Risultati per: Cardio-oncology: rivista open access

Yang X, He X, Pan D, et al. Intra-arterial alteplase for acute ischaemic stroke after mechanical thrombectomy (PEARL): rationale and design of a multicentre, prospective, open-label, blinded-endpoint, randomised controlled trial. BMJ Open 2024;14:e091059. doi: 10.1136/bmjopen-2024091059 This article was previously published with an error. The follow-up visit at ‘48±12 hours’ was inadvertently omitted from ‘Follow-up Procedures’ under the Methods section. To accurately reflect all key assessment points, the text has been updated to: Study visits will occur at 24±12 hours, 48±12 hours, day 7±1 or at discharge (whichever occurs first), and day 90±7. The follow-up schedule is displayed in table 1. Accordingly, table 1 has been updated to include the missing ‘48±12 hours after randomisation’ visit, during which NIHSS scores, adverse event monitoring, and concomitant medication use are documented. The missing ‘48±12 hours’ follow-up visit has also been added to the timeline in figure 2, to align with…

Palliative care has become standard in many inpatient settings, with about three-quarters of US hospitals currently offering such services. Although early integration of palliative care can yield substantial benefits for patients and their caregivers (eg, enhanced quality of life, psychological well-being, improved coping), the optimal timing and best clinical settings for initiating palliative care are not yet established.

Introduction
Glaucoma is one of the most common causes of blindness and affects more than 70 million people worldwide. The disease is characterised by the loss of retinal ganglion cells associated with a progressive optic neuropathy, resulting in an impairment of visual functions, for example, visual field loss. Nowadays, the only modifiable risk factor is the increase in intraocular pressure, and its treatment is to lower this pressure by medication, laser treatment or surgery to avoid disease progression. New methods for preventing and reversing vision loss are thus urgently needed. Several small and two multicentre studies have presented evidence that repetitive transorbital alternating current stimulation (rtACS) can lead to long-lasting visual field improvement. This could open a new and inexpensive therapeutic option for optic atrophy. However, the level of evidence for this method is still fairly rather poor, and further trials are needed. Therefore, this clinical trial aims to prove the effectiveness of rtACS compared with sham stimulation in patients with primary open-angle glaucoma (POAG).

Methods and analysis
VIRON (Vision Restoration in Optic Neuropathy) is a national, multicentre, prospective, randomised, placebo-controlled, double-blind trial with three arms. The primary objective is to assess the effectiveness of rtACS in patients with POAG compared with sham stimulation. The primary outcome is the change in mean defect (MD) in the visual field immediately after 10 sessions of rtACS (days 9, 16 and 23) compared with the values of initial perimetry (days –21 to –14 and 0) after applying electrical stimulation with a classical montage, compared with sham and electrical stimulation using individualised montage. Secondary outcome measures comprise a long-term effect with changes in MD at 24 weeks after stimulation, and data from the National Eye Institute Visual Function-25 and quality of life (Short Form 36) questionnaires. The target population are patients with glaucomatous optic atrophy and significant glaucomatous visual field defects (MD of 5–22 dB) due to POAG.
After randomisation, patients received either classical rtACS (group 1), individual rtACS (group 2) or sham stimulation (group 3) in daily 25 min stimulation sessions in two series of five consecutive days separated by a weekend interval. In group 1, active stimulation will be via the routinely applied montage using two electrodes affixed on the right and left side of the head, next to the eyes, with straightforward fixation. In group 2, the current flow will be individually modelled (MRI-based) to target areas of partial visual field defects by optimising electrode positions in conjunction with an optimised visual fixation direction. Group 3 with sham stimulation will serve as control.
The calculated sample size required to achieve a statistical power of 80% for a relevant effect size and allow for dropouts was 300 (100 per group). The trial has already begun with the first patient in July 2023. The planned recruitment period is 24 months with an estimated end of the study in November 2025 (last patient out). An adjusted extension of the study period is planned.

Ethics and dissemination
VIRON was approved by the Central Ethics Committee of the University Medical Center Göttingen (19 October 2022) and those of the individual participating centres (Bonn: 446/23-EP, Hamburg: 2023-200889-BO-bet, Cologne: 23-1487 and Mainz: 2023-17399-§23b). The study protocol complies with the Declaration of Helsinki, the national medicine device regulation (MDR) laws and the international standards of good clinical practice (GCP).
The study protocol (V.5, 24 November 2023) was designed following the Standard Protocol Items: Recommendations for Interventional Trials guidelines and is registered on https://drks.de/search/de/trial/DRKS00029129.
As study initiatior the University Medical Center Göttingen (UMG) is responsible for data ownership and data management of the VIRON study. The study data will be published within 6 months of the study being completed. After the publication of the primary results, all data are anonymised and published in an open-access journal to ensure access to the data for third parties.

Trial registration number
https://drks.de/search/de/trial/DRKS00029129.

Objectives
To explore the barriers to accessing quality trauma care after injury in Ghana.

Design
A qualitative study using semi-structured interviews and focus group discussions in one rural and one urban setting. Interviews and focus group discussions were audio recorded, transcribed and thematically analysed using the four-delay framework.

Participants
53 patient participants (n=39 men, n=14 women, mean age=41, SD=15.6, n=38 rural participants, n=15 urban participants) who had an injury not more than 6 months preceding the start of the study.

Settings
15 individual interviews (n=15) and 2 focus group discussions (n=23) were conducted in Yendi (rural setting in Ghana) and 10 individual interviews (n=10) and 1 focus group discussion (n=5) in the Tamale metropolis (urban setting in Ghana).

Results
Our findings showed that when an injury occurred, participants faced multiple barriers across all delays which prevented them from accessing quality injury care. Barriers were a mix of individual, community-level and health-system factors that were interrelated in many ways. Financial difficulties were one of the prominent barriers mentioned by the participants in both settings.

Conclusion
This study shows that multiple factors cause an injured patient to delay in seeking care, reaching care, receiving care and remaining in care. Therefore, there is a pressing need for comprehensive, community-driven strategies to strengthen health literacy at the community level. There is also a need for facility-based strategies that would improve the availability of medical and human resources to augment access to quality trauma care. Additionally, if policymakers focus on removing financial barriers to trauma care and strengthening referral systems, especially in the remote and rural areas, it would greatly improve access to quality trauma care in Ghana.

Introduction
All grade 2/3 gliomas are incurable and at the time of inevitable relapse, patients have significant unmet needs with few effective treatments. This study aims to improve outcomes by molecular profiling of patients at relapse, then matching them with the best available drug based on their molecular profile, maximising the chances of patient benefit while simultaneously testing multiple novel drugs.

Methods and analysis
Low & Anaplastic Grade Glioma Umbrella Study of MOlecular Guided TherapieS (LUMOS-2) will be an international, phase 2, multicentre, open-label, biomarker-directed, umbrella clinical trial for recurrent isocitrate dehydrogenase mutant, histologically grade 2/3 gliomas. Investigational treatment will be assigned based on molecular profiling of contemporaneous tissue obtained at disease relapse using next-generation sequencing. LUMOS-2 will begin with three therapeutic treatment arms: paxalisib, cadonilimab and selinexor. Patient molecular profiles will be assessed by an expert, multidisciplinary Molecular Tumour Advisory Panel. Patients whose molecular profile is considered suitable for a targeted agent like paxalisib will be allocated to that arm, others will be randomised to the available arms of the trial. The primary endpoint is progression-free survival at 6 months. Secondary objectives include assessment of overall survival, response rate, safety and quality of life measures. Two additional therapeutic arms are currently in development.

Ethics and dissemination
Central ethics approval was obtained from the Sydney Local Health District Ethics Review Committee, Royal Prince Alfred Hospital Zone, Sydney, Australia (Approval: 2022/ETH02230). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. A report describing the results of the study will be submitted to international meetings and peer-reviewed journals.

Trial registration number
ACTRN12623000096651.

Introduction
Methamphetamine use disorder is a significant public health concern. No pharmacological treatment options currently exist for methamphetamine use disorder, and psychotherapy is only moderately effective. Preliminary evidence suggests that ketamine-assisted psychotherapy produces sustained improvements in substance use and mental health symptomatology. In addition to direct antidepressant properties, ketamine is hypothesised to increase synaptogenesis and facilitate neuroplasticity, in turn prolonging and enhancing the effects of psychotherapy. Given the withdrawal-associated dysphoria and neurocognitive impairments characterising methamphetamine use disorder, ketamine-assisted psychotherapy may improve the efficacy of psychotherapy alone by addressing these features and facilitating therapeutic engagement. This pilot study aims to investigate the safety and feasibility (time taken to recruit sample, proportion of ineligible participants at pre-screening and screening, number of participants who complete four sessions of psychotherapy, retention rate over full duration of study, acceptability of the intervention) of subanaesthetic ketamine in combination with psychotherapy (cognitive behavioural therapy) for adults with methamphetamine use disorder. Changes in methamphetamine use, cravings and withdrawal, quality of life, and treatment satisfaction will also be explored.

Methods and analysis
This is an open-label, single-arm clinical trial. 20 adults meeting DSM-5-TR criteria for methamphetamine use disorder who are seeking to reduce or cease methamphetamine use will be enrolled in the study through a single-site specialist outpatient stimulant treatment service in inner Sydney (St Vincent’s Hospital, Sydney). A 4-week course with three subcutaneous ketamine doses (0.75 mg/kg to 0.9 mg/kg, titrated according to tolerability) at weekly intervals and four sessions of cognitive behavioural therapy (one at treatment initiation and three within 24–48 hours following each ketamine administration session) will be delivered. Safety and feasibility will be assessed over an 8-week period. Secondary outcomes (changes in methamphetamine use, cravings, withdrawal, quality of life and treatment satisfaction) will be assessed over a 24-week period.

Ethics and dissemination
This study has been approved by the St Vincent’s Hospital Human Research Ethics Committee, reference 2023/ETH00530. Study findings will be disseminated through articles in scientific, peer-reviewed journals, and at national and international conferences.

Trial registration number
ANZCTR: ACTRN12624000895583.

Protocol version
The trial protocol (Version 4.0) was approved on 24 June 2024.

Objective
This study investigates Saudi Arabian physiotherapists’ perspectives on direct access to physiotherapy (DAPT) services, focusing on perceived benefits, barriers and implementation in clinical practice.

Methods
A cross-sectional observational study design was used. Data collection occurred between December 2022 and June 2023 via an online structured questionnaire distributed through email and text messages. The DAPT section comprised items on awareness, endorsement, obstacles/barriers to implementation in Saudi Arabia, perceived benefits and expected benefits of various resources to guide evidence-based practice for physiotherapists. This section featured closed-ended questions using a 5-point Likert scale. The study included licensed physiotherapists currently working in Saudi Arabia.

Results
The study included 401 participants, with a nearly equal distribution of 203 males (50.6%) and 198 females (49.4%). The most common age group was 25–34 years, comprising 70.6% of the participants. A significant proportion (61.6%) were aware of DAPT, and 88% acknowledged its potential to reduce delays in care. However, 49.9% had not engaged with relevant literature. The primary barriers to DAPT identified were laws and regulations (mean=3.69, SD=1.21), physician support (mean=3.59, SD=0.99), entry-level education (mean=3.45, SD=1.17), patient beliefs (mean=3.38, SD=1.24), self-confidence (mean=3.35, SD=1.15) and professional autonomy (mean=3.34, SD=1.22).

Conclusion
Physiotherapists in Saudi Arabia demonstrate substantial awareness of direct access. Organisational initiatives and increased awareness are essential to promote direct access. This study highlights that direct patient access to physiotherapists offers significant benefits to patients, healthcare workers and the broader community.

Introduction
Methamphetamine use disorder is a global public health concern with no approved pharmacotherapies for its treatment. One recent randomised controlled trial conducted in the USA examined a combination of bupropion and naltrexone not readily available globally. Here, we report a trial protocol for an oral formulation of combined naltrexone and bupropion.

Methods and analysis
This single-arm, open-label pilot study will assess the safety and feasibility of oral naltrexone and bupropion (40 mg/450 mg daily in divided doses) in adults with methamphetamine use disorder. Participants (n=20) will be outpatients of a stimulant treatment program at an inner-city hospital in Sydney, Australia. The primary endpoint is Day 84. Participants will attend weekly study visits from Baseline to Week 12 and a follow-up telephone visit at Week 16. All participants will receive treatment as usual, such as psychosocial therapy. Primary outcomes are safety (measured by treatment-emergent adverse events (AEs)/adverse reactions) and feasibility (measured by the time taken to recruit, the proportion of ineligible participants, retention in the study and study medication adherence). Secondary outcomes will assess methamphetamine use, craving and withdrawal; treatment goals and expectations; physical and psychological well-being; depression and anxiety; and treatment satisfaction. Qualitative interviews will assess the acceptability of the intervention and outcome measures.

Ethics and dissemination
This study received ethics approval from the St Vincent’s Hospital Human Research Ethics Committee (2023/ETH00549). Results will be submitted to peer-reviewed journals and scientific conferences, and a video abstract will be created to ensure that the findings are accessible to participants and people who use methamphetamines.

Trial registration number
ANZCTR: ACTRN12623000866606 (protocol V.2.1 dated 08 April 2024).

Introduction
Hepatectomy is the primary treatment for malignant liver tumours. It is crucial to control bleeding during liver parenchymal transection. Methods to reduce central venous pressure (CVP), such as fluid restriction and the use of vasodilators, are essential for minimising bleeding but can lead to haemodynamic instability. Phosphodiesterase-3 (PDEIII) inhibitors such as milrinone have shown efficacy in managing low CVP and maintaining haemodynamic stability. This study investigates olprinone, another PDEIII inhibitor with a potentially strong vasodilatory effect, for its safety and efficacy in CVP management during hepatectomy.

Methods and analysis
This single-centre phase I trial at Shizuoka Cancer Center evaluates the intraoperative administration of olprinone for open and laparoscopic hepatectomy. The trial employs a 3+3 cohort study design to determine the maximum tolerated dose (MTD) and identify dose-limiting toxicities. The study also assesses the trends in CVP and circulatory dynamics using the FloTrac System, alongside safety evaluations. The trial aims to establish the safety and MTD of olprinone during hepatectomy, potentially offering a method to control CVP without causing haemodynamic instability. This could lead to reduced blood loss, shorter operative time and fewer postoperative complications.

Ethics and dissemination
The study protocol was approved by the Certified Review Board of Shizuoka Cancer Center (approval number CRB4180010).

Trial registration number
jRCTs041230110 and jRCTs041230111.

Introduction
Research into novel therapies for rare, immune-mediated inflammatory diseases (IMIDs) faces significant challenges, including small patient populations, complex clinical trial design and difficulties in patient recruitment. Patients with Behcet’s disease (BD), idiopathic inflammatory myopathies (IIM) and IgG4-related disease (IgG4-RD) typically undergo treatment involving prolonged administration of high-dose glucocorticoids and immunosuppressants. Both are associated with an increased risk of infection. Additionally, glucocorticoids carry long-term toxicity risks. Thus, there is an urgent need to develop more targeted and effective anti-inflammatory treatments. Given the activation of the type 1 interferon pathway in BD, IIM and IgG4-RD, inhibition of the Janus kinase (JAK) STAT pathway emerges as a promising therapeutic strategy. The Drug Rediscovery in IMIDs (DRIMID) consortium aims to conduct a prospective pilot basket trial to investigate the effects of filgotinib, a JAK1 preferential inhibitor approved for ulcerative colitis and rheumatoid arthritis, on disease activity, quality of life and safety in patients with refractory BD, IIM and IgG4-RD.

Methods and analysis
In this investigator-initiated, multicentre, open-label phase 2 study, up to 60 patients with rare IMIDs will be enrolled for a 26-week treatment period with filgotinib 200 mg once daily. The trial consists of two stages, each involving a consecutively treated cohort of up to 20 patients per disease. An interim analysis is conducted between these stages, where the trial will proceed only in diseases showing potential effectiveness. Baseline, 3-month and 6-month assessments will include data on quality of life, disease activity, corticosteroid toxicity and biomarkers. The coprimary endpoints are disease activity and quality of life across and within each disease.

Ethics and dissemination
The study received approval from the Medical Research Ethics Committee in Utrecht, Netherlands. A Data Safety Monitoring Board has been established to monitor the trial’s safety and progress.

Trial registration number
NCT06285539.

Introduction
The prognosis for epithelial ovarian cancer (EOC) is exceedingly poor, with patients diagnosed with stage III/IV tumours typically offered cytoreductive surgery in conjunction with chemotherapy as a standard treatment option. This approach is intended to reduce the risk of surgery and address ovarian cancers that are not amenable to surgical intervention. A promising alternative and important treatment option is neoadjuvant chemotherapy (NACT) in conjunction with interstitial tumour cytoreductive surgery. The combination of neoadjuvant immunotherapy with chemotherapy has recently demonstrated remarkable efficacy, particularly in melanoma and lung cancer, with notable pathological responses and therapeutic benefits in tumour tissue. The NeoAdjuvant chemotherapy with or without tIslelizumab followed by debulking surgery for oVarian cancEr(NAIVE) study aims to assess the clinical efficacy and safety of NACT in combination with tislelizumab (a monoclonal antibody for programmed cell death protein 1) for advanced EOC.

Methods and analysis
The NAIVE study is an investigator-initiated, prospective, single-centre, open-label, randomised controlled trial for advanced EOC with the International Federation of Gynaecology and Obstetrics (FIGO) stage IIIc with a Suidan CT score of 3 or greater or a Fagotti laparoscopic score of 8 or greater; or FIGO stage IV. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate, measured as the percentage of patients who are free of tumour progression or death for 1 year after receiving the first dose of study drug. The secondary endpoints encompassed the R0 resection rate, the clinical response rate and other relevant metrics. Enrolled patients will be randomly assigned in a 1:1 ratio to either the experimental arm, which will receive neoadjuvant platinum-based chemotherapy in combination with tislelizumab, or the control arm, which will receive neoadjuvant platinum-based chemotherapy. The study will enrol 40 patients, with enrolment scheduled to start in April 2021 and complete in April 2025, given a 1-year PFS rate of 60%. The study will provide new evidence regarding the clinical efficacy and safety of NACT in combination with tislelizumab for advanced ovarian cancer. The results will contribute to a deeper understanding of the clinical effects, safety profile and fundamental immunological processes. The findings will contribute to the growing body of evidence in support of the incorporation of immunotherapy into the treatment paradigm for ovarian cancer, thus facilitating the development of more personalised and efficacious therapeutic modalities.

Ethics and dissemination
This trial has received ethical approval from the Institutional Ethics Committee of the Second Affiliated Hospital of the Medical College of Zhejiang University. Presentations at scientific and professional meetings and publication in peer-reviewed journals will disseminate the results of the study.

Trial registration number
NCT04815408.

Introduction
A quarter of breast cancers show human epidermal growth factor-2 (HER2) overexpression, where targeted therapy dramatically improves survival. However, cancer therapy-related cardiac dysfunction (CTRCD) occurs in up to 15% of patients. With the interruption of HER2 therapy, if necessary, and the initiation of heart failure therapy (HFT), HER2 CTRCD recovers in over 80% of cases. The need to continue HFT in ‘recovered’ HER2 CTRCD following completion of HER2 therapy is unclear and there are potential significant impacts on patient’s quality of life (QoL). The Randomised Controlled Trial for the Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction (HER-SAFE) aims to evaluate whether HFT can be safely withdrawn in non-high cardiovascular (CV) risk patients with ‘recovered’ HER2 CTRCD.

Methods and analysis
This is a multicentre, open-label randomised controlled trial investigating whether withdrawal of HFT is non-inferior to continuation in non-high CV risk, breast cancer survivors with recovered HER2 CTRCD after cancer treatment completion. The primary endpoint is the incidence of guideline-defined cardiac dysfunction or clinical heart failure. Secondary endpoints include changes in cardiac blood biomarkers, cardiovascular magnetic resonance (CMR)-derived strain and tissue mapping and heart failure symptom questionnaires. The study will recruit 90 participants who will undergo serial clinical assessment over 12 months with advanced cardiovascular imaging (CMR scans with automated analysis at baseline, 6 and 12 months), cardiac biomarker measurement (six time points over 12 months), plus complete heart failure QoL and medication disutility questionnaires. This is the first multicentre study to address this significant clinical issue.

Ethics and dissemination
This study was approved by the research ethics committee (London—London Bridge, 23/LO/0152). The results will be disseminated in peer-reviewed scientific journals.

Trial registration number
NCT05880160.

A study has found that about 29% of the nearly 90 000 retail pharmacies in the US operating between 2010 and 2021 have closed, and they were more likely to shut down if they were in predominantly Black and Latino neighborhoods than in White neighborhoods, in urban vs rural neighborhoods, or were independent pharmacies rather than chains.

Introduction
As a result of improving survival rates, the adverse consequences of rectal cancer surgery are becoming increasingly recognised. Low anterior resection syndrome (LARS) is one such consequence and describes a constellation of bowel symptoms after rectal cancer surgery which includes urgency, faecal incontinence, stool clustering and incomplete evacuation. LARS has a significant adverse impact on quality of life (QoL) and symptoms are present in up to 75% of patients in the first year after surgery. Despite this, little is known about the natural history and there is poor evidence to support current treatment options.

Methods and analysis
The objectives of POLARiS are to explore the natural history of LARS and to evaluate the clinical and cost-effectiveness of transanal irrigation (TAI) or sacral neuromodulation (SNM) compared with optimised conservative management (OCM) for people with major LARS.
POLARiS is a prospective, international, open-label, multi-arm, phase 3 randomised superiority trial within a cohort design, with internal pilot phase, qualitative sub-study, process evaluation and economic evaluation. Approximately 1500 adult participants from UK hospitals and 500 from Australian hospitals who have undergone a high or low anterior resection for colorectal cancer in the last 10 years will be recruited into the cohort. Six-hundred participants from the UK and 200 participants from Australia, with major LARS symptoms, defined as a LARS score of ≥30, will be recruited to the randomised controlled trial (RCT) element. Participants entering the RCT will be randomised between OCM, TAI or SNM, all with equal allocation ratios.
Cohort and RCT participants will be followed up for a 24-month period, completing a series of questionnaires measuring LARS symptoms and QoL, as well as clinical review for those in the RCT. A process evaluation, qualitative sub-study and economic evaluation will also be conducted.
The primary outcome measure of the POLARiS cohort and RCT is the LARS score up to 24 months post-registration/randomisation. Analyses of the RCT will be conducted on an intention-to-treat basis. Comparative effectiveness analyses for each endpoint will consist of two pairwise treatment comparisons: TAI versus OCM and SNM versus OCM. Secondary outcomes include health-related QoL, adverse events, treatment compliance and cost-effectiveness (up to 24 months post-registration/randomisation).

Ethics and dissemination
Ethical approval has been granted by Wales REC 4 (reference: 23/WA/0171) in the UK and Sydney Local Health District HREC (reference: 2023/ETH00749) in Australia. The results of this trial will be disseminated to participants on request and published on completion of the trial in a peer-reviewed journal and at international conferences.

Trial registration number
ISRCTN12834598; ACTRN12623001166662.

Objective
This study aimed to investigate the trends and factors associated with congenital anomalies (CAs) among newborns in Eastern Ethiopia from 2015 to 2022.

Design
Open cohort study.

Setting
The Kersa Health and Demographic Surveillance System (KHDSS), which is located in the Kersa district of the Oromia region in Eastern Ethiopia, covering 24 kebeles.

Population
Newborns registered at birth in the database of the KHDSS site in Eastern Ethiopia.

Methods
The KHDSS tracks demographic and health changes in the community. Newborn data were extracted using a checklist. Trends in CAs over time (in years) were analysed and the associated factors were identified through logistic regression analysis.

Outcome measure
Newborn CAs, which are structural or functional abnormalities present at birth, were assessed through thorough physical examinations and detailed interviews conducted by trained data collectors using a standardised questionnaire.

Results
Between 2015 and 2022, a total of 27 350 newborns were recorded in the KHDSS, 104 of whom had CAs. The overall rate of CAs was 3.83 per 1000 live births (95% CI 3.19, 4.61). There was a significant increase in the trend of CAs over the study period, with a Mantel-Haenszel 2 of 82.76 (p=0.001). Factors associated with CA included maternal age over 35 years (adjusted OR (AOR)=1.68, 95% CI 1.07, 2.62), place of birth (AOR=2.04, 95% CI 1.04, 4.02) and normal birth weight (AOR=0.14, 95% CI 0.04, 0.47).

Conclusion
The data from the KHDSS revealed a rising trend in CAs. CA was associated with factors such as the mother’s age, place of birth and the baby’s birth weight. It is crucial for healthcare providers and stakeholders to consider these factors in efforts to reduce the prevalence of CAs.