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.

Great expectations? GPs' estimations of time required to deliver BMJ's '10 minute consultations'.

OBJECTIVES: To estimate the time required to undertake consultations according to BMJ's 10-minute consultation articles.To quantify the tasks recommended in 10-minute consultation articles.To determine if, and to what extent, the time required and the number of tasks recommended have increased over the past 22 years. DESIGN: Analysis of estimations made by four general practitioners (GPs) of the time required to undertake tasks recommended in BMJ's 10-minute consultation articles. SETTING: Primary care in the UK. PARTICIPANTS: Four doctors with a combined total of 79 years of experience in the UK National Health Service following qualification as GPs. MAIN OUTCOME MEASURES: Median minimum estimated consultation length (the estimated time required to complete tasks recommended for all patients) and median maximum estimated consultation length (the estimated time required to complete tasks recommended for all patients and the additional tasks recommended in specific circumstances). Minimum, maximum and median consultation lengths reported for each year and for each 5-year period. RESULTS: Data were extracted for 44 articles. The median minimum and median maximum estimated consultation durations were 15.7 minutes (IQR 12.6-20.9) and 28.4 minutes (IQR 22.4-33.8), respectively. A median of 17 tasks were included in each article. There was no change in durations required over the 22 years examined. CONCLUSIONS: The approximate times estimated by GPs to deliver care according to 10-minute consultations exceed the time available in routine appointments. '10 minute consultations' is a misleading title that sets inappropriate expectations for what GPs can realistically deliver in their routine consultations. While maintaining aspirations for high-quality care is appropriate, practice recommendations need to take greater account of the limited time doctors have to deliver routine care.

Exploring individuals' experiences of hope in mental health recovery: Having a sense of possibility.

WHAT IS KNOWN ON THE SUBJECT?: Mental health recovery is acknowledged as a process of transformation and a way of living a meaningful life despite the presence of mental ill-health. Experiencing hope has been articulated as intrinsic to service users experience of a meaningful life. The social construction of mental illness and stigma are recognised as barriers to experiencing hope. Mental health professionals have responsibility to positively influence the experience of hope. WHAT THIS ARTICLE ADDS TO EXISTING KNOWLEDGE?: Individuals in mental health recovery experience hope as the embodiment of having a sense of possibility in life. Individuals' sense of possibility in life is underpinned by a belief and confidence that they will be ok. This belief is informed by 'feeling safe' and 'feeling connected'. This article generates an increased understanding of the dynamic relational processes that unpin hope generation. WHAT ARE THE IMPLICATIONS FOR MENTAL HEALTH NURSING PRACTICE?: Mental health stakeholders need to be more explicit in exploring 'hope' and uncovering its therapeutic potential. Mental health practitioners need skill in enabling individuals to feel safe and connected while understanding its role in cultivating hope. ABSTRACT: Introduction The experience of hope is widely acknowledged and empirically supported as a key catalyst of mental health recovery. Lived experience accounts of hope are critical in accessing data on what has been termed a nebulous concept. This article is the second presentation of data from this study and provides further context to improve understanding of hope and optimise its therapeutic potential. Aim To explore how individuals describe and make sense of their experience of hope in mental health recovery. Method A qualitative Interpretative Phenomenological Analysis (IPA) approach was used. Results This article explores the second of three experiential group themes: Hope as Having a sense of possibility 'I will be ok' which is informed by feeling safe and feeling connected. Discussion Having a sense of possibility is easier when basic needs are met and people feel connected to self, others and the universe. The use of creativity as a pathway to the imagination is positively experienced. The role of family, friends and healthcare professionals as hope reservoirs is critical. Finally, the framing of medication use emerged as significant. Implications for Practice It is important that all stakeholders appreciate the interpretation of hope and use the understanding and skill in harnessing its therapeutic potential.

Multimodal assessment of mitochondrial function in Parkinson's disease.

The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = -0.55, P = 0.0016), higher mitochondrial counts (r = -0.72, P < 0.0001) and higher lysosomal counts (r = -0.62, P = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r = 0.37, P = 0.0319) and lysosomal counts (r = 0.48, P = 0.0044) as well as lower MMP in both short (r = -0.52, P = 0.0016) and long (r = -0.47, P = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r = 0.47, P = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease.

Site-Specific Dolasynthen Antibody-Drug Conjugates Exhibit Consistent Pharmacokinetic Profiles across a Wide Range of Drug-to-Antibody Ratios.

Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.

The implementation of artificial intelligence in radiology: a narrative review of patient perspectives.

Aim: To synthesise research on the view of the public and patients of the use of artificial intelligence (AI) in radiology investigations. Methods: A literature review of narrative synthesis of qualitative and quantitative studies that reported views of the public and patients toward the use of AI in radiology. Results: Only seven studies related to patient and public views were retrieved, suggesting that this is an underexplored area of research. Two broad themes, of confidence in the capabilities of AI, and the accountability and transparency of AI, were identified. Conclusions: Both optimism and concerns were expressed by participants. Transparency in the implementation of AI, scientific validation, clear regulation and accountability were expected. Combined human and AI interpretation of imaging was strongly favoured over AI acting autonomously. The review highlights the limited engagement of the public in the adoption of AI in a radiology setting. Successful implementation of AI in this field will require demonstrating not only adequate accuracy of the technology, but also its acceptance by patients.

Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer.

Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.

The effects of a two-week neuromuscular intervention on biopsychosocial variables in people with patellofemoral pain: an observational study.

Introduction: Patellofemoral pain (PFP) is common and predominately affects active populations. Altered biomechanics and psychosocial variables have been reported in people with PFP, but the effects of neuromuscular exercise on these variables is unknown. We aimed to investigate changes in biopsychosocial measures following a two-week neuromuscular intervention in people with PFP. Materials and Methods: We measured pain (visual analogue scale), function (Kujala), activity level (Tegner), psychological well-being (Orebro), lower-limb isometric strength (handheld dynamometry), three-dimensional (3D) lower limb kinematics, and surface electromyography (sEMG), in people with PFP. 3D lower-limb kinematics and sEMG were synchronously sampled during step-up, step-down, and overground running. All measures were repeated after participants had completed a two-week neuromuscular intervention consisting of three exercises completed once per day, five days per week. Results: 18 participants completed pre/post testing (60% females, mean age 30.6 years ±7.0, height 173.4cm ±10.4, mass 70.2kg ±12.4, symptom duration 39.0 months ±58.8), with three of 21 participants lost to follow-up. Across all clinical measures (muscle onsets, muscle activation and kinematics), the 95% bootstrapped confidence intervals (CI) of the mean difference contained the null hypothesis following the two-week neuromuscular intervention, indicating no significant differences. Conclusion: A two-week neuromuscular intervention did not change biomechanical or psychosocial measures in people with PFP. Interventions with a longer duration or greater load magnitude are required to fully evaluate the biopsychosocial mechanisms of effect for exercise in people with PFP.

Defining the road map to a UK national lung cancer screening programme.

Lung cancer screening with low-dose CT was recommended by the UK National Screening Committee (UKNSC) in September, 2022, on the basis of data from trials showing a reduction in lung cancer mortality. These trials provide sufficient evidence to show clinical efficacy, but further work is needed to prove deliverability in preparation for a national roll-out of the first major targeted screening programme. The UK has been world leading in addressing logistical issues with lung cancer screening through clinical trials, implementation pilots, and the National Health Service (NHS) England Targeted Lung Health Check Programme. In this Policy Review, we describe the consensus reached by a multiprofessional group of experts in lung cancer screening on the key requirements and priorities for effective implementation of a programme. We summarise the output from a round-table meeting of clinicians, behavioural scientists, stakeholder organisations, and representatives from NHS England, the UKNSC, and the four UK nations. This Policy Review will be an important tool in the ongoing expansion and evolution of an already successful programme, and provides a summary of UK expert opinion for consideration by those organising and delivering lung cancer screenings in other countries.