Demographic factors associated with within-individual variability of lung function for adults with cystic fibrosis: A UK registry study.

BACKGROUND: Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates has not been quantified. METHODS: We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1 (forced expiratory volume in 1 s) trajectories and FEV1 within-individual variability as a function of sex, age at annual review, diagnosis after first year of life, homozygous F508 genotype and birth cohort. RESULTS: Mean FEV1 decreased with age and lung function variability showed a near-quadratic trend by age. Males showed higher FEV1 mean and variability than females across the whole age range. Earlier diagnosis and homozygous F508 genotype were also associated with higher FEV1 mean and variability. Individuals who died during follow-up showed on average higher lung function variability than those who survived. CONCLUSIONS: Key variables known to be linked with mean lung function in cystic fibrosis are also associated with an individual's lung function variability. This work opens new avenues to understand the role played by lung function variability in disease progression and its utility in predicting key outcomes such as mortality.

Natural History of Nonmetastatic Prostate Cancer Managed With Watchful Waiting.

Importance: It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences. Objective: To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy. Design, Setting, and Participants: This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023. Exposure: Nonmetastatic PCa. Main Outcomes and Measures: Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling. Results: The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa. Conclusions and Relevance: These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.

Standards for the care of people with cystic fibrosis (CF); Planning for a longer life.

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Population-based study of disease trajectory after radical treatment for high-risk prostate cancer.

OBJECTIVES: To investigate long-term disease trajectories among men with high-risk localized or locally advanced prostate cancer (HRLPC) treated with radical radiotherapy (RT) or radical prostatectomy (RP). MATERIAL AND METHODS: Men diagnosed with HRLPC in 2006-2020, who received primary RT or RP, were identified from the Prostate Cancer data Base Sweden (PCBaSe) 5.0. Follow-up ended on 30 June 2021. Treatment trajectories and risk of death from prostate cancer (PCa) or other causes were assessed by competing risk analyses using cumulative incidence for each event. RESULTS: In total, 8317 men received RT and 4923 men underwent RP. The median (interquartile range) follow-up was 6.2 (3.6-9.5) years. After RT, the 10-year risk of PCa-related death was 0.13 (95% confidence interval [CI] 0.12-0.14) and the risk of death from all causes was 0.32 (95% CI 0.31-0.34). After RP, the 10-year risk of PCa-related death was 0.09 (95% CI 0.08-0.10) and the risk of death from all causes was 0.19 (95% CI 0.18-0.21). The 10-year risks of androgen deprivation therapy (ADT) as secondary treatment were 0.42 (95% CI 0.41-0.44) and 0.21 (95% CI 0.20-0.23) after RT and RP, respectively. Among men who received ADT as secondary treatment, the risk of PCa-related death at 10 years after initiation of ADT was 0.33 (95% CI 030-0.36) after RT and 0.27 (95% CI 0.24-0.30) after RP. CONCLUSION: Approximately one in 10 men with HRLPC who received primary RT or RP had died from PCa 10 years after diagnosis. Approximately one in three men who received secondary ADT, an indication of PCa progression, died from PCa 10 years after the start of ADT. Early identification and aggressive treatment of men with high risk of progression after radical treatment are warranted.

Time trends in the use of curative treatment in men 70 years and older with nonmetastatic prostate cancer.

BACKGROUND: Undertreatment of otherwise healthy men in their seventies with prostate cancer has been reported previously. MATERIAL AND METHODS: Using information in a Swedish prostate cancer research database, patterns of management and cancer-specific mortality were compared across age groups in over 70,000 men diagnosed with intermediate- or high-risk nonmetastatic prostate cancer between 2008 and 2020. Crude probabilities of death were estimated non-parametrically. Staging procedures, primary treatment, and cancer death were compared using regression models, adjusting for patient and tumor characteristics. RESULTS: During the study period, the proportion of men treated with curative intent increased in ages 70-74 (intermediate-risk from 45% to 72% and high-risk from 49% to 84%), 75-79 (intermediate-risk from 11% to 52% and high-risk from 12% to 70%), and 80-84 years (intermediate-risk from < 1% to 14% and high-risk from < 1% to 30%). Older age was associated with lower likelihoods of staging investigations and curative treatment, also after adjustment for tumor characteristics and comorbidity. Men treated with curative intent and those initially managed conservatively had lower crude risks of prostate cancer death than men receiving androgen deprivation treatment (ADT). In adjusted analyses, ADT was associated with higher prostate cancer mortality than curative treatment across ages and risk groups. Among men managed conservatively, prostate cancer mortality was higher in ages 70 and above. INTERPRETATION: Use of curative treatment increased substantially in older men with prostate cancer between 2008 and 2020. Our findings suggest reduced age-bias and under-treatment, likely reflecting improved individualized decision-making and adherence to guidelines recommending more active management of older men.

How are socioeconomic inequalities in preterm birth explained by maternal smoking and maternal body mass index: A mediation analysis.

BACKGROUND: Preterm birth affects between 7% and 8% of births in the UK and is a leading cause of infant mortality and childhood disability. Prevalence of preterm birth has been shown to have significant and consistent socioeconomic inequalities. OBJECTIVE: To estimate how much of the association between socioeconomic status (SES) and gestational age at birth is mediated by maternal smoking status and maternal body mass index (BMI). METHODS: Retrospective cohort study of a maternity hospital in the UK. The analysis included all singleton live births between April 2009 and March 2020 to mothers 18 years old and over, between 22 weeks and 43 weeks gestation. We estimate two measures of mediation for four low gestational age categories: (i) The proportion eliminated the percentage of the effect of SES on low gestational age at birth that would be eliminated by removing the mediators, through the Controlled Direct Effects estimated using serial log-binomial regressions; and (ii) The proportion mediated is the percentage of the effect removed by equalising the distribution of the mediators across socioeconomic groups, estimated using Interventional Disparity Measures calculated through Monte Carlo simulations. RESULTS: Overall, 81,219 births were included, with 63.7% low SES. The risk of extremely (0.3% of all births), very (0.7%) and moderately preterm birth (6.3%) was 1.71 (95% Confidence Interval [CI] 1.29, 2.31), 1.43 (95% CI 1.18, 1.73) and 1.26 (95% CI 1.19, 1.34) times higher in the low SES, compared to higher SES respectively. The proportion of this inequality eliminated by removing both maternal smoking and BMI was 43.4% for moderately preterm births. The proportion mediated for smoking was 33.9%, 43.0% and 48.4% respectively. CONCLUSIONS: Smoking during pregnancy is a key mediator of inequalities in preterm birth, representing an area for local action to reduce social inequalities in preterm birth.

Patient-reported Side Effects 1 Year After Radical Prostatectomy or Radiotherapy for Prostate Cancer: A Register-based Nationwide Study.

BACKGROUND: Data on functional and psychological side effects following curative treatment for prostate cancer are lacking from large, contemporary, unselected, population-based cohorts. OBJECTIVE: To assess urinary symptoms, bowel disturbances, erectile dysfunction (ED), and quality of life (QoL) 12 mo after robot-assisted radical prostatectomy (RARP) and radiotherapy (RT) using patient-reported outcome measures in the Swedish prostate cancer database. DESIGN, SETTING, AND PARTICIPANTS: This was a nationwide, population-based, cohort study in Sweden of men who underwent primary RARP or RT between January 1, 2018 and December 31, 2020. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Absolute proportions and odds ratios (ORs) were calculated using multivariable logistic regression, with adjustment for clinical characteristics. RESULTS AND LIMITATIONS: A total of 2557 men underwent RARP and 1741 received RT. Men who underwent RT were older (69 vs 65 yr) and had more comorbidities at baseline. After RARP, 13% of men experienced incontinence, compared to 6% after RT. The frequency of urinary bother was similar, at 18% after RARP and 18% after RT. Urgency to defecate was reported by 14% of men after RARP and 34% after RT. At 1 yr, 73% of men had ED after RARP, and 77% after RT. High QoL was reported by 85% of men after RARP and 78% of men after RT. On multivariable regression analysis, RT was associated with lower risks of urinary incontinence (OR 0.25, 95% confidence interval [CI] 0.19-0.33), urinary bother (OR 0.79, 95% CI 0.66-0.95), and ED (OR 0.54, 95% CI 0.46-0.65), but higher risk of bowel symptoms (OR 2.86, 95% CI 2.42-3.39). QoL was higher after RARP than after RT (OR 1.34, 95% CI 1.12-1.61). CONCLUSIONS: Short-term specific side effects after curative treatment for prostate cancer significantly differed between RARP and RT in this large and unselected cohort. Nevertheless, the risk of urinary bother was lower after RT, while higher QoL was common after RARP. PATIENT SUMMARY: In our study of patients treated for prostate cancer, urinary bother and overall quality of life are comparable at 1 year after surgical removal of the prostate in comparison to radiotherapy, despite substantial differences in other side effects.

Patient-reported outcomes during telehealth versus in-person follow-up visits for patients treated with extracorporeal shockwave therapy.

BACKGROUND: The limited research describing clinical outcomes using telehealth for management of musculoskeletal conditions is primarily within orthopedic surgery care. OBJECTIVE: To characterize differences in patient reported outcomes using telehealth compared with in-person follow-up visits in patients with Achilles tendinopathy (AT) or plantar fasciitis (PF) treated using extracorporeal shockwave therapy (ESWT). DESIGN: Retrospective chart review. SETTING: Outpatient sports medicine clinic. PATIENTS: 82 patients with AT and 46 patients with PF. INTERVENTIONS: In-person (n = 76) and telehealth (n = 52) follow-up visits. MAIN OUTCOME MEASUREMENTS: Victorian Institute of Sports Assessment-Achilles (VISA-A) for AT and Foot and Ankle Ability Measure (FAAM) for PF as well as billing level. RESULTS: There was significant improvement from baseline to final VISA-A (p < .01) and FAAM (p < .01) following ESWT. No significant difference existed in the proportion of patients who met the minimal clinically important difference based on in-person (71.1%) versus telehealth (71.2%) follow-up (p = .99). The in-person group demonstrated higher billing levels compared to the telehealth group (Level: 3.5 ± 0.6 vs. 2.8 ± 0.7, p < .01). CONCLUSIONS: Given no significant differences in outcomes between two modes of follow-ups, telehealth may serve as an alternative method to guide management of musculoskeletal injuries with ESWT and other procedures.

Risk of prostate cancer death after radical radiotherapy with neoadjuvant and adjuvant therapy with bicalutamide or gonadotropin-releasing hormone agonists.

BACKGROUND: Oncological outcome after radical radiotherapy (RRT) combined with neoadjuvant and adjuvant androgen suppression therapy (AST) may differ according to type of AST. The aim of this nationwide register-based study was to investigate risk of prostate cancer (Pca) death after different neoadjuvant and adjuvant ASTs; (i) bicalutamide, (ii) gonadotropin-releasing hormone agonists (GnRH) or (iii) combined bicalutamide and GnRH (CAB), together with RRT. MATERIALS AND METHODS: Data for 6882 men diagnosed with high-risk Pca between 2007 and 2020 and treated with primary RRT was retrieved from Prostate Cancer data Base Sweden (PCBaSe) 5.0. Time to Pca death according to type of neoadjuvant and adjuvant AST was assessed by use of Kaplan-Meier plots and Cox proportional hazard models adjusted for putative confounders. RESULTS: Data were stratified by RRT type since the effect of AST in risk of Pca death differed according to type of RRT. Compared with the reference RRT combined with neoadjuvant CAB/adjuvant GnRH, risk of Pca death for men treated with CAB/bicalutamide and conventionally fractionated external beam radiotherapy (CF-EBRT) was hazard ratio (HR) 0.73 (95% CI: 0.50-1.04), hypofractionated EBRT (HF-EBRT), HR 1.35 (95% CI: 0.65-2.81) and EBRT with high dose rate brachytherapy (EBRT-HDRBT), HR 0.85 (95% CI: 0.37-1.95). Risk of Pca death for men treated with bicalutamide/bicalutamide and: (i) CF-EBRT was HR 2.35 (95% CI: 1.42-3.90), (ii) HF-EBRT, HR 0.70 (95% CI: 0.26-1.85), (iii) HF-EBRT, HR 4.07 (95% CI: 1.88-8.77) vs the reference. CONCLUSION: In this observational study, risk of Pca death between men receiving different combinations of AST varied according to RRT type. No difference was found in risk of Pca death for men treated with bicalutamide or GnRH as adjuvant therapy to RRT following neoadjuvant CAB. Risk of Pca death was increased for men with monotherapy neo-/adjuvant bicalutamide in combination with CF-EBRT or EBRT-HDRBT.

Frequency of Biopsy and Tumor Grade Before vs After Introduction of Prostate Magnetic Resonance Imaging.

Importance: In randomized clinical trials (RCTs), magnetic resonance imaging (MRI) before prostate biopsy has been associated with fewer biopsies, decreased detection of Gleason score 6 cancers, and increased detection of Gleason score 7 or higher cancers. Objective: To study whether MRI of the prostate before the decision to biopsy is associated with biopsy frequency and distribution of Gleason score in clinical practice. Design, Setting, and Participants: This is a retrospective, population-based cohort study of men in Jönköping Region, Sweden. Men with prostate-specific antigen (PSA) level measured between November 2011 and 2020 were monitored until January 31, 2021. Men with known prostate cancer were excluded. Data analysis was performed from July to December 2022. Exposures: Data on repeated PSA measures, prostate biopsies, and MRI prostate were extracted from health care records, and cancer characteristics were obtained from The National Prostate Cancer Register. Main Outcomes and Measures: The proportions of men who underwent prostate biopsy and risk of Gleason score 6 or Gleason score 7 or higher cancer and negative biopsy before and after introduction of MRI were calculated. Results: In this cohort study of 23 802 men (mean [SD] age, 60.8 [13.6] years) who underwent PSA testing, when the use of MRI increased, fewer biopsies were performed (adjusted odds ratio [OR], 0.84; 95% CI, 0.72-0.97) and the odds of detecting Gleason score 6 cancer decreased (OR, 0.47; 95% CI, 0.33-0.64), whereas the odds of detecting Gleason score 7 or higher cancer increased (OR, 1.24; 95% CI, 1.02-1.50). Conclusions and Relevance: In this study, the introduction of MRI to clinical practice was associated with a decreased proportion of men who underwent a biopsy and decreased detection of Gleason score 6 cancer but increased detection of Gleason score 7 or higher cancer. These clinical data support the use of prostate MRI before biopsy in an effort to avoid unnecessary biopsies.

Making Surgery as Safe as It Should Be: A Qualitative Study.

Existing literature supports the view that adverse outcomes from surgical interventions are more likely to be the result of degraded nontechnical skills (NTS) rather than the technical skills of surgeons. In the present context, NTS comprise the behaviors and cognitions deployed by surgeons to make decisions, maintain awareness of the operating environment, communicate with and lead supporting personnel. A contemporary safety thesis suggests that focusing on what makes things go right (eg, NTS) is far more productive than retrospective analysis (learning from mistakes). The present qualitative research explored how surgeons deploy NTS to facilitate safe and effective outcomes from surgical interventions. The thematic analysis revealed that this surgical cohort engaged specific self-regulated NTS along an intervention construct consisting of planning, implementation, monitoring progress, and deliberate learning through reflection during the preoperative, operative, and postoperative phases of care. Behaviors supporting these contentions were identified in the data and used to amplify use of the construct.

A retrospective cohort study of differential attainment, COVID and chaos: taking the difference out of a terrible trinity.

BACKGROUND: This study aimed to evaluate core surgical training (CST) differential attainment related to coronavirus disease 2019 (COVID-19), gender and ethnicity. The hypothesis was that COVID-19 adversely influenced CST outcomes. METHODS: A retrospective cohort study of 271 anonymised CST records was undertaken at a UK Statutory Education Body. Primary effect measures were Annual Review of Competency Progression Outcome (ARCPO), Membership of the Royal College of Surgeons (MRCS) examination pass and Higher Surgical Training National Training Number (NTN) appointment. Data were collected prospectively at ARCP and analysed with non-parametric statistical methods in SPSS. RESULTS: CSTs numbering 138 completed training pre-COVID and 133 peri-COVID. ARCPO 1, 2 and 6 were 71.9% pre-COVID versus 74.4% peri-COVID ( P =0.844). MRCS pass rates were 69.6% pre-COVID versus 71.1% peri-COVID ( P =0.968), but NTN appointment rates diminished (pre-COVID 47.4% vs. peri-COVID 36.9%, P =0.324); none of the above varied by gender or ethnicity. Multivariable analyses by three models revealed: ARCPO was associated with gender [m:f 1:0.87, odds ratio (OR) 0.53, P =0.043] and CST theme (Plastics vs. General OR 16.82, P =0.007); MRCS pass with theme (Plastics vs. General OR 8.97, P =0.004); NTN with the Improving Surgical Training run-through programme (OR 5.00, P <0.001). Programme retention improved peri-COVID (OR 0.20, P =0.014) with pan University Hospital rotations performing better than Mixed or District General-only rotations (OR 6.63, P =0.018). CONCLUSION: Differential attainment profiles varied 17-fold, yet COVID-19 did not influence ARCPO or MRCS pass rates. NTN appointment fell by one-fifth peri-COVID, but overall training outcome metrics remained robust despite the existential threat.

Differential attainment in higher surgical training: scoping pan-specialty spectra.

INTRODUCTION: This study aimed to evaluate differential attainment during higher surgical training (HST; all specialties) related to three ethnic cohorts: White UK (WUKG), Black and Minority Ethnic UK Graduates (BMEUKG), and International Medical Graduates (IMG). METHOD: Anonymised records of 266 HSTs (126 WUKG, 65 BMEUKG, 75 IMG; 7 years) in a single UK Statutory Education Body were examined. Primary effect measures were Annual Record of Competency Progression Outcome (ARCPO) and Fellowship of the Royal College of Surgeons (FRCS) pass. RESULTS: ARCPOs related to ethnicity and specialty were similar with the exception of general surgery (GS) trainees, four of whom received ARCPO 4 (GS 4.9% (75% BME; p=0.025) vs all other 0%). ARCPO 3 was commoner in women (22/76, (28.9%) than men 27/190 (14.2%), OR 2.46, p=0.006). FRCS pass rates (WUKG vs BMEUKG vs IMG) were 76.9%, 52.9% and 53.9% respectively (p=0.064) but unrelated to gender (M 70.4% vs F 64.3%). On multivariable analyses: ARCPO 3 was associated with Female gender and Maternity Leave (OR 8.05, p=0.001); FRCS pass with ethnicity (OR 0.21, p=0.028) and Hirsch Indices of ≥5 (OR 11.17, p=0.001). CONCLUSION: Differential attainment was plain with BMEUKG FRCS performance almost a third poorer than WUKG, and women twofold more likely to receive adverse ARCPOs, with return from statutory leave independently associated with training extension. Focused counter measures targeted at non-operative technical skills (including academic reach), Keeping in Touch, Return to Work, and re-induction programmed support are urgently needed for trainees at risk.

Sharing decisions on reproductive goals: A mixed-methods study of the views of women who have cystic fibrosis.

BACKGROUND: There are complex medical, psychological, social and economic aspects to becoming a parent with Cystic Fibrosis (CF). A shared decision-making (SDM) approach could help women with CF make informed decisions about their reproductive goals that are sensitive to their individual values and preferences. This study investigated capability, opportunity, and motivation to participate in SDM from the perspective of women with CF. METHODS: Mixed-methods design. An international online survey was completed by 182 women with CF, to investigate participation in SDM in relation to reproductive goals, and measures of capability (information needs), opportunity (social environment) and motivation (SDM attitudes and self-efficacy) to engage in SDM. Twenty-one women were interviewed using a visual timelines method to explore their SDM experiences and preferences. Qualitative data were analysed thematically. RESULTS: Women with higher decision self-efficacy reported better experiences of SDM relating to their reproductive goals. Decision self-efficacy was positively associated with social support, age, and level of education, highlighting inequalities. Interviews indicated that women were highly motivated to engage in SDM, but their capability was compromised by lack of information, perception of insufficient opportunities for focused discussions about SDM. CONCLUSIONS: Women with CF are keen to engage in SDM about reproductive health, but currently lack sufficient information and support to do so. Interventions at patient, clinician and system levels are needed to support capability, opportunity and motivation to engage equitably in SDM in relation to their reproductive goals.

Cancer burden among adolescents and young adults in relation to childhood adversity: a nationwide life-course cohort study of 1.2 million individuals.

Background: Childhood adversity such as poverty, loss of a parent, and dysfunctional family dynamics may be associated with exposure to environmental and behavioral hazards, interfere with normal biological functions, and affect cancer care and outcomes. To explore this hypothesis, we assessed the cancer burden among young men and women exposed to adversity during childhood. Methods: We undertook a population-based study using Danish nationwide register data on childhood adversity and cancer outcomes. Children who were alive and resident in Denmark until their 16th birthday were followed into young adulthood (16-38 years). Group-based multi-trajectory modelling was used to categorize individuals into five distinct groups: low adversity, early material deprivation, persistent material deprivation, loss/threat of loss, and high adversity. We assessed the association with overall cancer incidence, mortality, and five-year case fatality; and cancer specific outcomes for the four most common cancers in this age group in sex-stratified survival analyses. Findings: 1,281,334 individuals born between Jan 1, 1980, and Dec 31, 2001, were followed up until Dec 31, 2018, capturing 8229 incident cancer cases and 662 cancer deaths. Compared to low adversity, women who experienced persistent material deprivation carried a slightly lower risk of overall cancer (hazard ratio (HR) 0.90; 95% CI 0.82; 0.99), particularly due to malignant melanoma and brain and central nervous system cancers, while women who experienced high adversity carried a higher risk of breast cancer (HR 1.71; 95% CI 1.09; 2.70) and cervical cancer incidence (HR 1.82; 95% CI 1.18; 2.83). While there was no clear association between childhood adversity and cancer incidence in men, those men who had experienced persistent material deprivation (HR 1.72; 95% CI 1.29; 2.31) or high adversity (HR 2.27; 95% CI 1.38; 3.72) carried a disproportionate burden of cancer mortality during adolescence or young adulthood compared to men in the low adversity group. Interpretation: Childhood adversity is associated with a lower risk of some subtypes of cancer and a higher risk of others, particular in women. Persistent deprivation and adversity are also associated with a higher risk of adverse cancer outcomes for men. These findings may relate to a combination of biological susceptibility, health behaviors and treatment-related factors. Funding: None.

CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum.

OBJECTIVE: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence. METHODS: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation. RESULTS: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering. CONCLUSION: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort.

OBJECTIVE: Prior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. METHODS: The Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. RESULTS: For 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. CONCLUSIONS: No difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease.

Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.

Diagnostic activity impacts lifetime risk of prostate cancer diagnosis more strongly than life expectancy.

The main aim of the study was to determine the impact of diagnostic activity and life expectancy on the lifetime risk of a prostate cancer diagnosis. We used a state transition simulation model based on Swedish population-based data to simulate life trajectories for 2,000,000 men from age 40 to 100 in order to estimate the lifetime risk of a prostate cancer diagnosis. Risk estimates were determined by the level of diagnostic activity and estimated life expectancy. Higher exposure to diagnostic activity resulted in more prostate cancer diagnoses. This was especially true for men diagnosed with low or intermediate grade disease. Men exposed to high diagnostic compared to low diagnostic activity had a five-fold increased lifetime risk (22% vs. 5%) of being diagnosed with a low or intermediate-risk prostate cancer and half the risk of being diagnosed with a high-risk prostate cancer (6% vs. 13%). Men with a long life expectancy had a higher lifetime risk of a prostate cancer diagnosis both overall (21% vs. 15%) and in all risk categories when compared to men with a short life expectancy. The lifetime risk of a prostate cancer diagnosis is strongly influenced by diagnostic activity and to a lesser degree by life expectancy.