MTHFR C677T and A1298C polymorphism's effect on risk of colorectal cancer in Lynch syndrome.

Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10-80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.

The Impact of Podiatric Intervention on the Quality of Life and Pain in Children and Adolescents with Hypermobility.

The purpose of this study was to evaluate the effect of custom-made orthotics on pain, health-related quality of life (HRQoL), function and fatigue in children and adolescents with generalised joint hypermobility (GJH) and lower limb pain. Fifty-three children aged 5-18 years were fitted with custom-made polypropylene orthotics. Visual analogue scale (VAS) assessed lower limb pain severity, Paediatric Quality of Life Inventory assessed HRQoL and fatigue and six-minute walk test (6 MWT) measured functional endurance at baseline, at 1 month and 3 months post-intervention. A mixed model including a random intercept for participant and a fixed effect for time was used to assess differences in outcomes over time. Fifty-two children completed the study (mean age 10.6-years). Children reported significantly reduced pain (mean VAS reduction -27/100, 95%CI: -33, -21), improved HRQoL (mean total improvement 11/100, 95%CI: 7, -15), functional capacity (mean 6MWT improvement 27 m, 95%CI: 18, -36) and fatigue (mean total improvement 13/100, 95%CI: 9, -17) after 1 month of wearing the custom-made orthotics. From 1 month to 3 months there was further statistically but not clinically significant reduction in pain while benefit on other outcomes was maintained. In this study, children with GJH reported reduced lower limb pain, improved HRQoL, functional endurance and fatigue after a month post-fitting of custom-made orthotics which was maintained over a 3 month period. Orthotics were well-tolerated with no serious adverse events reported.

Preparation for Cancer Treatment: A Cross-Sectional Study Examining Patient Self-Reported Experiences and Correlates.

Given the significant physical and psychosocial side-effects cancer treatment has on individuals, it is important to ensure patients receive adequate preparation prior to treatment. The purpose of this study was to explore, among Australian oncology patients, (i) the self-reported treatment preparation information they received; and (ii) the patient characteristics associated with the treatment preparation information received. Patients in the early stages of cancer treatment were invited to complete a survey exploring their receipt of information about treatment preparation. Items assessed patients' self-report of whether they had received information about the treatment process. A total of 165 participants completed the survey. Patients most frequently reported receiving information about how they might feel physically (94%) and what side effects to watch for (93%). One in five patients reported not receiving information about how to cope with any stress or worry related to treatment. Females reported receiving significantly fewer items of care compared to males (p = 0.0083). This study suggests that while self-reported preparation for cancer treatment is generally high, components of preparation related to psychosocial concerns could be improved. Survey data could be used as a feedback tool for centres to monitor delivery of care.

A pilot randomised controlled trial of abrupt versus gradual smoking cessation in combination with vaporised nicotine products for people receiving alcohol and other drug treatment.

BACKGROUND: Vaporised nicotine products (VNPs) may be a potential quit smoking strategy. Most research has permitted participants to use VNPs ad libitum. This is the first study to examine combining the use of a VNP with a gradual or abrupt cessation guideline. This study aims to test the potential feasibility of a quit smoking strategy (abrupt verses gradual cessation) in combination with vaporised nicotine products among people in AOD treatment. METHODS: We conducted a pilot randomised controlled trial between April 2018 and July 2019. Participants were recruited from AOD programs located within one area health service in Australia. Participants were provided with two VNPs, a 12-week supply of nicotine e-liquid and randomised to either the abrupt (assigned a quit date the day they were provided their VNP) or gradual quit smoking strategy (reduce baseline number of cigarettes per day by 25% over a 4 week period), no further behavioral support was provided. Feasibility was assessed through successful recruitment rates, retention, and adherence to study conditions. Participant perceived helpfulness and satisfaction assessed acceptability. RESULTS: Among 80 interested individuals, 66 were eligible and consented (100% recruitment rate). From the 66 participants that consented and completed the baseline survey, 60 received the intervention assigned at a 1:1 ratio with 30 in the gradual cessation and 30 in the abrupt cessation group. Retention was 86.4% (n = 52) at 12-weeks post-intervention commencement. Ninety-six percent (n = 25) of participants in the gradual and 95.8% (n = 23) of participants in the abrupt group were using the VNPs at 12-weeks (p = 0.66). There was no difference in adherence to the assigned quit plan between gradual cessation 44% (n = 11) and abrupt cessation 71% (n = 17) groups (p = 0.117). Median perceived helpfulness of VNPs was high for both gradual (10/10) and abrupt (9/10) groups (p = 0.813). Similarly, median perceived satisfaction of VNPs was high for both gradual (9 /10) and abrupt (8/10) groups (p = 0.414). CONCLUSIONS: AOD participants found an intervention that involved VNPs to be satisfying and helpful. Future large scale trials are needed to elucidate whether a gradual or abrupt cessation guideline is more beneficial in main a quit attempt with a VNP.

Assessing the impact of magnetic resonance treatment simulation (MRSIM) on target volume delineation and dose to organs at risk for oropharyngeal radiotherapy.

INTRODUCTION: Assessing the use of a radiation therapy (RT) planning MRI performed in the treatment position (pMRI) on target volume delineation and effect on organ at risk dose for oropharyngeal cancer patients planned with diagnostic MRI (dMRI) and CT scan. METHODS: Diagnostic MRI scans were acquired for 26 patients in a neutral patient position using a 3T scanner (dMRI). Subsequent pMRI scans were acquired on the same scanner with a flat couch top and the patient in their immobilisation mask. Each series was rigidly registered to the patients planning CT scan and volumes were first completed with the CT/dMRI. The pMRI was then made available for volume modification. For the group with revised volumes, two IMRT plans were developed to demonstrate the impact of the modification. Image and registration quality was also evaluated. RESULTS: The pMRI registration led to the modification of target volumes for 19 of 26 participants. The pMRI target volumes were larger in absolute volume resulting in reduced capacity for organ sparing. Predominantly, modifications occurred for the primary gross tumour volume (GTVp) with a mean Dice Similarity Coefficient (DSC) of 0.7 and the resulting high risk planning target volume, a mean DSC of 0.89. Both MRIs scored similarly for image quality, with the pMRI demonstrating improved registration quality and efficiency. CONCLUSIONS: A pMRI provides improvement in registration efficiency, quality and a higher degree of oncologist confidence in target delineation. These results have led to a practice change within our department, where a pMRI is acquired for all eligible oropharyngeal cancer patients.

Addressing smoking in sheltered homelessness with intensive smoking treatment (ASSIST project): A pilot feasibility study of varenicline, combination nicotine replacement therapy and motivational interviewing.

BACKGROUND: This pilot study aimed to test the feasibility of providing varenicline in combination with nicotine replacement therapy (NRT) and motivational interviewing (MI) to adult male smokers attending a clinic in a hostel for homeless people. METHODS: A single group pre- and post-treatment (12 weeks following intervention commencement) design with embedded process evaluation (at weekly counselling and fortnightly safety check-ins). Participants were 20 male smokers attending a health clinic within a homelessness service in Sydney, Australia, between December 2019 and March 2020. Participants set a target quit date 7-days post intervention commencement. Adverse events, self-reported abstinence, cigarettes per day, treatment adherence and acceptability of the study interventions were assessed 12 weeks post intervention commencement. Abstinence was biochemically verified. Results are complete cases. RESULTS: Retention was 65% at 12-weeks post-intervention commencement (n = 13). No related adverse events were reported. Three participants (15%) reported continuous abstinence. Two participants self-reported 30-day point prevalence abstinence (10%), confirmed by CO level. Participants who did not quit smoking (n = 10), reported a significant reduction in the number of cigarettes smoked per day (19.4 vs 4.7, p < .01). Cravings, withdrawal symptoms, and psychological distress significantly decreased from baseline to 12-week follow-up (all < 0.01). Adherence to the pharmacological interventions was good, most used combination NRT and varenicline. Adherence to the counselling sessions was low, attending three of 12 sessions. Both NRT and MI were rated as highly acceptable. Some participants expressed concerns about the safety of varenicline. CONCLUSIONS: The intervention was feasible and acceptable and associated with short-term smoking cessation and significant reductions in the number of cigarettes smoked-per-day.

Screening for Cognitive Impairment among Community-Dwelling Older Adults: A Comparison of 2 Screening Instruments.

INTRODUCTION: Community aged care services provide support to older adults living in their own homes. Cognitive impairment may increase the complexity of the support required. There is a need to ensure suitable brief screening tools are available to community aged care providers to assess possible cognitive impairment. This study aimed to examine the agreement between 2 validated cognitive impairment screening tools, the Mini-Cog, and Abbreviated Mental Test Score (AMTS), and the perceptions the individuals case manager of Case Manager's. METHODS: A cross-sectional survey study was undertaken with clients of a community aged care provider. Clients were administered both the screening tools via an electronic survey by their Case Manager. RESULTS: In total, 158 (54%) eligible participants consented to participate. There was a 70% agreement between the Mini-Cog and AMTS measures, indicating a moderate agreement which was not statistically different from chance (Kappa 0.08, 95% CI -0.04-0.19). Case Managers identified 37% (n = 48/130) of participants as possibly having cognitive impairment, of which, 15% (n = 20) were also identified via a screening tool. CONCLUSIONS: The findings indicate poor agreement across the 3 measures. To ensure adequate supports are offered to those with cognitive impairment, the use of validated tools that can be administered by non-medical staff in a community setting is a priority. This study highlights a need for further work to determine the most suitable tool for use by community-based aged care services.

Preadmission Statin Prescription and Inpatient Myocardial Infarction in Geriatric Hip Fracture.

Statins have been shown to reduce myocardial infarction (MI) in cardiac and vascular surgery. MI is common in hip fracture. This study aims to investigate whether statins decrease MI in hip fracture surgery and reduce mortality resulting from MI. Patients aged 65 years and above with a low-energy hip fracture were identified between January 2015 and December 2017. Demographics, comorbidities, predictive scores, medications and outcomes were assessed retrospectively. The primary outcome was inpatient MI. The secondary outcome was inpatient mortality resulting from MI, for which fatal and non-fatal MI were modelled. Regression analysis was conducted with propensity score weighting. Hip fracture occurred in 1166 patients, of which 391 (34%) were actively taking statins. Thirty-one (2.7%) patients were clinically diagnosed with MI. They had a higher inpatient mortality than those who did not sustain an MI (35% vs. 5.3%, p < 0.0001). No reduction was seen between statin use and the occurrence of MI (OR = 0.97, 95% CI: 0.45-2.11; p = 0.942) including Fluvastatin-equivalent dosage (OR = 1.00, 95% CI: 0.96-1.03, p = 0.207). Statins were not associated with having a non-fatal MI (OR 1.47, 95% CI: 0.58-3.71; p = 0.416) or preventing fatal MI (OR = 0.40, 95% CI: 0.08-1.93; p = 0.255). Preadmission statin use and associations with clinically diagnosed inpatient MI or survival after inpatient MI were not able to be established.

Direct Oral Anticoagulants and Timing of Hip Fracture Surgery.

Abstract: Timely surgical intervention in hip fracture has been linked to improved outcomes. Direct Oral Anticoagulants (DOACs) are an emerging class of anticoagulants without evidence-based guidelines on surgical timing. This study aims to investigate how DOACs affect surgical timing and hence perioperative outcomes. A retrospective database/registry review was conducted for geriatric hip fracture patients aged 65 and over between 2011 and 2018. Primary outcome was 30-day mortality. Secondary outcomes included serious adverse events (SAE), transfusion and postoperative day (POD) 1 haemoglobin (Hb) levels. From a cohort of 3264 patients, 112 admitted subjects were taking DOACs; the annual proportion on DOACs increased over time. Mean time to surgery from last dose (Ts) was 2.2 (±1.0 SD) days. The primary outcome, 30-day mortality, occurred in 16 (14%) patients with secondary outcomes of SAEs in 25 (22%) patients and transfusion in 30 (27%) patients. Ts (days) did not significantly affect 30-day mortality (odds ratio (OR): 1.37, 95% confidence interval (CI): 0.80-2.33; p = 0.248), SAE (hazard ratio (HR): 1.03, 95% CI: 0.70-1.52; p = 0.885), transfusion (OR: 0.72 95% CI: 0.45 to 1.16; p = 0.177) or POD 1 Hb (OR: 1.99, 95% CI: -0.59 to 4.57; p = 0.129). Timing of surgery does not influence common surgical outcomes such as 30-day mortality, SAE, transfusion, and POD1 Hb in patients taking DOACs on admission.

Comparing Breast Conservation Surgery Seromas Contoured by Radiation Therapists versus those Contoured by a Radiation Oncologist in Radiation Therapy Planning for Early-Stage Breast Cancer.

INTRODUCTION: In the management of early-stage breast cancer using radiation therapy, computed tomography (CT) simulation is used to identify the breast conservation surgery (BCS) seroma as a proxy for the tumour bed. The delineation or contouring of the seroma is generally a task performed by a radiation oncologist (RO). With increasing patient numbers and other demands placed on ROs, the scope of practice for radiation therapists (RTs) is continually expanding, and the need for skills transfer from one profession to another has been investigated in recent years. This study aims to compare the BCS seroma volumes contoured by RTs with those contoured by ROs to add evidence in support of expanding the RTs' role in the treatment planning process in the management of early-stage breast cancer. METHODS: A study was undertaken using the CT-simulation (CT-sim) data sets of patients with early-stage breast cancer treated in 2013. The CT-sim data sets had BCS seromas contoured by 1 of 5 ROs as part of routine clinical management. This study involved 4 RTs who each used the patient information to identify and contour breast seromas on 50 deidentified CT-sim data sets. Metrics used to compare RT versus RO contours included volume size, overlap between volumes, and geographical distance from the centre of volumes. RESULTS: There were 50 CT-sim data sets with 1 RO contour and 4 RT contours analysed. The contour volumes of the 4 RTs and the ROs were assessed. Although there were 50 CT-sim data sets presented to each RT, analysis was carried out on 45, 43, 46, and 45 CT-sim data sets. There were no comparisons made where contours were not delineated. The contour volumes of the 4 RTs and the ROs were assessed with an interclass correlation coefficient, with a result of excellent reliability (0.975, 95% [0.963, 0.985]). The DICE similarity coefficient was used to compare the overlap of each RT contour with the RO contour; the results were favourable with mean (95% CI) DSCs 0.685, 0.640, 0.678, and 0.681, respectively. Comparing the RT and RO geographical centre of the seroma volumes, good to excellent reliability between the RTs and ROs was demonstrated (95% CI mean RO vs RT distances (mm): 3.75, 4.99, 7.71, and 3.39). There was no statistically significant difference between the distances (P = 0.65). CONCLUSION: BCS seromas contoured by RTs compared well with those contoured by an RO. This research has provided further evidence to support RTs in assuming additional contouring responsibilities in radiation therapy planning for patients with early-stage breast cancer.

Prescription of opioids to post-operative orthopaedic patients at time of discharge from hospital: a prospective observational study.

BACKGROUND AND AIMS: Excessive opioid prescribing can lead to adverse consequences including stockpiling, misuse, dependency, diversion and mortality. Increased prescriptions to post-operative inpatients as part of their discharge planning may be a significant contributor. Primary aims included comparing the amount of opioids prescribed, consumed, left unused and their relationship with pain and functionality. METHODS: A total of 132 consecutive patients who underwent elective orthopaedic surgery were prospectively audited. Daily oral morphine equivalent (DME) of opioids prescribed was compared with opioids consumed and amount left unused 7-10 days after discharge. For analysis, patients were split into three groups: total knee replacement (TKR), hand surgery (Hands), and miscellaneous (Misc). RESULTS: The mean dose of opioid prescribed per patient was 108.5 mg DME. TKR consumed 33-35% more opioids than Misc (p=0.0283) and Hands (p=0.0975). Age was a significant independent factor for opioid consumption in the 50th and 75th percentiles of Hands (p≤0.05). An average of 36 mg DME per patient was left unused with Hands having the highest median DME (37 mg) unused. In the total cohort, 26% of patients were discharged with more DME than their last 24 h as an inpatient and had at least 50% of their tablets left unused at follow-up. CONCLUSIONS: Over-prescription of opioids occurs at discharge which can increase the risk of harm. New intervention is needed to optimise prescribing practises. IMPLICATIONS: Changes to prescribing habits and workplace culture are required to minimise unnecessary opioid prescribing but will be challenging to implement. A multi-layered approach of electronic prescribing, opioid stewardship and targeted educational awareness programmes is recommended.