Valgus-impacted subcapital neck of femur fractures: a systematic review, meta-analysis with cost analysis of fixation in-situ versus nonoperative management.

BACKGROUND: The management of the valgus-impacted neck of femur fracture (AO/OTA 31-B1) remains contentious. The objective of this study was to determine whether operative intervention is cost-effective. METHODS: We conducted a systematic review using electronic databases (Medline, Embase, Cochrane, Ebsco, Scholar) identifying studies published in the English language concerning valgus-impacted neck of femur fractures until June 2022. Additional studies were identified through hand searches of major orthopaedic journals, and bibliographies of major orthopaedic textbooks. MeSH terms (hip fracture and femoral neck fracture) and keywords (undisplaced, valgus-impacted, valgus, subcapital, Garden) connected by the Boolean operators "AND" and "OR" were used to identify studies. 2 reviewers independently extracted the data using standardised forms and recording spreadsheet. Methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-analysis of Statistics Assessment and Review Instrument. Meta-analysis was undertaken. Outcome measures were rate of displacement, avascular necrosis, non-union, mortality and requirement of further operative intervention. A cost utility analysis was then conducted to compare the 2 groups on the basis of the cost of initial treatment and the potential requirement of secondary intervention to hemiarthroplasty. RESULTS: 47 studies met the inclusion criteria. Meta-analysis data demonstrated a significant difference in the displacement rate of 22.8% and 2.8% between the nonoperative and internal fixation groups respectively (p = 0.05). The overall incidence of further operative intervention for each group was 23% and 10% respectively. There was no significant difference with respect to avascular necrosis, mortality or union rates. The cost utility analysis revealed nonoperative management to be approximately 60% more costly than initial internal fixation when the costs of subsequent surgery were included. CONCLUSIONS: This meta-analysis of the existing literature concludes that whilst nonoperative management is possible for valgus impacted neck of femur fractures, it is associated with higher complication rates and greater expense than management by internal fixation.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK.

OBJECTIVE: To monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects. METHODS: Retrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018-2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends. RESULTS: Across nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%-58.6%) and 52.9% (52.2%-53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1-2 weeks before lockdown and fell by 31%-88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93-0.95; total hospital admissions RR 0.96, 0.95-0.97) and after lockdown (attendances RR 0.63, 0.62-0.64; admissions RR 0.59, 0.57-0.60). There was limited recovery towards usual levels of some activities from mid-April 2020. CONCLUSIONS: Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently.

Current assessment of polo-like kinases as anti-tumor drug targets.

INTRODUCTION: Polo-like kinase (PLK)1 is the most studied of the PLK family and is a serine/threonine kinase that plays pivotal roles in many aspects of mitosis and hence its deregulation is prevalent in various malignant tumor types. AREAS COVERED: In this review, the authors discuss the relevancy of PLK1 and other PLK members as oncology targets in light of known roles of these kinases and the observed phenotypic consequence of downregulating their activity, depending on how they are targeted. Furthermore, they also discuss the pathways mutated in cancer that have been shown to enhance sensitivity toward PLK1 inhibitors in the context of tumor types that possess these molecular defects. They also summarize preclinical and clinical investigations that have been undertaken for both ATP and non-ATP competitive inhibitors. EXPERT OPINION: PLKs 2, 3 and 5 are primarily linked with tumor suppressor functions and as PLK1 is the most validated anticancer drug target, selective inhibitors for its activities are most likely to result in effective therapeutics with reduced side effects. In this regard, the polo box domain can be targeted to generate selective inhibitors of PLK1 while preventing inhibition of kinases outside of this family. Recent studies confirming the synthetic lethality of other molecular defects with PLK1 can be exploited to obtain tumor selective apoptosis in p53, KRAS and PTEN mutant cancers.

Whole organism based techniques and approaches in early stage oncology drug discovery-patents and trends.

Discovery of new cancer drugs is important for the improvement of disease treatment and management. In addition to the clear medical needs there are also economic considerations: Much drug discovery is performed in the private sector. The high cost of some drug treatments, which can run to tens of thousands of US$ per patient for single courses of therapy has led to the perception of high profitability in the industry. But drug discovery and development is a very expensive and lengthy process, with an ongoing trend of fewer drugs brought to market per dollar invested in R&D Biochemical-based in vitro screens for hosts of targets have produced early stage drug candidates and led to drugs reaching the market, but there remains a great need to evaluate in vivo efficacy, toxicity and potential off-target effects as early as possible in the discovery process. Using whole organisms much earlier in cancer (and other) drug discovery is a potential approach to improve R&D productivity. Here, we provide an overview of recent patenting activity and take a brief look at possible new developments in the field.