.86 (95% confidence interval, 0.78-0.95), which indicates good discrimination. The Hosmer-Lemeshow goodness-of-fit test had a P value of .30, which indicates good fit., Conclusions: This is the first external validation of the VQI survival prediction model. The good model performance suggests that this model can be used in different CLTI populations, including no-option CLTI, and underlines its contributory role in this challenging population., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Aberrant fetal growth remains a leading cause of perinatal morbidity and mortality and is associated with a risk of developing non-communicable diseases later in life. We performed a systematic review and meta-analysis combining human and animal studies to assess whether prenatal amino acid (AA) supplementation could be a promising approach to promote healthy fetal growth. PubMed, Embase and Cochrane libraries were searched to identify studies orally supplementing the following AA groups during gestation: (1) arginine family; (2) branched chain (BCAA); (3) methyl donors. Primary outcome was fetal/birth weight. 22 human and 89 animal studies were included in the systematic review. The arginine family, and especially arginine itself, was studied most. Our meta-analysis showed beneficial effects of arginine and ( N -Carbamyl) glutamate (NCG), but not aspartic acid and citrulline on fetal/birth weight. However, no effects were reported when isonitrogenous control diet was included. BCAA and methyl donor supplementation did not affect fetal/birth weight. Arginine family supplementation, in particular arginine and NCG, improves fetal growth in complicated pregnancies. BCAA and methyl donor supplementation do not seem to be as promising to target fetal growth. Well controlled research in complicated pregnancies is needed before ruling out AA supplements or preferring arginine above other AAs.

Background: Chronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease and has a large impact on quality of life, morbidity, and mortality. Interventions are aimed at improving tissue perfusion and averting amputation and secondary cardiovascular complications with an optimal risk-benefit ratio. Several prediction models regarding postprocedural outcomes in CLTI patients have been developed on the basis of randomized controlled trials to improve clinical decision-making. We aimed to determine model performance in predicting clinical outcomes in selected CLTI cohorts., Methods: This study validated the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular registry (FINNVASC), and Prevention of Infrainguinal Vein Graft Failure (PREVENT III) models in data sets from a peripheral artery disease registry study (Athero-Express) and two randomized controlled trials of CLTI in The Netherlands, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) and Percutaneous Transluminal Angioplasty and Drug-eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI). Receiver operating characteristic (ROC) curve analysis was used to calculate their predictive capacity. The primary outcome was amputation-free survival (AFS); secondary outcomes were all-cause mortality and amputation at 12 months after intervention., Results: The BASIL and PREVENT III models showed predictive values regarding postintervention mortality in the JUVENTAS cohort with an area under the ROC curve (AUC) of 81% and 70%, respectively. Prediction of AFS was poor to fair (AUC, 0.60-0.71) for all models in each population, with the highest predictive value of 71% for the BASIL model in the JUVENTAS population. The FINNVASC model showed the highest predictive value regarding amputation risk in the PADI population with AUC of 78% at 12 months., Conclusions: In general, all models performed poor to fair in predicting mortality and amputation. Because the BASIL model performed best in predicting AFS, we propose use of the BASIL model to aid in the clinical decision-making process in CLTI. However, improvements in performance have to be made for any of these models to be of real additional value in clinical practice., (Copyright © 2019 Society for Vascular Surgery. All rights reserved.)