A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

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.

Best practice guide for patellofemoral pain based on synthesis of a systematic review, the patient voice and expert clinical reasoning.

OBJECTIVE: Define a best practice guide for managing people with patellofemoral pain (PFP). METHODS: A mixed-methods convergent segregated synthesis of meta-analysed data with a thematic analysis of semistructured interviews and focus groups. Agreement between subproject results informed the strength of clinical recommendation for interventions eligible for best practice recommendation. DATA SOURCES: Medline, Web of Science, Scopus, reference lists and citation tracking; semistructured interviews of people with PFP; and semistructured interviews and focus groups with clinical experts. ELIGIBILITY CRITERIA: High-quality (PEDro scale >7) randomised controlled trials (RCTs) were retained for efficacy estimation using meta-analysis. People with PFP were required to have experienced an episode of care in the past 6 months and clinical experts were required to have>5 years of clinical experience alongside direct involvement in research. RESULTS: Data from 65 high-quality RCTs involving 3796 participants informed 11 meta-analyses of interventions. Interviews with 12 people with PFP led to 3 themes and interviews with 19 clinical experts led to 4 themes. These were further explored in three clinical expert focus groups. Best practice for PFP should first involve understanding a patient's background risk factors, their reasons for seeking care, greatest symptoms, and physical impairments, to inform treatment selection. Synthesis led to six distinct interventions being recommended. Knee-targeted±hip-targeted exercise therapy underpinned by education should be delivered, with additional supporting interventions such as prefabricated foot orthoses, manual therapy, movement/running retraining, or taping decided on and tailored to a patient's needs and preferences. CONCLUSION: A best practice guide based on a synthesis of three data streams recommends that exercise therapy and education be delivered as the primary intervention for people with PFP. Prescription of other supporting interventions should be aligned with the individual patient's particular presentation following a thorough assessment.

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.

Incidence trends for twelve cancers in younger adults-a rapid review.

Many cancer referral guidelines use patient's age as a key criterium to decide who should be referred urgently. A recent rise in the incidence of colorectal cancer in younger adults has been described in high-income countries worldwide. Information on other cancers is more limited. The aim of this rapid review was to determine whether other cancers are also increasing in younger age groups, as this may have important implications for prioritising patients for investigation and referral. We searched MEDLINE, Embase and Web of Science for studies describing age-related incidence trends for colorectal, bladder, lung, oesophagus, pancreas, stomach, breast, ovarian, uterine, kidney and laryngeal cancer and myeloma. 'Younger' patients were defined based on NICE guidelines for cancer referral. Ninety-eight studies met the inclusion criteria. Findings show that the incidence of colorectal, breast, kidney, pancreas, uterine cancer is increasing in younger age groups, whilst the incidence of lung, laryngeal and bladder cancer is decreasing. Data for oesophageal, stomach, ovarian cancer and myeloma were inconclusive. Overall, this review provides evidence that some cancers are increasingly being diagnosed in younger age groups, although the mechanisms remain unclear. Cancer investigation and referral guidelines may need updating in light of these trends.

Characterizing the molecular etiology of arthrogryposis multiplex congenita in patients with LGI4 mutations.

Disruption of axon-glia interactions in the peripheral nervous system has emerged as a major cause of arthrogryposis multiplex congenita (AMC), a condition characterized by multiple congenital postural abnormalities involving the major joints. Several genes crucially important to the biology of Schwann cells have now been implicated with AMC. One such gene is LGI4 which encodes a secreted glycoprotein. LGI4 is expressed and secreted by Schwann cells and binds its receptor ADAM22 on the axonal membrane to drive myelination. Homozygous mutations in LGI4 or ADAM22 results in severe congenital hypomyelination and joint contractures in mice. Recently bi-allelic LGI4 loss of function mutations has been described in three unrelated families with severe AMC. Two individuals in a fourth, non-consanguineous family were found to be compound heterozygous for two LGI4 missense mutations. It is not known how these missense mutations affect the biology of LGI4. Here we investigated whether these missense mutations affected the secretion of the protein, its ADAM22 binding capacity, or its myelination-promoting function. We demonstrate that the mutations largely affect the progression of the mutant protein through the endomembrane system resulting in severely reduced expression. Importantly, binding to ADAM22 and myelination-promoting activity appear largely unaffected, suggesting that treatment with chemical chaperones to improve secretion of the mutant proteins might prove beneficial.

Identification of patients with potential palliative care needs: A systematic review of screening tools in primary care.

BACKGROUND: Despite increasing evidence of the benefits of early access to palliative care, many patients do not receive palliative care in a timely manner. A systematic approach in primary care can facilitate earlier identification of patients with potential palliative care needs and prompt further assessment. AIM: To identify existing screening tools for identification of patients with advanced progressive diseases who are likely to have palliative care needs in primary healthcare and evaluate their accuracy. DESIGN: Systematic review (PROSPERO registration number CRD42019111568). DATA SOURCES: Cochrane, MEDLINE, Embase and CINAHL were searched from inception to March 2019. RESULTS: From 4,127 unique articles screened, 25 reported the use or development of 10 screening tools. Most tools use prediction of death and/or deterioration as a proxy for the identification of people with potential palliative care needs. The tools are based on a wide range of general and disease-specific indicators. The accuracy of five tools was assessed in eight studies; these tools differed significantly in their ability to identify patients with potential palliative care needs with sensitivity ranging from 3% to 94% and specificity ranging from 26% to 99%. CONCLUSION: The ability of current screening tools to identify patients with advanced progressive diseases who are likely to have palliative care needs in primary care is limited. Further research is needed to identify standardised screening processes that are based not only on predicting mortality and deterioration but also on anticipating the palliative care needs and predicting the rate and course of functional decline. This would prompt a comprehensive assessment to identify and meet their needs on time.

Cesarean delivery: Trend in indications over three decades within a major city hospital network.

INTRODUCTION: The cesarean delivery rate has been increasing globally in recent decades. The reasons for this are complex and subject to ongoing debate. Investigation of the indications for cesarean delivery and how these have changed over an extended period of time could provide insight into the reasons for changing obstetric practice. Our objective was to explore contributing factors to the increasing rate of cesarean delivery by examining the incidence of and indications for cesarean delivery over the past three decades at our institutions. MATERIAL AND METHODS: We conducted a retrospective observational study of all cesarean deliveries, from 24 weeks' gestational age onwards, within an inner-city hospital network in Sydney, Australia, between August 1989 and December 2016. The primary outcome measures were the rates of and indications for emergency and planned cesarean delivery. We also examined our data within the Robson 10-Group Classification system. RESULTS: There were 147 722 births over the study period, with 37 309 cesarean deliveries for an overall rate of 25.3%. The rate of cesarean delivery increased from 18.7% in 1989-1994 (8.7% emergency, 10% planned) to 30.4% in 2010-2016 (11.4% emergency, 19% planned). Emergency cesarean delivery for slow progress increased from 3.4% to 5.5% of all births (a relative increase of 62%) and other emergency cesareans mainly performed for suspected intrapartum fetal compromise increased from 5.2% to 5.6% (a relative increase of 8%). Previous uterine surgery (predominantly cesarean section) was the largest contributor to the increase in planned procedures from 3.8% to 9.0% of all births, and 29% of all cesarean deliveries. Primary cesarean delivery for planned antenatal fetal indications, previous pregnancy problems, multiple gestation and maternal choice all increased substantially in combined rate from 0.7% to 4.9%. Cesarean rates in Robson groups 6, 7 and 8 (term breech and multiple gestations) increased most over time. CONCLUSIONS: The increased rate of cesarean delivery is mainly attributable to a greater number of procedures performed for slow progress in labor, breech presentation or repeat cesarean section.

Facilitating educational experiences in a paediatric handover: A qualitative case study.

AIM: Handovers have been established as a valuable educational tool; nevertheless, a paucity of literature exists evaluating contributors to the educational experience. Our study aimed to investigate participants' educational experiences based on a paediatric handover, and the facilitators and barriers towards teaching and learning during this process. METHODS: A case study was conducted using semi-structured interviews. Data were collected exploring participants' perspectives of their educational experiences within a handover. An inductive, thematic content analysis was performed to identify key themes, assisted by nVivo software. RESULTS: Four key themes contributing to the educational experience within a handover were identified related to the organisation of a handover, team dynamics, teaching and learning moments and tensions between the clinical tasks and education. A model is proposed aimed at optimising education within this context. CONCLUSIONS: Our study identified contributing factors towards the educational experiences at handovers and provides strategies to optimise these.

Outcomes of induction of labour in nulliparous women at 38 to 39 weeks pregnancy by clinical indication: An observational study.

BACKGROUND: Knowledge of the outcomes of induction of labour for different indications is sparse. AIMS: To describe the mode of birth and other outcomes for nulliparous women induced at 38-39 weeks gestational age by indication for induction of labour. MATERIAL AND METHODS: This was a retrospective observational study in a tertiary referral hospital, and a metropolitan teaching hospital in Sydney. The study population was nulliparous women with induction of labour at 38 or 39 completed weeks of pregnancy and a singleton, cephalic presenting baby planning a vaginal birth, from 2009 to 2016. The indication for induction of labour was classified into 12 groups. Mode of birth and other maternal and perinatal outcomes were described in each group, for women who spontaneously laboured at 38 or 39 weeks, and for women who gave birth from 40 completed weeks onward. The main outcome measure was mode of birth. RESULTS: There were 3330 women with induction of labour at 38 or 39 weeks gestation. Rates of vaginal birth varied widely, ranging from 54% when the indication for induction was suspected large fetus, to 82% when the indication was suspected fetal compromise, and was 74% overall. Indications for caesarean delivery also varied by indication for induction. Among women giving birth ≥40 weeks gestational age, 75% had a vaginal birth. CONCLUSIONS: In nulliparous women, rates of vaginal birth following induction of labour at 38 or 39 weeks gestation vary widely according to the indication for induction. These data are useful for antenatal counselling.

The association between induction of labour at 38 to 39 weeks pregnancy and indication for caesarean delivery: An observational study.

BACKGROUND: Induction of labour is associated with a reduction in caesarean delivery, but the mechanism of action and which groups of women might benefit remain unknown. AIMS: To assess the association between induction of labour at 38-39 weeks pregnancy, and caesarean delivery: (i) overall; (ii) for slow progress in labour; and (iii) for suspected fetal compromise. MATERIAL AND METHODS: Retrospective observational study in two Sydney hospitals from 2009 to 2016, among nulliparous women with induction of labour at 38 or 39 completed weeks pregnancy and a singleton, cephalic presenting fetus. The comparator was all planned vaginal births beyond 39(+1/7) weeks, whether or not labour was induced. Binary and multinomial multiple logistic regressions adjusting for multiple confounders were performed. RESULTS: There were 2388 and 15 259 women in the study and comparison groups respectively. Induction of labour was associated with caesarean delivery overall only for women <25 years of age (adjusted odds ratio 1.63; 95% CI 1.17-2.27) and was not associated with caesarean delivery for slow progress. Induction of labour was positively associated with increased caesarean delivery for suspected fetal compromise among young women (<30 years), with the association weakening as maternal age increased. The association between induction of labour and caesarean delivery was different for slow progress compared with suspected compromise (P = 0.005). CONCLUSIONS: Induction of labour has different effects on the likelihood of caesarean delivery for slow progress and for suspected fetal compromise. Women <30 years of age are at higher risk of caesarean delivery for suspected fetal compromise, potentially due to uterine hyperstimulation.

General practitioners' perceptions of irritable bowel syndrome: a Q-methodological study.

Background: Irritable bowel syndrome (IBS) is a common disorder that imposes a significant burden upon societies, health care and quality of life, worldwide. While a diverse range of patient viewpoints on IBS have been explored, the opinions of the GPs they ideally need to develop therapeutic partnerships with are less well defined. Objective: To explore how GPs perceive IBS, using Q-methodology, which allows quantitative interpretation of qualitative data. Design and Setting: A Q-methodological study of GPs in Leeds, UK. Method: Thirty-three GPs completed an online Q-sort in which they ranked their level of agreement with 66 statements. Factor analysis of the Q-sorts was performed to determine the accounts that predominated in understandings of IBS. Ten of the GPs were interviewed in person and responses to the statements recorded to help explain the accounts. Results: Analysis yielded one predominant account shared by all GPs-that IBS was a largely psychological disorder. This account overshadowed a debate represented by a minority, polarized between those who viewed IBS as almost exclusively psychological, versus those who believed IBS had an organic basis, with a psychological component. The overwhelming similarity in responses indicates that all GPs shared a common perspective on IBS. Interviews suggested degrees of uncertainty and discomfort around the aetiology of IBS. Conclusion: There was overwhelming agreement in the way GPs perceived IBS. This contrasts with the range of patient accounts of IBS and may explain why both GPs and their patients face difficult negotiations in achieving therapeutic relationships.

Problems and solutions for patients with fibromyalgia: Building new helping relationships.

AIM: The aim of this study was to identify the main biological, psychological and sociological problems and potential solutions for patients diagnosed with fibromyalgia by use of Group Problem-Solving Therapy. BACKGROUND: Group Problem-Solving Therapy is a technique for identifying and solving problems, increasing assertiveness, self-esteem and eliminating negative thoughts. DESIGN: Qualitative phenomenological interpretive design: Group Problem-Solving Therapy sessions conducted with patients suffering fibromyalgia were studied; participants recruited via the Rheumatology Department at a general hospital and associations in Catalonia, Spain with sessions conducted in nearby university setting. METHODS: The study included 44 people diagnosed with fibromyalgia (43 female, 1 male) from 6 Group Problem-Solving Therapy sessions. Data collected from March-June 2013. A total of 24 sessions were audio recorded, all with prior informed consent. Data were transcribed and then analysed in accordance with established methods of inductive thematic analysis, via a process of reduction to manage and classify data. FINDINGS: Five themes were identified: (1) Current problems are often related to historical trauma; (2) There are no "one size fits all" solutions; (3) Fibromyalgia is life-changing; (4) Fibromyalgia is widely misunderstood; (5) Statistically Significant impacts on physical, psychological and social are described. CONCLUSION: The majority of patients' problems were associated with their previous history and the onset of fibromyalgia; which may be related to trauma in adolescence, early adulthood or later. The solutions provided during the groups appeared to be accepted by the participants. These findings can improve the self-management of fibromyalgia patients by helping to enhance adaptive behaviours and incorporating the female gender approach.

Repression of inflammasome by Francisella tularensis during early stages of infection.

Francisella tularensis is an important human pathogen responsible for causing tularemia. F. tularensis has long been developed as a biological weapon and is now classified as a category A agent by the Centers for Disease Control because of its possible use as a bioterror agent. F. tularensis represses inflammasome; a cytosolic multi-protein complex that activates caspase-1 to produce proinflammatory cytokines IL-1ß and IL-18. However, the Francisella factors and the mechanisms through which F. tularensis mediates these suppressive effects remain relatively unknown. Utilizing a mutant of F. tularensis in FTL_0325 gene, this study investigated the mechanisms of inflammasome repression by F. tularensis. We demonstrate that muted IL-1ß and IL-18 responses generated in macrophages infected with F. tularensis live vaccine strain (LVS) or the virulent SchuS4 strain are due to a predominant suppressive effect on TLR2-dependent signal 1. Our results also demonstrate that FTL_0325 of F. tularensis impacts proIL-1ß expression as early as 2 h post-infection and delays activation of AIM2 and NLRP3-inflammasomes in a TLR2-dependent fashion. An enhanced activation of caspase-1 and IL-1ß observed in FTL_0325 mutant-infected macrophages at 24 h post-infection was independent of both AIM2 and NLRP3. Furthermore, F. tularensis LVS delayed pyroptotic cell death of the infected macrophages in an FTL_0325-dependent manner during the early stages of infection. In vivo studies in mice revealed that suppression of IL-1ß by FTL_0325 early during infection facilitates the establishment of a fulminate infection by F. tularensis. Collectively, this study provides evidence that F. tularensis LVS represses inflammasome activation and that F. tularensis-encoded FTL_0325 mediates this effect.

Effect of localizer radiograph on radiation dose associated with automatic exposure control: human cadaver and patient study.

PURPOSE: To evaluate the effect of localizing radiograph on computed tomography (CT) radiation dose associated with automatic exposure control with a human cadaver and patient study. MATERIALS AND METHODS: Institutional review board approved the study with a waiver of informed consent. Two chest CT image series with fixed tube current and combined longitudinal-angular automatic exposure control (AEC) were acquired in a human cadaver (64-year-old man) after each of the 8 combinations of localizer radiographs (anteroposterior [AP], AP lateral, AP-posteroanterior [PA], lateral AP, lateral PA, PA, PA-AP, and PA lateral). Applied effective milliampere second, volume CT dose index (CTDIvol) and image noise were recorded for all 24-image series. Volume CT dose indexes were also recorded in 20 patients undergoing chest and abdominal CT after PA and PA-lateral radiographs with the use of AEC. Data were analyzed using analysis of variance and linear correlation tests. RESULTS: With AEC, the CTDIvol fluctuates with the number and projection of localizer radiographs (P < 0.0001). Lowest CTDIvol values are seen when 2 orthogonal localizer radiographs are acquired, whereas highest values are seen when single PA or AP-PA projection localizer radiographs are acquired for planning (P < 0.0001). In 20 patients, CT scanning with AEC after acquisition of 2 orthogonal projection localizer radiographs was associated with significant reduction in radiation dose compared to PA projection radiographs alone (P < 0.0001). CONCLUSIONS: When scanning with AEC, acquisition of 2 orthogonal localizer radiographs is associated with lower CTDIvol compared to a single localizer radiograph.

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.

Beam Position Projection Algorithms in Proton Pencil Beam Scanning.

Beam position uncertainties along the beam trajectory arise from the accelerator, beamline, and scanning magnets (SMs). They can be monitored in real time, e.g., through strip ionization chambers (ICs), and treatments can be paused if needed. Delivery is more reliable and accurate if the beam position is projected from monitored nozzle parameters to the isocenter, allowing for accurate online corrections to be performed. Beam position projection algorithms are also used in post-delivery log file analyses. In this paper, we investigate the four potential algorithms that can be applied to all pencil beam scanning (PBS) nozzles. For some combinations of nozzle configurations and algorithms, however, the projection uses beam properties determined offline (e.g., through beam tuning or technical commissioning). The best algorithm minimizes either the total uncertainty (i.e., offline and online) or the total offline uncertainty in the projection. Four beam position algorithms are analyzed (A1-A4). Two nozzle lengths are used as examples: a large nozzle (1.5 m length) and a small nozzle (0.4 m length). Three nozzle configurations are considered: IC after SM, IC before SM, and ICs on both sides. Default uncertainties are selected for ion chamber measurements, nozzle entrance beam position and angle, and scanning magnet angle. The results for other uncertainties can be determined by scaling these results or repeating the error propagation. We show the propagation of errors from two locations and the SM angle to the isocenter for all the algorithms. The best choice of algorithm depends on the nozzle length and is A1 and A3 for the large and small nozzles, respectively. If the total offline uncertainty is to be minimized (a better choice if the offline uncertainty is not stable), the best choice of algorithm changes to A1 for the small nozzle for some hardware configurations. Reducing the nozzle length can help to reduce the gantry size and make proton therapy more accessible. This work is important for designing smaller nozzles and, consequently, smaller gantries. This work is also important for log file analyses.

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.