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Abstract Background Enhanced recovery programs (ERPs) imply early discharge but few papers have assessed the effect of ERPs on post-discharge mortality (PDM). Methods A multicenter nationwide case control study based on administrative data was carried out between March and December 2019. Coding for every episode of care whether in the setting of ERP or not is mandatory for hospital funding (public or private). Twelve surgical specialties or procedures were included. The episodes of care coded with ERP were matched with those without ERP code for several factors such as the type of hospital (public or private), age, gender, month of discharge, and updated Charlson score. Ninety-day PDM was the main outcome. Results Of 420,031 patients in the database, 78,119 had an ERP code. Finally, 132,600 patients with 66,300 matched pairs were considered for the study. Overall, PDM was significantly reduced after ERPs: 0.075% vs 0.138% (p = 0.00042). Significant one-half and two-thirds reduction in PDM was observed respectively after hip arthroplasty (odds ratio 0.48 [95% CI 0.21–0.99]) and colectomy (odds ratio 0.36 [95% CI 0.16–0.74]). Conclusion The findings, based on a large database and a rigorous matching, strongly suggest that ERPs reduce PDM particularly after colectomy and hip arthroplasty. This is likely due to better post-operative care in ERPs.

Here the authors probe the cleavage and gate opening of single-stranded DNA by the human topoisomerase TRR using a unique single-molecule strategy to reveal structural plasticity in response to both double-stranded DNA and the helicase BLM.

Abstract Background Study of the medico economic impact of enhanced rehabilitation after surgery (ERAS), by comparing the cost of patient care with or without ERAS, both from the point of view of the hospitals and the Social Security Health Insurance Program. Methods Retrospective longitudinal study on matched data from March 1, 2019 to December 31, 2019. The data are extracted from the French prospective payment system. We studied 12 of the most commonly performed in ERAS business segments. The primary outcome was the reduction of the average length of hospital stay and its implications on production costs and excess capacity. We also studied the impact on hospital incomes and Social Security Insurance Program expenses. The potential gain in hospital days was computed by comparing the length of stay of ERAS and non-ERAS cases. The cost reduction was estimated using the mean number of avoidable days of hospitalization, and the mean cost of the stays obtained from the national cost study. Finally, we studied an approximation of the additional expense for the Social Security Health Insurance Program on costs standardized by applying public sector rates. Results The average length of stay reduction attributed to ERAS is 1.45 (CI 95% 1.42 to 1.48) day per stay, translating to a cost reduction for the hospitals of € 1060 (CI 95% 995 to 1125) per patient and a total of €65 million (CI 95% 61 to 69). At the same time, the additional expenses for the Social Security Insurance Program can conservatively be approximated to € 1.6 million, breaking into a € 2.2 million increase partially compensated by cost savings of € 0.6 million over subsequent stays for complications. Overall, for each percent of additional ERAS activity over the scope of the study, the marginal cost reduction for the hospitals can be estimated to € 1.8 million (CI 95% 1.7 million to 2.0 million). Conclusions Associated with previously known clinical benefits for the patients, these convincing results in terms of economic gain strongly support expanding the adoption of ERAS.

Repair of DNA double-strand breaks via homologous recombination can produce double Holliday junctions (dHJs) that require enzymatic separation. Topoisomerase IIIα (TopIIIα) together with RMI1 disentangles the final hemicatenane intermediate obtained once dHJs have converged. How binding of RMI1 to TopIIIα influences it to behave as a hemicatenane dissolvase, rather than as an enzyme that relaxes DNA topology, is unknown. Here, we present the crystal structure of human TopIIIα complexed to the first oligonucleotide-binding domain (OB fold) of RMI1. TopIII assumes a toroidal type 1A topoisomerase fold. RMI1 attaches to the edge of the gate in TopIIIα through which DNA passes. RMI1 projects a 23-residue loop into the TopIIIα gate, thereby influencing the dynamics of its opening and closing. Our results provide a mechanistic rationale for how RMI1 stabilizes TopIIIα-gate opening to enable dissolution and illustrate how binding partners modulate topoisomerase function.

Summary: PICH is a DNA translocase necessary for the resolution of ultrafine anaphase DNA bridges and to ensure the fidelity of chromosomal segregation. Here, we report the generation of an animal model deficient for PICH that allowed us to investigate its physiological relevance. Pich KO mice lose viability during embryonic development due to a global accumulation of DNA damage. However, despite the presence of chromosomal instability, extensive p53 activation, and increased apoptosis throughout the embryo, Pich KO embryos survive until day 12.5 of embryonic development. The absence of p53 failed to improve the viability of the Pich KO embryos, suggesting that the observed developmental defects are not solely due to p53-induced apoptosis. Moreover, Pich-deficient mouse embryonic fibroblasts exhibit chromosomal instability and are resistant to RASV12/E1A-induced transformation. Overall, our data indicate that PICH is essential to preserve chromosomal integrity in rapidly proliferating cells and is therefore critical during embryonic development and tumorigenesis. : Albers et al. show that PICH is essential for mouse embryonic development and that PICH deficiency limits oncogenic-induced cellular transformation. These findings suggest that PICH activity is critical during events requiring rapid cell proliferation such as embryonic development and tumorigenesis. Keywords: Pich, Ercc6l, ultrafine anaphase DNA bridges, UFBs, genomic instability, DNA damage, X chromosome inactivation

In fast proliferating embryonic stem cells (ESC) the DNA damage response is activated by mechanisms that are as yet elusive. Here, Ahuja et al.link the DNA damage response to replication stress in mouse ESCs, caused by a short G1 phase, and propose fork remodelling as maintaining genome stability in embryos.

Cystic Fibrosis is a lethal monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The most frequent mutation is the deletion of phenylalanine at position 508 of the protein. This F508del-CFTR mutation leads to misfolded protein that is detected by the quality control machinery within the endoplasmic reticulum and targeted for destruction by the proteasome. Modulating quality control proteins as molecular chaperones is a promising strategy for attenuating the degradation and stabilizing the mutant CFTR at the plasma membrane. Among the molecular chaperones, the small heat shock protein HspB1 and HspB4 were shown to promote degradation of F508del-CFTR. Here, we investigated the impact of HspB5 expression and phosphorylation on transport to the plasma membrane, function and stability of F508del-CFTR. We show that a phosphomimetic form of HspB5 increases the transport to the plasma membrane, function and stability of F508del-CFTR. These activities are further enhanced in presence of therapeutic drugs currently used for the treatment of cystic fibrosis (VX-770/Ivacaftor, VX-770+VX-809/Orkambi). Overall, this study highlights the beneficial effects of a phosphorylated form of HspB5 on F508del-CFTR rescue and its therapeutic potential in cystic fibrosis.