Spermatogonial kinetics in humans

The human spermatogonial compartment is essential for daily production of millions of sperm. Despite this crucial role, the molecular signature, kinetic behavior and regulation of human spermatogonia are poorly understood. Using human testis biopsies with normal spermatogenesis and by studying marker protein expression, we have identified for the first time different subpopulations of spermatogonia. MAGE-A4marks all spermatogonia, KITmarks all Bspermatogonia and UCLH1 all Apale-dark (Ap-d) spermatogonia. We suggest that at the start of the spermatogenic lineage there are Ap-d spermatogonia that are GFRA1High, likely including the spermatogonial stem cells. Next, UTF1 becomes expressed, cells become quiescent and GFRA1 expression decreases. Finally, GFRA1 expression is lost and subsequently cells differentiate into B spermatogonia, losing UTF1 and acquiring KIT expression. Strikingly, most human Ap-d spermatogonia are out of the cell cycle and even differentiating type B spermatogonial proliferation is restricted. A novel scheme for human spermatogonial development is proposed that will facilitate further research in this field, the understanding of cases of infertility and the development of methods to increase sperm output

Association Between Colchicine Treatment and Clinical Outcomes in Patients with Coronary Artery Disease: Systematic Review and Meta-analysis

Background: The authors examined the association between colchicine treatment and clinical outcomes in patients with coronary artery disease. Methods: They performed a meta-analysis of randomised controlled trials (RCTs) involving patients with coronary artery disease receiving add-on colchicine to standard treatment compared with standard treatment. They used a mixed-effects Poisson regression model with random intervention effects to estimate the pooled incidence rate ratios (IRR) with 95% CI. Results: Ten RCTs were identified, including 12,819 participants followed up for a median of 6 months. Colchicine was associated with a lower risk of major adverse cardiovascular events (IRR 0.69; 95% CI [0.60–0.79]; number needed to treat for an additional beneficial outcome [NNTB] = 28); MI (IRR 0.77; 95% CI [0.64–0.93]; NNTB = 95) and ischaemic stroke (IRR 0.48; 95% CI [0.30–0.76]; NNTB = 155) and with a higher risk of gastrointestinal adverse events (IRR 1.69; 95% CI [1.12–2.54]; number needed to treat for an additional harmful outcome [NNTH] = 10). Colchicine did not affect all-cause death (IRR 1.09; 95% CI [0.85–1.40]), or cardiovascular death (IRR 0.75; 95% CI [0.51–1.12]), while it was associated with a higher risk of non-cardiovascular death (IRR 1.45; 95% CI [1.04–2.02]; NNTH = 396). Conclusion: The meta-analysis showed that the relative and absolute beneficial treatment effects of colchicine on cardiovascular outcomes outweigh the potential harm for non-cardiovascular mortality. Registration: PROSPERO 2021 CRD42021248874

Years of life that could be saved from prevention of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour 65 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost

Rationale and Design of the PARTHENOPE Trial: A Two-by-Two Factorial Comparison of Polymer-Free vs. Biodegradable-Polymer Drug-Eluting Stents and Personalized vs. Standard Duration of Dual Antiplatelet Therapy in All-Comers Undergoing PCI.

BACKGROUND Over the past few decades, percutaneous coronary intervention (PCI) has undergone significant advancements as a result of the combination of device-based and drug-based therapies. These iterations have led to the development of polymer-free drug-eluting stents. However, there is a scarcity of data regarding their clinical performance. Furthermore, while various risk scores have been proposed to determine the optimal duration of dual antiplatelet therapy (DAPT), none of them have undergone prospective validation within the context of randomized trials. DESIGN The PARTHENOPE trial is a phase IV, prospective, randomized, multicenter, investigator-initiated, assessor-blind study being conducted at 13 centers in Italy (NCT04135989). It includes 2,107 all-comers patients with minimal exclusion criteria, randomly assigned in a 2-by-2 design to receive either the Cre8 amphilimus-eluting stent or the SYNERGY everolimus-eluting stent, along with either a personalized or standard duration of DAPT. Personalized DAPT duration is determined by the DAPT score, which accounts for both bleeding and ischemic risks. Patients with a DAPT score <2 (indicating higher bleeding than ischemic risk) receive DAPT for 3 or 6 months for chronic or acute coronary syndrome, respectively, while patients with a DAPT score ≥2 (indicating higher ischemic than bleeding risk) receive DAPT for 24 months. Patients in the standard DAPT group receive DAPT for 12 months. The trial aims to establish the non-inferiority between stents with respect to a device-oriented composite endpoint of cardiovascular death, target-vessel myocardial infarction, or clinically-driven target-lesion revascularization at 12 months after PCI. Additionally, the trial aims to demonstrate the superiority of personalized DAPT compared to a standard approach with respect to a net clinical composite of all-cause death, any myocardial infarction, stroke, urgent target-vessel revascularization, or type 2 to 5 bleeding according to the Bleeding Academic Research Consortium criteria at 24-months after PCI. SUMMARY The PARTHENOPE trial is the largest randomized trial investigating the efficacy and safety of a polymer-free DES with a reservoir technology for drug-release and the first trial evaluating a personalized duration of DAPT based on the DAPT score. The study results will provide novel insights into the optimizing the use of drug-eluting stents and DAPT in patients undergoing PCI

Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Walking the Line with Ticagrelor: Meta-Analysis Comparing the Safety and Efficacy of Ticagrelor Monotherapy after a Short Course of Ticagrelor-Based Dual Antiplatelet Therapy versus Standard Therapy in Complex Percutaneous Coronary Intervention

(1) Shorter-duration dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy has been shown to significantly reduce bleeding events while preserving anti-ischemic effects in patients undergoing conventional percutaneous coronary interventions (PCI). Whether this strategy is also safe and effective in complex PCI remains elusive; (2) A systematic search of randomized controlled trials comparing a short course of ticagrelor-based DAPT versus standard DAPT in patients undergoing complex PCI was performed; (3) Of 10,689 studies screened, 3 were identified for a total of 4176 participants on ticagrelor monotherapy after a short course of ticagrelor-based DAPT, and 4209 on standard DAPT. The pooled analysis revealed no difference in the outcomes of major bleeding, myocardial infarction, definite or probable stent thrombosis and ischemic stroke. A significant reduction in the risk of cardiovascular death (incidence rate ratio (IRR) 0.52; 95% CI 0.28&ndash;0.96; p = 0.04), all-cause death (IRR 0.65; 95% CI 0.49&ndash;0.86; p = 0.003), and any bleeding events (IRR 0.62; 95% CI 0.47&ndash;0.81; p &lt; 0.001) was seen in the shorter DAPT group; (4) Among patients undergoing complex PCI, ticagrelor monotherapy after a short course of ticagrelor-based DAPT significantly reduced bleeding risk without increasing ischemic risk. More data are needed to definitively explain mortality benefits