Protocol for a systematic review and meta-analysis of the impact of cervical cancer prevention initiatives in Ghana

by Emmanuel Timmy Donkoh, Iddrisu Wahab Abdul, Abraham Kwadzo Ahiakpa, Isaac Williams, Rita Nyaaba Akologo, Stephen Danyo, Chrysantus Kubio, Kofi Effah, Joseph Emmanuel Amuah

Background

Cervical cancer, though preventable, remains the second most diagnosed cancer and the primary cause of cancer-related deaths among females in Sub-Saharan Africa. The significance of coordinated screening programmes for reducing the burden of cervical cancer in Africa is not well documented. This systematic review will summarize published reports from key databases, grey literature and programme reports to assess the performance of cervical cancer prevention programmes in Ghana.

Methods

To be eligible for inclusion, interventions must target Ghanaian women with cervical cancer screening and prevention strategies using methods such as visual inspection with acetic acid (VIA), mobile colposcopy, HPV DNA testing, cytology (Pap smear), and treatment approaches such as cryotherapy, thermal ablation, loop electrosurgical excision procedure (LEEP). A comprehensive electronic search strategy will be used to identify studies published since database inception, and indexed in MEDLINE, EMBASE, CINAHL and Web of Science. The search strategy will include MeSH terms (and synonyms) relevant to cervical cancer, screening/treatment methods, geographic focus and implementing institution. We will include searches for grey literature, recognizing the value of programmatic and governmental reports that might not appear in traditional databases. Search results will be summarized in line with PRISMA guidelines. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach will be used to evaluate and document evidence certainty for all outcomes, internal validity of included reports, inconsistency, indirectness, imprecision, and publication bias. Where sufficient homogeneity exists among included studies in terms of interventions, study designs, populations, and outcome measures, we will perform a meta-analysis to calculate pooled effect estimates and their corresponding 95% confidence intervals.

Significance

This systematic review will assess the performance and impact of cervical cancer screening and prevention programmes conducted in Ghana to date and identify what contextual strategies have delivered the most impact as well as highlight what gaps remain in our understanding of how a nationwide screening programme can be properly construed for maximum impact.

Toward an all-in-one recombinant adeno-associated virus vector for functionally ablating the prion gene using CRISPR-Cas technology

by Claire Verkuyl, Ari Belotserkovsky, Thomas Zerbes, Declan Williams, Medha R. Krishnan, Sabrina Zhu, Sophie Grunnesjӧ, Shehab Eid, Cunjie Zhang, Wenda Zhao, Leo Xu, Eleanore Lin, Teaghan O’Shea, Benjamin Draper, Andreas Jungman, Patrick Most, Gerold Schmitt-Ulms

Any strategy that can selectively and persistently lower the brain levels of the cellular prion protein (PrP^C) is expected to extend survival in prion diseases. Recent advances in the virus-mediated delivery of gene therapies prompted us to explore if a recombinant adeno-associated virus (rAAV) vector delivering a CRISPR-Cas-based gene editor can be devised that induces a functional knockout of the prion gene. Whereas the eventual objective is to assess the therapeutic potency of an optimized vector in prion-infected mice, in this proof-of-concept study, we evaluated tools and methods that are suited to achieve this goal. The result of these efforts is a first-generation all-in-one rAAV vector that codes for a prion gene-specific guide RNA and a small Cas9 endonuclease, whose expression is controlled by a truncated neural cell adhesion molecule 1 (NCAM1) promoter that is active in PrP^C expressing cells. We also constructed a second rAAV vector coding for a prion gene-specific ‘traffic light reporter’ (TLR). The TLR can be used to monitor prion gene-editing efficacy by coding for red and green fluorescent proteins separated by a segment of the prion gene that is targeted by the gene editor. For the purification of AAVs, we adopted a robust and scalable rAAV vector assembly pipeline and undertook proof-of-concept prion gene editing experiments in human cells and mice, which to date yielded prion gene editing rates of approximately 20% and 5%, respectively. Finally, we compared brain distributions of rAAV vectors following intrathalamic versus retro-orbital injection, and selected the 9P31 capsid for future studies based on a 7.5-fold higher heterologous gene expression level as compared to the PHP.eB capsid.

An exploratory machine learning study on paediatric abdominal pain phenotyping and prediction

by Kazuya Takahashi, Michalina Lubiatowska, Huma Shehwana, James K. Ruffle, John A. Williams, Animesh Acharjee, Shuji Terai, Georgios V. Gkoutos, Humayoon Satti, Qasim Aziz

Background

The exact mechanisms underlying paediatric abdominal pain (AP) remain unclear due to patient heterogeneity. This preliminary study aimed to identify AP phenotypes and develop predictive models to explore associated factors, with the goal of guiding future research.

Methods

In 13,790 children from a large birth cohort, data on paediatric and maternal demographics and comorbidities were extracted from general practitioner records. Machine learning (ML) clustering was used to identify distinct AP phenotypes, and an ML-based predictive model was developed using demographics and clinical features.

Results

1,274 children experienced AP (9.2%) (average age: 8.4 ± 1.1 years, male/female: 615/659), who clustered into three distinct phenotypes: Phenotype 1 with an allergic predisposition (n = 137), Phenotype 2 with maternal comorbidities (n = 676), and Phenotype 3 with minimal other comorbidities (n = 340). As the number of allergic diseases or maternal comorbidities increased, so did the frequency of AP, with 17.6% of children with ≥ 3 allergic diseases and 25.6% of children with ≥ 3 maternal comorbidities. The predictive model demonstrated moderate performance in predicting paediatric AP (AUC 0.67), showing that a child’s ethnicity, paediatric allergic diseases, and maternal comorbidities were key predictive factors. When stratified by ML-predicted probability, observed AP rates were 18.9% in the  60% group.

Conclusions

This study identified distinct AP phenotypes and key risk factors using ML. Furthermore, the predictive ML model enabled risk stratification for paediatric AP. These analyses provide valuable insights to guide future investigations into the mechanisms of AP and may facilitate research aimed at identifying targeted interventions to improve patient outcomes.

Quality indicators for rural surgical and obstetrical care: A modified Delphi consensus study

by Anshu Parajulee, Abdo Souraya, Nancy Humber, Sean Ebert, Kim Williams, Tom Skinner, Jude Kornelsen

Objective

To identify contextually relevant indicators to measure the quality of surgical and obstetrical care in low-volume rural hospitals using a consensus-based methodology.

Methods

A modified Delphi process was implemented in which participants were asked to rate the priority of proposed evaluation metrics over two rounds. Two Delphi surveys were electronically administered in 2019, approximately one month apart. Fifty-one health care professionals from across Canada, including rural proceduralists and quality improvement experts, were invited to participate. All quality measures in the first round were proposed by the study team. The second round included measures that did not reach consensus in the first round and measures suggested by respondents during the first round.

Results

Thirty individuals participated in Round 1 (59% response rate). Of the 30 respondents from Round 1, 23 participated in Round 2 (77% response rate). 115 of 177 proposed measures (65%) reached positive consensus in Round 1 or 2. Expert participants agreed that these measures should be prioritized/included when evaluating surgical and/or obstetrical quality in rural hospitals. No measure reached negative consensus in either round. Open-text comments offered practical guidance on how to interpret and use surgical and obstetrical quality data within a rural context. Many respondents believed that rare adverse outcomes have low relevance at rural hospitals where volumes are low, procedures are almost all lower complexity day cases (Cesarean section being the major exception), and patients are typically healthy.

Conclusion

The modified Delphi process resulted in the identification of surgical and obstetrical quality indicators that are contextually embedded in the realities of rural practice. The methodology allowed for the consideration of factors often overlooked by normative urban-based approaches, including team-based care characteristic of rural hospitals and limited access to specialist care and imaging services.