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.

Long-term outcomes of SARS-CoV-2 variants and other respiratory infections: evidence from the Virus Watch prospective cohort in England.

This study compared the likelihood of long-term sequelae following infection with SARS-CoV-2 variants, other acute respiratory infections (ARIs) and non-infected individuals. Participants (n=5,630) were drawn from Virus Watch, a prospective community cohort investigating SARS-CoV-2 epidemiology in England. Using logistic regression, we compared predicted probabilities of developing long-term symptoms (>2 months) during different variant dominance periods according to infection status (SARS-CoV-2, other ARI, or no infection), adjusting for confounding by demographic and clinical factors and vaccination status. SARS-CoV-2 infection during early variant periods up to Omicron BA.1 was associated with greater probability of long-term sequalae (adjusted predicted probability (PP) range 0.27, 95% CI = 0.22-0.33 to 0.34, 95% CI = 0.25-0.43) compared with later Omicron sub-variants (PP range 0.11, 95% CI 0.08-0.15 to 0.14, 95% CI 0.10-0.18). While differences between SARS-CoV-2 and other ARIs (PP range 0.08, 95% CI 0.04-0.11 to 0.23, 95% CI 0.18-0.28) varied by period, all post-infection estimates substantially exceeded those for non-infected participants (PP range 0.01, 95% CI 0.00, 0.02 to 0.03, 95% CI 0.01-0.06). Variant was an important predictor of SARS-CoV-2 post-infection sequalae, with recent Omicron sub-variants demonstrating similar probabilities to other contemporaneous ARIs. Further aetiological investigation including between-pathogen comparison is recommended.

The patatin-like protein PlpD forms structurally dynamic homodimers in the Pseudomonas aeruginosa outer membrane.

Members of the Omp85 superfamily of outer membrane proteins (OMPs) found in Gram-negative bacteria, mitochondria and chloroplasts are characterized by a distinctive 16-stranded ß-barrel transmembrane domain and at least one periplasmic POTRA domain. All previously studied Omp85 proteins promote critical OMP assembly and/or protein translocation reactions. Pseudomonas aeruginosa PlpD is the prototype of an Omp85 protein family that contains an N-terminal patatin-like (PL) domain that is thought to be translocated across the OM by a C-terminal ß-barrel domain. Challenging the current dogma, we find that the PlpD PL-domain resides exclusively in the periplasm and, unlike previously studied Omp85 proteins, PlpD forms a homodimer. Remarkably, the PL-domain contains a segment that exhibits unprecedented dynamicity by undergoing transient strand-swapping with the neighboring ß-barrel domain. Our results show that the Omp85 superfamily is more structurally diverse than currently believed and suggest that the Omp85 scaffold was utilized during evolution to generate novel functions.

Effects of the COVID-19 associated United Kingdom lockdown on physical activity in older adults at high risk of cardiovascular disease: a mixed methods perspective from the MedEx-UK multicenter trial.

Introduction: Physical inactivity and sedentary behaviour are linked to increased risk of cardiovascular disease, infections and dementia, as well as placing a significant economic burden on healthcare systems. The implementation of COVID-19 pandemic lockdown measures aimed at reducing virus transmission posed challenges to the opportunity to be physically active. This study investigates how the first UK COVID-19 lockdown affected objectively measured physical activity in older adults at higher risk of cardiovascular disease. Methods: We studied 48 individuals aged 55-74 years (81.3% female) with self-reported PA levels < 90 min/week and a QRISK2 score ≥ 10 (indicative of a ≥ 10% risk of a major cardiovascular event in the next 10 years) without mild cognitive impairment or dementia. Physical activity data was collected using objective wrist-based activity monitors and analysed across three time periods, usual activity (pre-pandemic), the precautionary phase when the UK began advising on limiting social contact and finally during the first UK lockdown period was collected (27 January 2020 and 07 June 2020). Data was analysed using linear mixed effects model was used to investigate PA levels over the measured 12-week period. Effects of BMI, age, deprivation score and baseline PA levels on PA across the three measurement periods were also examined. Focus-group and individual interviews were conducted, and data were thematically analysed. Results: Average daily step count (-34% lower, p < 0.001) and active energy expenditure (-26% lower, p < 0.001) were significantly lower during the precautionary period compared with the usual activity period. Physical activity remained low during the UK lockdown period. Participants with a lower BMI engaged in significantly more (+45% higher daily steps p < 0.001) physical activity and those over 70 years old were more physically active than those under 70 years across the 12-week period (+23% higher daily steps p < 0.007). The risk of COVID-19 infection and restrictions because of lockdown measures meant some individuals had to find alternative methods to staying physical active. Participants described a lack of access to facilities and concerns over health related to COVID-19 as barriers to engaging in physical activity during lockdown. For some, this resulted in a shift towards less structured activities such as gardening or going for a walk. Discussion: The data presented shows that lockdown measures during the COVID-19 pandemic significantly reduced physical activity among older individuals at risk of cardiovascular disease, particularly those with a higher body mass index. To support this population group in staying active during future lockdowns, a multifaceted strategy is needed, emphasizing psychosocial benefits and home-based physical activity. The MedEx-UK study was pre-registered with ClinicalTrials.gov (NCT03673722).

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.

Cost and economic evidence for asset-based approaches to health improvement and their evaluation methods: a systematic review.

BACKGROUND: Asset-based approaches (ABAs) tackle health inequalities by empowering people in more disadvantaged communities, or targeted populations, to better utilise pre-existing local community-based resources. Using existing resources supports individuals to better manage their own health and its determinants, potentially at low cost. Targeting individuals disengaged with traditional service delivery methods offers further potential for meaningful cost-savings, since these people often require costly care. Thus, improving prevention, and management, of ill-health in these groups may have considerable cost implications. AIM: To systematically review the extent of current cost and economic evidence on ABAs, and methods used to develop it. METHODS: Search strategy terms encompassed: i) costing; ii) intervention detail; and iii) locality. Databases searched: Medline, CENTRAL and Wed of Science. Researchers screened 9,116 articles. Risk of bias was assessed using the Critical Appraisal Skills Programme (CASP) tool. Narrative synthesis summarised findings. RESULTS: Twelve papers met inclusion criteria, representing eleven different ABAs. Within studies, methods varied widely, not only in design and comparators, but also in terms of included costs and outcome measures. Studies suggested economic efficiency, but lack of suitable comparators made more definitive conclusions difficult. CONCLUSION: Economic evidence around ABAs is limited. ABAs may be a promising way to engage underserved or minority groups, that may have lower net costs compared to alternative health and wellbeing improvement approaches. ABAs, an example of embedded services, suffer in the context of economic evaluation, which typically consider services as mutually exclusive alternatives. Economics of the surrounding services, mechanisms of information sharing, and collaboration underpin the success of assets and ABAs. The economic evidence, and evaluations in general, would benefit from increased context and detail to help ensure more nuanced and sophisticated understanding of the economics of ABAs. Further evidence is needed to reach conclusions about cost-effectiveness of ABAs.

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.

Short-Term Ambient Air Pollution and Urticaria in Guangzhou, China: Estimating the Association and Population Attributable Fraction.

Limited evidence is available regarding the association between acute exposure to ambient air pollutants and the risk of urticaria, even though the skin is an organ with direct contact with the external environment. This study utilized generalized additive models to investigate the association between particulate matter with an aerodynamic diameter smaller than 10 µm (PM10) and 2.5 µm (PM2.5), nitrogen dioxide (NO2) and sulfur dioxide (SO2), and daily outpatient visits for urticaria in Guangzhou, China from 2013 to 2017. We also estimated the attributable fraction of urticaria outpatient visits due to air pollution. A total of 216,648 outpatient visits due to urticaria occurred during the study period. All air pollutants were significantly associated with an increased excess risk of urticaria. Each 10 µg/m3 increase in PM2.5, PM10, NO2, and SO2 was associated with an increase of 1.23% (95% CI: 0.42%, 2.06%), 0.88% (95% CI: 0.28%, 1.49%), 3.09% (95% CI: 2.16%, 4.03%), and 2.82% (95% CI: 0.93%, 4.74%) in hospital visits for urticaria at lag05, respectively. It was estimated that 3.77% (95% CI: 1.26%, 6.38%), 1.91% (95% CI: 0.60%, 3.26%), 6.36% (95% CI: 4.38%, 8.41%), and 0.08% (95% CI: 0.03%, 0.14%) of urticaria outpatient visits were attributable to PM2.5, PM10, NO2, and SO2 using the World Health Organization's air quality guideline as the reference. Relatively stronger associations were observed during the cold season. This study indicates that short-term air pollution may play a significant role in outpatient visits for urticaria, and that such relationships could be modified by season.

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.

Developmental origin and local signals cooperate to determine septal astrocyte identity.

Astrocyte specification during development is influenced by both intrinsic and extrinsic factors, but the precise contribution of each remains poorly understood. Here we show that septal astrocytes from Nkx2.1 and Zic4 expressing progenitor zones are allocated into non-overlapping domains of the medial (MS) and lateral septal nuclei (LS) respectively. Astrocytes in these areas exhibit distinctive molecular and morphological features tailored to the unique cellular and synaptic circuit environment of each nucleus. Using single-nucleus (sn) RNA sequencing, we trace the developmental trajectories of cells in the septum and find that neurons and astrocytes undergo region and developmental stage-specific local cell-cell interactions. We show that expression of the classic morphogens Sonic hedgehog (Shh) and Fibroblast growth factors (Fgfs) by MS and LS neurons respectively, functions to promote the molecular specification of local astrocytes in each region. Finally, using heterotopic cell transplantation, we show that both morphological and molecular specifications of septal astrocytes are highly dependent on the local microenvironment, regardless of developmental origins. Our data highlights the complex interplay between intrinsic and extrinsic factors shaping astrocyte identities and illustrates the importance of the local environment in determining astrocyte functional specialization.

A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli.

When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lacking Nkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.

Succimer chelation does not produce lasting reductions of blood lead levels in a rodent model of retained lead fragments.

Retained lead fragments from nonfatal firearm injuries pose a risk of lead poisoning. While chelation is well-established as a lead poisoning treatment, it remains unclear whether chelation mobilizes lead from embedded lead fragments. Here, we tested whether 1) DMSA/succimer or CaNa2EDTA increases mobilization of lead from fragments in vitro, and 2) succimer is efficacious in chelating fragment lead in vivo, using stable lead isotope tracer methods in a rodent model of embedded fragments. DMSA was > 10-times more effective than CaNa2EDTA in mobilizing fragment lead in vitro. In the rodent model, succimer chelation on day 1 produced the greatest blood lead reductions, and fragment lead was not mobilized into blood. However, with continued chelation and over 3-weeks post-chelation, blood lead levels rebounded with mobilization of lead from the fragments. These findings suggest prolonged chelation will increase fragment lead mobilization post-chelation, supporting the need for long-term surveillance in patients with retained fragments.

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 .

"Taking from Peter to pay Paul": The experience of people in receipt of fuel and food vouchers from a UK foodbank.

For people on very low incomes, household fuel and food environments are increasingly uncertain. Many live in precarious situations with little control over their lives. In addition to food parcels, many foodbanks also supply emergency fuel payments. There has been a surge in demand due to the cost of living crisis in the United Kingdom. This qualitative study, using semi-structured interviews, explored the lived experience of people who received a fuel voucher via a foodbank to gain insights into food preparation, eating practices and heating and appliance use in their homes. All participants (n = 6) described a change in life circumstances leaving them at crisis point with overwhelming uncertainty. Using Thematic Analysis, we identified four themes: (1) Bewilderment in using foodbank services; (2) The need to make trade-offs between food and fuel; (3) Feeling shame at using the services and (4) Missing out on pleasurable eating practices. Three case studies give fuller insights and context. All interviewees had acute and complex needs and described being 'at rock bottom', with fuel vouchers viewed as a 'lifeline' to address essential cooking, heating and electrical appliance needs. We, therefore, suggest the need for extra support and follow-up for first-time users who are in a state of denial and shock when seeking help. Further research is needed on how to best help organisations develop strategies to address and ameliorate a sense of powerlessness and shame felt by their clients which likely limits them from seeking help, despite being in acute, complex and dire need.

Group Prenatal Care.

Group prenatal care (GPC) is a novel model of health care delivery for pregnant patients. In GPC, a small group of patients of similar gestational age meet at scheduled intervals for both medical care and facilitated educational discussions. This care model encourages better communication and engages patients and providers in a supportive community. There is evidence that GPC leads to improved patient and provider satisfaction, health equity, and maternal and neonatal outcomes. Delivery of prenatal care in a group setting is a significant change from the traditional model and takes willingness, planning, and commitment for implementation and continued success.

The patatin-like protein PlpD forms novel structurally dynamic homodimers in the Pseudomonas aeruginosa outer membrane.

Members of the Omp85 superfamily of outer membrane proteins (OMPs) found in Gram-negative bacteria, mitochondria and chloroplasts are characterized by a distinctive 16-stranded ß-barrel transmembrane domain and at least one periplasmic POTRA domain. All previously studied Omp85 proteins promote critical OMP assembly and/or protein translocation reactions. Pseudomonas aeruginosa PlpD is the prototype of an Omp85 protein family that contains an N-terminal patatin-like (PL) domain that is thought to be translocated across the OM by a C-terminal ß-barrel domain. Challenging the current dogma, we found that the PlpD PL-domain resides exclusively in the periplasm and, unlike previously studied Omp85 proteins, PlpD forms a homodimer. Remarkably, the PL-domain contains a segment that exhibits unprecedented dynamicity by undergoing transient strand-swapping with the neighboring ß-barrel domain. Our results show that the Omp85 superfamily is more structurally diverse than currently believed and suggest that the Omp85 scaffold was utilized during evolution to generate novel functions.

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.

Caregiving for older people living with chronic pain: analysis of the English longitudinal study of ageing and health survey for England.

Background: Chronic pain is a disabling condition. Many people with chronic pain seek informal support for everyday activities of daily living (ADL). However, there remains uncertainty on the type of people with chronic pain who access this support, what types of support they need and who provides such support. The purpose of this analysis was to answer these uncertainties. Methods: Data from the Health Survey for England (HSE) and English Longitudinal Study of Ageing (ELSA) were accessed. People who reported chronic pain (moderate or above for minimum of 12 months) were identified. From these cohorts, we determined if individuals self-reported receiving informal care. Data on caregiver profiles and caregiving activities were reported through descriptive statistics. Logistic regression analyses were performed to compare health status outcomes between people with pain who received and who did not receive informal care. Results: 2178 people with chronic pain from the ELSA cohort and 571 from the HSE cohort were analysed. People who received care were frequently female, older aged with several medical morbidities including musculoskeletal diseases such as arthritis. People with chronic pain received informal care for several diverse tasks. Most frequently these related to instrumental activities of daily living (IADL) such as shopping and housework. They were most frequently provided by partners or their children. Although they reported greater disability and symptoms (p < 0.001), people who received care did not report differences in health status, loneliness or wellbeing (p = 0.27; p = 0.46). Conclusions: Whilst it may be possible to characterise people living in chronic pain who receive informal care, there is some uncertainty on the impact of informal caregiving on their health and wellbeing. Consideration should now be made on how best to support both care recipients and informal caregivers, to ensure their health and quality of life is promoted whilst living with chronic pain.

Informal caregiver training for people with chronic pain in musculoskeletal services (JOINT SUPPORT): protocol for a feasibility randomised controlled trial.

INTRODUCTION: Chronic musculoskeletal (bone, joint or muscle) pain is disabling. People with it frequently have difficulties in managing everyday activities. Individuals may rely on family members or friends to support them. These people are known as informal caregivers. No interventions have previously addressed the health needs of people with chronic musculoskeletal pain and their caregivers. In response, the JOINT SUPPORT programme was developed. In this study, we will assess the feasibility and acceptability of conducting a pragmatic, multicentre, randomised controlled trial (RCT) to test the clinical and cost-effectiveness of the JOINT SUPPORT programme to support these individuals. METHODS AND ANALYSIS: This will be a mixed-methods feasibility RCT. We will recruit 80 patients with chronic musculoskeletal pain with their informal caregivers. Patients will be randomised to usual National Health Service (NHS) care OR usual NHS care plus a caregiver-patient dyad training programme (JOINT SUPPORT). This programme comprises of five, 1-hour, group-based sessions for patients and caregivers, delivered by trained physiotherapists or occupational therapists. It includes developing skills in: understanding pain, pacing, graded activity, fear avoidance and goal-setting, understanding benefits of physical activity and skills in medication management. This will be re-enforced with a workbook. After the group-based sessions, patients and caregivers will be supported through three telephone sessions with a therapist. Data collected at baseline and 3 months will include: screening logs, intervention logs, fidelity checklists and clinical outcomes on quality of life, physical and emotional outcomes, adverse events and resource use. Qualitative research with 24 patient-caregiver dyads and 12 healthcare professionals will explore the acceptability of trial processes. Stop-go criteria will inform the progression to a full trial. ETHICS AND DISSEMINATION: Ethical approval was obtained on 22 February 2022 (National Research Ethics Committee Number: 22/NW/0015). Results will be reported at conferences, peer-review publications and across social media channels. TRIAL REGISTRATION NUMBER: ISRCTN78169443.