Nuclear actin structure regulates chromatin accessibility.

Polymerized ß-actin may provide a structural basis for chromatin accessibility and actin transport into the nucleus can guide mesenchymal stem cell (MSC) differentiation. Using MSC, we show that using CK666 to inhibit Arp2/3 directed secondary actin branching results in decreased nuclear actin structure, and significantly alters chromatin access measured with ATACseq at 24 h. The ATAC-seq results due to CK666 are distinct from those caused by cytochalasin D (CytoD), which enhances nuclear actin structure. In addition, nuclear visualization shows Arp2/3 inhibition decreases pericentric H3K9me3 marks. CytoD, alternatively, induces redistribution of H3K27me3 marks centrally. Such alterations in chromatin landscape are consistent with differential gene expression associated with distinctive differentiation patterns. Further, knockdown of the non-enzymatic monomeric actin binding protein, Arp4, leads to extensive chromatin unpacking, but only a modest increase in transcription, indicating an active role for actin-Arp4 in transcription. These data indicate that dynamic actin remodeling can regulate chromatin interactions.

Contemporary burden and trends of opioid-overdose mortality in New York State.

BACKGROUND: Limited research exists on contemporary opioid overdose mortality burden and trends in New York State, with most studies focusing on New York City. This study aimed to assess opioid overdose burden and death trends in New York State by age, sex, race/ethnicity, geographic area, opioid type, and overdose intent from 1999 to 2020. METHODS: Mortality data were obtained from the Centers for Disease Control and Prevention's WONDER database. Opioid overdose decedents were identified using relevant International Classification of Diseases, 10th Revision codes. Joinpoint regression analyzed trends, estimating annual and average annual percentage changes in age-adjusted mortality rates (AAMR). 95% confidence intervals were derived using the Parametric Method. RESULTS: From 1999 to 2020, New York State recorded 34,109 opioid overdose deaths (AAMR = 7.9 per 100,000 persons; 95% CI: 7.8-7.9). The overall trend increased by 12.6% per year (95% CI: 10.8, 14.4) from 2004 to 2020. Subgroups exhibited varying trends, with an 11.1% yearly increase among Non-Hispanic White persons from 2007 to 2020 (95% CI: 9.0, 13.2), a 24.6% annual rise among Non-Hispanic Black persons from 2012 to 2020 (95% CI: 17.7, 31.8), and an 18.3% increase yearly among Hispanic individuals from 2011 to 2020 (95% CI: 14.0, 22.9). Recent trends have worsened in both males and females, across all age groups, in both New York City (NYC) and areas outside NYC, and for heroin, natural and semisynthetic opioids, and synthetic opioids. CONCLUSIONS: Opioid overdose mortality in New York State has worsened significantly in the last two decades. Further research is essential to identify driving factors for targeted public health interventions.

Functional outcomes following anterior resection for colorectal cancer: a needs assessment and proposal of a nurse-led remote management algorithm.

AIM: With the rise of structured, remote follow-up of colorectal cancers, there is the potential risk of underdiagnosing and undermanaging low anterior resection syndrome (LARS). This cohort study aims to determine the rate of LARS and its patterns of care, with the aim of generating a risk-stratified management algorithm that can be employed for nurse-led follow-up. METHOD: Patients who underwent elective anterior resection for the management of colorectal cancer between 1 January 2017 and 31 December 2021 were sent quality-of-life questionnaires (EORTC-QLQ-CR29 and LARS score) and surveyed for LARS symptoms and management utilized. RESULTS: Out of 70 patients who completed questionnaires, 71.4% had LARS and 42.9% had major LARS. The international Delphi consensus definition identified more patients (n = 50) with LARS than the LARS score (n = 41). Tumours located <8 cm from the anal verge, ULAR, and temporary stoma were predictive of major LARS on univariate analysis. However, only temporary stoma was predictive for LARS (OR 7.89 (1.15-53.95), P = 0.035) and majors LARS (8.14 (1.79-37.01), P = 0.007) on multivariate analysis. Forty-four percent of patients with LARS did not have input from any health professional for this condition. Consultation with specialist allied health and/or colorectal surgeons ranged from 4% to 22%. CONCLUSIONS: Our study highlights that with the current remote follow-up system focused on cancer outcomes a significant proportion of patients with LARS are overlooked, resulting in the underutilization of relevant health professionals and management options. We propose a nurse-led management algorithm to address this issue while still minimizing surgical outpatient load.

Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.

A systematic review of the use of the concept family resilience in interventions with families with children and young people.

OBJECTIVE: To review the evidence on using family resilience as a concept in interventions by public health nurses/health visitors with families with children and young people as part of an evaluation of the evidence base for the Family Resilience Assessment Instrument and Tool (FRAIT). FRAIT was developed by University faculty with Health Visitors and a Community of Practice in Wales, and is used by Health Visitors in Wales with families with children under 5 years to assess family resilience. METHOD: A standard Cochrane Systematic Review methodology was used to review published literature. A protocol (crd.york.ac.uk/PROSPERO/display_record.php?RecordID = 230845) was submitted to Prospero in September 2021, and reviewing began in January 2022. Title and abstract searching were undertaken 12 databases and results were captured using PRISMA and Excel spreadsheet. Second reviewers reviewed title and abstract screening, and full-text extraction. RESULTS: Initial title screening brought back 1350 papers across 12 databases. Titles and abstract screening reduced these to 106, 44 papers were considered for full-text extraction, with 25 papers included for review. DISCUSSION: Results demonstrated a focus on specific demographics, and use of family resilience with families living with specific health problems. Existing family resilience scales showed improved results in selected specific demographic groups, albeit in a reactive way. FRAIT has originality within the literature as it is used in a universal, preventative way with all families regardless of demographic or health issues. There is evidence to show that using a family resilience program in this way has originality and implications for the physical and mental health of children and young people. NO PATIENT OR PUBLIC CONTRIBUTION: This was a systematic review of existing literature so public or patient contribution would not have been appropriate.

Good Gone Bad: Complications of Chemotherapy, Immunotherapy, and Radiotherapy on the CNS.

With recent advancements in cancer therapy, especially immunotherapy, overall survival of many cancers has increased and patient toxicity has been reduced. However, many complications of traditional cancer therapy are still prevalent and complications of novel therapies are just beginning to appear. The neuroradiologist may be the first to visualize signs of these complications on imaging. This article describes the notable imaging findings of several unique and characteristic complications of CNS cancer therapy, including toxicities of chemotherapies, immunotherapies, and radiotherapy. Complications of chemotherapeutic agents covered include methotrexate-induced and disseminated necrotizing leukoencephalopathy, and chemotherapy-induced myelopathy. Immunotherapy complications included are Tacrolimus-related Optic Neuropathy, Rituximab and Immune reconstitution inflammatory syndrome-associated Progressive Multifocal Leukoencephalopathy, Bevacizumab-associated late radiation-induced neurotoxicity, and Ipilimumab-induced hypophysitis. Lastly, radiation-induced neurotoxicities are covered, including myelopathy, radiation necrosis, cerebral atrophy, leukoencephalopathy, optic neuropathy, mineralizing microangiopathy, stroke-like migraine attacks, osteonecrosis, and vasculopathies. Neuroradiologists will increasingly encounter patients who have undergone treatment with more than 1 therapeutic modality, resulting in overlapping findings as well. Recognition of the common complications of these therapies on imaging is critical to minimizing the effects of these potential short- and long-term complications.

Uterine Leiomyoma in the Context of Uterine Didelphys: A Case Report.

Uterine leiomyomas are one of the most common reproductive pathologies in born females. The majority of women within reproductive age will develop a leiomyoma, most of which will be asymptomatic. Though there has been extensive research regarding this pathology alone, there is more to be learned about leiomyomas that affect women with other comorbidities. This case study reviews the medical and surgical management of a woman born with two uteri, medically termed congenital uterus didelphys. Within her reproductive years, she develops symptomatic leiomyomas in each of her uteri and seeks surgical management. This case study aims to widen the scientific knowledge surrounding these subsets of women with a common diagnosis superimposed on an extremely rare diagnosis.

Colorectal cancer detection and treatment with engineered probiotics.

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition. We show that, after oral administration, adenomas can be monitored over time by recovering EcN from stool. We also demonstrate specific colonization of EcN to solitary neoplastic lesions in an orthotopic murine model of CRC. We then exploit this neoplasia-homing property of EcN to develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate, and demonstrate that oral delivery of this strain results in significantly increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. We also assess EcN engineered to locally release immunotherapeutics at the neoplastic site. Oral delivery to mice bearing adenomas, reduced adenoma burden by ∻50%, with notable differences in the spatial distribution of T cell populations within diseased and healthy intestinal tissue, suggesting local induction of robust anti-tumor immunity. Together, these results support the use of EcN as an orally-delivered platform to detect disease and treat CRC through its production of screening and therapeutic molecules.

Poor engagement and adherence predict neoplasia in inflammatory bowel disease: a case-control study.

BACKGROUND: Colorectal adenocarcinoma is an important and preventable complication of inflammatory bowel disease (IBD). A previous case series suggested mental health issues and poor engagement in care as novel risk factors. AIMS: To confirm the role of patient engagement in care in the development of neoplasia using a case-control methodology. METHODS: Patients in a single referral centre from 2007 to 2017 with colorectal adenocarcinoma, high-grade dysplasia or multifocal low-grade dysplasia were included as neoplasia cases. Each case was assigned up to three matched controls (matched for age, gender, underlying disease, IBD type and phenotype and disease duration). Novel and known risk factors were compared between groups. RESULTS: Thirty-two cases with 88 matched controls were included. Patients with neoplasia were more likely to have poor adherence to, or engagement with, care (odds ratio (OR) 4.79). They were also more likely to have chronic use of opioids (OR 3.86) and long-term prednisolone (OR 2.97). Of note, no difference was found in measures of socioeconomic disadvantage, reflecting equitable access to healthcare in the public institution where the care was studied. As previously shown, patients with neoplasia had multiple markers of increased cumulative burden of inflammation, including more IBD-related hospital admissions, elevated inflammatory markers and severe inflammation at colonoscopy. CONCLUSIONS: This study confirms poor adherence or engagement with care as a new risk factor for colorectal adenocarcinoma in patients with IBD; identifying a vulnerable group whom clinicians should endeavour to engage in order to avoid this catastrophic complication.

Influence of income on diet quality and daily iron and zinc intake: analysis of the National Diet and Nutrition Survey of British females aged 11-14 and 15-18 years.

PURPOSE: A negative socio-economic gradient exists for diet and health outcomes. Since cheaper diets are associated with increased energy and lower nutrient density, we investigated the influence of income on iron and zinc intakes and overall diet quality for adolescent (DQI-A) females aged 11-18 years. METHODS: National Diet and Nutrition Survey (NDNS years 7 and 8) data for iron and zinc intake and overall diet quality was assessed by household income quintile across females aged 11-18 years. RESULTS: Equivalised household income positively correlated with Diet quality index for adolescents (DQI-A) (P < 0.001) Females aged 15-18 years in income quintiles (IQs) I and 2, had a greater proportion of respondents with low to intermediate DQI-A score compared to higher IQs (P = 0.002). NDNS data showed intake was negatively influenced by income amongst females aged 11-14 years for iron (P = 0.009) and zinc (P = 0.001) with those from the lowest incomes consistently consuming significantly less than those from the highest. DQI-A was positively correlated with iron intakes for 11-14 (P = 0.001) and 15-18 years (P < 0.001). Forty-one percent of 15-18-year-olds plasma ferritin stores were below the 15 µg L-1 and 21% had some form of anaemia. Cereal and cereal products were the greatest contributors to iron in all groups. CONCLUSION: Females in the lowest income groups are at greater risk of lower overall diet quality and inadequate iron and zinc intakes. Amongst older adolescents, there is evidence of iron stores being depleted and an increased prevalence of anaemia.

Establishing a state-wide pelvic exenteration multidisciplinary team meeting in South Australia.

BACKGROUND: Pelvic exenteration surgery is complex, necessitating co-ordinated multidisciplinary input and improved referral pathways. A state-wide pelvic exenteration multidisciplinary team (MDT) meeting was established in SA and the outcomes of this were audited and compared with historical data. METHODS: All patients referred for discussion between August 2021 and July 2022 to the SA State-wide Pelvic Exenteration MDT were included in this study. MDT discussion centred around disease resectability, risk versus benefit of surgery, and need for local or interstate referral. Prospective data collection included patient demographics and MDT recommendations of surgery, palliation, or referral. Patients referred for surgery locally or interstate were compared with a retrospective patient cohort treated previously between January and December 2020. RESULTS: Over 12 months, 91 patients were discussed (including nine multiple times), by a mean of 18 meeting participants each month. Forty-eight patients (58.5%) had primary malignancy, 25 (30.5%) recurrent malignancy, and 9 (11.0%) had non-malignant disease. Colorectal cancer was the most common presentation (56.1%), followed by gynaecological (30.5%) and urological (6.1%) malignancy. Pelvic exenteration surgery was recommended to be performed locally in 53.7% of patients and the remainder for non-surgical treatment, palliation, or re-discussion. During this time, 44 patients underwent surgery locally (versus 34 in 2020) and only 4 referred interstate (versus 8 in 2020). CONCLUSION: The establishment of a dedicated state-wide pelvic exenteration MDT has resulted in better coordination of care for patients with locally advanced pelvic malignancy in SA, and significantly reduced the need for interstate referral.

Personalized total neoadjuvant therapy (pTNT) for advanced rectal cancer with tailored treatment sequencing based on clinical stage at presentation.

BACKGROUND: This study aimed to assess short-term outcomes of a personalized total neoadjuvant treatment (pTNT) protocol, with treatment sequencing based on clinical stage at presentation. METHODS: A multidisciplinary pTNT protocol was implemented across two metropolitan hospitals. This consists of two-schema based on clinical stage: patients with distant failure risk were offered induction chemotherapy before chemoradiation (nCRT), and patients with locoregional failure risk received nCRT followed by consolidation chemotherapy. Patients underwent surgical resection unless a complete clinical response (cCR) was achieved, in which case non-operative management (NOM) was offered. A prospective cohort analysis of all patients with rectal cancer who underwent pTNT with curative intent between Jan 2019 and Aug 2022 was performed. RESULTS: Of 270 patients referred with rectal cancer, 102 received pTNT with curative intent and 79 have completed their treatment thus far. Thirty-three patients (41.8%) received induction chemotherapy and 46 (58.2%) received consolidation chemotherapy per protocol. The percentage of patients with EMVI, resectable M1 disease, cT4 disease, and positive lateral lymph nodes were 54.4%, 36.7%, 27.8% and 15.2%, respectively. Overall, 32 (40.5%) patients had cCR and 4 (5.1%) pCR, and 40 (50.6%) patients had non-operative management. Grade 3 toxicity was reported in 10.1% of patients and only three patients (3.8%) experienced Grade 4 chemotherapy-related toxicity, with no treatment related mortality. CONCLUSION: Early results with a defined two-schema pTNT protocol are encouraging and suggest that tailoring sequencing to disease risk at presentation may represent the optimal balance between local and distant disease control, as well as treatment toxicity.

A Multimedia Strategy to Integrate Introductory Broad-Based Radiation Science Education in US Medical Schools.

US physicians in multiple specialties who order or conduct radiological procedures lack formal radiation science education and thus sometimes order procedures of limited benefit or fail to order what is necessary. To this end, a multidisciplinary expert group proposed an introductory broad-based radiation science educational program for US medical schools. Suggested preclinical elements of the curriculum include foundational education on ionizing and nonionizing radiation (eg, definitions, dose metrics, and risk measures) and short- and long-term radiation-related health effects as well as introduction to radiology, radiation therapy, and radiation protection concepts. Recommended clinical elements of the curriculum would impart knowledge and practical experience in radiology, fluoroscopically guided procedures, nuclear medicine, radiation oncology, and identification of patient subgroups requiring special considerations when selecting specific ionizing or nonionizing diagnostic or therapeutic radiation procedures. Critical components of the clinical program would also include educational material and direct experience with patient-centered communication on benefits of, risks of, and shared decision making about ionizing and nonionizing radiation procedures and on health effects and safety requirements for environmental and occupational exposure to ionizing and nonionizing radiation. Overarching is the introduction to evidence-based guidelines for procedures that maximize clinical benefit while limiting unnecessary risk. The content would be further developed, directed, and integrated within the curriculum by local faculties and would address multiple standard elements of the Liaison Committee on Medical Education and Core Entrustable Professional Activities for Entering Residency of the Association of American Medical Colleges.

The Impact of the COVID-19 Pandemic on the Food Security of UK Adults Aged 20-65 Years (COVID-19 Food Security and Dietary Assessment Study).

The first UK lockdown greatly impacted the food security status of UK adults. This study set out to establish if food procurement was adapted differently for different income groups and if this impacted dietary intakes disproportionately. Adults (n = 515) aged 20-65 years participated in an online survey with 56 completing a 3-4 day diet diary. Food availability was a significant factor in the experience of food insecurity. Similar proportions of food secure and food insecure adapted food spend during lockdown, spending similar amounts. Food insecure (n = 85, 18.3%) had a 10.5% lower income and the money spent on food required a greater proportion of income. Access to food was the biggest driver of food insecurity but monetary constraint was a factor for the lowest income group. The relative risk of food insecurity increased by 0.07-fold for every 1% increase in the proportion of income spent on food above 10%. Micronutrient intakes were low compared to the reference nutrient intake (RNI) for most females, with riboflavin being 36% lower in food insecure groups (p = 0.03), whilst vitamin B12 was 56% lower (p = 0.057) and iodine 53.6% lower (p = 0.257) these were not significant. Coping strategies adopted by food insecure groups included altering the quantity and variety of fruit and vegetables which may have contributed to the differences in micronutrients.

A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR.

Pathophysiology associated with Huntington's disease (HD) has been studied extensively in various cell and animal models since the 1993 discovery of the mutant huntingtin (mHtt) with abnormally expanded polyglutamine (polyQ) tracts as the causative factor. However, the sequence of early pathophysiological events leading to HD still remains elusive. To gain new insights into the early polyQ-induced pathogenic events, we expressed Htt exon1 (Httex1) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants. Here, we show that transgenic plants accumulated Httex1 proteins with corresponding polyQ tracts, and mHttex1 induced protein aggregation and affected plant growth, especially root and root hair development, in a polyQ length-dependent manner. Quantitative proteomic analysis of young roots from severely affected Httex1Q63 and unaffected Httex1Q21 plants showed that the most reduced protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many of its related one-carbon (C1) metabolic pathway enzymes. GTPCH is a key enzyme involved in folate biosynthesis in plants and tetrahydrobiopterin (BH4) biosynthesis in mammals. Validating studies in 4-week-old R6/2 HD mice expressing a mHttex1 showed reduced levels of GTPCH and dihydrofolate reductase (DHFR, a key folate utilization/alternate BH4 biosynthesis enzyme), and impaired C1 and BH4 metabolism. Our findings from mHttex1 plants and mice reveal impaired expressions of GTPCH and DHFR and may contribute to a better understanding of mHtt-altered C1 and BH4 metabolism, and their roles in the pathogenesis of HD.

The Magnetosome Protein, Mms6 from Magnetospirillum magneticum Strain AMB-1, Is a Lipid-Activated Ferric Reductase.

Magnetosomes of magnetotactic bacteria consist of magnetic nanocrystals with defined morphologies enclosed in vesicles originated from cytoplasmic membrane invaginations. Although many proteins are involved in creating magnetosomes, a single magnetosome protein, Mms6 from Magnetospirillum magneticum strain AMB-1, can direct the crystallization of magnetite nanoparticles in vitro. The in vivo role of Mms6 in magnetosome formation is debated, and the observation that Mms6 binds Fe3+ more tightly than Fe2+ raises the question of how, in a magnetosome environment dominated by Fe3+, Mms6 promotes the crystallization of magnetite, which contains both Fe3+ and Fe2+. Here we show that Mms6 is a ferric reductase that reduces Fe3+ to Fe2+ using NADH and FAD as electron donor and cofactor, respectively. Reductase activity is elevated when Mms6 is integrated into either liposomes or bicelles. Analysis of Mms6 mutants suggests that the C-terminal domain binds iron and the N-terminal domain contains the catalytic site. Although Mms6 forms multimers that involve C-terminal and N-terminal domain interactions, a fusion protein with ubiquitin remains a monomer and displays reductase activity, which suggests that the catalytic site is fully in the monomer. However, the quaternary structure of Mms6 appears to alter the iron binding characteristics of the C-terminal domain. These results are consistent with a hypothesis that Mms6, a membrane protein, promotes the formation of magnetite in vivo by a mechanism that involves reducing iron.

Cost of postoperative ileus following colorectal surgery: A cost analysis in the Australian public hospital setting.

AIM: Postoperative ileus (POI) following surgery results in significant morbidity, drastically increasing hospital costs. As there are no specific Australian data, this study aimed to measure the cost of POI after colorectal surgery in an Australian public hospital. METHODS: A cost analysis was performed, for major elective colorectal surgical cases between 2018 and 2021 at the Royal Adelaide Hospital. POI was defined as not achieving GI-2, the validated composite measure, by postoperative day 4. Demographics, length of stay and 30-day complications were recorded retrospectively. Costings in Australian dollars were collected from comprehensive hospital billing data. Univariate and multivariate analyses were performed. RESULTS: Of the 415 patients included, 34.9% (n = 145) developed POI. POI was more prevalent in males, smokers, previous intra-abdominal surgery, and converted laparoscopic surgery (p < 0.05). POI was associated with increased length of stay (8 vs. 5 days, p < 0.001) and with higher rates of complications such as pneumonia (15.2% vs. 8.1%, p = 0.027). Total cost of inpatient care was 26.4% higher after POI (AU$37,690 vs. AU$29,822, p < 0.001). POI was associated with increased staffing costs, as well as diagnostics, pharmacy, and hospital services. On multivariate analysis POI, elderly patients, stoma formation, large bowel surgery, prolonged theatre time, complications and length of stay were predictive of increased costs (p < 0.05). CONCLUSION: In Australia, POI is significantly associated with increased complications and higher costs due to prolonged hospital stay and increased healthcare resource utilisation. Efforts to reduce POI rates could diminish its morbidity and associated expenses, decreasing the burden on the healthcare system.

Systematic review and meta-analysis of long-term oncological outcomes of lateral lymph node dissection for metastatic nodes after neoadjuvant chemoradiotherapy in rectal cancer.

BACKGROUND: Standard Western management of rectal cancers with pre-treatment metastatic lateral lymph nodes (LLNs) is neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision (TME). In recent years, there is growing interest in performing an additional lateral lymph node dissection (LLND). The aim of this systematic review and meta-analysis was to investigate long-term oncological outcomes of nCRT followed by TME with or without LLND in patients with pre-treatment metastatic LLNs. METHODS: PubMed, Ovid MEDLINE, Embase, Cochrane Library and Clinicaltrials.gov were searched to identify comparative studies reporting long-term oncological outcomes in pre-treatment metastatic LLNs of nCRT followed by TME and LLND (LLND+) vs. nCRT followed by TME only (LLND-). Newcastle-Ottawa risk-of-bias scale was used. Outcomes of interest included local recurrence (LR), disease-free survival (DFS), and overall survival (OS). Summary meta-analysis of aggregate outcomes was performed. RESULTS: Seven studies, including 946 patients, were analysed. One (1/7) study was of good-quality after risk-of-bias analysis. Five-year LR rates after LLND+ were reduced (range 3-15%) compared to LLND- (11-27%; RR = 0.40, 95%CI [0.25-0.62], p < 0.0001). Five-year DFS was not significantly different after LLND+ (range 61-78% vs. 46-79% for LLND-; RR = 0.72, 95%CI [0.51-1.02], p = 0.143), and neither was five-year OS (range 69-91% vs. 72-80%; RR = 0.72, 95%CI [0.45-1.14], p = 0.163). CONCLUSION: In rectal cancers with pre-treatment metastatic LLNs, nCRT followed by an additional LLND during TME reduces local recurrence risk, but does not impact disease-free or overall survival. Due to the low quality of current data, large prospective studies will be required to further determine the value of LLND.

Using an integrated competence model to evaluate a health visitor cascade training programme for the Family Resilience Assessment Instrument and Tool (FRAIT).

This paper reports on an evaluation of health visitor trainers' experience of a cascade training programme delivered in Wales, UK. Health visitors used Driscoll's model (What, So What, Now What) to organise their feedback and an integrated competence model developed by Weeks et al. was used to analyse the feedback via category analysis of free text. As well as feedback on the logistics of running the training, the evaluation allowed for cognitive and functional competence to be identified along with personal and meta competence. There was limited scope for identifying ethical competence in the Health Visitor cascade trainer feedback. Suggestions are made for how this may be addressed.

The Antianginal Drug Perhexiline Displays Cytotoxicity against Colorectal Cancer Cells In Vitro: A Potential for Drug Repurposing.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Perhexiline, a prophylactic anti-anginal drug, has been reported to have anti-tumour effects both in vitro and in vivo. Perhexiline as used clinically is a 50:50 racemic mixture ((R)-P) of (-) and (+) enantiomers. It is not known if the enantiomers differ in terms of their effects on cancer. In this study, we examined the cytotoxic capacity of perhexiline and its enantiomers ((-)-P and (+)-P) on CRC cell lines, grown as monolayers or spheroids, and patient-derived organoids. Treatment of CRC cell lines with (R)-P, (-)-P or (+)-P reduced cell viability, with IC50 values of ~4 µM. Treatment was associated with an increase in annexin V staining and caspase 3/7 activation, indicating apoptosis induction. Caspase 3/7 activation and loss of structural integrity were also observed in CRC cell lines grown as spheroids. Drug treatment at clinically relevant concentrations significantly reduced the viability of patient-derived CRC organoids. Given these in vitro findings, perhexiline, as a racemic mixture or its enantiomers, warrants further investigation as a repurposed drug for use in the management of CRC.