Irish general practitioner (GP) perspectives on impact of direct access radiology on patient care in the community: results from a mixed-methods study.

BACKGROUND: Since winter 2020/21, general practitioners (GPs) in the Republic of Ireland (RoI) have been granted access to diagnostic imaging studies on a new publicly funded pathway, expediting access to services previously obtained via hospital-based doctors. AIMS: Outline GP perspectives on imaging studies obtained via the new "GP Access to Community Diagnostics" initiative. METHODS: A mixed-methods design was employed. Referrals over the first six months of 2019 and 2021 were collated by a private imaging provider, and a randomly selected subset of 2021 studies (maximum 30 referrals per GP) was returned to participating GPs to provide detail on the impact on each patient's care. In-depth qualitative interviews were also conducted with participating GPs. RESULTS: Eleven GPs supplied detailed information on 81 studies organized through the new initiative. GPs reported that the initiative had led to a large proportion of cases being managed solely in general practice, with an 81% reduction in referrals to acute hospital settings and a 58% reduction in referrals to secondary care clinics. GPs felt imaging studies improved patient care in 86% of cases and increased GP workload in 58% of cases. GP qualitative interviews revealed four key themes: improved patient care, increased GP workload, reduction in hospital referrals, and opinions on ongoing management of such initiatives, including guidelines. CONCLUSIONS: GPs felt enhancing access to diagnostics improved patient care by expediting diagnosis, decision-making, and treatment and by reducing hospital referrals. GPs were generally positive about the initiative and made some suggestions on future management of the initiative.

Impact of enhancing GP access to diagnostic imaging: A scoping review.

BACKGROUND: Direct access to diagnostic imaging in General Practice provides an avenue to reduce referrals to hospital-based specialities and emergency departments, and to ensure timely diagnosis. Enhanced GP access to radiology imaging could potentially reduce hospital referrals, hospital admissions, enhance patient care, and improve disease outcomes. This scoping review aims to demonstrate the value of direct access to diagnostic imaging in General Practice and how it has impacted on healthcare delivery and patient care. METHODS: A search was conducted of 'PubMed', 'Cochrane Library', 'Embase' and 'Google Scholar' for papers published between 2012-2022 using Arksey and O'Malley's scoping review framework. The search process was guided by the PRISMA extension for Scoping Reviews checklist (PRISMA-ScR). RESULTS: Twenty-three papers were included. The studies spanned numerous geographical locations (most commonly UK, Denmark, and Netherlands), encompassing several study designs (most commonly cohort studies, randomised controlled trials and observational studies), and a range of populations and sample sizes. Key outcomes reported included the level of access to imaging serves, the feasibility and cost effectiveness of direct access interventions, GP and patient satisfaction with direct access initiatives, and intervention related scan waiting times and referral process. CONCLUSION: Direct access to imaging for GPs can have many benefits for healthcare service delivery, patient care, and the wider healthcare ecosystem. GP focused direct access initiatives should therefore be considered as a desirable and viable health policy directive. Further research is needed to more closely examine the impacts that access to imaging studies have on health system operations, especially those in General Practice. Research examining the impacts of access to multiple imaging modalities is also warranted.

GPs at the Edge: a quantitative description of Irish Rural General Practice.

INTRODUCTION: Currently, more than 1.6 million Irish people live rurally. Rural populations in Ireland are older and have more health needs compared with younger urban areas. Meanwhile, since 1982, the proportion of general practices in rural areas has decreased by 10%. In this study, we look at new survey data to investigate the needs and challenges of rural general practice in Ireland. METHODS: This study will make use of survey responses from the 2021 membership survey by the Irish College of General Practitioners (ICGP). The anonymous, online, survey was sent by email to the ICGP membership in late 2021, with a series of questions pertaining to practice location, and prior experience of living and working in a rural area designed specifically for this project. A series of statistical tests will be undertaken as appropriate for the data. RESULTS: This study is ongoing; we aim to present data on the demographics of those working in rural general practice and related factors. DISCUSSION: Previous research has shown that people who grew up or trained in rural areas are more likely to work there after qualifying. As the analysis of this survey continues, it will be important to see if this pattern is evident here as well.

Heartwatch: an Irish cardiovascular secondary prevention programme in primary care, a secondary analysis of patient outcomes.

OBJECTIVES: To investigate patient follow-up data from Heartwatch: Ireland's secondary prevention programme for cardiovascular disease delivered in general practice. DESIGN: Retrospective descriptive study based on secondary analysis of routinely collected data from Heartwatch. SETTING: Heartwatch targeted 20% of general practices in Ireland and recruited 475 general practitioners across 325 practices. PARTICIPANTS: The patient population included people with a history of acute myocardial infarction, percutaneous transluminal coronary angioplasty or a coronary artery bypass graft. Over 16 000 patients entered the programme however, to assess the long-term progress of patients, we identified a cohort of 5700 patients with at least 8 years in the programme. INTERVENTIONS: A standard protocol for continuing care of patients for the secondary prevention of cardiovascular disease was administered by general practices. The programme was designed using WHO and European Society of Cardiology guidelines on secondary prevention. OUTCOME MEASURES: A Continuing Care (CCare) score out of eight was the primary outcome measure used. It was calculated based on programme targets for well-known cardiovascular risk factors: exercise, systolic blood pressure, LDL cholesterol, optimally controlled glucose, smoking status, and pharmacological treatment. RESULTS: After 1 year, 37% of the 8-year cohort had achieved a CCare score >5 increasing to 44% after year 8. Patient sex was predictive of better scores; male patients had almost a half-point advantage (0.432, 99% CI: 0.335 to 0.509). Patients who enrolled earlier following their qualifying event and patients with more frequent visits were also more likely to achieve higher CCare scores. CONCLUSIONS: Overall, patients are not likely to meet all targets set by secondary prevention guidelines, however, supporting patient self-management may impact on this. Early enrolment after a cardiac event and frequent structured care visits should be priorities in the design and implementation of similar programmes. Ongoing evaluation of them is necessary to improve outcomes.

Treatable but not curable cancer in England: a retrospective cohort study using cancer registry data and linked data sets.

OBJECTIVES: This study estimates the prevalence of cancers that are categorised as treatable but not curable (TbnC) in England. It provides a quantification of the population and a framework to aid identification of this group to enable the design of tailored support services. DESIGN: Through consultation with clinical and data experts an algorithmic definition of TbnC was developed. Using cancer registry data sets, with five other linked data sets held by the National Disease Registration Service, the algorithm was applied as part of this retrospective cohort study to estimate the size and characteristics of the TbnC population. SETTING AND PARTICIPANTS: The health data records of 1.6 million people living with cancer in England in 2015, following a cancer diagnosis between 2001 and 2015, were retrospectively assessed for TbnC status. RESULTS: An estimated 110 615 people in England were living with TbnC cancer at the end of 2015, following identification of TbnC cancer between 2012 and 2015. In addition, 51 946 people fit the initial search criteria but were found to have been in their last year of life at the end of 2015 and therefore considered separately here as end of life cases. A further 57 117 people in England were initially identified as being at high risk of recurrence or having their life being shortened by cancer but did not fit the TbnC conceptual framework and were excluded, but their results are also reported under 'group B'. CONCLUSIONS: A population living with TbnC cancer can be identified using data currently collected on a national scale in England. This large population living with TbnC cancer requires personalised treatment and support.

A high-throughput alpha particle irradiation system for monitoring DNA damage repair, genome instability and screening in human cell and yeast model systems.

Ionizing radiation (IR) is environmentally prevalent and, depending on dose and linear energy transfer (LET), can elicit serious health effects by damaging DNA. Relative to low LET photon radiation (X-rays, gamma rays), higher LET particle radiation produces more disease causing, complex DNA damage that is substantially more challenging to resolve quickly or accurately. Despite the majority of human lifetime IR exposure involving long-term, repetitive, low doses of high LET alpha particles (e.g. radon gas inhalation), technological limitations to deliver alpha particles in the laboratory conveniently, repeatedly, over a prolonged period, in low doses and in an affordable, high-throughput manner have constrained DNA damage and repair research on this topic. To resolve this, we developed an inexpensive, high capacity, 96-well plate-compatible alpha particle irradiator capable of delivering adjustable, low mGy/s particle radiation doses in multiple model systems and on the benchtop of a standard laboratory. The system enables monitoring alpha particle effects on DNA damage repair and signalling, genome stability pathways, oxidative stress, cell cycle phase distribution, cell viability and clonogenic survival using numerous microscopy-based and physical techniques. Most importantly, this method is foundational for high-throughput genetic screening and small molecule testing in mammalian and yeast cells.

Radon exposure is rising steadily within the modern North American residential environment, and is increasingly uniform across seasons.

Human-made buildings can artificially concentrate radioactive radon gas of geologic origin, exposing occupants to harmful alpha particle radiation emissions that damage DNA and increase lung cancer risk. We examined how North American residential radon exposure varies by modern environmental design, occupant behaviour and season. 11,727 residential buildings were radon-tested using multiple approaches coupled to geologic, geographic, architectural, seasonal and behavioural data with quality controls. Regional residences contained 108 Bq/m3 geometric mean radon (min < 15 Bq/m3; max 7,199 Bq/m3), with 17.8% ≥ 200 Bq/m3. Pairwise analysis reveals that short term radon tests, despite wide usage, display limited value for establishing dosimetry, with precision being strongly influenced by time of year. Regression analyses indicates that the modern North American Prairie residential environment displays exceptionally high and worsening radon exposure, with more recent construction year, greater square footage, fewer storeys, greater ceiling height, and reduced window opening behaviour all associated with increased radon. Remarkably, multiple test approaches reveal minimal winter-to-summer radon variation in almost half of properties, with the remainder having either higher winter or higher summer radon. This challenges the utility of seasonal correction values for establishing dosimetry in risk estimations, and suggests that radon-attributable cancers are being underestimated.

The CHD6 chromatin remodeler is an oxidative DNA damage response factor.

Cell survival after oxidative DNA damage requires signaling, repair and transcriptional events often enabled by nucleosome displacement, exchange or removal by chromatin remodeling enzymes. Here, we show that Chromodomain Helicase DNA-binding protein 6 (CHD6), distinct to other CHD enzymes, is stabilized during oxidative stress via reduced degradation. CHD6 relocates rapidly to DNA damage in a manner dependent upon oxidative lesions and a conserved N-terminal poly(ADP-ribose)-dependent recruitment motif, with later retention requiring the double chromodomain and central core. CHD6 ablation increases reactive oxygen species persistence and impairs anti-oxidant transcriptional responses, leading to elevated DNA breakage and poly(ADP-ribose) induction that cannot be rescued by catalytic or double chromodomain mutants. Despite no overt epigenetic or DNA repair abnormalities, CHD6 loss leads to impaired cell survival after chronic oxidative stress, abnormal chromatin relaxation, amplified DNA damage signaling and checkpoint hypersensitivity. We suggest that CHD6 is a key regulator of the oxidative DNA damage response.

ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses.

Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase with a master regulatory function in the DNA damage response. In this role, ATM commands a complex biochemical network that signals the presence of oxidative DNA damage, including the dangerous DNA double-strand break, and facilitates subsequent repair. Here, we review the current state of knowledge regarding ATM-dependent chromatin remodelling and epigenomic alterations that are required to maintain genomic integrity in the presence of DNA double-strand breaks and/or oxidative stress. We will focus particularly on the roles of ATM in adjusting nucleosome spacing at sites of unresolved DNA double-strand breaks within complex chromatin environments, and the impact of ATM on preserving the health of cells within the mammalian central nervous system.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.

Comprehensive survey of household radon gas levels and risk factors in southern Alberta.

BACKGROUND: The inhalation of naturally occurring radon (222Rn) gas from indoor air exposes lung tissue to α-particle bombardment, a highly mutagenic form of ionizing radiation that damages DNA and increases the lifetime risk of lung cancer. We analyzed household radon concentrations and risk factors in southern Alberta, including Calgary, the third-largest Canadian metropolis. METHODS: A total of 2382 residential homes (2018 in Calgary and 364 in surrounding townships) from an area encompassing 82% of the southern Alberta population were tested for radon, per Health Canada guidelines, for at least 90 days (median 103 d) between 2013 and 2016. Participants also provided home metrics (construction year, build type, foundation type, and floor and room of deployment of the radon detector) via an online survey. Homes that were subsequently remediated were retested to determine the efficacy of radon reduction techniques in the region. RESULTS: The average indoor air radon level was 126 Bq/m3, which equates to an effective absorbed radiation dose of 3.2 mSv/yr. A total of 1135 homes (47.6%) had levels of 100 Bq/m3 or higher, and 295 homes (12.4%) had levels of 200 Bq/m3 or higher; the range was less than 15 Bq/m3 to 3441 Bq/m3. Homes built in 1992 or later had radon levels 31.5% higher, on average, than older homes (mean 142 Bq/m3 v. 108 Bq/m3). For 90 homes with an average radon level of 575 Bq/m3 before mitigation, radon suppression successfully reduced levels to an average of 32.5 Bq/m3. INTERPRETATION: Our findings show that radon exposure is a genuine public health concern in southern Alberta, suggest that modern building practices are associated with increased indoor air radon accumulation, legitimatize efforts to understand the consequences of radon exposure to the public, and suggest that radon testing and mitigation are likely to be impactful cancer prevention strategies.

The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation--no simple task.

High linear energy transfer (LET) ionising radiation (IR) such as radon-derived alpha particles and high mass, high energy (HZE) particles of cosmic radiation are the predominant forms of IR to which humanity is exposed throughout life. High-LET forms of IR are established carcinogens relevant to human cancer, and their potent mutagenicity is believed, in part, to be due to a greater incidence of clustered DNA double strand breaks (DSBs) and associated lesions, as ionization events occur within a more confined genomic space. The repair of such DNA damage is now well-documented to occur with slower kinetics relative to that induced by low-LET IR, and to be more reliant upon homology-directed repair pathways. Underlying these phenomena is the relative inability of non-homologous end-joining (NHEJ) to adequately resolve high-LET IR-induced DSBs. Current findings suggest that the functionality of the DNA-dependent protein kinase (DNA-PK), comprised of the Ku70-Ku80 heterodimer and the DNA-PK catalytic subunit (DNA-PKcs), is particularly perturbed by high-LET IR-induced clustered DSBs, rendering DNA-PK dependent NHEJ less relevant to resolving these lesions. By contrast, the NHEJ-associated DNA processing endonuclease Artemis shows a greater relevance to high-LET IR-induced DSB repair. Here, we will review the cellular response to high-LET irradiation, the implications of the chronic, low-dose modality of this exposure and molecular pathways that respond to high-LET irradiation induced DSBs, with particular emphasis on NHEJ factors.

CHD chromatin remodelling enzymes and the DNA damage response.

The protein and DNA complex known as chromatin is a dynamic structure, adapting to alter the spatial arrangement of genetic information within the nucleus to meet the ever changing demands of life. Following decades of research, a dizzying array of regulatory factors is now known to control the architecture of chromatin at nearly every level. Amongst these, ATP-dependent chromatin remodelling enzymes play a key role, required for the establishment, maintenance and re-organization of chromatin through their ability to adjust the contact points between DNA and histones, the spacing between individual nucleosomes and the over-arching chromatin superstructure. Utilizing energy from ATP hydrolysis, these enzymes serve as the gatekeepers of genomic access and are essential for transcriptional regulation, DNA replication and cell division. In recent years, a vital role in DNA Double Strand Break (DSB) repair has emerged, particularly within complex chromatin environments such as heterochromatin, or regions undergoing energetic transactions such as transcription or DNA replication. Here, we will provide an overview of what is understood about ATP-dependent chromatin remodelling enzymes in the context of the DNA damage response. We will first touch upon all four major chromatin remodelling enzyme families and then focus chiefly on the nine members of the Chromodomain, Helicase, DNA-binding (CHD) family, particularly CHD3, CHD4, CHD5 and CHD6. These four proteins have established and emerging roles in DNA repair, the oxidative stress response, the maintenance of genomic stability and/or cancer prevention.