Conectar
by Abigail Obuobi, Neils B. Quashie, Nancy Odurowah Duah-Quashie, Jon R. Sayers
Plasmodium falciparum malaria is fatal if left untreated. Treatment is hampered by drug-resistant variants of the malaria parasite, highlighting the need to explore unique pathways for the development of new drugs with different mechanisms of action. Kinases in the inositol phosphate signaling pathway (IPP), and its products play many important roles in energy metabolism and signal transduction, making them attractive drug targets. In this exploratory study we investigated the potential of P. falciparum IPP as a novel and attractive pathway for antimalarial drug discovery, employing a combined in silico and molecular approach. The sequences and structures of the putative P. falciparum inositol phosphate kinases were characterized in silico. Experimental validation across laboratory strains and a clinical isolate confirmed the p.Pro375Gln substitution in IPMK1, providing the first evidence of this variant in field isolates. We provide molecular evidence of the existence of IPP genes in P. falciparum and suggest that targeting this pathway could be detrimental to the parasite. We identify P. falciparum inositol polyphosphate multikinase (IPMK) as a promising drug target due to its unique sequence and structural characteristics. These results serve as a guide for future experimental validation.Understanding the prognostic factors associated with the failure of total elbow replacement (TER) is crucial for informing patients about risks and enabling shared decision-making regarding TER as a definitive management option. This protocol outlines the planned analysis of National Joint Registry (NJR) data to investigate prognostic factors for TER failure.
The primary analysis will use the NJR elbow dataset, including all eligible patients who underwent TER surgery between April 2012 and December 2023. To incorporate ethnicity and comorbidities as potential prognostic factors, the NJR will be linked to the National Health Service (NHS) England Hospital Episode Statistics-Admitted Patient Care (HES-APC) data for a secondary analysis. The analysis will adhere to the REporting recommendations for tumour MARKer prognostic studies guidelines. The primary outcome under investigation is TER failure, defined as requiring revision surgery. Initially, the overall prognosis of TER will be examined using unadjusted net implant failure via the Kaplan-Meier method. The list of potential prognostic factors to be investigated in this study has been informed by a systematic review on this topic, input from patient and public involvement and engagement (PPIE) groups and a survey shared with healthcare professionals providing TER services. The relationship between each potential prognostic factor and failure will be assessed using univariable regression methods. Based on the findings from our systematic review, the univariable association will also be adjusted for age, sex and indication for TER surgery using multivariable regression methods. The extent of missing data will be reported, and the reasons for missing data will be explored. A very high degree of data completeness is expected, and a complete case analysis will be performed as the primary analysis. Multiple imputations will be considered as a sensitivity analysis.
The NJR research committee approved this analysis, and the NHS Health Research Authority tool guidance dictates that the secondary use of such data for research does not require approval from a research ethics committee. The results from this analysis will be published in a peer-reviewed journal and presented at scientific conferences.
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