Risk of cardiovascular events following intermittent and continuous androgen deprivation therapy in patients with nonmetastatic prostate cancer.

BACKGROUND: Intermittent androgen deprivation therapy (iADT) alleviates some side effects of continuous (c) ADT in patients with prostate cancer (PC), but its relative impact on ADT-associated comorbidities is uncertain. We assessed real-world use of iADT and cADT and associated risk of cardiovascular and endocrine/metabolic events in patients with nonmetastatic (nm) PC. METHODS: This retrospective longitudinal cohort study included patients with nmPC initiating systemic ADT with gonadotropin-releasing hormone agonists (goserelin, histrelin, leuprolide, and triptorelin) or antagonists (degarelix) in the US Surveillance, Epidemiology and End Results-Medicare database (2010-2017), who had ≥ 36 months of continuous insurance coverage, unless death occurred, and did not receive chemotherapy or next-generation hormonal therapies during follow-up (through 2019). Risk of major adverse cardiovascular events (MACE [myocardial infarction, stroke, cardiomyopathy/heart failure, pulmonary embolism, ischemic heart disease, all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, and osteoporosis) were examined between cohorts. Inverse probability of treatment-weighted Cox regression models estimated adjusted hazard ratios (HRs) of the outcomes. RESULTS: Of 10,655 eligible patients, 2,095 (19.7%) received iADT and 8,560 (80.3%) cADT. Median follow-up was 43.9 and 48.4 months and median ADT duration (excluding iADT gaps) was 22.0 and 13.5 months for the iADT and cADT cohorts, respectively. Patients receiving cADT had a lower risk of MACE vs. iADT (HR 0.90; 95% confidence interval [CI] 0.83-0.96). No difference in risk of endocrine/metabolic events was observed (HR 0.97; 95% CI 0.92-1.03). Subgroup analysis found that the difference in MACE was maintained in patients with a history of cardiovascular disease (HR 0.90; 95% CI 0.83-0.98) and eliminated in patients without (HR 0.94; 95% CI 0.82-1.08). CONCLUSIONS: Patients with nmPC who received cADT had a lower risk of MACE and similar risk of endocrine/metabolic events vs. those who received iADT. Further research assessing both regimens is needed to inform treatment decisions.

Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase (DPYD) Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

PURPOSE: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. METHODS: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. RESULTS: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence. CONCLUSION: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.

Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer.

Importance: Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. Objective: To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. Design, Setting, and Participants: This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Interventions: Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Main Outcomes and Measures: Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Results: Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). Conclusions and Relevance: The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Hospital-based caregiver intervention for people following hip fracture surgery (HIP HELPER): multicentre randomised controlled feasibility trial with embedded qualitative study in England.

OBJECTIVES: To assess the feasibility of conducting a pragmatic, multicentre randomised controlled trial (RCT) to test the clinical and cost-effectiveness of an informal caregiver training programme to support the recovery of people following hip fracture surgery. DESIGN: Two-arm, multicentre, pragmatic, open, feasibility RCT with embedded qualitative study. SETTING: National Health Service (NHS) providers in five English hospitals. PARTICIPANTS: Community-dwelling adults, aged 60 years and over, who undergo hip fracture surgery and their informal caregivers. INTERVENTION: Usual care: usual NHS care. EXPERIMENTAL: usual NHS care plus a caregiver-patient dyad training programme (HIP HELPER). This programme comprised three, 1 hour, one-to-one training sessions for a patient and caregiver, delivered by a nurse, physiotherapist or occupational therapist in the hospital setting predischarge. After discharge, patients and caregivers were supported through three telephone coaching sessions. RANDOMISATION AND BLINDING: Central randomisation was computer generated (1:1), stratified by hospital and level of patient cognitive impairment. There was no blinding. MAIN OUTCOME MEASURES: Data collected at baseline and 4 months post randomisation included: screening logs, intervention logs, fidelity checklists, acceptability data and clinical outcomes. Interviews were conducted with a subset of participants and health professionals. RESULTS: 102 participants were enrolled (51 patients; 51 caregivers). Thirty-nine per cent (515/1311) of patients screened were eligible. Eleven per cent (56/515) of eligible patients consented to be randomised. Forty-eight per cent (12/25) of the intervention group reached compliance to their allocated intervention. There was no evidence of treatment contamination. Qualitative data demonstrated the trial and HIP HELPER programme was acceptable. CONCLUSIONS: The HIP HELPER programme was acceptable to patient-caregiver dyads and health professionals. The COVID-19 pandemic impacting on site's ability to deliver the research. Modifications are necessary to the design for a viable definitive RCT. TRIAL REGISTRATION NUMBER: ISRCTN13270387.

Testosterone Recovery for Relugolix Versus Leuprolide in Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study.

BACKGROUND: In the HERO study, relugolix demonstrated sustained testosterone suppression superior to that of leuprolide acetate (97% vs 89%; difference 7.9% [95% confidence interval, 4.1-12%; p < 0.001]). OBJECTIVE: To analyze testosterone recovery in a prespecified subset of men from the HERO study not indicated to continue androgen deprivation therapy. DESIGN, SETTING, AND PARTICIPANTS: Men (N = 934) were randomized (2:1) to receive relugolix 120 mg orally daily or leuprolide acetate injections every 12 wk for 48 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Testosterone recovery was assessed in 184 men who completed 48 wk of treatment. During the 90-d recovery period, assessments included time to testosterone recovery (>280 ng/dl; ≥80% of baseline testosterone), serum levels of prostate-specific antigen and pituitary hormones, and adverse events. RESULTS AND LIMITATIONS: The cumulative incidence rate of testosterone recovery to >280 ng/dl at 90 d following drug discontinuation was significantly higher in the relugolix cohort (n = 137) than in the leuprolide acetate cohort (n = 47; 54% vs 3.2%; nominal p = 0.002). The median time to testosterone recovery was faster following relugolix treatment than with leuprolide acetate treatment (86.0 d vs 112.0 d). Compared with leuprolide acetate, more men treated with relugolix achieved ≥80% of baseline testosterone levels (39% vs 2.1%). Men ≤65 yr and those with baseline testosterone greater than the median had a higher incident rate of testosterone recovery. Adverse events were generally similar between treatment groups. One limitation is the short testosterone recovery follow-up period. CONCLUSIONS: Oral relugolix had faster and more complete recovery of testosterone to normal levels after treatment discontinuation than leuprolide acetate in a subset of men from the HERO study. The clinical implications of a faster testosterone recovery with relugolix may be significant for men being treated with androgen deprivation therapy and influence treatment decisions. PATIENT SUMMARY: The male hormone testosterone is reduced during androgen deprivation therapy for prostate cancer. Reduced testosterone levels cause side effects, impacting patient quality of life. When treatment is stopped, the side effects lessen over time as the levels of testosterone come back to pretreatment range (testosterone recovery). In this study, we found that the time to testosterone recovery was faster with relugolix than with leuprolide acetate.

Perspectives of informal caregivers who support people following hip fracture surgery: a qualitative study embedded within the HIP HELPER feasibility trial.

OBJECTIVES: This study aims to illuminate the perspectives of informal caregivers who support people following hip fracture surgery. DESIGN: A qualitative study embedded within a now completed multicentre, feasibility randomised controlled trial (HIP HELPER). SETTING: Five English National Health Service hospitals. PARTICIPANTS: We interviewed 20 participants (10 informal caregivers and 10 people with hip fracture), following hip fracture surgery. This included one male and nine females who experienced a hip fracture; and seven male and three female informal caregivers. The median age was 72.5 years (range: 65-96 years), 71.0 years (range: 43-81 years) for people with hip fracture and informal caregivers, respectively. METHODS: Semistructured, virtual interviews were undertaken between November 2021 and March 2022, with caregiver dyads (person with hip fracture and their informal caregiver). Data were analysed thematically. FINDINGS: We identified two main themes: expectations of the informal caregiver role and reality of being an informal caregiver; and subthemes: expectations of care and services; responsibility and advocacy; profile of people with hip fracture; decision to be a caregiver; transition from hospital to home. CONCLUSION: Findings suggest informal caregivers do not feel empowered to advocate for a person's recovery or navigate the care system, leading to increased and unnecessary stress, anxiety and frustration when supporting the person with hip fracture. We suggest that a tailored information giving on the recovery pathway, which is responsive to the caregiving population (ie, considering the needs of male, younger and more active informal caregivers and people with hip fracture) would smooth the transition from hospital to home. TRIAL REGISTRATION NUMBER: ISRCTN13270387.Cite Now.

Impact of Concomitant Cardiovascular Therapies on Efficacy and Safety of Relugolix vs Leuprolide: Subgroup Analysis from HERO Study in Advanced Prostate Cancer.

INTRODUCTION: Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study. METHODS: In HERO, 930 men with advanced prostate cancer (APC) were randomized 2:1 and treated with relugolix (120 mg orally once daily; after single 360 mg loading dose) or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies (LMAs), as well as the most common drug classes (> 10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks and safety. RESULTS: Antihypertensives, antithrombotics, and LMAs were utilized by 52.7%, 39.1%, and 39.6% of men in HERO, respectively. In the main subgroups, point estimates for sustained castration rates were generally consistent with overall estimates of relugolix and leuprolide observed in the overall population. Sustained castration rates were also mostly consistent for men taking the most common drug classes and individual agents in each class (losartan [n = 103]: relugolix, 95.4% vs leuprolide, 80.6%; amlodipine [n = 229]: 97.2% vs 85.5%; metoprolol [n = 88]: 95.7% vs 86.9%; acetylsalicylic acid [n = 259]: 97.0% vs 92.1%; clopidogrel [n = 43]: 96.4% vs 86.7%; simvastatin [n = 78]: 98.0% vs 87.3%). Incidence and types of adverse events (AEs) among men who received these medications were mostly consistent with overall population results, with some increases in grade ≥ 3 and fatal AEs. CONCLUSION: Relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents. TRIAL REGISTRATION: Clinical Trial ID NCT03085095. PRIOR PRESENTATION: Data presented at 15th Annual Genitourinary Cancers Symposium; February 17-19, 2022, San Francisco, CA, USA [Abstract 101, Poster board E11]. The published abstract from this presentation can be found at https://ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.101 .

Addressing barriers to increased adoption of DPYD genotyping at a large multisite cancer center.

PURPOSE: To describe the implementation of an in-house genotyping program to detect genetic variants linked to impaired dihydropyrimidine dehydrogenase (DPD) metabolism at a large multisite cancer center, including barriers to implementation and mechanisms to overcome barriers to facilitate test adoption. SUMMARY: Fluoropyrimidines, including fluorouracil and capecitabine, are commonly used chemotherapy agents in the treatment of solid tumors, such as gastrointestinal cancers. DPD is encoded by the DPYD gene, and individuals classified as DPYD intermediate and poor metabolizers due to certain genetic variations in DPYD can experience reduced fluoropyrimidine clearance and an increased risk of fluoropyrimidine-related adverse events. Although pharmacogenomic guidelines provide evidence-based recommendations for DPYD genotype-guided dosing, testing has not been widely adopted in the United States for numerous reasons, including limited education/awareness of clinical utility, lack of testing recommendations by oncology professional organizations, testing cost, lack of accessibility to a comprehensive in-house test and service, and prolonged test turnaround time. Based on stakeholder feedback regarding barriers to testing, we developed an in-house DPYD test and workflow to facilitate testing in multiple clinic locations at Levine Cancer Institute. Across 2 gastrointestinal oncology clinics from March 2020 through June 2022, 137 patients were genotyped, and 13 (9.5%) of those patients were heterozygous for a variant and identified as DPYD intermediate metabolizers. CONCLUSION: Implementation of DPYD genotyping at a multisite cancer center was feasible due to operationalization of workflows to overcome traditional barriers to testing and engagement from all stakeholders, including physicians, pharmacists, nurses, and laboratory personnel. Future directions to scale and sustain testing in all patients receiving a fluoropyrimidine across all Levine Cancer Institute locations include electronic medical record integration (eg, interruptive alerts), establishment of a billing infrastructure, and further refinement of workflows to improve the rate of pretreatment testing.

Requested withdrawal of gastrostomy feeding in motor neurone disease.

NICE (National Institute for Health & Care Excellence) guidance recommends that healthcare professionals with expertise in palliative care should be an integral part of the multidisciplinary team in managing patients with motor neuron disease (MND). Those in the poorest prognostic group may benefit from early referral to help manage rapidly progressive symptoms, psychological distress and offer additional support with complex decision-making and early robust advance care planning. Patients frequently develop dysphagia and gastrostomy feeding can be used to prolong survival and improve quality of life. As the disease progresses patients may request withdrawal of life-sustaining treatment such as gastrostomy feeding; however, a literature search found no evidence or guidance on how best to facilitate this. We present the case of a patient with MND admitted to the hospice inpatient unit requesting withdrawal of gastrostomy feeding, outline the challenges and need for further consensus guidelines to inform practice.

A feasibility study to assess the design of a multicentre randomized controlled trial of the clinical and cost-effectiveness of a caregiving intervention for people following hip fracture surgery.

AIMS: This study aims to assess the feasibility of conducting a pragmatic, multicentre randomized controlled trial (RCT) to test the clinical and cost-effectiveness of an informal caregiver training programme to support the recovery of people following hip fracture surgery. METHODS: This will be a mixed-methods feasibility RCT, recruiting 60 patients following hip fracture surgery and their informal caregivers. Patients will be randomized to usual NHS care, versus usual NHS care plus a caregiver-patient dyad training programme (HIP HELPER). This programme will comprise of three, one-hour, one-to-one training sessions for the patient and caregiver, delivered by a nurse, physiotherapist, or occupational therapist. Training will be delivered in the hospital setting pre-patient discharge. It will include practical skills for rehabilitation such as: transfers and walking; recovery goal setting and expectations; pacing and stress management techniques; and introduction to the HIP HELPER Caregiver Workbook, which provides information on recovery, exercises, worksheets, and goal-setting plans to facilitate a 'good' recovery. After discharge, patients and caregivers will be supported in delivering rehabilitation through three telephone coaching sessions. Data, collected at baseline and four months post-randomization, will include: screening logs, intervention logs, fidelity checklists, quality assurance monitoring visit data, and clinical outcomes assessing quality of life, physical, emotional, adverse events, and resource use outcomes. The acceptability of the study intervention and RCT design will be explored through qualitative methods with 20 participants (patients and informal caregivers) and 12 health professionals. DISCUSSION: A multicentre recruitment approach will provide greater external validity across population characteristics in England. The mixed-methods approach will permit in-depth examination of the intervention and trial design parameters. The findings will inform whether and how a definitive trial may be undertaken to test the effectiveness of this caregiver intervention for patients after hip fracture surgery. Cite this article: Bone Jt Open 2021;2(11):909-920.

A model of impaired Langerhans cell maturation associated with HPV induced epithelial hyperplasia.

Langerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers.

Feasibility and acceptability of a multi-domain intervention to increase Mediterranean diet adherence and physical activity in older UK adults at risk of dementia: protocol for the MedEx-UK randomised controlled trial.

INTRODUCTION: Dementia prevalence continues to increase, and effective interventions are needed to prevent, delay or slow its progression. Higher adherence to the Mediterranean diet (MedDiet) and increased physical activity (PA) have been proposed as strategies to facilitate healthy brain ageing and reduce dementia risk. However, to date, there have been no dementia prevention trials in the UK focussed on combined dietary and PA interventions. This study aims to: (1) assess feasibility and acceptability of a theory-underpinned digital and group-based intervention for dementia risk reduction in an 'at risk' UK cohort; (2) evaluate behaviour change responses to the intervention; and, (3) provide information on cognitive, neurological, vascular and physiological outcomes to inform the design of a follow-on, full-scale efficacy trial. METHODS: One hundred and eight participants aged 55 to 74 years with a QRISK2 score of ≥10% will be recruited to take part in this 24-week multi-site study. Participants will be randomised into three parallel arms: (1) Control; (2) MedDiet; and, (3) MedDiet+PA. The study will evaluate a personalised website, group session and food delivery intervention to increase MedDiet adherence and PA in older adults at risk of dementia. Diet and PA will be monitored prior to, during and following the intervention. Feasibility, acceptability and hypothesised mediators will be assessed in addition to measures of cognitive function, brain structure/perfusion (MRI), vascular function and metabolic markers (blood, urine and faecal) prior to, and following, the intervention. DISCUSSION: This trial will provide insights into the feasibility, acceptability and mechanism of effect of a multi-domain intervention focussed on the MedDiet alone and PA for dementia risk reduction in an 'at risk' UK cohort. ETHICS AND DISSEMINATION: The study has received NHS REC and HRA approval (18/NI/0191). Findings will be disseminated via conference presentations, public lectures, and peer-reviewed publications. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov NCT03673722.

Health behaviour change during the UK COVID-19 lockdown: Findings from the first wave of the C-19 health behaviour and well-being daily tracker study.

OBJECTIVES: To provide baseline cohort descriptives and assess change in health behaviours since the UK COVID-19 lockdown. DESIGN: A prospective cohort (N = 1,044) of people recruited online, purposively targeting vulnerable populations. METHODS: After a baseline survey (April 2020), participants completed 3 months of daily ecological momentary assessments (EMA). Dietary, physical activity, alcohol, smoking, vaping and substance use behaviours collected retrospectively for the pre-COVID-19 period were compared with daily EMA surveys over the first 30 days during early lockdown. Predictors of behaviour change were assessed using multivariable regression models. RESULTS: 30% of the cohort had a COVID-19 at risk health condition, 37% were classed as deprived and 6% self-reported a mental health condition. Relative to pre-pandemic levels, participants ate almost one portion of fruit and vegetables less per day (vegetables mean difference -0.33, 95% CI -0.40, -0.25; fruit -0.57, 95% CI -0.64, -0.50), but showed no change in high sugar portions per day (-0.03, 95% CI -0.12, 0.06). Participants spent half a day less per week doing ≥30 min of moderate to vigorous physical activity (-0.57, 95% CI -0.73, -0.40) but slightly increased days of strength training (0.21, 95% CI 0.09, 0.34), increased alcohol intake (AUDIT-C score change 0.25, 95% CI 0.13, 0.37), though did not change smoking, vaping or substance use behaviour. Worsening health behaviour change was associated with being younger, female and higher body mass index. CONCLUSIONS: The cohort reported worsening health behaviours during early lockdown. Longer term changes will be investigated using further waves of data collection.

Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomised trials.

BACKGROUND: The relationship between long-chain omega-3 (LCn3), alpha-linolenic acid (ALA), omega-6 and total polyunsaturated fatty acid (PUFA) intakes and cancer risk is unclear. METHODS: We searched Medline, Embase, CENTRAL and trials registries for RCTs comparing higher with lower LCn3, ALA, omega-6 and/or total PUFA, that assessed cancers over ≥12 months. Random-effects meta-analyses, sensitivity analyses, subgrouping, risk of bias and GRADE were used. RESULTS: We included 47 RCTs (108,194 participants). Increasing LCn3 has little or no effect on cancer diagnosis (RR1.02, 95% CI 0.98-1.07), cancer death (RR0.97, 95% CI 0.90-1.06) or breast cancer diagnosis (RR1.03, 95% CI 0.89-1.20); increasing ALA has little or no effect on cancer death (all high/moderate-quality evidence). Increasing LCn3 (NNTH 334, RR1.10, 95% CI 0.97-1.24) and ALA (NNTH 334, RR1.30, 95% CI 0.72-2.32) may slightly increase prostate cancer risk; increasing total PUFA may slightly increase risk of cancer diagnosis (NNTH 125, RR1.19, 95% CI 0.99-1.42) and cancer death (NNTH 500, RR1.10, 95% CI 0.48-2.49) but total PUFA doses were very high in some trials. CONCLUSIONS: The most extensive systematic review to assess the effects of increasing PUFAs on cancer risk found increasing total PUFA may very slightly increase cancer risk, offset by small protective effects on cardiovascular diseases.

Single-cell RNA sequencing reveals cell type-specific HPV expression in hyperplastic skin lesions.

Human Papillomavirus infection is highly prevalent worldwide. While most types of HPV cause benign warts, some high-risk types are known to cause cervical cancer, as well as cancer of the oral cavity and head and neck. Persistent cutaneous HPV infection can be particularly problematic in patients with chronic immunosuppression, for example following organ transplantation. Due to unknown mechanisms, these patients may develop numerous warts, as well as present with a dramatically increased skin cancer prevalence. Despite an association between HPV persistence in the epidermis and excessive wart or squamous cancer development, the molecular mechanisms linking immunosuppression, HPV expression and excessive epidermal proliferation have not been determined, largely due to low-sensitivity methodology to capture rare viral transcription events. Here, we use single-cell RNA sequencing to profile HPV-positive skin lesions from an immunosuppressed patient that were found to express the alphapapillomavirus HPV78 in basal keratinocytes, suprabasal keratinocytes and hair follicle stem cells. This method can be applied to detect and investigate HPV transcripts in cutaneous lesions, allowing mechanistic links between immunosuppression-induced HPV life cycle and epidermal hyperproliferation to be uncovered.

Cancer risk in socially marginalised women: An exploratory study.

BACKGROUND: Cancer is a leading cause of premature death in women worldwide, and is associated with socio-economic disadvantage. Yet many interventions designed to reduce risk and improve health fail to reach the most marginalised with the greatest needs. Our study focused on socially marginalised women at two women's centres that provide support and training to women in the judicial system or who have experienced domestic abuse. METHODS: This qualitative study was framed within a sociological rather than behavioural perspective involving thirty participants in individual interviews and focus groups. It sought to understand perceptions of, and vulnerability to, cancer; decision making (including screening); cancer symptom awareness; and views on health promoting activities within the context of the women's social circumstances. FINDINGS: Women's experiences of social adversity profoundly shaped their practices, aspirations and attitudes towards risk, health and healthcare. We found that behaviours such as unhealthy eating and smoking need to be understood in the context of inherently risky lives. They were a coping mechanism whilst living in extreme adverse circumstances, navigating complex everyday lives and structural failings. Long term experiences of neglect, harm and violence, often by people they should be able to trust, led to low self-esteem and influenced their perceptions of risk and self-care. This was reinforced by negative experiences of navigating state services and a lack of control and agency over their own lives. CONCLUSION: Women in this study were at high risk of cancer, but it would be better to understand these risk factors as markers of distress and duress. Without appreciating the wider determinants of health and systemic disadvantage of marginalised groups, and addressing these with a structural rather than an individual response, we risk increasing cancer inequities by failing those who are in the greatest need.

Ectrodactyly ectodermal dysplasia clefting (EEC) syndrome: a rare cause of congenital lacrimal anomalies.

A 9-year-old girl with a medical history significant for ectrodactyly ectodermal dysplasia clefting (EEC) syndrome was referred for evaluation of congenital left-sided epiphora. The patient had undergone successful right external dacryocystorhinostomy at age 5 to treat congenital right-sided epiphora. On examination, several ocular anomalies were noted, including absence of the upper eyelid puncta, absence of the left inferior punctum, a left lacrimal fistula opening at the left caruncle, increased left tear lake, bilateral hypoplastic meibomian glands, mild conjunctival injection, and thin eyelid cilia and brow hair. Systemic findings included cleft lip and palate status-post repair, ectrodactyly of the hands and feet, adontia and microdontia, a pointed nose, and lightly pigmented, dry hair and skin. The patient underwent examination under anesthesia and left conjunctivodacryocystorhinostomy with insertion of a Jones tube with resolution of lacrimation postoperatively. To the authors' knowledge, this is the second report detailing management of congenital lacrimal anomalies in EEC syndrome, and the first describing management of punctal atresia with conjunctivodacryocystorhinostomy and Jones tube placement.

Halogenated flame retardants: do the fire safety benefits justify the risks?

Since the 1970s, an increasing number of regulations have expanded the use of brominated and chlorinated flame retardants. Many of these chemicals are now recognized as global contaminants and are associated with adverse health effects in animals and humans, including endocrine and thyroid disruption, immunotoxicity, reproductive toxicity, cancer, and adverse effects on fetal and child development and neurologic function. Some flame retardants such as polybrominated diphenyl ethers (PBDEs) have been banned or voluntarily phased out by manufacturers because of their environmental persistence and toxicity, only to be replaced by other organohalogens of unknown toxicity. Despite restrictions on further production in some countries, consumer products previously treated with banned retardants are still in use and continue to release toxic chemicals into the environment, and the worldwide use of organohalogen retardants continues to increase. This paper examines major uses and known toxic effects of commonly-used organohalogen flame retardants, replacements for those that have been phased out, their combustion by-products, and their effectiveness at reducing fire hazard. Policy and other solutions to maintain fire safety while reducing toxicity are suggested. The major conclusions are: (1) Flammability regulations can cause greater adverse environmental and health impacts than fire safety benefits. (2) The current options for end-of-life disposal of products treated with organohalogens retardants are problematic. (3) Life-cycle analyses evaluating benefits and risks should consider the health and environmental effects of the chemicals, as well as their fire safety impacts. (4) Most fire deaths and most fire injuries result from inhaling carbon monoxide, irritant gases, and soot. The incorporation of organohalogens can increase the yield of these toxic by-products during combustion. (5) Fire-safe cigarettes, fire-safe candles, child-resistant lighters, sprinklers, and smoke detectors can prevent fires without the potential adverse effects of flame retardant chemicals. (6) Alternatives to organohalogen flame retardant chemicals include using less flammable materials, design changes, and safer chemicals. To date, before evaluating their health and environmental impacts, many flame retardant chemicals have been produced and used, resulting in high levels of human exposure. As a growing literature continues to find adverse impacts from such chemicals, a more systematic approach to their regulation is needed. Before implementing new flammability standards, decision-makers should evaluate the potential fire safety benefit versus the health and environmental impacts of the chemicals, materials, or technologies likely to be used to meet the standard. Reducing the use of toxic or untested flame retardant chemicals in consumer products can protect human and animal health and the global environment without compromising fire safety.

Computer-aided detection of breast carcinoma in standard mammographic projections with digital mammography.

PURPOSE: A retrospective evaluation of the ability of computer-aided detection (CAD) ability to identify breast carcinoma in standard mammographic projections. MATERIALS AND METHODS: Forty-five biopsy proven lesions in 44 patients imaged digitally with CAD applied at examination were reviewed. Forty-four screening BIRADS category 1 digital mammography examinations were randomly identified to serve as a comparative normal/control population. Data included patient age; BIRADS breast density; lesion type, size, and visibility; number, type, and location of CAD marks per image; CAD ability to mark lesions; needle core and surgical pathologic correlation. RESULTS: The CAD lesion/case sensitivity of 87% (n = 39), image sensitivity of 69% (n = 31) for mediolateral oblique view and 78% (n = 35) for the craniocaudal view was found. The average false positive rate in 44 normal screening cases was 2.0 (range 1-8). The 2.0 figure is based on 88 reported false positive CAD marks in 44 normal screening exams: 98% (n = 44) lesions proceeded to excision; initial pathology upgraded at surgical excision from in situ to invasive disease in 24% (n = 9) lesions. CONCLUSION: CAD demonstrated potential to detect mammographically visible cancers in standard projections for all lesion types.