Direct oral anticoagulants (DOACs) and neck of femur fractures: Standardising the perioperative management and time to surgery

Demographic projections for hip fragility fractures indicate a rising annual incidence by virtue of a multimorbid, ageing population with more noncommunicable diseases (NCDs). NCDs are characterised by slow progression and long duration ranging from ischaemic cardiovascular disease, cerebrovascular disease, diabetes, chronic obstructive pulmonary disease to various cancers. Management of this disease burden often involves commencing patients on oral anticoagulants to reduce the risk of thromboembolic events. The use of direct oral anticoagulants (DOACs) in clinical practice has increased due to their rapid onset of action, short half-life and predictable anticoagulant effects, without the need for routine monitoring. Safe and timely surgical intervention relies on reversal of anticoagulants. However, the lack of specific evidence-based guidelines for the perioperative management of patients on DOACs with hip fractures has proved challenging; in particular, the accessibility of DOAC-specific assays, justification of the cost-benefit ratio of targeted reversal agents and indications for neuraxial anaesthesia. This has led to potentially avoidable delays in surgical intervention. Following a literature review of the pharmacokinetic and pharmacodynamics of commonly used DOACs in our region including the role of surrogate markers, we propose a systematic, evidence-based guideline to the perioperative management of hip fractures DOACs. We believe this standardised protocol can be easily replicated between hospitals. We recommend that if patients are deemed suitable for a general anaesthesia, with satisfactory renal function, optimal surgical time should be 24 h following the last ingested dose of DOAC.     

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Proteases and their inhibitors as prognostic factors for high-grade serous ovarian cancer

Ovarian carcinoma is one of the most lethal malignancies, but only very few prognostic biomarkers are known. The degradome, comprising proteases, protease non-proteolytic homologues and inhibitors, have been involved in the prognosis of many cancer types, including ovarian carcinoma. The prognostic significance of the whole degradome family has not been specifically studied in high-grade serous ovarian cancer. A targeted DNA microarray known as the CLIP-CHIP microarray was used to identify potential prognostic factors in ten high-grade serous ovarian cancer women who had early recurrence (<1.6 years) or late/no recurrence after first line surgery and chemotherapy. In women with early recurrence, we identified seven upregulated genes (TMPRSS4, MASP1/3, SPC18, PSMB1, IGFBP2, CFI – encoding Complement Factor I – and MMP9) and one down-regulated gene (ADAM-10). Using immunohistochemistry, we evaluated the prognostic effect of these 8 candidate genes in an independent cohort of 112 high-grade serous ovarian cancer women. Outcomes were progression, defined according to CA-125 criteria, and death. Multivariate Cox proportional hazard regression models were done to estimate the associations between each protein and each outcome. High ADAM-10 expression (intensity of 2–3) was associated with a lower risk of progression (adjusted hazard ratio (HR): 0.51; 95% confidence interval (CI): 0.29-0.87). High complement factor I expression (intensity 2–3) was associated with a higher risk of progression (adjusted HR: 2.30, 95% CI: 1.17–4.53) and death (adjusted HR: 3.42; 95% CI: 1.72–6.79). Overall, we identified the prognostic value of two proteases, ADAM-10 and complement factor I, for high-grade serous ovarian cancer which could have clinical significance.     

Factors associated with provision of depot medroxyprogesterone acetate to adolescents by US health care providers

ObjectiveIdentify factors associated with healthcare providers' frequency of depot medroxyprogesterone acetate (DMPA) provision to adolescents.Study designWe analyzed data from surveys mailed to a nationally representative sample of public-sector providers and office-based physicians (n=1984). We estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of factors associated with frequent DMPA provision to adolescents in the past year.ResultsAlthough most providers (>95%) considered DMPA safe for adolescents, fewer reported frequent provision (89% of public-sector providers; 64% of office-based physicians). Among public-sector providers, factors associated with lower odds of frequent provision included working in settings without Title X funding (aOR 0.44, 95% CI 0.30–0.64), reporting primary care as their primary clinical focus versus reproductive or adolescent health (aOR 0.42, 95% CI 0.28–0.61), and providing fewer patients with family planning services. Among office-based physicians, factors associated with lower odds of frequent provision included specializing in obstetrics/gynecology (aOR 0.50, 95% CI 0.27–0.91) and family medicine (aOR 0.21, 95% CI 0.09–0.47) versus adolescent medicine, completing training ≥15 versus <5 years ago (aOR 0.27, 95% CI 0.09–0.83), and reporting that 0–24% of patients pay with Medicaid or other government healthcare assistance versus ≥50% (aOR 0.23, 95% CI 0.09–0.61). The reason most commonly reported by providers for infrequent DMPA provision was patient preference for another method.ConclusionsWhile most providers reported frequently providing DMPA to adolescents, training on evidence-based recommendations for contraception, focused on subgroups of providers with lower odds of frequent DMPA provision, may increase adolescents' access to contraception.ImplicationsAlthough >95% of providers considered depot medroxyprogesterone (DMPA) a safe contraceptive for adolescents, only 89% of public-sector providers and 64% of office-based physicians reported frequently providing DMPA to adolescents. Provider training on evidence-based recommendations for contraception counseling and provision may increase adolescents' access to DMPA and all methods of contraception.