Objectives
To evaluate the health impact and cost‐effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia.
Design, setting, ...participants
We investigated the impact of LS testing strategies in a micro‐simulation model (Policy1–Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at‐risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance.
Main outcome measures
Cost‐effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost‐effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years).
Results
The cost‐effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life‐year saved (LYS) (indicative willingness‐to‐pay threshold: $30 000–$50 000/LYS). These strategies could avert 184–189 CRC deaths with an additional 30 597–31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164–166 additional colonoscopies/death averted). The most cost‐effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost‐effectiveness ratio ICER, $28 915/LYS). Universal germline gene panel testing was not cost‐effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost‐effective at all age limits when paired with 2‐yearly colonoscopic surveillance (ICER, $11 525–$32 153/LYS), and required 4778–15 860 additional colonoscopies to avert 46–181 CRC deaths (88–103 additional colonoscopies/death averted).
Conclusions
Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost‐effective compared with no testing. Universal germline gene panel testing would not currently be cost‐effective.
Cyanide represents a persistent threat for accidental or malicious misuse due to easy conversion into a toxic gas and access to large quantities through several industries. The high safety index of ...hydroxocobalamin is a cornerstone quality as a cyanide scavenger. Unfortunately, intravenous infusion of hydroxocobalamin limits the utility in a mass casualty setting. We previously reported platinum(II) Pt(II) complexes with trans-directing sulfur ligands as an efficacious alternative to hydroxocobalamin when delivered by a bolus intramuscular injection in mice and rabbits. Thus, to enable Pt(II) as an alternative to hydroxocobalamin, a high safety factor is needed. The objective is to maintain efficacy and mitigate the risk for nephrotoxicity. Platinum amino acid complexes with the ability to form five- or six-membered rings and possessing either carboxylates or carboxamides are evaluated in vitro for cyanide scavenging. In vivo efficacy was evaulated in the zebrafish and mice cyanide exposure models. In addition, Pt(II) complex toxicity and pharmacokinetics were evaluated in a cyanide naive Sprague-Dawley model. Doses for toxicity are escalated to 5x from the efficacious dose in mice using a body surface area adjustment. The results show the carboxamide ligands display a time and pH dependence on cyanide scavenging in vitro and efficacy in vivo. Additionally, exchanging the carboxylate for carboxamide showed reduced indications of renal injury. A pharmacokinetic analysis of the larger bidentate complexes displayed rapid absorption by intramuscular administration and having similar plasma exposure. These findings point to the importance of pH and ligand structures for methionine carboxamide complexes with Pt(II).
Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged 40–69 years. Prospective studies of older women aged ≥70 years have been limited. We ...assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6339 older women aged ≥70 years (mean age 75 years) enrolled into the ASPREE trial, a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. We evaluated incident BC diagnoses over a median follow-up time of 4.7 years. A multivariable Cox regression model including conventional BC risk factors was applied to prospective data, and re-evaluated after adding the PRS. We also assessed the association of rare pathogenic variants (PVs) in BC susceptibility genes (BRCA1/BRCA2/PALB2/CHEK2/ATM). The PRS, as a continuous variable, was an independent predictor of incident BC (hazard ratio (HR) per standard deviation (SD) = 1.4, 95% confidence interval (CI) 1.3–1.6) and hormone receptor (ER/PR)-positive disease (HR = 1.5 (CI 1.2–1.9)). Women in the top quintile of the PRS distribution had over two-fold higher risk of BC than women in the lowest quintile (HR = 2.2 (CI 1.2–3.9)). The concordance index of the model without the PRS was 0.62 (95% CI 0.56–0.68), which improved after addition of the PRS to 0.65 (95% CI 0.59–0.71). Among 41 (0.6%) carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Our study demonstrates that a PRS predicts incident BC risk in women aged 70 years and older, suggesting potential clinical utility extends to this older age group.
Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE ...study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.
PURPOSELynch syndrome-related colorectal cancer (CRC) risk substantially varies by mismatch repair (MMR) gene. We evaluated the health impact and cost-effectiveness of MMR gene-tailored colonoscopic ...surveillance. METHODSWe first estimated sex- and MMR gene-specific cumulative lifetime risk of first CRC without colonoscopic surveillance using an optimization algorithm. Next, we harnessed these risk estimates in a microsimulation model, "Policy1-Lynch," and compared 126 colonoscopic surveillance strategies against no surveillance. RESULTSThe most cost-effective strategy was 3-yearly surveillance from age 25 to 70 years (pathogenic variants path_ in MLH1 path_MLH1, path_MSH2) with delayed surveillance for path_MSH6 (age 30-70 years) and path_PMS2 (age 35-70 years) heterozygotes (incremental cost-effectiveness ratio = Australian dollars (A) $8,833/life-year saved). This strategy averted 60 CRC deaths (153 colonoscopies per death averted) over the lifetime of 1000 confirmed patients with Lynch syndrome (vs no surveillance). This also reduced colonoscopies by 5% without substantial change in health outcomes (vs nontailored 3-yearly surveillance from 25-70 years). Generally, starting surveillance at age 25 (vs 20) years was more cost-effective with minimal effect on life-years saved and starting 5 to 10 years later for path_MSH6 and path_PMS2 heterozygotes (vs path_MLH1 and path_MSH2) further improved cost-effectiveness. Surveillance end age (70/75/80 years) had a minor effect. Three-yearly surveillance strategies were more cost-effective (vs 1 or 2-yearly) but prevented 3 fewer CRC deaths. CONCLUSIONMMR gene-specific colonoscopic surveillance would be effective and cost-effective.
Purpose: The role of healthcare leaders is becoming increasingly complex, and carries great responsibility for patients, employees, and the quality of service delivery. This study explored the ...barriers and enablers that department leaders in nursing homes encounter when managing the dual responsibilities in Health, Safety and Environment (HSE) and Quality and Patient Safety (QPS). Methodology: Case study design with data collected through semi structured interviews with 16 department leaders in five Norwegian municipalities. We analyzed the data using qualitative content analysis. Results: Data analysis resulted in four themes explaining what department leaders in nursing homes experience as barriers and enablers when handling the dual responsibility of HSE and QPS: Temporal capacity: The importance of having enough time to create a health-promoting work environment that ensures patient safety. Relational capacity: Relationships have an impact on work process and outcomes. Professional competence: Competence affects patient safety and leadership strategies. Organizational structure: Organizational frameworks influence how the dual responsibilities are handled. Conclusion: Evidence from this study showed that external contextual factors (eg, legislations and finances) and internal factors (eg, relationships and expectations) are experienced as barriers and enablers when department leaders are enacting the dual responsibility of HSE and QPS. Of these, relationships were found to be the most significant contributor. Keywords: leadership, patient safety, quality, human factors, staff safety
MUTYH carriers have an increased colorectal cancer risk in case-control studies, with loss of heterozygosity (LOH) as the presumed mechanism. We evaluated cancer risk among carriers in a prospective, ...population-based cohort of older adults. In addition, we assessed if cancers from carriers demonstrated mutational signatures (G:C>T:A transversions) associated with early LOH. We calculated incident risk of cancer and colorectal cancer among 13,131 sequenced study participants of the ASPirin in Reducing Events in the Elderly cohort, stratified by sex and adjusting for age, smoking, alcohol use, BMI, polyp history, history of cancer, and aspirin use. MUTYH carriers were identified among 13,033 participants in The Cancer Genome Atlas and International Cancer Genome Consortium, and somatic signatures of cancers were analyzed. Male MUTYH carriers demonstrated an increased risk for overall cancer incidence multivariable HR, 1.66; 95% confidence interval (CI), 1.03-2.68; P = 0.038 driven by increased colorectal cancer incidence (multivariable HR, 3.55; 95% CI, 1.42-8.78; P = 0.007), as opposed to extracolonic cancer incidence (multivariable HR, 1.40; 95% CI, 0.81-2.44; P = 0.229). Female carriers did not demonstrate increased risk of cancer, colorectal cancer, or extracolonic cancers. Analysis of mutation signatures from cancers of MUTYH carriers revealed no significant contribution toward early mutagenesis from widespread G:C>T:A transversions among gastrointestinal epithelial cancers. Among cancers from carriers, somatic transversions associated with base-excision repair deficiency are uncommon, suggestive of diverse mechanisms of carcinogenesis in carriers compared with those who inherit biallelic MUTYH mutations.
Despite absence of loss of heterozygosity in colorectal cancers, elderly male MUTYH carriers appeared to be at increased of colorectal cancer.
The role of healthcare leaders is becoming increasingly complex, and carries great responsibility for patients, employees, and the quality of service delivery. This study explored the barriers and ...enablers that department leaders in nursing homes encounter when managing the dual responsibilities in Health, Safety and Environment (HSE) and Quality and Patient Safety (QPS).
Case study design with data collected through semi structured interviews with 16 department leaders in five Norwegian municipalities. We analyzed the data using qualitative content analysis.
Data analysis resulted in four themes explaining what department leaders in nursing homes experience as barriers and enablers when handling the dual responsibility of HSE and QPS: Temporal capacity: The importance of having enough time to create a health-promoting work environment that ensures patient safety. Relational capacity: Relationships have an impact on work process and outcomes. Professional competence: Competence affects patient safety and leadership strategies. Organizational structure: Organizational frameworks influence how the dual responsibilities are handled.
Evidence from this study showed that external contextual factors (eg, legislations and finances) and internal factors (eg, relationships and expectations) are experienced as barriers and enablers when department leaders are enacting the dual responsibility of HSE and QPS. Of these, relationships were found to be the most significant contributor.
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