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Biological samples are often frozen and stored for years and/or thawed multiple times, thus assessing their stability on long-term storage and repeated freeze-thaw cycles is crucial. The study aims were to assess:-the long-term stability of two major enzymatic and non-enzymatic metabolites of arachidonic acid, i.e. urinary 11-dehydro-thromboxane-(Tx) B 2 , 8-iso-prostaglandin (PG)F 2α , and creatinine in frozen urine samples;-the effect of multiple freeze-thaw cycles. Seven-hundred and three urine samples measured in previously-published studies, stored at -40 °C, and measured for a second time for 11-dehydro-TxB 2 (n = 677) and/or 8-iso-PGF 2α (n = 114) and/or creatinine (n = 610) were stable over 10 years and the 2 measurements were highly correlated (all rho = 0.99, P < 0.0001). Urine samples underwent 10 sequential freeze-thaw cycles, with and without the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (10 mM); urinary 11-dehydro-TxB 2 and creatinine were stable across all cycles (11-dehydro-TxB 2 : 100.4 ± 21%; creatinine: 101 ± 7% of baseline at cycle ten; n = 17), while 8-iso-PGF 2α significantly increased by cycle 6 (151 ± 22% of baseline at cycle ten, n = 17, P < 0.05) together with hydrogen peroxide only in the absence of antioxidant. Arachidonic acid metabolites and creatinine appear stable in human urines stored at -40 °C over 10 years. Multiple freeze-thaw cycles increase urinary 8-iso-PGF 2α in urine samples without antioxidants. These data are relevant for studies using urine samples stored over long-term and/or undergoing multiple freezing-thawing., (© 2024. The Author(s).)

Background and Objectives: There is limited research on management of metastatic anal canal squamous cell carcinoma (SCC) to the liver. This study aimed to describe outcomes for patients undergoing liver resection of anal SCC metastases., Methods: A multicenter, retrospective cohort study was conducted by three tertiary-referral centers. Patients undergoing liver surgery between 2008 and 2022 were included. Cox regression analysis was performed to evaluate predictors of recurrence and survival and Kaplan-Meier analysis was performed for 1-, 3-, and 5-year survival., Results: Twenty-one patients underwent liver resection and/or ablation. None were HIV positive and 24% had known HPV infection. 20/21(95%) patients had undergone Nigro protocol for management of the primary tumor with 12/21 (57%) patients experiencing complete response. 4/21 (19%) patients had synchronous liver metastases at time of diagnosis. Median tumor size was 5.0 cm and median tumor number was one. At analysis, 52% remained alive. Median overall survival was 32.2 months. 5-year overall survival was 50%. Median recurrence-free survival was 7.7 months and 5-year recurrence-free survival was 30%. Need for salvage abdominoperineal resection was negatively associated with recurrence-free survival. The most common site of recurrence was the liver., Conclusions: Liver resection for metastatic anal SCC can be beneficial for appropriately selected patients., (© 2023 Wiley Periodicals LLC.)

Purpose: To investigate if a 12-week community-based exercise program ( FitSkills ) fostered positive attitudes towards disability among university student mentors., Methods: A stepped-wedge cluster randomised trial was completed with 4 clusters. Students were eligible to be a mentor if enrolled in an entry-level health degree (any discipline, any year) at one of three universities. Each mentor was matched with a young person with a disability and the pair exercised together at the gym twice a week for an hour (24 sessions total). At 7 times over 18 months, mentors completed the Disability Discomfort Scale to indicate their level of discomfort when interacting with people with disability. Data were analysed according to the intention to treat principles using linear mixed-effects models to estimate changes in scores over time., Results: A total of 207 mentors completed the Disability Discomfort Scale at least once, of whom 123 participated in FitSkills . Analysis found an estimated reduction of 32.8% (95% confidence interval (CI) -36.8 to -28.4) in discomfort scores immediately after exposure to FitSkills across all four clusters. These decreases were sustained throughout the remainder of the trial., Conclusions: Mentors reported more positive attitudes towards interacting with people with disability after completing FitSkills with changes retained for up to 15 months.

Background and Aims: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration-approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed., Methods: Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib., Results: A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib., Conclusion: These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.govNCT02273362)., (© 2024 The Authors.)

The World Health Organization (WHO) recommends the consideration of introducing routine hepatitis A vaccination into national immunization schedules for children ≥ 1 years old in countries with intermediate HAV endemicity. Recent data suggest that South Africa is transitioning from high to intermediate HAV endemicity, thus it is important to consider the impact and cost of potential routine hepatitis A vaccination strategies in the country. An age-structured compartmental model of hepatitis A transmission was calibrated with available data from South Africa, incorporating direct costs of hepatitis A treatment and vaccination. We used the calibrated model to evaluate the impact and costs of several childhood hepatitis A vaccination scenarios from 2023 to 2030. We assessed how each scenario impacted the burden of hepatitis A (symptomatic hepatitis A cases and mortality) as well as calculated the incremental cost per DALY averted as compared to the South African cost-effectiveness threshold. All costs and outcomes were discounted at 5%. For the modelled scenarios, the median estimated cost of the different vaccination strategies ranged from USD 1.71 billion to USD 2.85 billion over the period of 2023 to 2030, with the cost increasing for each successive scenario and approximately 39-52% of costs being due to vaccination. Scenario 1, which represented the administration of one dose of the hepatitis A vaccine in children < 2 years old, requires approximately 5.3 million vaccine doses over 2023-2030 and is projected to avert a total of 136,042 symptomatic cases [IQR: 88,842-221,483] and 31,106 [IQR: 22,975-36,742] deaths due to hepatitis A over the period of 2023 to 2030. The model projects that Scenario 1 would avert 8741 DALYs over the period of 2023 to 2030; however, it is not cost-effective against the South African cost-effectiveness threshold with an ICER per DALY averted of USD 21,006. While Scenario 3 and 4 included the administration of more vaccine doses and averted more symptomatic cases of hepatitis A, these scenarios were absolutely dominated owing to the population being infected before vaccination through the mass campaigns at older ages. The model was highly sensitive to variation of access to liver transplant in South Africa. When increasing the access to liver transplant to 100% for the baseline and Scenario 1, the ICER for Scenario 1 becomes cost-effective against the CET (ICER = USD 2425). Given these findings, we recommend further research is conducted to understand the access to liver transplants in South Africa and better estimate the cost of liver transplant care for hepatitis A patients. The modelling presented in this paper has been used to develop a user-friendly application for vaccine policy makers to further interrogate the model outcomes and consider the costs and benefits of introducing routine hepatitis A vaccination in South Africa.

Background: The global benchmark cut-offs were set for laparoscopic liver resection procedures: left lateral sectionectomy, left hepatectomy, and right hepatectomy. We aimed to compare the performance of our North American center with the established global benchmarks., Methods: This is a single-center study of adults who underwent laparoscopic liver resection between 2010 to 2022 at the Toronto General Hospital. Fourteen benchmarking outcomes were assessed: operation time, intraoperative blood transfusion, estimated blood loss, blood loss ≥500 mL, blood loss ≥1000mL, open-conversion, postoperative length of stay, return to operation, postoperative morbidity, postoperative major-morbidity, 30-day mortality, 90-day mortality, R1 resection, and failure to rescue. Low-risk benchmark cases were defined as follows: patients aged 18 to 70 years, American Society of Anesthesiologist score ≤ 2, tumor size <10 cm, and Child-Pugh score ≤A. Cases involving bilio-enteric anastomosis, hilar dissection, or concomitant major procedures were excluded from the low-risk category. Cases that did not meet the criteria for low-risk selection were considered high-risk cases., Results: A total of 178 laparoscopic liver resection cases were analyzed (109 left lateral sectionectomies, 45 left hepatectomies, 24 right hepatectomies). Forty-four (25%) cases qualified as low-risk cases (23 left lateral sectionectomies, 16 left hepatectomies, 5 right hepatectomies). The postoperative major morbidity and 90-day mortality after left lateral sectionectomy, left hepatectomy, and right hepatectomy for the low-risk cases were 0%, 0%, and 0%, and 0%, 0%, and 0%, respectively. For the high-risk cases post-2017, the outcomes in the same order were 0%, 0%, and 12%; 0%, 0%, and 0%, respectively. For the high-risk cases operated pre2017, the outcomes in the same order were 9%∗, 16%∗, and 18%; 2%∗, 0%, and 9%∗ (asterisks indicate not meeting the global cut-off), respectively., Conclusion: A North American center was able to achieve outcomes comparable to the established global benchmark for laparoscopic liver resection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: We assessed the accuracy of preoperative gallium-68 DOTA-Tyr3-octreotate (DOTATATE) positron emission tomography (PET) imaging in estimating multifocality and nodal metastases of small bowel neuroendocrine tumors (sbNETs)., Methods: A multicenter analysis was performed on patients with sbNETs who underwent preoperative DOTATATE PET imaging and surgical resection, with manual palpation of the entire length of the small bowel, between January 2016 and August 2022. Preoperative imaging reports and blinded secondary imaging reviews were compared to the final postoperative pathology reports. Descriptive statistics were applied., Results: One-hundred and four patients met inclusion criteria. Pathology showed 53 (51%) patients had multifocal sbNETs and 96 (92%) had nodal metastases. The original preoperative DOTATATE PET imaging identified multifocal sbNET in 28 (27%) patients and lymph node (LN) metastases in 80 (77%) patients. Based on original radiology reports, sensitivity for multifocal sbNET identification was 45%, specificity was 92%, positive predictive value (PPV) was 86%, and negative predictive value (NPV) was 62%. For the identification of LN metastases, sensitivity was 82%, specificity was 88%, PPV was 99%, and NPV was 29%., Conclusions: Although DOTATATE PET imaging is specific and relatively accurate, sensitivity and NPV are insufficient to guide surgical planning. Preoperative use should not replace open palpation to identify additional synchronous lesions or to omit regional lymphadenectomy., (© 2023 Wiley Periodicals LLC.)

Background: Most patients with localized cholangiocarcinoma (CCA) endure cancer relapse after curative resection underscoring the importance of systemic therapy. The current study attempts to determine the impact of perioperative chemotherapy (PC) on survival in patients with CCA undergoing resection., Methods: Patients diagnosed with CCA undergoing curative-intent resection between January 1, 2000, and December 31, 2019, in a tertiary care center were included. Cox proportional hazard modeling was used to determine the impact of PC on disease-free survival (DFS) and overall survival (OS). In addition, a nomogram was constructed to estimate 3-year DFS., Results: Among the 182 patients included in the analysis, 102 underwent surgery alone, and 80 received surgery plus PC. Forty-two patients received neoadjuvant therapy, and 38 patients received adjuvant therapy. On multivariate analysis, PC was significantly associated with an improved DFS (HR, 95% CI: 0.63, 0.41-0.98; p = 0.04) and OS (HR, 95% CI: 0.46, 0.27-0.78; p < 0.01). In the interaction analysis, the survival benefit was especially seen in patients with positive resection margins and tumor size > 5 cm., Conclusion: In patients with CCA undergoing curative resection, receipt of PC was associated with improved DFS and OS. The nomogram constructed from this database provides an estimate of 3-year DFS after surgical resection. Randomized trials are needed to define the optimal regimen and sequence., Competing Interests: Declaration of competing interest None., (© 2023 Published by Elsevier Ltd.)

Aim: To identify implementation strategies and safety outcomes (adverse events) of community-based physical activity interventions for adolescents and adults with complex cerebral palsy (CP)., Method: Five electronic databases were systematically searched to April 2022. Data were extracted on the implementation and safety of physical activity interventions for adolescents and adults with CP, classified in Gross Motor Function Classification System (GMFCS) levels IV and V, delivered in a community setting., Results: Seventeen studies with 262 participants (160 participants classified in GMFCS levels IV or V) were included. Community settings included schools (n = 4), participants' homes (n = 3), gymnasia (n = 2), swimming pools (n = 2), and other settings (n = 4). Most studies specified medical or safety exclusion criteria. Implementation strategies included pre-exercise screening, use of adapted equipment, familiarization sessions, supervision, physical assistance, and physiological monitoring. Attendance was high and attrition low. Nine studies reported non-serious, expected, and related events. Four studies reported minor soreness and four studies reported minor fatigue post-exercise. Serious adverse events related to exercise were infrequent (reported for 4 of 160 participants [<2%]: three participants withdrew from an exercise programme and one participant ceased exercise for a short period). Most frequently reported was pain, requiring temporary exercise cessation or programme change, or study withdrawal (three participants)., Interpretation: For most adolescents and adults with CP classified in GMFCS levels IV and V, physical activity interventions can be safely performed in a community setting, without post-exercise pain or fatigue, or serious adverse events., What This Paper Adds: Supervised community-based physical activity interventions can be safely performed by people with complex cerebral palsy. Post-exercise pain or fatigue was not common among those classified in Gross Motor Function Classification System levels IV or V. Serious adverse events are infrequent when exercising in community settings, with safety strategies., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Objective: To compare minimally invasive (MILR) and open liver resections (OLRs) for hepatocellular carcinoma (HCC) in patients with metabolic syndrome (MS)., Background: Liver resections for HCC on MS are associated with high perioperative morbidity and mortality. No data on the minimally invasive approach in this setting exist., Material and Methods: A multicenter study involving 24 institutions was conducted. Propensity scores were calculated, and inverse probability weighting was used to weight comparisons. Short-term and long-term outcomes were investigated., Results: A total of 996 patients were included: 580 in OLR and 416 in MILR. After weighing, groups were well matched. Blood loss was similar between groups (OLR 275.9±3.1 vs MILR 226±4.0, P =0.146). There were no significant differences in 90-day morbidity (38.9% vs 31.9% OLRs and MILRs, P =0.08) and mortality (2.4% vs 2.2% OLRs and MILRs, P =0.84). MILRs were associated with lower rates of major complications (9.3% vs 15.3%, P =0.015), posthepatectomy liver failure (0.6% vs 4.3%, P =0.008), and bile leaks (2.2% vs 6.4%, P =0.003); ascites was significantly lower at postoperative day 1 (2.7% vs 8.1%, P =0.002) and day 3 (3.1% vs 11.4%, P <0.001); hospital stay was significantly shorter (5.8±1.9 vs 7.5±1.7, P <0.001). There was no significant difference in overall survival and disease-free survival., Conclusions: MILR for HCC on MS is associated with equivalent perioperative and oncological outcomes to OLRs. Fewer major complications, posthepatectomy liver failures, ascites, and bile leaks can be obtained, with a shorter hospital stay. The combination of lower short-term severe morbidity and equivalent oncologic outcomes favor MILR for MS when feasible., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Cows are known carriers of Cryptosporidium parvum ( C. parvum ), a protozoa that can cause the gastrointestinal illness cryptosporidiosis in humans. Despite this potential exposure, dairy farmers tend to wear personal protective equipment (PPE) to protect the milk from contamination, rather than to protect themselves from zoonotic diseases, such as cryptosporidiosis. In this study, cow feces were collected from individual cattle on dairy farms and analyzed for C. parvum using qPCR. Quantitative microbial risk assessment (QMRA) was used to determine the risk of cryptosporidiosis to the dairy farmer with and without the use of handwashing and PPE (gloves and masks). The annualized risk of cryptosporidiosis to dairy farmers was 29.08% but was reduced significantly in each of the three interventions. Among the individual interventions, glove use provided the greatest reduction in risk, bringing the annual risk of cryptosporidiosis to 4.82%. Implementing regular handwashing, the use of gloves and a mask brought the annual risk of cryptosporidiosis to 1.29%. This study provides evidence that handwashing and PPE use can significantly reduce the risk of cryptosporidiosis to farmers and is worth implementing despite potential barriers such as discomfort and cost.

Background: Patient engagement has emerged as a key focus in the research literature to facilitate patients' recovery. The term is commonly used by researchers, yet without working definitions. This lack of clarity is further complicated by the interchangeable use of a few terms., Objectives: This systematic review aimed at identifying how patient engagement was conceptualised and operationalised in perioperative settings., Methods: MEDLINE, EMBASE, CINAHL and the Cochrane Library were searched for publications in English discussing patient engagement during the perioperative phase. Three reviewers conducted study selection and methodological assessment using Joanna Briggs Institute mixed methods review framework. Reflexive thematic analysis was used to analyse qualitative data and descriptive analysis for quantitative data., Findings: Twenty-nine studies were included with a total sample of 6289. Study types included qualitative (n = 14) and quantitative (n = 15) with different types of surgery. Sample sizes ranged from n = 7 to n = 1315. Only 38% (n = 11) of included studies offered an explicit definition. Four themes associated with operationalisation included provision of information, which was most studied theme, communication, decision-making and action-taking behaviours. All four themes were interconnected and co-dependent on each other., Conclusions: Patient engagement in perioperative settings is a complex and multifaceted concept. The conceptual void in the literature calls for more theoretically informed and comprehensive approaches to researching surgical patient engagement. Future research should aim to better understand the factors that influence patient engagement, as well as the impact of different forms of engagement on patient outcomes through the whole surgical journey of a patient., (© 2023 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Background: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases., Methods: Urinary 11-dehydro-thromboxane B 2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values., Results: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg., Conclusions: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin., (© 2023. The Author(s).)

Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors., Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes., Results: A total of 1,395 patients were included. Primary tumors included non-small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07-1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03-1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16-2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04-1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (P = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM., Conclusions: In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population., (©2023 American Association for Cancer Research.)

Enteropathogenic Escherichia coli (EPEC) is a diarrheagenic bacterium that predominantly infects infants in developing countries. EPEC forms attaching and effacing (A/E) lesions on the apical surface of the small intestine, leading to diarrhea. The locus of enterocyte effacement (LEE) is both necessary and sufficient for A/E lesion morphogenesis by EPEC. Gene expression from this virulence determinant is controlled by an elaborate regulatory web that extends beyond protein-based transcriptional regulators and includes small regulatory RNA (sRNA) that exert their effects posttranscriptionally. To date, only 4 Hfq-dependent sRNAs-MgrR, RyhB, McaS, and Spot42-have been identified that affect the LEE of EPEC by diverse mechanisms and elicit varying regulatory outcomes. In this study, we demonstrate that the paralogous Hfq-dependent sRNAs OmrA and OmrB globally silence the LEE to diminish the ability of EPEC to form A/E lesions. Interestingly, OmrA and OmrB do not appear to directly target a LEE-encoded gene; rather, they repress transcription from the LEE1 promoter indirectly, by means of an as-yet-unidentified transcriptional factor that binds within 200 base pairs upstream of the transcription start site to reduce the expression of the LEE master regulator Ler, which, in turn, leads to reduced morphogenesis of A/E lesions. Additionally, OmrA and OmrB also repress motility in EPEC by targeting the 5' UTR of the flagellar master regulator, flhD., (© 2022. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Background: Metabolic syndrome (MS) is rapidly growing as risk factor for HCC. Liver resection for HCC in patients with MS is associated with increased postoperative risks. There are no data on factors associated with postoperative complications., Aims: The aim was to identify risk factors and develop and validate a model for postoperative major morbidity after liver resection for HCC in patients with MS, using a large multicentric Western cohort., Materials and Methods: The univariable logistic regression analysis was applied to select predictive factors for 90 days major morbidity. The model was built on the multivariable regression and presented as a nomogram. Performance was evaluated by internal validation through the bootstrap method. The predictive discrimination was assessed through the concordance index., Results: A total of 1087 patients were gathered from 24 centers between 2001 and 2021. Four hundred and eighty-four patients (45.2%) were obese. Most liver resections were performed using an open approach (59.1%), and 743 (68.3%) underwent minor hepatectomies. Three hundred and seventy-six patients (34.6%) developed postoperative complications, with 13.8% major morbidity and 2.9% mortality rates. Seven hundred and thirteen patients had complete data and were included in the prediction model. The model identified obesity, diabetes, ischemic heart disease, portal hypertension, open approach, major hepatectomy, and changes in the nontumoral parenchyma as risk factors for major morbidity. The model demonstrated an AUC of 72.8% (95% CI: 67.2%-78.2%) ( https://childb.shinyapps.io/NomogramMajorMorbidity90days/ )., Conclusions: Patients undergoing liver resection for HCC and MS are at high risk of postoperative major complications and death. Careful patient selection, considering baseline characteristics, liver function, and type of surgery, is key to achieving optimal outcomes., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Paediatric pulmonary diseases are the leading causes of mortality amongst children under five globally. Economic evaluations (EEs) seek to guide decision-makers on which health care interventions to adopt to reduce the paediatric pulmonary disease burden. This study aims to systematically review economic evaluations on different aspects of the inpatient management of paediatric pulmonary diseases globally., Methods: We systematically reviewed EEs published between 2010 and 2020, with a subsequent search conducted for 2020-2022. We searched PubMed, Web of Science, MEDLINE, Paediatric Economic Database Evaluation (PEDE) and the Cochrane library. We extracted data items guided by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. We collected qualitative and quantitative data which we analysed in Microsoft Excel and R software., Results: Twenty-two articles met the inclusion criteria. Six of the articles were cost-effectiveness analyses, six cost-utility analyses, two cost-minimisation analyses and eight cost analyses. Twelve articles were from high-income countries (HICs) and ten were from low- and middle-income countries (LMICs). Eight articles focused on asthma, eleven on pneumonia, two on asthma and pneumonia, and one on tuberculosis., Conclusion: Conducting more EEs for paediatric pulmonary diseases in LMICs could allow for more evidence-based decision-making to improve paediatric health outcomes., (© 2023. The Author(s).)

Multisite collection and preservation of peripheral blood mononuclear cells (PBMCs) for centralized analysis is an indispensable strategy for large cohort immune phenotyping studies. However, the absence of cross-site standardized protocols introduces unnecessary sample variance. Here we describe the protocol implemented by the Province of Ontario Neurodevelopmental Disorders (POND) Network's immune platform for the multisite collection, processing, and cryopreservation of PBMCs. We outline quality control standards and evaluate the performance of our PBMC processing and storage protocol. We also describe the Child Immune History Questionnaire results, an assessment tool evaluating pre-existing immune conditions in children with neurodevelopmental disorders (NDDs). Cell viability was assessed in samples from 178 participants based on strict quality control criteria. Overall, 83.1% of samples passed quality control standards. Samples collected and processed at the same site had higher quality control pass rates than samples that were collected and subsequently shipped to another site for processing. We investigated if freezer time impacted sample viability and found no difference in mean freezer time between samples that passed and failed quality control. The Child Immune History Questionnaire had a response rate of 87.1%. The described protocol produces viable samples that may be used in future immune phenotyping experiments., (© 2023. The Author(s).)

Summary Dr. Paul Greig is an icon of surgical education, transplantation, hepatobiliary surgery and Canadian surgery. Dr. Greig has trained experts in these fields all over the world and is regarded as one of the most important surgical educators in the past 25 years., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

Common mental disorders (CMDs) constitute a major public health and economic burden on low- and middle-income countries (LMICs). Systematic reviews of economic evaluations of psychological treatments for CMDs are limited. This systematic review examines methods, reports findings and appraises the quality of economic evaluations of psychological treatments for CMDs in LMICs. We searched a range of bibliographic databases (including PubMed, EconLit, APA-PsycINFO and Cochrane library) and the African Journals Online (AJoL) and Google Scholar platforms. We used a pre-populated template to extract data and the Drummond & Jefferson checklist for quality appraisal. We present results as a narrative synthesis. The review included 26 studies, mostly from Asia (12) and Africa (9). The majority were cost-effectiveness analyses (12), some were cost-utility analyses (5), with one cost-benefit analysis or combinations of economic evaluations (8). Most interventions were considered either cost-effective or potentially cost-effective (22), with 3 interventions being not cost-effective. Limitations were noted regarding appropriateness of conclusions drawn on cost-effectiveness, the use of cost-effectiveness thresholds and application of 'societal' incremental cost-effectiveness ratios to reflect value for money (VfM) of treatments. Non-specialist health workers (NSHWs) delivered most of the treatments (16) for low-cost delivery at scale, and costs should reflect the true opportunity cost of NSHWs' time to support the development of a sustainable cadre of health care providers. There is a 4-fold increase in economic evaluations of CMD psychological treatments in the last decade over the previous one. Yet, findings from this review highlight the need for better application of economic evaluation methodology to support resource allocation towards the World Health Organization recommended first-line treatments of CMDs. We suggest impact inventories to capture societal economic gains and propose a VfM assessment framework to guide researchers in evaluating cost-effectiveness., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Background: Multiple myeloma is an incurable haematological malignancy that is associated with a high probability of relapse. The survival of relapsed patients has been greatly improved by the development of novel drugs such as lenalidomide and bortezomib. We assessed the cost-effectiveness of these drugs as second-line treatment for relapsed/refractory multiple myeloma (RRMM) patients in the South African public health care system., Methods: We modelled 3 treatment strategies for second-line RRMM treatment: dexamethasone (standard of care), bortezomib (BORT) and lenalidomide plus dexamethasone (LEN/DEX) from the South African public health perspective. For each strategy we modelled a hypothetical cohort of relapsed/refractory multiple myeloma patients using a three-state Markov model over a 15-year time horizon. Efficacy and utilization data were obtained from the MM009/010 and APEX trials and external studies. Price and cost data were from local sources and presented in 2021 South African Rands. Outcomes were reported in quality adjusted life years (QALYs). Incremental cost effectiveness ratios (ICERs) were calculated for BORT and LEN/DEX and compared to a local cost-effectiveness threshold of R38 500 per DALY averted using the assumption that 1 DALY averted is equal to 1 QALY gained. A budget impact analysis was conducted to evaluate the financial impact of the introduction of BORT and LEN/DEX, respectively. Deterministic sensitivity analysis was undertaken to account for parameter uncertainties., Results: The modelled total costs of DEX, BORT and LEN/DEX were estimated to be R8 312, R234 996 and R1 135 323, respectively. DEX treatment provided 1.14 QALYs while BORT and LEN/DEX treatments provided 1.49 and 2.22 QALYs, respectively. The ICER of BORT versus DEX was R654 649 and that of LEN/DEX versus BORT was R1 225 542. Both BORT and LEN/DEX treatments were not cost-effective relative to a cost-effectiveness threshold of R38 500 per DALY averted. Both BORT and LEN/DEX significantly increase the 1 year budget-cost of RRMM treatment., Conclusion: Both BORT and LEN/DEX treatments are unlikely to be cost-effective strategies for second-line treatment of RRMM in South Africa. The results indicate that the drug prices of lenalidomide and bortezomib are key drivers of value for money. Price reductions could potentially make BORT more cost-effective., (© 2022. The Author(s).)

Studies have shown that school-based sexual health promotion interventions can improve adolescent sexual and reproductive health outcomes. However, there has been insufficient evidence on the cost and cost-effectiveness of such programmes, driving poor and inconsistent investment and prioritization. This paper analyses the costs of the SKILLZ Health for Girls programme, a sports-based sexual education intervention targeted at adolescent girls in the secondary school environment. Costs were collected alongside a cluster-randomized trial, including 38 secondary schools in Cape Town, South Africa. The analysis was conducted from a provider (multi-sector) perspective and used a mixed-methods costing approach. We developed a cost data collection tool to compile cost information from one-on-one interviews, administrative data and non-participant observations of the intervention. Costs were analysed for 2019, representing a full academic year of programme implementation. The intention-to-treat analysis revealed an average cost per learner per session of $9.92, and the cost per learner reached was estimated at $69.43. Sensitivity analysis indicated that these costs were sensitive to the participation rates of the learners who did not complete the intervention. The cumulative cost for the scale-up scenario for the Western Cape Province based on the base-case analysis (maximizing coverage of schools but only including 30% of eligible learners within schools) was estimated at $5 311 453.00 for a 3-year period, which exceeds the provincial conditional grant allocation dedicated to the human immunodeficiency virus and acquired immune deficiency syndrome (life skills education) for the same period, yet is comparable to the expenditure for a similar donor-funded programme within the province. The study's results will contribute to decision-making for implementing sexual education interventions in schools in South Africa and similar contexts., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Age-related remodelling of the arterial wall shifts the load bearing from the compliant elastin network to the stiffer collagen fibres. While this phenomenon has been widely investigated in animal models, human studies are lacking due to shortage of donors' arteries. This work aimed to characterise the effect of ageing on the mechanical properties of the human aortic wall in the circumferential direction. N = 127 thoracic aortic rings (age 18-81 years) were subjected to circumferential tensile testing. The tangential elastic modulus (K θθθθ ) was calculated at pressure-equivalent stresses ranging 60-100 mmHg. Further, the mechanical data were fitted using the Holzpafel-Gasser-Ogden hyperelastic strain energy function (HGO-SEF), modelling the superimposed response of an isotropic matrix (elastin) reinforced by collagen fibres. K θθθθ increased with age across at all considered pressures (p < 0.001), although more strongly at higher pressures. Indeed, the slope of the linear K θθθθ -pressure relationship increased by 300% from donors <30 to ≥70 years (4.72± 2.95 to 19.06± 6.82 kPa/mmHg, p < 0.001). The HGO-SEF elastin stiffness-like parameter dropped by 31% between 30 and 40 years (p < 0.05) with non-significant changes thereafter. Conversely, changes in HGO-SEF collagen parameters were observed later at age>60 years, with the exponential constant increasing by ∼20-50 times in the investigated age range (p < 0.001). The results provided evidence that the human thoracic aorta undergoes stiffening during its life-course. Constitutive modelling suggested that these changes in arterial mechanics are related to the different degeneration time-courses of elastin and collagen; likely due to considerable fragmentation of elastin first, with the load bearing shifting from the compliant elastin to the stiffer collagen fibres. This process leads to a gradual impairment of the aortic elastic function with age., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Intrahepatic Cholangiocarcinoma (iCCA) is an aggressive cancer with diverse mutational profiles. An important molecular subtype is fibroblast growth factor receptor 2 (FGFR2) fusion. The effect of FGFR2 fusions on prognosis is unknown. Our aim was to assess the outcomes in resected CCA patients in relation to FGFR2 status., Methods: Surgically treated CCA patients from a single institution were retrospectively reviewed between 2008 and 2014. FGFR rearrangements were detected by fluorescence in situ hybridization (FISH). Data included patient demographics, tumor pathology, disease-free survival (DFS) and overall survival (OS)., Results: Ninety-five patients underwent surgical resection for iCCA. Twelve (13%) of these were found to have FGFR2 fusion, none of which were treated with FGFR targeted therapy. Patients with FGFR2 fusions were found to have a longer 5-year (83 vs. 32%, p = 0.01) and 10-year (46 vs. 22%, p = 0.04) OS. Five and 10-year DFS was also increased (68 vs. 33% p = 0.04) and (68 vs. 25 %, p = 0.02,). FGFR2 fusion status was the strongest independent factor associated with improved OS (HR 0.23, 0.09-0.62, p=0.003) and DFS (HR 0.18, 0.05-0.67, p=0.01)., Conclusion: Patients with CCA FGFR2 fusion have improved OS and DFS following surgical resection., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The globally growing demand for complementary and alternative medicine (CAM) has attracted educators' attention to integrate CAM into conventional nursing programs. This systematic review aimed to understand the status quo of nursing students (NSs)' overall rated knowledge of, attitude/belief toward, and practice/previous use or experience (KAP) of CAM in surveys, given these factors may influence NSs' receptivity to CAM curricula, and may be of value in guiding the development of effective teaching strategies., Methods: Formally published cross-sectional quantitative studies investigating the primary outcome of KAP toward CAM by NSs were searched for from eight databases from their inception through to 28 April 2022. PRISMA 2020 guidelines were followed., Results: Twenty-six studies were included for analysis, 25 of which were judged to be of moderate to high quality. Despite limited and poorly informed knowledge of CAM therapies, the majority of NSs generally viewed them in a positive light. Furthermore, NSs usually reported an interest in further learning, and supported and welcomed the integration of CAM curricula, at least as elective modules, into existing nursing programs. Lack of evidence was perceived as a major barrier to the use or integration of CAM. Mass media and the internet were the main sources via which NSs access CAM information. Measurement of KAP in all included studies was via self-designed questionnaires/scales or adapted from previously developed questionnaires/scales., Conclusions: The need for integrating and strengthening CAM curricula into current nursing education is identified. Besides theoretical knowledge and matched clinical placement, skills training in literature searching and evidence-based practice are advised to be included in the curricula design. The experiential learning mode is strongly recommended for delivering specific CAM modalities. In addition, a standard instrumentation for determining NSs' KAP toward CAM should be designed and examined for use in different cultural settings., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?RecordID=300602, identifier: PROSPERO CRD42022300602., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Kennedy, Cleary, Conduit, Zhang, Fu and Zheng.)

Background: HIV incidence among pregnant and postpartum women remains high in South Africa. Pre-exposure prophylaxis (PrEP) use remains suboptimal in this population, particularly during the postpartum period when women's engagement with routine clinic visits outside PrEP decreases. Key barriers to sustained PrEP use include the need for ongoing contact with the health facility and suboptimal counseling around effective PrEP use., Methods: Stepped Care to Optimize PrEP Effectiveness in Pregnant and Postpartum women (SCOPE-PP), is a two-stepped unblinded, individually randomized controlled trial (RCT) that aims to optimize peripartum and postpartum PrEP use by providing a stepped package of evidence-based interventions. We will enroll 650 pregnant women (> 25 weeks pregnant) who access PrEP at a busy antenatal clinic in Cape Town at the time of recruitment and follow them for 15 months. We will enroll and individually randomize pregnant women > 16 years who are not living with HIV who are either on PrEP or interested in starting PrEP during pregnancy. In step 1, we will evaluate the impact of enhanced adherence counselling and biofeedback (using urine tenofovir tests for biofeedback) and rapid PrEP collection (to reduce time required) on PrEP use in early peripartum compared to standard of care (SOC) (n = 325 per arm). The primary outcome is PrEP persistence per urine tenofovir levels and dried blood spots of tenofovir diphosphate (TFV-DP) after 6-months. The second step will enroll and individually randomize participants from Step 1 who discontinue taking PrEP or have poor persistence in Step 1 but want to continue PrEP. Step 2 will test the impact of enhanced counseling and biofeedback plus rapid PrEP collection compared to community PrEP delivery with HIV self-testing on PrEP use (n = up to 325 postpartum women). The primary outcome is PrEP continuation and persistence 6-months following second randomization (~ 9-months postpartum). Finally, we will estimate the cost effectiveness of SCOPE-PP vs. SOC per primary outcomes and disability-adjusted life-years (DALYs) averted in both Step 1 and 2 using micro-costing with trial- and model-based economic evaluation., Discussion: This study will provide novel insights into optimal strategies for delivering PrEP to peripartum and postpartum women in this high-incidence setting., Trial Registration: NCT05322629 : Date of registration: April 12, 2022., (© 2022. The Author(s).)

Purpose: To investigate the outcomes of radiation segmentectomy (RS) versus standard-of-care surgical resection (SR)., Materials and Methods: A multisite, retrospective analysis of treatment-naïve patients who underwent either RS or SR was performed. The inclusion criteria were solitary hepatocellular carcinoma ≤8 cm in size, Eastern Cooperative Oncology Cohort performance status of 0-1, and absence of macrovascular invasion or extrahepatic disease. Target tumor and overall progression, time to progression (TTP), and overall survival rates were assessed. Outcomes were censored for liver transplantation., Results: A total of 123 patients were included (RS, 57; SR, 66). Tumor size, Child-Pugh class, albumin-bilirubin score, platelet count, and fibrosis stage were significantly different between cohorts (P ≤ .01). Major adverse events (AEs), defined as grade ≥3 per the Clavien-Dindo classification, occurred in 0 patients in the RS cohort vs 13 (20%) patients in the SR cohort (P < .001). Target tumor progression occurred in 3 (5%) patients who underwent RS and 5 (8%) patients who underwent SR. Overall progression occurred in 19 (33%) patients who underwent RS and 21 (32%) patients who underwent SR. The median overall TTP was 21.9 and 29.4 months after RS and SR, respectively (95% confidence interval [CI], 15.5-28.2 and 18.5-40.3, respectively; P = .03). Overall TTP subgroup analyses showed no difference between treatment cohorts with fibrosis stages 3-4 (P = .26) and a platelet count of <150 × 10 9 /L (P = .29). The overall progression hazard ratio for RS versus SR was not significant per the multivariate Cox regression analysis (1.16; 95% CI, 0.51-2.63; P = .71). The median overall survival was not reached for either of the cohorts. Propensity scores were calculated but were too dissimilar for analysis., Conclusions: RS and SR were performed in different patient populations, which limits comparison. RS approached SR outcomes, with a lower incidence of major AEs, in patients who were not eligible for hepatectomy., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Polypectomy may be performed at colonoscopy and then subsequent surveillance undertaken. It is thought that faecal haemoglobin concentration (f-Hb), estimated by quantitative faecal immunochemical tests (FIT), might be a useful tumour marker., Methods: Consecutive patients enrolled in colonoscopy surveillance were approached at two hospitals. A specimen for FIT was provided before colonoscopy and, ideally after 3 weeks, a second FIT sample from those who had polypectomy. A single FIT system (OC-Sensor io, Eiken Chemical Co., Ltd) was used to generate f-Hb., Results: 1103 Patients were invited; 643 returned a FIT device (uptake: 58.3%). Four patients had known inflammatory bowel disease (IBD) and were excluded, leaving 639 (57.9%) with an age range of 25-90 years (median 64 years), 54.6% male. Of 593 patients who had a f-Hb result and completed colonoscopy, advanced neoplasia was found in 41 (6.9%); four colorectal cancer (CRC): 0.7% and 37 advanced adenoma (AA): 6.3%, and a further 127 (21.4%) had non-advanced adenoma (NAA). The median f-Hb was significantly greater in AA as compared to NAA; 6.0 versus 1.0 μg Hb/g faeces, p < 0.0001.134/164 (81.7%) of invited patients returned a second FIT device: 28 were patients with AA in whom median pre-polypectomy f-Hb was 19.2, falling to 3.5 μg Hb/g faeces post-polypectomy, p = 0.01, and 106 with NAA had median pre-polypectomy f-Hb 0.8 compared to 1.0 μg Hb/g faeces post-polypectomy, p = 0.96., Conclusions: Quantitative FIT could provide a good tumour marker in post-polypectomy surveillance, reduce colonoscopy requirements and minimise potential risk to patients.

Introduction: Despite the rapid advance of psychedelic science and possible translation of psychedelic therapy into the psychiatric clinic, very little is known about mental health service user attitudes., Objectives: To explore mental health service user attitudes to psychedelics and psilocybin therapy., Methods: A questionnaire capturing demographics, diagnoses, previous psychedelic and other drug use, and attitudes to psychedelics and psilocybin therapy was distributed to mental health service users., Results: Ninety-nine participants completed the survey (52% female, mean age 42 years). The majority (72%) supported further research, with 59% supporting psilocybin as a medical treatment. A total of 27% previously used recreational psilocybin, with a male preponderance (p = 0.01). Younger age groups, those with previous psychedelic experience, and those with non-religious beliefs were more likely to have favourable attitudes towards psilocybin. A total of 55% of the total sample would accept as a treatment if doctor recommended, whereas 20% would not. Fewer people with depression/anxiety had used recreational psychedelics (p = 0.03) but were more likely to support government funded studies (p = 0.02). A minority (5%) of people with conditions (psychosis and bipolar disorder) that could be exacerbated by psilocybin thought it would be useful for them. One fifth of the total sample viewed psychedelics as addictive and unsafe even under medical supervision. Concerns included fear of adverse effects, lack of knowledge, insufficient research, illegality, and relapse if medications were discontinued., Conclusions: The majority supported further research into psilocybin therapy. Younger people, those with previous recreational psychedelic experience, and those with non-religious beliefs were more likely to have favourable attitudes towards psilocybin therapy., (© 2021. The Author(s).)

Background: Sexually transmitted infections (STIs) during pregnancy are associated with adverse birth outcomes, including preterm birth, low birth weight, perinatal death, and congenital infections such as increased mother-to-child HIV transmission. Prevalence of STIs among pregnant women in South Africa remains high, with most women being asymptomatic for their infection(s). Unfortunately, most STIs remain undetected and untreated due to standard practice syndromic management in accordance with World Health Organization (WHO) guidelines. Although lab-based and point-of-care molecular tests are available, optimal screening strategies during pregnancy, their health impact, and cost-effectiveness are unknown., Methods: We will implement a 3-arm (1:1:1) type-1 hybrid effectiveness-implementation randomized-controlled trial (RCT). We will enroll 2500 pregnant women attending their first antenatal care (ANC) visit for their current pregnancy at participating health facilities in Buffalo City Metro District, Eastern Cape Province, South Africa. Participants allocated to arms 1 and 2 (intervention) will receive GeneXpert® point-of-care diagnostic testing for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, with same-day treatment for detected infection(s). Arm 1 will additionally receive a test-of-cure 3 weeks post-treatment, while Arm 2 will receive a repeat test at 30-34 weeks' gestation. Those allocated to Arm 3 will receive syndromic management (standard-of-care). The RE-AIM framework will be used to guide collection of implementation indicators to inform potential future scale up. Primary outcome measures include (1) frequency of adverse birth outcomes among study arms, defined by a composite measure of low birth weight and pre-term delivery, and (2) change in STI prevalence between baseline and birth outcome among intervention arms and compared to standard-of-care. Estimates and comparative costs of the different screening strategies relative to standard-of-care and the costs of managing adverse birth outcomes will be calculated. Cost-effectiveness will be assessed per STI and disability-adjusted life year averted., Discussion: This trial is the first RCT designed to identify optimal, cost-effective screening strategies that decrease the burden of STIs during pregnancy and reduce adverse birth outcomes. Demonstrating the impact of diagnostic screening and treatment, compared to syndromic management, on birth outcomes will provide critical evidence to inform changes to WHO guidelines for syndromic management of STIs during pregnancy., Trial Registration: ClinicalTrials.gov NCT04446611 . Registered on 25 June 2020., (© 2022. The Author(s).)

South Africa has embarked on major health policy reform to deliver universal health coverage through the establishment of National Health Insurance (NHI). The aim is to improve access, remove financial barriers to care, and enhance care quality. Health technology assessment (HTA) is explicitly identified in the proposed NHI legislation and will have a prominent role in informing decisions about adoption and access to health interventions and technologies. The specific arrangements and approach to HTA in support of this legislation are yet to be determined. Although there is currently no formal national HTA institution in South Africa, there are several processes in both the public and private healthcare sectors that use elements of HTA to varying extents to inform access and resource allocation decisions. Institutions performing HTAs or related activities in South Africa include the National and Provincial Departments of Health, National Treasury, National Health Laboratory Service, Council for Medical Schemes, medical scheme administrators, managed care organizations, academic or research institutions, clinical societies and associations, pharmaceutical and devices companies, private consultancies, and private sector hospital groups. Existing fragmented HTA processes should coordinate and conform to a standardized, fit-for-purpose process and structure that can usefully inform priority setting under NHI and for other decision makers. This transformation will require comprehensive and inclusive planning with dedicated funding and regulation, and provision of strong oversight mechanisms and leadership.

The major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient's MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumor. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape., (© 2021. The Author(s).)

Background: The extent of resection required in advanced gallbladder cancer is controversial. We aimed to describe the management and outcomes in patients with resected stage T2 and T3 gallbladder cancer., Methods: In this population-based study, all T2 and T3 gallbladder cancer cases from Jan. 1, 2002, to Mar. 31, 2012, were identified from the Ontario Cancer Registry; pathology reports were linked and abstracted. The type of resection was classified as extended (cholecystectomy + liver resection, with or without bile duct resection) or simple (cholecystectomy only). We used Kaplan-Meier survival analysis to model time to death and evaluated factors associated with overall survival using the Cox proportional hazards regression model., Results: A total of 370 patients were included, 232 with T2 disease and 138 with T3 disease. The proportions who underwent extended resection were 24.1% (56/232) and 37.0% (51/138), respectively. The unadjusted 5-year overall survival rates for simple and extended resection were 39.7% and 49.5%, respectively, for T2 disease ( p = 0.03), and 13.5% and 22.8%, respectively, for T3 disease ( p = 0.05). In adjusted analysis, extended resection significantly improved overall survival among patients with T2 disease (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.97), whereas higher grade of differentiation, presence of lymphovascular invasion and positive lymph nodes led to worse survival. Extended resection was not associated with improved survival in the T3 group; however, in subgroup analysis stratified by lymph node status, a trend toward improved overall survival with extended resection was seen in node-negative patients (HR 0.20, 95% CI 0.03-1.06)., Conclusion: Extended resection improved overall survival in T2 disease regardless of nodal status but appeared most beneficial in node-negative T3 disease. The finding that extended resection was offered only to a small proportion of eligible patients highlights the need for improved knowledge translation at national surgical meetings., Competing Interests: Competing interests: Jennifer Flemming reports consulting fees from Gilead Sciences for participation in an academic conference planning committee. Sean Cleary reports consulting fees from Olympus, Ethicon and Erbe, and honoraria from Ethicon. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Background: While some evidence has been demonstrated the cost-effectiveness of routine hepatitis A vaccination in middle-income countries, the evidence is still limited in other settings including in South Africa. Given this, the evidence base around the cost of care for hepatitis A needs to be developed towards considerations of introducing hepatitis A vaccines in the national immunisation schedule and guidelines., Objectives: To describe the severity, clinical outcomes, and cost of hepatitis A cases presenting to two tertiary healthcare centers in Cape Town, South Africa., Methods: We conducted a retrospective folder review of patients presenting with hepatitis A at two tertiary level hospitals providing care for urban communities of metropolitan Cape Town, South Africa. Patients included in this folder review tested positive for hepatitis A immunoglobulin M between 1 January 2008 and 1 March 2018., Results: In total, 239 folders of hepatitis A paediatric patients < 15 years old and 212 folders of hepatitis A adult patients [Formula: see text] 15 years old were included in the study. Before presenting for tertiary level care, more than half of patients presented for an initial consultation at either a community clinic or general physician. The mean length of hospital stay was 7.45 days for adult patients and 3.11 days for paediatric patients. Three adult patients in the study population died as a result of hepatitis A infection and 29 developed complicated hepatitis A. One paediatric patient in the study population died as a result of hepatitis A infection and 27 developed complicated hepatitis A, including 4 paediatric patients diagnosed with acute liver failure. The total cost per hepatitis A hospitalisation was $1935.41 for adult patients and $563.06 for paediatric patients, with overhead costs dictated by the length of stay being the largest cost driver., Conclusion: More than 1 in every 10 hepatitis A cases (13.3%) included in this study developed complicated hepatitis A or resulted in death. Given the severity of clinical outcomes and high costs associated with hepatitis A hospitalisation, it is important to consider the introduction of hepatitis A immunisation in the public sector in South Africa to potentially avert future morbidity, mortality, and healthcare spending., (© 2022. The Author(s).)

Purpose: This study presents the validation of an index that defines and measures a patient-centered approach to quality survivorship care., Methods: We conducted a national survey of 1,278 survivors of breast, prostate, and colorectal cancers to identify their priorities for cancer survivorship care. We identified 42 items that were "very important or absolutely essential" to study participants. We then conducted exploratory and confirmatory factor analyses (EFA/CFA) to develop and validate the Patient-Centered Survivorship Care Index (PC-SCI)., Results: A seven-factor structure was identified based on EFA on a randomly split half sample and then validated by CFA based on the other half sample. The seven factors include: (1) information and support in survivorship (7 items), (2) having a medical home (10 items) (3) patient engagement in care (3 items), (4) care coordination (5 items), (5) insurance navigation (3 items), (6) care transitions from oncologist to primary care (3 items), and (7) prevention and wellness services (5 items). All factors have excellent composite reliabilities (Cronbach's alpha 0.84-0.94, Coefficient of Omega: 0.81-0.94)., Conclusions: Providing quality post-treatment care is critical for the long-term health and well-being of survivors. The PC-SCI defines a patient-centered approach to survivorship care to complement clinical practice guidelines. The PC-SCI has acceptable composite reliability, providing the field with a valid instrument of patient-centered survivorship care. The PC-SCI provides cancer centers with a means to guide, measure and monitor the development of their survivorship care to align with patient priorities of care., Trial Registration: ClinicalTrials.gov ID: NCT02362750 , 13 February 2015., (© 2021. The Author(s).)

Introduction: The burden of type 2 diabetes is steadily increasing in low-and-middle-income countries, thereby posing a major threat from both a treatment, and funding standpoint. Although simulation modelling is generally relied upon for evaluating long-term costs and consequences associated with diabetes interventions, no recent article has reviewed the characteristics and capabilities of available models used in low-and-middle-income countries. We review the use of computer simulation modelling for the management of type 2 diabetes in low-and-middle-income countries., Methods: A search for studies reporting computer simulation models of the natural history of individuals with type 2 diabetes and/or decision models to evaluate the impact of treatment strategies on these populations was conducted in PubMed. Data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed using modelling checklists. Publications before the year 2000, from high-income countries, studies involving animals and analyses that did not use mathematical simulations were excluded. The full text of eligible articles was sourced and information about the intervention and population being modelled, type of modelling approach and the model structure was extracted., Results: Of the 79 articles suitable for full text review, 44 studies met the inclusion criteria. All were cost-effectiveness/utility studies with the majority being from the East Asia and Pacific region (n = 29). Of the included studies, 34 (77.3%) evaluated the cost-effectiveness of pharmacological interventions and approximately 75% of all included studies used HbA1c as one of the treatment effects of the intervention. 32 (73%) of the publications were microsimulation models, and 29 (66%) were state-transition models. Most of the studies utilised annual cycles (n = 29, 71%), and accounted for costs and outcomes over 20 years or more (n = 38, 86.4%)., Conclusions: While the use of simulation modelling in the management of type 2 diabetes has been steadily increasing in low-and-middle-income countries, there is an urgent need to invest in evaluating therapeutic and policy interventions related to type 2 diabetes in low-and-middle-income countries through simulation modelling, especially with local research data. Moreover, it is important to improve transparency and credibility in the reporting of input data underlying model-based economic analyses, and studies., (© 2021. The Author(s).)

Introduction/aims: In this study we evaluated the effects of lung volume recruitment treatment (LVR), a low-tech, low-cost, manual "breath-stacking" technique used to help people cough with enough force to clear their airways, thereby reducing the risk of aspiration and choking, on five volitional airway clearance and protection behaviors used by people living with amyotrophic lateral sclerosis (PwALS)., Methods: Using a repeated-measures cross-over design, 29 PwALS performed five volitional airway clearance and protection behaviors in LVR treatment and in no-treatment, control conditions. Peak cough flow (PCF) was used to measure maximum expiratory rate during forced expiration, throat clearing, hawking, post-swallow coughing, and the supraglottic swallowing maneuver. Comparisons were made as a function of condition (treatment or control) and three time-points (pretreatment, and 15 and 30 minutes posttreatment)., Results: LVR treatment had a significant positive effect on maximum expiratory rates during all tested airway clearance and protection behaviors. Increased PCF values lasted for up to 30 minutes post-LVR for all tested behaviors in the treatment condition., Discussion: We found that LVR treatment could increase control over airway clearance in PwALS, as well as provide improved airway protection for up to 30 minutes, the duration of a typical meal. This study has implications for patient care. These include offering patients control over some of the most feared symptoms of ALS, particularly choking during activities of daily living, and enhanced ALS respiratory care in low-resource settings. Findings may have implications for other neurodegenerative disorders in which dysphagia occurs with retained sensory function., (© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Supervision and delegation are important leadership skills that nurses require when practising within the multi-tiered nursing team. In response to increasing demands globally on healthcare systems, Nursing Assistants are becoming more prevalent members of the nursing workforce in the acute care setting. An exploratory descriptive research design was used to examine supervision and delegation of Nursing Assistants in an acute hospital setting in Victoria, Australia. It was found that supervision and delegation in the context of a multi-tier nursing team required a complex assessment and decision-making process which was influenced by multiple factors. This research promotes developing transparent nursing practices and mutual understanding in the multi-tier nursing team to facilitate effective supervision and delegation based on informed decision-making and culture of openness and trust. Pre-registration education and continuing education and support for nurses are important to build transparent supervision and delegation practices and teamwork, empowering the nursing team to practice to their full scope of practice to provide high-quality patient care., (© 2021 John Wiley & Sons Ltd.)

Background: Respiratory illness is a leading cause of morbidity in adults and the number one cause of mortality in children, yet billions of people lack access to medical imaging to assist in its diagnosis. Although ultrasound is highly sensitive and specific for respiratory illness such as pneumonia, its deployment is limited by a lack of sonographers. As a solution, we tested a standardised lung ultrasound volume sweep imaging (VSI) protocol based solely on external body landmarks performed by individuals without prior ultrasound experience after brief training. Each step in the VSI protocol is saved as a video clip for later interpretation by a specialist., Methods: Dyspneic hospitalised patients were scanned by ultrasound naive operators after 2 hours of training using the lung ultrasound VSI protocol. Separate blinded readers interpreted both lung ultrasound VSI examinations and standard of care chest radiographs to ascertain the diagnostic value of lung VSI considering chest X-ray as the reference standard. Comparison to clinical diagnosis as documented in the medical record and CT (when available) were also performed. Readers offered a final interpretation of normal, abnormal, or indeterminate/borderline for each VSI examination, chest X-ray, and CT., Results: Operators scanned 102 subjects (0-89 years old) for analysis. Lung VSI showed a sensitivity of 93% and a specificity of 91% for an abnormal chest X-ray and a sensitivity of 100% and a specificity of 93% for a clinical diagnosis of pneumonia. When any cases with an indeterminate rating on chest X-ray or ultrasound were excluded (n=38), VSI lung ultrasound showed 92% agreement with chest X-ray (Cohen's κ 0.83 (0.68 to 0.97, p<0.0001)). Among cases with CT (n=21), when any ultrasound with an indeterminate rating was excluded (n=3), there was 100% agreement with VSI., Conclusion: Lung VSI performed by previously inexperienced ultrasound operators after brief training showed excellent agreement with chest X-ray and high sensitivity and specificity for a clinical diagnosis of pneumonia. Blinded readers were able to identify other respiratory diseases including pulmonary oedema and pleural effusion. Deployment of lung VSI could benefit the health of the global community., Competing Interests: Competing interests: Benjamin Castaneda has financial stake in the company Medical Innovation and Technology which seeks to bring ultrasound to rural communities. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cost-effective and efficient body composition measurement devices that are reliable and valid are necessary for identifying health risk as well as for understanding the effectiveness of lifestyle interventions. The objective of this study was to evaluate the test-retest reliability and validity of three body composition measurement devices. Forty-nine adults (mean age (SD) = 31.5 (10.7) y; BMI = 23.5 (3.0) kg/m 2 ) completed a reference air displacement plethysmography (ADP) measure, and duplicate measures using skinfold callipers (Lange), ultrasound (BodyMetrix A-mode) and a 3-dimensional photonic scanner (3DPS; Fit3D ProScanner). Skinfold thickness was measured at seven sites using callipers and ultrasound; percent body fat (%BF) was then estimated using population-specific algorithms. The 3DPS was used to measure body circumferences, and then %BF was estimated using its beta-software. While skinfold callipers showed poor absolute reliability (mean differences (Δ) [95% CI] = 0.54% [0.22, 0.87], standard error of measurement (SEM) = 0.63%), ultrasound and the 3DPS showed excellent absolute (Δ = 0.17% [-0.25, 0.58], SEM = 0.78%; and Δ = -0.01% [-0.43, 0.40], SEM = 0.67%, respectively) and relative reliability (ICC 2,1  = 0.988 [0.979, 0.993]; and ICC 2,1  = 0.983 [0.968, 0.991], respectively). Compared to ADP (n = 43), skinfold callipers underestimated %BF (Δ = -4.53 [-7.72, -1.34]; p = 0.003), while ultrasound (Δ = -0.32 [-3.51, 2.87]; p = 0.99) and the 3DPS (Δ = 1.06 [-2.12. 4.26]; p = 0.77) were not significantly different. Bland-Altman plots showed a minimal bias of ultrasound [95% limit of agreement (LOA) = -7.87, 7.23] and the 3DPS [95% LOA = -6.66, 8.79]. In conclusion, estimating %BF from subcutaneous fat measurements using ultrasound and body circumferences using a 3DPS may be reliable and valid methods that require minimal technician expertise., (© 2021 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Aims: The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF., Materials and Methods: A retrospective review was conducted on patients with stages I-III pancreatic adenocarcinoma who underwent surgery at our institution (2005-2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF., Results: In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5-52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P < 0.001)., Conclusion: This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Diploidy has profound implications for population genetics and susceptibility to genetic diseases. Although two copies are present for most genes in the human genome, they are not necessarily both active or active at the same level in a given individual. Genomic imprinting, resulting in exclusive or biased expression in favor of the allele of paternal or maternal origin, is now believed to affect hundreds of human genes. A far greater number of genes display unequal expression of gene copies due to cis -acting genetic variants that perturb gene expression. The availability of data generated by RNA sequencing applied to large numbers of individuals and tissue types has generated unprecedented opportunities to assess the contribution of genetic variation to allelic imbalance in gene expression. Here we review the insights gained through the analysis of these data about the extent of the genetic contribution to allelic expression imbalance, the tools and statistical models for gene expression imbalance, and what the results obtained reveal about the contribution of genetic variants that alter gene expression to complex human diseases and phenotypes.

Objectives: To evaluate the concordance between maternal report of antepartum tetanus, diphtheria, pertussis (Tdap) vaccination and vaccination status documented in the electronic medical record (EMR), as well as factors associated with discordance., Study Design: A survey was completed by a convenience sample of postpartum patients in a New York metropolitan hospital. The survey collected patients' demographic information, health beliefs, and whether they received Tdap vaccine during this pregnancy. The patient's Tdap vaccination status was abstracted from the EMR, a combination of data gathered from the obstetrician and patient's hospital record. Kappa statistics measured the agreement between maternal report and EMR on antepartum Tdap vaccination. Univariate and multivariable logistic regression analyses were performed to identify maternal characteristics associated with discordance., Results: Of the 1571 patients with Tdap status available in the EMR, 1549 patients (92%) reported on receipt status for Tdap vaccination during pregnancy; 1328 maternal reports (86%) agreed with the EMR for Tdap status (kappa = 0.72, 95% CI 0.68-0.75). Several factors were statistically significant in multivariable analyses: lower income was associated with greater discordance (ie, overreporting; P = .02), as well as certain health beliefs including "Pregnant women should be concerned about the possibility of pertussis in their babies" (aOR 2.86, 95% CI 1.02-8.04) and "My friends would probably think getting a Tdap vaccine is a good idea" (aOR 2.36, 95% CI 1.11-4.99)., Conclusions: Maternal recall of Tdap vaccination during pregnancy is consistent with the EMR. This supports the value of maternal report in determining Tdap vaccination status, which is especially important when vaccination records are not available., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background:  The viability of obstetric practice in the private sector has been threatened as a result of steep increases in professional indemnity fees over the past 10 years. Despite this, empirical research investigating key aetiological factors to target risk management interventions has been lacking., Objectives: To explore private practice medicolegal data linked to obstetricians and gynaecologists (O&Gs) to identify factors in clinical practice associated with claims, for the purposes of guiding future research and risk management solutions., Methods:  This was a retrospective, observational study of private sector O&Gs' medicolegal case histories. All incidents declared to a prominent local professional indemnity insurer were categorised in terms of medicolegal case type, as well as clinical parameters. To allow for risk-adjusted calculations of case incidence, year of entry into private practice was estimated for all practitioners., Results:  Steep increases in medicolegal investigations and demands were demonstrated for both obstetrics- and gynaecology-related cases from about 2003 to 2012. Whereas the total numbers of claims, regulatory complaints and requests for records were similar for obstetrics and gynaecology in recent years (accounting for 52% v. 48% of known cases, respectively), a significantly greater percentage of demands and paid settlements related to gynaecology rather than obstetrics (58% and 76% v. 42% and 24% of cases, respectively). In obstetrics, about half of all cases on record with a paid settlement were in the context of severe neonatal birth-related neurological injury (n=9). For gynaecology, procedure-related complications accounted for 92% of settlements, of which at least 41% were for intraoperative injuries to internal organs and vessels. Laparoscopic procedures were most frequently associated with such intraoperative injuries, followed by vaginal and abdominal hysterectomies/oophorectomies and caesarean sections. For O&Gs in private practice for &gt;2 years, 50/458 (11%) accounted for 138/228 (61%) of demands over a 10-year period., Conclusions:  The higher number of gynaecological demands and settlements in comparison with obstetric cases was unexpected and is contrary to international experiences and public sector findings, calling for more research to identify reasons for this finding. Other than further exploring surgical outcomes in private sector gynaecological patients, aspects of surgical training and accreditation standards in gynaecology may need review. Regarding birth-related injuries, the contribution of system failures needs quantification and further interrogation. The high contribution towards the medicolegal burden by a small group of practitioners suggests a need for doctor-focused interventions, including strengthening of peer review and regulatory oversight.

Despite access to a safe and effective vaccine, mother-to-child transmission (MTCT) of hepatitis B virus (HBV) persists in Africa. This is of concern since perinatally-infected infants are at highest risk of developing hepatocellular carcinoma, a life-threatening consequence of chronic HBV infection. While tools to prevent HBV MTCT are available, the cost implications of these interventions need consideration prior to implementation. A Markov model was developed to determine the costs and health outcomes of (1) universal HBV birth dose (BD) vaccination, (2) universal BD vaccination and targeted hepatitis B immunoglobulin (HBIG), (3) maternal antiviral prophylaxis using sequential HBV viral load testing added to HBV BD vaccination and HBIG, and (4) maternal antiviral prophylaxis using sequential HBeAg testing combined with HBV BD vaccination and HBIG. Health outcomes were assessed as the number of paediatric infections averted and disability-adjusted life years (DALYs) averted. Primary cost data included consumables, human resources, and hospital facilities. HBV epidemiology, transitions probabilities, disability weights, and the risks of HBV MTCT were extracted from the literature. Incremental cost-effectiveness ratios (ICERs) were calculated to compare successive more expensive interventions to the previous less expensive one. One-way sensitivity analyses were conducted to test the robustness of the model's outputs. At the Namibian cost/DALY averted threshold of US$3 142, the (1) BD vaccination + targeted HBIG, and (2) maternal antiviral prophylaxis with sequential HBeAg testing interventions were cost-effective. These interventions had ICERs equal to US$1909.03/DALY and US$2598.90/DALY averted, respectively. In terms of effectiveness, the maternal antiviral prophylaxis with sequential HBeAg testing intervention was the intervention of choice. The analysis showed that elimination of HBV MTCT is achievable using maternal antiviral prophylaxis with active and passive immunization. There is an urgent need for low cost diagnostic tests to identify those women who will most benefit from drug therapy to attain this laudable goal., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In South Africa, replacing smear microscopy with Xpert-MTB/RIF (Xpert) for tuberculosis diagnosis did not reduce mortality and was cost-neutral. The unchanged mortality has been attributed to suboptimal Xpert implementation. We developed a mathematical model to explore how complementary investments may improve cost-effectiveness of the tuberculosis diagnostic algorithm., Methods: Complementary investments in the tuberculosis diagnostic pathway were compared to the status quo. Investment scenarios following an initial Xpert test included actions to reduce pre-treatment loss-to-follow-up; supporting same-day clinical diagnosis of tuberculosis after a negative result; and improving access to further tuberculosis diagnostic tests following a negative result. We estimated costs, deaths and disability-adjusted-life-years (DALYs) averted from provider and societal perspectives. Sensitivity analyses explored the mediating influence of behavioural, disease- and organisational characteristics on investment effectiveness., Findings: Among a cohort of symptomatic patients tested for tuberculosis, with an estimated active tuberculosis prevalence of 13%, reducing pre-treatment loss-to-follow-up from ~20% to ~0% led to a 4% (uncertainty interval [UI] 3; 4%) reduction in mortality compared to the Xpert scenario. Improving access to further tuberculosis diagnostic tests from ~4% to 90% among those with an initial negative Xpert result reduced overall mortality by 28% (UI 27; 28) at $39.70/ DALY averted. Effectiveness of investment scenarios to improve access to further diagnostic tests was dependent on a high return rate for follow-up visits., Interpretation: Investing in direct and indirect costs to support the TB diagnostic pathway is potentially highly cost-effective., Competing Interests: The authors have declared that no competing interests exist.

Iron-sulfur (Fe-S) cluster biosynthesis involves the action of a variety of functionally distinct proteins, most of which are evolutionarily conserved. Mutations in these Fe-S scaffold and trafficking proteins can cause diseases such as multiple mitochondrial dysfunctions syndrome (MMDS), sideroblastic anemia, and mitochondrial encephalopathy. Herein, we investigate the effect of Ile67Asn substitution in the BOLA3 protein that results in the MMDS2 phenotype. Although the exact functional role of BOLA3 in Fe-S cluster biosynthesis is not known, the [2Fe-2S]-bridged complex of BOLA3 with GLRX5, another Fe-S protein, has been proposed as a viable intermediary cluster carrier to downstream targets. Our investigations reveal that the Ile67Asn substitution impairs the ability of BOLA3 to bind its physiological partner GLRX5, resulting in a failure to form the [2Fe-2S]-bridged complex. Although no drastic structural change in BOLA3 arises from the substitution, as evidenced by wild-type and mutant BOLA3 1H-15N HSQC and ion mobility native mass spectrometry experiments, this substitution appears to influence cluster reconstitution on downstream proteins leading to the disease phenotype. By contrast, substituted derivatives of the holo homodimeric form of BOLA3 are formed and remain active toward cluster exchange., (© The Author(s) 2021. Published by Oxford University Press.)

Health systems strengthening (HSS) is firmly on the global health and development agenda. While a growing evidence base seeks to understand the effectiveness of HSS, there is limited evidence regarding cost and cost-effectiveness. Without such evidence, it is hard to argue that HSS represents value for money and the level of investment needed cannot be quantified. This paper seeks to review the literature regarding the economic evaluation of HSS from low- and middle-income country (LMIC) settings, and to contribute towards the development of methods for the economic evaluation of HSS. A systematic search for literature was conducted in PubMed, Scopus and the Health Systems Evidence database. MeSH terms related to economic evaluation were combined with key words related to the concept of HSS. Of the 204 records retrieved, 52 were retained for full text review and 33 were included. Of these, 67% were published between January 2015 and June 2019. While many HSS interventions have system wide impacts, most studies (71%) investigated these impacts using a disease-specific lens (e.g. the impact of quality of care improvements on uptake of facility deliveries). HSS investments were categorized, with the majority being investments in platform efficiency (e.g. quality of care), followed by simultaneous investment in platform efficiency and platform capacity (e.g. quality of care and task shifting). This review identified a growing body of work seeking to undertake and/or conceptualize the economic evaluation of HSS in low- and middle-income countries. The majority assess HSS interventions using a disease-specific or programmatic lens, treating HSS in a similar manner to the economic evaluation of medicines and diagnostics. While this approach misses potential economies of scope from HSS investments, it allows for a preliminary understanding of relative value for money. Future research is needed to complement the emerging evidence base., (© The Author(s) 2020. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)