Development of CNS tropic AAV1-like variants with reduced liver-targeting following systemic administration in mice.

Directed evolution of natural AAV9 using peptide display libraries have been widely used in the search for an optimal recombinant AAV (rAAV) for transgene delivery across the blood-brain barrier (BBB) to the CNS following intravenous ( IV) injection. In this study, we used a different approach by creating a shuffled rAAV capsid library based on parental AAV serotypes 1 through 12. Following selection in mice, 3 novel variants closely related to AAV1, AAV-BBB6, AAV-BBB28, and AAV-BBB31, emerged as top candidates. In direct comparisons with AAV9, our novel variants demonstrated an over 270-fold improvement in CNS transduction and exhibited a clear bias toward neuronal cells. Intriguingly, our AAV-BBB variants relied on the LY6A cellular receptor for CNS entry, similar to AAV9 peptide variants AAV-PHP.eB and AAV.CAP-B10, despite the different bioengineering methods used and parental backgrounds. The variants also showed reduced transduction of both mouse liver and human primary hepatocytes in vivo. To increase clinical translatability, we enhanced the immune escape properties of our new variants by introducing additional modifications based on rational design. Overall, our study highlights the potential of AAV1-like vectors for efficient CNS transduction with reduced liver tropism, offering promising prospects for CNS gene therapies.

Future cancer risk after urgent suspected cancer referral in England when cancer is not found: a national cohort study.

BACKGROUND: Following referral for investigation of urgent suspected cancer within the English National Health Service referral system, 7% of referred individuals are diagnosed with cancer. This study aimed to investigate the risk of cancer occurrence within 1-5 years of finding no cancer following an urgent suspected cancer referral. METHODS: This national cohort study used urgent suspected cancer referral data for England from the Cancer Waiting Times dataset and linked it with cancer diagnosis data from the National Cancer Registration dataset. Data were extracted for the eight most commonly referred to urgent suspected cancer referral pathways (breast, gynaecological, head and neck, lower and upper gastrointestinal, lung, skin, and urological) for the period April 1, 2013, to March 31, 2014, with 5-year follow-up for individuals with no cancer diagnosis within 1 year of referral. The primary objective was to investigate the occurrence and type of subsequent cancer in years 1-5 following an urgent suspected cancer referral when no cancer was initially found, both overall and for each of the eight referral pathways. The numbers of subsequent cancers were compared with expected cancer incidence in years 1-5 following referral, using standardised incidence ratios (SIRs) based on matched age-gender distributions of expected cancer incidence in England for the same time period. The analysis was repeated, stratifying by referral group, and by calculating the absolute and expected rate of all cancers and of the same individual cancer as the initial referral. FINDINGS: Among 1·18 million referrals without a cancer diagnosis in years 0-1, there were 63 112 subsequent cancers diagnosed 1-5 years post-referral, giving an absolute rate of 1338 (95% CI 1327-1348) cancers per 100 000 referrals per year (1038 [1027-1050] in females, 1888 [1867-1909] in males), compared with an expected rate of 1054 (1045-1064) cancers per 100 000 referrals per year (SIR 1·27 [95% CI 1·26-1·28]). The absolute rate of any subsequent cancer diagnosis 1-5 years after referral was lowest following suspected breast cancer referral (746 [728-763] cancers per 100 000 referrals per year) and highest following suspected urological (2110 [2070-2150]) or lung cancer (1835 [1767-1906]) referral. For diagnosis of the same cancer as the initial referral pathway, the highest absolute rates were for the urological and lung pathways (1011 [984-1039] and 638 [598-680] cancers per 100 000 referrals per year, respectively). The highest relative risks of subsequent diagnosis of the same cancer as the initial referral pathway were for the head and neck pathway (SIR 3·49 [95% CI 3·22-3·78]) and lung pathway (3·00 [2·82-3·20]). INTERPRETATION: Cancer risk was higher than expected in the 5 years following an urgent suspected cancer referral. The potential for targeted interventions, such as proactive monitoring, safety-netting, and cancer awareness or risk reduction initiatives should be investigated. FUNDING: Cancer Research UK.

Factors contributing to nurse resignation during COVID-19: A qualitative descriptive study.

AIMS: To explore and describe registered nurses' perceptions and experiences of work well-being extending from what inspired them to join the healthcare organization, what created a great day at work for them, through to what may have supported them to stay. DESIGN: Qualitative descriptive study. METHODS: Thirty-nine Australian nurses who resigned in 2021 from two metropolitan healthcare organizations in Victoria were interviewed in 2022, each for 30-60 min. The semi-structured interview transcripts were transcribed verbatim and analysed inductively and thematically. RESULTS: Four themes were constructed for each of the key research questions. Inspiration to join the organizations transpired through organizational reputation, recruitment experiences, right position and right time, fit and feel. A great day at work was created through relationships with colleagues, experiences with managers, adequate resourcing and delivering quality care. Factors contributing to nurses resigning included COVID-19, uncertainty of role, workload and rostering, and finally, not feeling supported, respected and valued. Factors that may have supported the nurses to stay included flexible work patterns and opportunities, improved workplace relationships, workload management and support, and supportive systems and environments. Cutting across these themes were five threads: (1) relationships, (2) communication, (3) a desire to learn and develop, (4) work-life balance and (5) providing quality patient care. CONCLUSIONS: Novel ways of working and supporting individuals, teams and organizations are needed to maintain and sustain nurses. The nurses' inspiration, what created a great day at work, and support needed to stay highlighted the importance of workplace initiatives to build nursing career pathways, provide equitable opportunities for professional development, workload and roster flexibility and implement professional relationship-enhancing actions to foster authentic civility. IMPACT: This study contributes an in-depth exploration of the perceptions and experiences of nurses who resigned from two healthcare organizations and provides a description of (1) what inspired these nurses to initially join the organization, (2) what they perceived created a great day at work for them, (3) the factors contributing to their resignation and (4) what may have supported them to stay. The reasons nurses resign from an organization were identified as complex and multi-factorial, with opportunities for promoting nursing career pathways, addressing equity in opportunities and implementing professional relationship-enhancing actions. These contributions add both context and opportunity to strengthen organizational initiatives to attract, sustain and retain nurses.

"Whilst you are here " Acceptability of providing advice about screening and early detection of other cancers as part of the breast cancer screening programme.

OBJECTIVES: This research aimed to assess women's willingness to receive advice about cervical and bowel cancer screening participation and advice on cancer symptom awareness when attending breast cancer screening. METHODS: Women (n = 322) aged 60-64 years, living in the United Kingdom, who had previously taken part in breast cancer screening were recruited via a market research panel. They completed an online survey assessing willingness to receive advice, the potential impact of advice on breast screening participation, prospective acceptability and preferences for mode and timing of advice. RESULTS: Most women would be willing to receive information about cervical (86%) and bowel cancer screening (90%) and early symptoms of other cancers (92%) at a breast cancer screening appointment. Those who were not up to date with cervical cancer screening were less willing. Prospective acceptability was high for all three forms of advice and was associated with willingness to receive advice. Women would prefer to receive advice through a leaflet (41%) or discussion with the mammographer (30%) either before the appointment (27%), at the appointment (44%) or with their results (22%). CONCLUSIONS: While there is high willingness and high acceptability towards using breast cancer screening as a teachable moment for advice about prevention and early detection of other cancers, some women find it unacceptable and this may reduce their likelihood of attending a breast screening appointment. PATIENT OR PUBLIC CONTRIBUTION: This study focused on gaining women's insights into potential future initiatives to encourage screening and early diagnosis of cancer. Members of the public were also involved in piloting the questionnaire.

Women's appraisal, interpretation and help-seeking for possible symptoms of breast and cervical cancer in South Africa: a qualitative study.

BACKGROUND: In South Africa, breast cancer is the most commonly diagnosed cancer and cervical cancer the leading cause of cancer mortality. Most cancers are diagnosed at a late-stage and following symptomatic presentation. The overall purpose of the study was to inform interventions aimed at improving timely diagnosis of breast and cervical cancer. METHODS: In-depth interviews were conducted with women with potential breast or cervical cancer symptoms from urban and rural South Africa. Participants were recruited from a community-based cross-sectional study on breast and cervical cancer awareness. Data were analysed using a thematic analysis approach. RESULTS: Eighteen women were interviewed (10 urban, 8 rural): the median age was 34.5 years (range 22-58). Most were unemployed, and five were HIV positive. Themes included impact and attribution of bodily changes; influence of social networks and health messaging in help-seeking; management of symptoms and help-seeking barriers. Breast changes were often attributed to manual activities or possible cancer. Women were often unsure how to interpret vaginal symptoms, attributing them to HIV, hormonal contraceptives, or partner infidelity. Concerns about cancer were based on health information from the radio, social networks, or from primary care providers. Prompt care seeking was triggered by impact of symptoms on personal lives. Rural women, especially with possible symptoms of cervical cancer, experienced challenges during help-seeking including judgmental attitudes of clinic staff. Most participants were skeptical of traditional medicine. CONCLUSIONS: This is the first study exploring interpretation of possible breast and cervical cancer symptoms at a community level in South Africa. The process of interpreting bodily changes, symptom attribution and help-seeking is complex and influenced by women's everyday life experiences. Timely diagnosis interventions should not only include cancer symptom awareness but also address individual, structural and health systems related barriers to care.

Impact of a novel home-based exercise intervention on health indicators in inactive premenopausal women: a 12-week randomised controlled trial.

PURPOSE: This study tested the hypothesis that a novel, audio-visual-directed, home-based exercise training intervention would be effective at improving cardiometabolic health and mental well-being in inactive premenopausal women. METHODS: Twenty-four inactive premenopausal women (39 ± 10 years) were randomly assigned to an audio-visual-directed exercise training group (DVD; n = 12) or control group (CON; n = 12). During the 12-week intervention period, the DVD group performed thrice-weekly training sessions of 15 min. Training sessions comprised varying-intensity movements involving multiplanar whole-body accelerations and decelerations (average heart rate (HR) = 76 ± 3% HRmax). CON continued their habitual lifestyle with no physical exercise. A series of health markers were assessed prior to and following the intervention. RESULTS: Following the DVD intervention, HDL cholesterol (pre: 1.83 ± 0.45, post: 1.94 ± 0.46 mmol/L) and mental well-being, assessed via the Warwick Edinburgh Mental Well-Being Scale, improved (P < 0.05). Conversely, [LDL cholesterol], [triglycerides], fasting [glucose], body composition and resting blood pressure and HR were unchanged following the DVD intervention (P > 0.05). There were no pre-post intervention changes in any of the outcome variables in the CON group (P > 0.05). CONCLUSION: The present study suggests that a novel, audio-visual-directed exercise training intervention, consisting of varied-intensity movements interspersed with spinal and lower limb mobility and balance tasks, can improve [HDL cholesterol] and mental well-being in premenopausal women. Therefore, home-based, audio-visual-directed exercise training (45 min/week) appears to be a useful tool to initiate physical activity and improve aspects of health in previously inactive premenopausal women.

Denture use and osteoradionecrosis following radiotherapy for head and neck cancer: A systematic review.

BACKGROUND: It is strongly recommended to extract teeth with poor prognosis in head and neck cancer (HaNC) patients prior starting treatment with radiotherapy to avoid need for extraction post-radiotherapy and prevent development of osteoradionecrosis (ORN). Dental extraction means that patients are often left with insufficient teeth leading to psychological problems and reducing their quality of life post-radiotherapy. Some clinicians do not advocate the use of dentures in HaNC patients claiming that dentures might lead to soft tissue irritation followed by ORN when constructed on irradiated jaws. AIMS: This systematic review aimed to investigate the existing evidence regarding the impact of denture use on the development of ORN in HaNC patients post-radiotherapy. METHODS: This systematic review followed the Preferred Reporting Item for Systematic Review and Meta-analyses (PRISMA) guideline. Three database systems were used: Ovid Medline, EMBASE and PsycINFO. PROSPERO was searched for ongoing or recently completed systematic reviews. The https://ClinicalTrials.gov was searched for ongoing or recently completed trials. The Joanna Briggs Institute critical appraisal tools were used to assess quality of studies being reviewed. RESULTS: Only three retrospective case-control studies were included. Numbers of participants included in the three studies are limited with incomparable types of mucosal dentures. None of the studies described the method of measurement of the exposure (denture use) in a standard, validated and reliable way. CONCLUSION: The three included studies suggested no link between denture use and development of ORN. However, very little evidence exists and the robustness of the studies is questionable. Well-powered studies are needed.

Do cognitive heuristics underpin symptom appraisal for symptoms of cancer?: A secondary qualitative analysis across seven cancers.

OBJECTIVES: To explore the evidence for cognitive heuristics or "rules of thumb" used within patients' reports of symptom appraisal and decisions to seek help for symptoms of cancer. METHODS: A secondary analysis of interviews from existing studies that explored symptom appraisal in patients who had sought help for potential symptoms of cancer. Transcripts from n = 50 in-depth interviews with patients referred with symptoms suspicious of cancer (pancreas, colorectal, oral, lung, melanoma, breast, and prostate) were re-analysed using a deductive thematic approach underpinned by the heuristics outlined in the Common Sense Model of Illness Self-regulation as set within the Model of Pathways to Treatment. RESULTS: The most dominant heuristic in patient reports was the Rate of change rule (ie, symptoms that are worsening, increasing, or have a sudden onset [rather than improving, stable or decreasing in number] are more likely to indicate illness). There was also support for the Duration rule, Pattern rule, Chronology rule, Severity (of interference) rule, Age-illness rule, Novelty rule, Similarity rule, Location rule, and Optimistic bias rule. There was a lack of evidence for the Prevalence and Stress-illness rules. CONCLUSIONS: People do appear to use heuristics to guide their appraisal of symptoms and their perceived need for healthcare. Heuristics may be an important aspect underlying symptom misinterpretation, thus making them key targets for interventions. For instance, campaigns could tackle cognitive biases rather than focusing on specific symptom awareness. Myth-busting messages could highlight that intermittent, mild symptoms, and symptoms that are not worsening can be signs of a serious health problem.

The Aarhus statement on cancer diagnostic research: turning recommendations into new survey instruments.

BACKGROUND: Over recent years there has been a growth in cancer early diagnosis (ED) research, which requires valid measurement of routes to diagnosis and diagnostic intervals. The Aarhus Statement, published in 2012, provided methodological guidance to generate valid data on these key pre-diagnostic measures. However, there is still a wide variety of measuring instruments of varying quality in published research. In this paper we test comprehension of self-completion ED questionnaire items, based on Aarhus Statement guidance, and seek input from patients, GPs and ED researchers to refine these questions. METHODS: We used personal interviews and consensus approaches to generate draft ED questionnaire items, then a combination of focus groups and telephone interviews to test comprehension and obtain feedback. A framework analysis approach was used, to identify themes and potential refinements to the items. RESULTS: We found that many of the questionnaire items still prompted uncertainty in respondents, in both routes to diagnosis and diagnostic interval measurement. Uncertainty was greatest in the context of multiple or vague symptoms, and potentially ambiguous time-points (such as 'date of referral'). CONCLUSIONS: There are limits on the validity of self-completion questionnaire responses, and refinements to the wording of questions may not be able to completely overcome these limitations. It's important that ED researchers use the best identifiable measuring instruments, but accommodate inevitable uncertainty in the interpretation of their results. Every effort should be made to increase clarity of questions and responses, and use of two or more data sources should be considered.

Correlating structural and energetic changes in glycine receptor activation.

Pentameric ligand-gated ion channels (pLGICs) mediate fast chemoelectrical transduction in the nervous system. The mechanism by which the energy of ligand binding leads to current-conducting receptors is poorly understood and may vary among family members. We addressed these questions by correlating the structural and energetic mechanisms by which a naturally occurring M1 domain mutation (α1(Q-26'E)) enhances receptor activation in homo- and heteromeric glycine receptors. We systematically altered the charge of spatially clustered residues at positions 19' and 24', in the M2 and M2-M3 linker domains, respectively, which are known to be critical to efficient receptor activation, on a background of α1(Q-26'E). Changes in the durations of single receptor activations (clusters) and conductance were used to determine interaction coupling energies, which we correlated with conformational displacements as measured in pLGIC crystal structures. Presence of the α1(Q-26'E) enhanced cluster durations and reduced channel conductance in homo- and heteromeric receptors. Strong coupling between α1(-26') and α1(19') across the subunit interface suggests an important role in receptor activation. A lack of coupling between α1(-26') and α1(24') implies that 24' mutations disrupt activation via other interactions. A similar lack of energetic coupling between α1(-26') and reciprocal mutations in the ß subunit suggests that this subunit remains relatively static during receptor activation. However, the channel effects of α1(Q-26'E) on α1ß receptors suggests at least one α1-α1 interface per pentamer. The coupling-energy change between α1(-26') and α1(19') correlates with a local structural rearrangement essential for pLGIC activation, implying it comprises a key energetic pathway in activating glycine receptors and other pLGICs.

Member Checking: A Tool to Enhance Trustworthiness or Merely a Nod to Validation?

The trustworthiness of results is the bedrock of high quality qualitative research. Member checking, also known as participant or respondent validation, is a technique for exploring the credibility of results. Data or results are returned to participants to check for accuracy and resonance with their experiences. Member checking is often mentioned as one in a list of validation techniques. This simplistic reporting might not acknowledge the value of using the method, nor its juxtaposition with the interpretative stance of qualitative research. In this commentary, we critique how member checking has been used in published research, before describing and evaluating an innovative in-depth member checking technique, Synthesized Member Checking. The method was used in a study with patients diagnosed with melanoma. Synthesized Member Checking addresses the co-constructed nature of knowledge by providing participants with the opportunity to engage with, and add to, interview and interpreted data, several months after their semi-structured interview.

Patterns and predictors of disclosure of a diagnosis of cancer.

BACKGROUND: The value of talking (i.e. disclosing ones innermost thoughts and feelings) has been recognised as playing an important role in helping people work through their difficulties. Although disclosing a diagnosis of cancer has been identified to be one of the hardest aspects of having the disease, relatively little is known about the extent to which people talk about their diagnosis of cancer. This study aimed to identify disclosure patterns among patients with cancer and to determine the factors associated with disclosure. METHODS: Patients (n = 120) who had received a diagnosis of either lung, colorectal or skin cancer completed a questionnaire assessing potential psychosocial predictors of disclosure. RESULTS: Results indicated that the majority of patients (95%) found it helpful to disclose information and did so to a variety of social targets, with the highest levels of disclosure being reported to medical personnel (38% talked 'very much'), followed by family members (24%) and then friends (12%). There were no differences in disclosure across cancer types, with the exception of patients with colorectal cancer who disclosed information more to nurses and other cancer patients. Men disclosed information more than women to some social targets. Dispositional openness (B = .233, p < 0.05) and treatment type (B = -.240, p < 0.01) were found to predict 13% of the variance in degree of disclosure. CONCLUSIONS: The results suggest that individual differences and social and clinical factors impact on disclosure and that medical professionals play an important role in the disclosure process.

The role of emotions in time to presentation for symptoms suggestive of cancer: a systematic literature review of quantitative studies.

BACKGROUND: Emotions may be important in patients' decisions to seek medical help for symptoms suggestive of cancer. OBJECTIVES: The aim of this systematic literature review was to examine quantitative literature on the influence of emotion on patients' help-seeking for symptoms suggestive of cancer. The objectives were to identify the following: (a) which types of emotions influence help-seeking behaviour, (b) whether these form a barrier or trigger for seeking medical help and (c) how the role of emotions varies between different cancers and populations. METHODS: We searched four electronic databases and conducted a narrative synthesis. Inclusion criteria were studies that reported primary, quantitative research that examined any emotion specific to symptom appraisal or help-seeking for symptoms suggestive of cancer. RESULTS: Thirty-three papers were included. The studies were heterogeneous in their methods and quality, and very few had emotion as the main focus of the research. Studies reported a limited range of emotions, mainly related to fear and worry. The impact of emotions appears mixed, sometimes acting as a barrier to consultation whilst at other times being a trigger or being unrelated to time to presentation. It is plausible that different emotions play different roles at different times prior to presentation. CONCLUSIONS: This systematic review provides some quantitative evidence for the role of emotions in help-seeking behaviour. However, it also highlighted widespread methodological, definition and design issues among the existing literature. The conflicting results around the role of emotions on time to presentation may be due to the lack of definition of each specific emotion.

Late effects in survivors of childhood CNS tumors treated on Head Start I and II protocols.

BACKGROUND: Due to the devastating late effects associated with cranial irradiation in young children with central nervous system (CNS) tumors, treatment for these patients has evolved to include the use of intensive chemotherapy to either avoid or postpone irradiation. While survival outcomes have improved, late effects data in survivors treated on such regimens are needed. OBJECTIVE: This multi-institutional study comprehensively describes late effects in survivors treated on the Head Start I/II protocols. METHODS: Survivors of CNS tumors treated on Head Start I/II protocols were enrolled. Late effects data were collected using a validated parent-report questionnaire. Social, emotional, and behavioral functioning and quality of life were assessed using parent-report on the BASC-2 and CHQ-PF50 questionnaires. RESULTS: Twenty-one survivors (medulloblastoma = 13, sPNET = 4, ATRT = 1, ependymoma = 3) were enrolled. Ten (48%) were irradiation-free. Late effects (frequency; median time of onset since diagnosis) included ≥ grade III hearing loss (67%; 3.9 years), vision (67%; 4.1 years), hypothyroidism (33%; 4 years), growth hormone (GH) deficiency (48%; 4.7 years), dental (52%; 7.1 years), and no cases of secondary leukemia. Irradiation-free (vs. irradiated) survivors reported low rates of hypothyroidism (0/10 vs. 7/11; P = 0.004) and GH deficiency (2/10 vs. 8/11; P = 0.03). The BASC-2 and CHQPF-50 mean composite scores were within average ranges relative to healthy comparison norms. Neither age at diagnosis nor irradiation was associated with these scores. CONCLUSIONS: Irradiation-free Head Start survivors have lower risk of hypothyroidism and GH deficiency. Secondary leukemias are not reported. With extended follow-up, survivors demonstrate quality of life, social, emotional, and behavioral functioning within average ranges.

"Notification! You May Have Cancer." Could Smartphones and Wearables Help Detect Cancer Early?

This viewpoint paper considers the authors' perspectives on the potential role of smartphones, wearables, and other technologies in the diagnosis of cancer. We believe that these technologies could be valuable additions in the pursuit of early cancer diagnosis, as they offer solutions to the timely detection of signals or symptoms and monitoring of subtle changes in behavior that may otherwise be missed. In addition to signal detection, technologies could assist symptom interpretation and guide and facilitate access to health care. This paper aims to provide an overview of the scientific rationale as to why these technologies could be valuable for early cancer detection, as well as outline the next steps for research and development to drive investigation into the potential for smartphones and wearables in this context and optimize implementation. We draw attention to potential barriers to successful implementation, including the difficulty of the development of signals and sensors with sufficient utility and accuracy through robust research with the target group. There are regulatory challenges; the potential for innovations to exacerbate inequalities; and questions surrounding acceptability, uptake, and correct use by the intended target group and health care practitioners. Finally, there is potential for unintended consequences on individuals and health care services including unnecessary anxiety, increased symptom burden, overinvestigation, and inappropriate use of health care resources.

Risk-Adapted Breast Screening for Women at Low Predicted Risk of Breast Cancer: An Online Discrete Choice Experiment.

BACKGROUND: A risk-stratified breast screening program could offer low-risk women less screening than is currently offered by the National Health Service. The acceptability of this approach may be enhanced if it corresponds to UK women's screening preferences and values. OBJECTIVES: To elicit and quantify preferences for low-risk screening options. METHODS: Women aged 40 to 70 y with no history of breast cancer took part in an online discrete choice experiment. We generated 32 hypothetical low-risk screening programs defined by 5 attributes (start age, end age, screening interval, risk of dying from breast cancer, and risk of overdiagnosis), the levels of which were systematically varied between the programs. Respondents were presented with 8 choice sets and asked to choose between 2 screening alternatives or no screening. Preference data were analyzed using conditional logit regression models. The relative importance of attributes and the mean predicted probability of choosing each program were estimated. RESULTS: Participants (N = 502) preferred all screening programs over no screening. An older starting age of screening, younger end age of screening, longer intervals between screening, and increased risk of dying had a negative impact on support for screening programs (P < 0.01). Although the risk of overdiagnosis was of low relative importance, a decreased risk of this harm had a small positive impact on screening choices. The mean predicted probabilities that risk-adapted screening programs would be supported relative to current guidelines were low (range, 0.18 to 0.52). CONCLUSIONS: A deintensified screening pathway for women at low risk of breast cancer, especially one that recommends a later screening start age, would run counter to women's breast screening preferences. Further research is needed to enhance the acceptability of offering less screening to those at low risk of breast cancer. HIGHLIGHTS: Risk-based breast screening may involve the deintensification of screening for women at low risk of breast cancer.Low-risk screening pathways run counter to women's screening preferences and values.Longer screening intervals may be preferable to a later start age.Work is needed to enhance the acceptability of a low-risk screening pathway.

Understanding GPs' referral decisions for younger patients with symptoms of cancer: a qualitative interview study.

BACKGROUND: Cancer incidence increases with age, so some clinical guidelines include patient age as one of the criteria used to decide whether a patient should be referred through the urgent suspected cancer (USC) pathway. Little is known about how strictly GPs adhere to these age criteria and what factors might influence their referral decisions for younger patients. AIM: To understand GPs' clinical decision making for younger patients with concerning symptoms who do not meet the age criteria for USC referral. DESIGN AND SETTING: Qualitative study using in-depth, semi-structured interviews with GPs working in surgeries across England. METHOD: Participants (n = 23) were asked to recall consultations with younger patients with cancer symptoms, describe factors influencing their clinical decisions, and discuss their overall attitude to age thresholds in cancer referral guidelines. A thematic analysis guided by the Framework approach was used to identify recurring themes. RESULTS: GPs' decision making regarding younger patients was influenced by several factors, including personal experiences, patients' views and behaviour, level of clinical concern, and ability to bypass system constraints. GPs weighted potential benefits and harms of a referral outside guidelines both on the patient and the health system. If clinical concern was high, GPs used their knowledge of local systems to ensure patients were investigated promptly even when not meeting the age criteria. CONCLUSION: While most GPs interpret age criteria flexibly and follow their own judgement and experience when making clinical decisions regarding younger patients, system constraints may be a barrier to timely investigation.

The Connection Between Resistance Training, Climbing Performance, and Injury Prevention.

BACKGROUND: Climbing is an intricate sport composed of various disciplines, holds, styles, distances between holds, and levels of difficulty. In highly skilled climbers the potential for further strength-specific adaptations to increase performance may be marginal in elite climbers. With an eye on the upcoming 2024 Paris Olympics, more climbers are trying to maximize performance and improve training strategies. The relationships between muscular strength and climbing performance, as well as the role of strength in injury prevention, remain to be fully elucidated. This narrative review seeks to discuss the current literature regarding the effect of resistance training in improving maximal strength, muscle hypertrophy, muscular power, and local muscular endurance on climbing performance, and as a strategy to prevent injuries. MAIN BODY: Since sport climbing requires exerting forces against gravity to maintain grip and move the body along the route, it is generally accepted that a climber`s absolute and relative muscular strength are important for climbing performance. Performance characteristics of forearm flexor muscles (hang-time on ledge, force output, rate of force development, and oxidative capacity) discriminate between climbing performance level, climbing styles, and between climbers and non-climbers. Strength of the hand and wrist flexors, shoulders and upper limbs has gained much attention in the scientific literature, and it has been suggested that both general and specific strength training should be part of a climber`s training program. Furthermore, the ability to generate sub-maximal force in different work-rest ratios has proved useful, in examining finger flexor endurance capacity while trying to mimic real-world climbing demands. Importantly, fingers and shoulders are the most frequent injury locations in climbing. Due to the high mechanical stress and load on the finger flexors, fingerboard and campus board training should be limited in lower-graded climbers. Coaches should address, acknowledge, and screen for amenorrhea and disordered eating in climbers. CONCLUSION: Structured low-volume high-resistance training, twice per week hanging from small ledges or a fingerboard, is a feasible approach for climbers. The current injury prevention training aims to increase the level of performance through building tolerance to performance-relevant load exposure and promoting this approach in the climbing field.