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Objective The purpose of this study is to analyze how the largest insurance companies support their medical necessity policies regarding osteochondral allograft transplantation (OCA) and to determine whether the literature they cite in their policies is of a high level of evidence (LOE).Design The 10 largest national health insurance companies were identified. Each payer was contacted via phone or email to obtain their coverage policy regarding OCA. For each policy, the medical necessity criteria were recorded, and all cited references were screened. For all references applicable to OCA, the LOE was recorded, and each reference was screened to determine whether they mentioned the specific criteria reported in the policies.Results The medical policies for 6 of the 10 national health insurance companies were identified. These 6 policies cited a collective total of 102 applicable references. Most of these studies were an LOE of IV (n= 58, 56.9%) and an LOE of V (n= 18, 17.6%). There were similarities amongst the medical necessity criteria between different commercial payers; however, most criteria were poorly supported by the cited literature.Conclusions Our results demonstrate that commercial insurance companies utilize studies that are of a low LOE when justifying their medical necessity criteria. Moreover, these cited studies infrequently support or mention the commercial payers’ criteria. Future studies should continue to explore how well-supported insurance policies are with the goal of potentially increasing access and authorization for well-supported treatment modalities.

Context: While current literature has explored the outcomes of athletes who return to sport (RTS) after anterior cruciate ligament (ACL) injuries, less is known about the outcomes of those who are unsuccessful in returning to sport.Objective: To determine the rate of athletes who did not RTS after primary ACL reconstruction (ACLR) and to identify the specific subjective reasons for failure to RTS.Data Sources: A comprehensive search of the PubMed/MEDLINE, Scopus, and Web of Science databases was conducted through April 2021.Study Selection: Eligible studies included those explicitly reporting the rate of failure for RTS after ACLR as well as providing details on reasons for athletes’ inability to return; 31 studies met the inclusion criteria.Study Design: Systematic review and meta-analysis.Level of Evidence: Level 2 to 4.Data Extraction: The reasons for failure to RTS referred to in our study are derived from those established previously in the studies included. Data were collected on the number of athletes, mean age, mean follow-up time, type of sport played, failure to RTS rate, and specific reasons for failure to return.Results: The weighted rate of failure to RTS after ACLR was 25.5% (95% CI, 19.88-31.66). The estimated proportion of psychosocial-related reasons cited for failure to RTS was significantly greater than knee-related reasons for failure RTS (55.4% vs 44.6%, P< 0.01). The most cited reason for failure to RTS was fear of reinjury (33.0%).Conclusion: This study estimates the rate of failure to RTS after ACLR to be 25.5%, with the majority of athletes citing fear of reinjury as the major deterrent for returning to sports. We highlight how factors independent of surgical outcomes may impact an athlete’s ability to return to play given that the predominant reason for no RTS after ACLR was unrelated to the knee.

Explicit funding and industry affiliation are believed to potentially impact medical research. There have been an increasing number of studies that have evaluated this relationship. The purpose of this study is to determine whether industry affiliation influences the outcomes of randomized controlled trials that investigate the effectiveness of platelet-rich plasma (PRP) in the treatment of lateral epicondylitis.

Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2. SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non–DNA damaging agent, l-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and SETD2 mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy. Consistent with local recruitment of DDR, genomic regions with higher H3K36me3 had a lower mutation rate, which was increased with SETD2 mutation. Heterozygous conditional inactivation of Setd2 in a murine model decreased the latency of MLL-AF9–induced leukemia and caused resistance to cytarabine treatment in vivo, whereas homozygous loss delayed leukemia formation. Treatment with JIB-04, an inhibitor of the H3K9/36me3 demethylase KDM4A, restored H3K36me3 levels and sensitivity to cytarabine. These findings establish SETD2 alteration as a mechanism of resistance to DNA-damaging chemotherapy, consistent with a local loss of DDR, and identify a potential therapeutic strategy to target SETD2-mutant leukemias.

Mutations in SETD2,encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of SETD2mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2. SETD2mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non–DNA damaging agent, l-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and SETD2mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy. Consistent with local recruitment of DDR, genomic regions with higher H3K36me3 had a lower mutation rate, which was increased with SETD2 mutation. Heterozygous conditional inactivation of Setd2in a murine model decreased the latency of MLL-AF9–induced leukemia and caused resistance to cytarabine treatment in vivo, whereas homozygous loss delayed leukemia formation. Treatment with JIB-04, an inhibitor of the H3K9/36me3 demethylase KDM4A, restored H3K36me3 levels and sensitivity to cytarabine. These findings establish SETD2alteration as a mechanism of resistance to DNA-damaging chemotherapy, consistent with a local loss of DDR, and identify a potential therapeutic strategy to target SETD2-mutant leukemias.