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Background: Although genetic testing has improved our ability to diagnose Lynch syndrome (LS), there is still limited information on the extent of variations in the clinical and genetic landscape among LS variant heterozygotes (LSVH) in Africa. We sought to investigate the cancer spectrum, cumulative risk, and survival outcomes of LSVH with pathogenic/likely pathogenic variants (P/LPVs) in the MLH1 and MSH2 genes using a LS registry in South Africa over the last 30 years. Methods: A retrospective study was conducted to retrieve demographic, clinical, and genetic data of all LSVH with P/LPVs in the MLH1 and MSH2 genes from our LS registry. Genetic data were analyzed according to cancer spectrum, cumulative risk, and crude survival. We used the Chi-squared and t-test to assess differences between groups, and Kaplan–Meier survival analyses were used to analyze the cumulative risk and crude survival outcomes. A p-value < 0.05 at a 95% confidence interval was considered statistically significant. Results: We analyzed a total of 577 LSVH from 109 families. About 450 (78%) and 127 (22%) LSVH harbored a disease-causing mutation in MLH1 and MSH2, respectively. A South African founder PV (MLH1:c.1528C>T) accounted for 74% (n = 426) of all LSVH. CRC was the most common diagnosed cancer in both MLH1 and MSH2 LSVH. MLH1 LSVH had a younger age at cancer diagnosis than MSH2 LSVH (43 vs. 47 years, respectively, p = 0.015). Extracolonic cancers were predominantly higher in female LSVH (n = 33, 35%) than in male LSVH (n = 8, 7%) with the MLH1:c.1528C>T founder PV. The cumulative risk of any cancer and CRC at any age was higher in MLH1 LSVH than in MSH2 LSVH (p = 0.020 and p = 0.036, respectively). LSVH with the MLH1:c.1528C>T PV had a better 10-year overall survival after the first cancer diagnosis, particularly for CRC. Conclusions: LSVH with P/LPVs in the MLH1 and MSH2 genes exhibited significant gene- and sex-specific differences in cancer spectrum, cumulative risk and survival outcomes. Cancer risk and survival estimates described in this study can be used to guide surveillance and genetic counselling for LSVH in our population. [ABSTRACT FROM AUTHOR]

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan–Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini–Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01–4.08], p = 0.034 and Adj HR: 1.53 [1.09–2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48–0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06–2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37–0.73], and Adj HR: 0.51 [CI: 0.36–0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of developing various solid cancers, but mostly colorectal cancer (CRC). Despite having the same germline pathogenic variant (PV) in one of the mis-match repair genes or the EPCAM gene, Lynch syndrome variant heterozygotes (LSVH) exhibit a remarkable phenotypic variability in the risk of developing cancer. The role of human leukocyte antigen (HLA) in modifying cancer development risk prompted our hypothesis into whether HLA variations act as potential genetic modifiers influencing the age at cancer diagnosis in LSVH. To investigate this, we studied a unique cohort of 426 LSVH carrying the same germline PV in the hMLH1 gene (MLH1:c.1528C > T) in South Africa. We intuitively selected 100 LSVH with the greatest diversity in age at cancer diagnosis (N = 80) and the oldest cancer unaffected LSVH (N = 20) for a high-throughput HLA genotyping of 11 HLA class I and class II loci using the shotgun next-generation sequencing (NGS) technique on the Illumina MiSeq platform. Statistical analyses employed Kaplan–Meier survival analyses with log-rank tests, and Cox proportional hazards using binned HLA data to minimize type I error. Significant associations were observed between young age at cancer diagnosis and HLA-DPB1*04:02 (mean age: 37 y (25–50); hazard ratio (HR) = 3.37; corrected p-value (q) = 0.043) as well as HLA-DPB1 binned alleles (including HLA-DPB1*09:01, HLA-DPB1*10:01, HLA-DPB1*106:01, HLA-DPB1*18:01, HLA-DPB1*20:01, HLA-DPB1*26:01, HLA-DPB1*28:01, HLA-DPB1*296:01, and HLA-DPB1*55:01) (mean age: 37 y (17–63); HR = 2.30, q = 0.045). The involvement of HLA-DPB1 alleles in the age at cancer diagnosis may highlight the potential role of HLA class II in the immune response against cancer development in LSVH. When validated in a larger cohort, these high-risk HLA-DPB1 alleles could be factored into cancer risk prediction models for personalized cancer screening in LSVH. [ABSTRACT FROM AUTHOR]

This document presents the results of an international consensus study on core standards and core outcomes for prehabilitation in colorectal surgery. The study involved healthcare professionals and patients from various countries and aimed to establish a common set of standards and outcomes for future research in prehabilitation. The study used a systematic review, Delphi surveys, and consensus meetings to gather input and reach consensus on the core standards and outcomes. The final list includes 33 core standards and 21 core outcomes, which researchers are encouraged to use as a minimum standard in prehabilitation research. The implementation of these core standards and outcomes is expected to improve standardization and facilitate comparisons between studies, ultimately benefiting colorectal surgical patients. [Extracted from the article]

Objective: The irrational use of antibiotics is a leading contributor to antibiotic resistance. Antibiotic stewardship (AS) interventions predominantly focus on prescribers. This study investigated the influence and participation of inpatients in infection‐related care, including antibiotic decision‐making, within and across two tertiary hospitals in South Africa (Cape Town) and India (Kerala). Methods: Through ethnographic enquiry of clinical practice in surgical pathways, including direct nonparticipant observation of clinical practices, healthcare worker (HCW), patient and carer interactions in surgical ward rounds and face‐to‐face interviews with participants (HCWs and patients), we sought to capture the implicit and explicit influence that patients and carers have in infection‐related care. Field notes and interview transcripts were thematically coded, aided by NVivo 12® Pro software. Results: Whilst observational data revealed the nuanced roles that patients/carers play in antibiotic decision‐making, HCWs did not recognize these roles. Patients and carers, though invested in patient care, are not routinely involved, nor are they aware of the opportunities for engagement in infection‐related decision‐making. Patients associated clinical improvement with antibiotic use and did not consider hospitalization to be associated with infection acquisition or transmission, highlighting a lack of understanding of the threat of infection and antibiotic resistance. Patients' economic and cultural positionalities may influence their infection‐related behaviours. In the study site in India, cultural norms mean that carers play widespread but unrecognized roles in inpatient care, participating in infection prevention activities. Conclusion: For patients to have a valuable role in AS and make informed decisions regarding their infection‐related care, a mutual understanding of their role in this process among HCWs and patients is crucial. The observed differences between the two study sites indicate the critical need for understanding and addressing the contextual drivers that impact effective patient‐centred healthcare delivery. Patient or Public Contribution: Ethnographic observations and interviews conducted in this study involved patients as participants. Patients were recruited for interviews after obtaining signed informed consent forms. Patients' identities were completely anonymized when presenting the study findings. [ABSTRACT FROM AUTHOR]

Background The effect of team dynamics on infection management and antimicrobial stewardship (AMS) behaviours is not well understood. Using innovative visual mapping, alongside traditional qualitative methods, we studied how surgical team dynamics and communication patterns influence infection-related decision making. Materials/methods Between May and November 2019, data were gathered through direct observations of ward rounds and face-to-face interviews with ward round participants in three high infection risk surgical specialties at a tertiary hospital in South Africa. Sociograms, a visual mapping method, mapped content and flow of communication and the social links between participants. Data were analysed using a grounded theory approach. Results Data were gathered from 70 hours of ward round observations, including 1024 individual patient discussions, 60 sociograms and face-to-face interviews with 61 healthcare professionals. AMS and infection-related discussions on ward rounds vary across specialties and are affected by the content and structure of the clinical update provided, consultant leadership styles and competing priorities at the bedside. Registrars and consultants dominate the discussions, limiting the input of other team members with recognised roles in AMS and infection management. Team hierarchies also manifest where staff position themselves, and this influences their contribution to active participation in patient care. Leadership styles affect ward-round dynamics, determining whether nurses and patients are actively engaged in discussions on infection management and antibiotic therapy and whether actions are assigned to identified persons. Conclusions The surgical bedside ward round remains a medium of communication between registrars and consultants, with little interaction with the patient or other healthcare professionals. A team-focused and inclusive approach could result in more effective decision making about infection management and AMS. [ABSTRACT FROM AUTHOR]

Background: No standardized written or volumetric definition exists for 'loss of domain' (LOD). This limits the utility of LOD as a morphological descriptor and as a predictor of peri- and postoperative outcomes. Consequently, our aim was to establish definitions for LOD via consensus of expert abdominal wall surgeons. Methods: A Delphi study involving 20 internationally recognized abdominal wall reconstruction (AWR) surgeons was performed. Four written and two volumetric definitions of LOD were identified via systematic review. Panelists completed a questionnaire that suggested these definitions as standardized definitions of LOD. Consensus on a preferred term was pre-defined as achieved when selected by ≥80% of panelists. Terms scoring <20% were removed. Results: Voting commenced August 2018 and was completed in January 2019. Written definition: During Round 1, two definitions were removed and seven new definitions were suggested, leaving nine definitions for consideration. For Round 2, panelists were asked to select all appealing definitions. Thereafter, common concepts were identified during analysis, from which the facilitators advanced a new written definition. This received 100% agreement in Round 3. Volumetric definition: Initially, panelists were evenly split, but consensus for the Sabbagh method was achieved. Panelists could not reach consensus regarding a threshold LOD value that would preclude surgery. Conclusions: Consensus for written and volumetric definitions of LOD was achieved from 20 internationally recognized AWR surgeons. Adoption of these definitions will help standardize the use of LOD for both clinical and academic activities. [ABSTRACT FROM AUTHOR]