A conceptual framework for cautious escalation of anticancer treatment: How to optimize overall benefit and obviate the need for de-escalation trials.

BACKGROUND: The developmental workflow of the currently performed phase 1, 2 and 3 cancer trial stages lacks essential information required for the determination of the optimal efficacy threshold of new anticancer regimens. Due to this there is a serious risk of overdosing and/or treating for an unnecessary long time, leading to excess toxicity and a higher financial burden for society. But often post-approval de-escalation trials for dose-optimization and treatment de-intensification are not performed due to failing resources and time. Therefore, the developmental workflow needs to be restructured toward cautious systemic cancer treatment escalation, in order to guarantee optimal efficacy and sustainability. METHODS: In this manuscript we discuss opportunities to produce the information needed for cautious escalation, based on models of cancer growth and cancer kill kinetics as well as exploratory biomarkers, for the purpose of designing the optimal phase 3 superiority trial. Subsequently, we compare the sample size needed for a phase 3 superiority trial, followed by a necessary de-escalation trial with the sample size needed for a multi-arm phase 3 trial with intervention arms of differing intensity. All essential items are structured within a Framework for Cautious Escalation (FCE). The discussion uses illustrations from the breast cancer setting, but aims to be applicable for all cancers. RESULTS: The FCE is a promising model of clinical development in oncology to prevent overtreatment and associated issues, especially with regard to the number of repetitive treatment cycles. It will hopefully increase the relevance and success rate of clinical trials, to deliver improved patient-centric outcomes.

Hospital-wide healthcare-associated carbapenemase-producing Enterobacterales outbreak: risks of electric floor scrubbers in catering facilities and kitchens.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are associated with poor clinical outcomes and can spread rapidly in healthcare settings. Environmental reservoirs are increasingly recognized as playing an important part in some nosocomial outbreaks. AIM: To describe the investigation and control of a CPE outbreak, lasting several years, across two separate hospital sites within one organization. METHODS: Investigation of multiple ward-level CPE cross-transmissions with a number of sporadic cases. Environmental sampling of ward environments, catering facilities and electric floor scrubbers was undertaken. FINDINGS: Eleven patients over a 19-month period were identified as carrying healthcare-associated New Delhi metallo-beta-lactamase (NDM)-producing Enterobacter cloacae, and a further patient carried NDM Escherichia coli. E. cloacae isolates were indistinguishable on pulsed-field gel electrophoresis typing, supporting acquisition with a single point source. Environmental sampling found contamination of the electric floor scrubbers used for cleaning the hospital catering facilities and in the associated toilets. Standard outbreak response measures achieved control of ward outbreaks. Sporadic cases and hospital-wide cross-transmission were controlled after interventions on the central food-handling unit and by decommissioning affected floor scrubbers. Electric floor scrubbers were found to have the potential to disperse Gram-negative bacteria into the surrounding environment under experimental conditions. CONCLUSION: This outbreak report demonstrates that catering facilities and kitchens can be involved in widespread healthcare outbreaks of enteric organisms. This is also the first report of the potential role of electric floor scrubbers in causing significant environmental contamination with CPE which may indicate a role in nosocomial transmission.

Effectiveness of full Pulpotomy compared with Root canal treatment in managing teeth with signs and symptOms indicative of irreversible pulpitis: a protocol for prospectiVE meta-analysis of individual participant data of linked randomised clinical trials (PROVE).

BACKGROUND: Full pulpotomy has been proposed as an alternative to root canal treatment in teeth with signs and symptoms indicative of irreversible pulpitis (IRP), but the evidence is limited, relying on underpowered studies with a high risk of bias. The aim of this study is to conduct a prospective meta-analysis (PMA) of individual participant data of a series of individual randomised trials to provide robust evidence on the clinical and cost-effectiveness of pulpotomy compared with root canal treatment. METHODS: Individual participant data will be obtained from a series of randomised trials designed and conducted by a consortium of multi-national investigators with an interest in vital pulp treatment. These individualised trials will be conducted using a specified protocol, defined outcomes, and outcome measures. Ten parallel-group randomised trials currently being conducted in 10 countries will provide data from more than 500 participants. The primary outcome is a composite measure defined as (1) the absence of pain indicative of IRP, (2) the absence of signs and symptoms indicative of acute or chronic apical periodontitis, and (3) the absence of radiographic evidence of failure including radiolucency or resorption. Individual participant data will be obtained, assessed, and checked for quality by two independent reviewers prior to the PMA. Pooled estimates on treatment effects will be generated using a 2-stage meta-analysis approach. The first stage involves a standard regression analysis in each trial to produce aggregate data on treatment effect estimates followed by an inverse variance weighted meta-analysis to combine these aggregate data and produce summary statistics and forest plots. Cost-effectiveness analysis based on the composite outcome will be undertaken as a process evaluation to evaluate treatment fidelity and acceptability by patients and dentists. RESULTS: The research question and trial protocol were developed and approved by investigators in all 10 sites. All sites use shared resources including study protocols, data collection forms, participant information leaflets, and consent forms in order to improve flow, consistency, and reproducibility. Each site obtained its own Institutional Review Board approval, and trials were registered in appropriate open access platforms. Patient recruitment has started in most sites, as of July 2023. DISCUSSION: PMA offers a rigorous, flexible, and efficient methodology to answer this important research question and provide results with improved generalisability and external validity compared with traditional trials and retrospective meta-analyses. The results of this study will have implications for both the delivery of clinical practice and structured clinical guidelines' development. TRIAL REGISTRATION: PROSPERO CRD42023446809. Registered on 08 February 2023.

Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML.

The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.

Expression dynamics of metalloproteinases during mandibular bone formation: association with Myb transcription factor.

As the dentition forms and becomes functional, the alveolar bone is remodelled. Metalloproteinases are known to contribute to this process, but new regulators are emerging and their contextualization is challenging. This applies to Myb, a transcription factor recently reported to be involved in bone development and regeneration. The regulatory effect of Myb on Mmps expression has mostly been investigated in tumorigenesis, where Myb impacted the expression of Mmp1, Mmp2, Mmp7, and Mmp9. The aim of this investigation was to evaluate the regulatory influence of the Myb on Mmps gene expression, impacting osteogenesis and mandibular bone formation. For that purpose, knock-out mouse model was used. Gene expression of bone-related Mmps and the key osteoblastic transcription factors Runx2 and Sp7 was analysed in Myb knock-out mice mandibles at the survival limit. Out of the metalloproteinases under study, Mmp13 was significantly downregulated. The impact of Myb on the expression of Mmp13 was confirmed by the overexpression of Myb in calvarial-derived cells causing upregulation of Mmp13. Expression of Mmp13 in the context of other Mmps during mandibular/alveolar bone development was followed in vivo along with Myb, Sp7 and Runx2. The most significant changes were observed in the expression of Mmp9 and Mmp13. These MMPs and MYB were further localized in situ by immunohistochemistry and were identified in pre/osteoblastic cells as well as in pre/osteocytes. In conclusion, these results provide a comprehensive insight into the expression dynamics of bone related Mmps during mandibular/alveolar bone formation and point to Myb as another potential regulator of Mmp13.

A qualitative evaluation of a telehealth healthy lifestyle intervention for people with serious mental illness.

OBJECTIVES: There are high levels of nutritional and metabolic, cardiovascular, and respiratory tract diseases among people diagnosed with serious mental illness (SMI). Consequently, we developed a pragmatic, affordable nutritional and exercise intervention: Choices4Health. Due to the COVID-19 pandemic, we modified this intervention so it could be delivered online. The aim of this study was to explore the experience of participating in online Choices4Health, in a real-world clinical setting, from the perspectives of service users with SMI. METHODS: The study aim was addressed using thematic analysis. Service users who had attended online Choices4Health, received a SMI diagnosis (defined as a schizophrenia spectrum disorder or an affective disorder), and resided in a South Dublin catchment were invited to participate. Nine participants were purposefully sampled. Semi-structured interviews were conducted by telephone. Data analysis was guided by thematic analysis procedures. RESULTS: Six themes were generated: Being ready and not overburdened (Engagement); Gaining knowledge and implementing it (Learning and doing); Viewing the intervention as appropriate and effective (Targeted impact); Being at home with others online (Belonging); Having a positive affective attitude towards the intervention (Feeling); and Perceiving problems with intervention delivery (Recommended change). CONCLUSIONS: Findings suggest that online Choices4Health is, broadly speaking, acceptable from a service user perspective, but that further refinement is required to address specific issues participants identified. These relate to follow-up or programme extension, technology access, in-person contact preference, and participant inclusion criteria. Further research is required into online Choices4Health efficacy, innovations to reduce digital exclusion, and managing group dynamics in telehealth interventions.

A portable primary-standard level graphite calorimeter for absolute dosimetry in clinical pencil beam scanning proton beams.

Objective. To report the use of a portable primary standard level graphite calorimeter for direct dose determination in clinical pencil beam scanning proton beams, which forms part of the recommendations of the proposed Institute of Physics and Engineering in Medicine (IPEM) Code of Practice (CoP) for proton therapy dosimetry.Approach. The primary standard proton calorimeter (PSPC) was developed at the National Physical Laboratory (NPL) and measurements were performed at four clinical proton therapy facilities that use pencil beam scanning for beam delivery. Correction factors for the presence of impurities and vacuum gaps were calculated and applied, as well as dose conversion factors to obtain dose to water. Measurements were performed in the middle of 10 × 10 × 10 cm3homogeneous dose volumes, centred at 10.0, 15.0 and 25.0 g·cm-2depth in water. The absorbed dose to water determined with the calorimeter was compared to the dose obtained using PTW Roos-type ionisation chambers calibrated in terms of absorbed dose to water in60Co applying the recommendations in the IAEA TRS-398 CoP.Main results.The relative dose difference between the two protocols varied between 0.4% and 2.1% depending on the facility. The reported overall uncertainty in the determination of absorbed dose to water using the calorimeter is 0.9% (k= 1), which corresponds to a significant reduction of uncertainty in comparison with the TRS-398 CoP (currently with an uncertainty equal or larger than 2.0% (k= 1) for proton beams).Significance. The establishment of a purpose-built primary standard and associated CoP will considerably reduce the uncertainty of the absorbed dose to water determination and ensure improved accuracy and consistency in the dose delivered to patients treated with proton therapy and bring proton reference dosimetry uncertainty in line with megavoltage photon radiotherapy.

COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain.

OBJECTIVE: Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a multiplatform strategy. METHODS: Brain tissues from coronavirus disease 2019 (COVID-19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT-qPCR), and immunodetection methods. RESULTS: SARS-CoV-2 RNA was detected in the CNS of 4 patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11ß, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 compared to ODC patients (p < 0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p < 0.05). INTERPRETATION: COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. ANN NEUROL 2023;94:531-546.

A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.

Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem (ES) cells, which can be adapted to any ES cell derived cell type. We show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals terminating at signalling responsive transcription factors. Our work provides an important resource for studies of hematopoietic specification and highlights the mechanisms of how and where extrinsic signals program a cell type-specific chromatin landscape driving hematopoietic differentiation.

Psychiatric and psychosocial morbidity 1 year after epilepsy surgery.

OBJECTIVES: There is a high rate of psychiatric comorbidity in patients with epilepsy. However, the impact of surgical treatment of refractory epilepsy on psychopathology remains under investigation. We aimed to examine the impact of epilepsy surgery on psychopathology and quality of life at 1-year post-surgery in a population of patients with epilepsy refractory to medication. METHODS: This study initially assessed 48 patients with refractory epilepsy using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), the Hospital Anxiety and Depression Scale (HADS) and the Quality of Life in Epilepsy Inventory 89 (QOLIE-89) on admission to an Epilepsy Monitoring Unit (EMU) as part of their pre-surgical assessment. These patients were again assessed using the SCID-I, QOLIE-89 and HADS at 1-year follow-up post-surgery. RESULTS: There was a significant reduction in psychopathology, particularly psychosis, following surgery at 1-year follow-up (p < 0.021). There were no new cases of de novo psychosis and surgery was also associated with a significant improvement in the quality of life scores (p < 0.001). CONCLUSIONS: This study demonstrates the impact of epilepsy surgery on psychopathology and quality of life in a patient population with refractory surgery. The presence of a psychiatric illness should not be a barrier to access surgical treatment.

Socio-demographic and clinical characteristics of migrants to Ireland presenting with a first episode of psychosis.

OBJECTIVES: When presenting with a first episode of psychosis (FEP), migrants can have different demographic and clinical characteristics to the native-born population and this was examined in an Irish Early Intervention for Psychosis service. METHODS: All cases of treated FEP from three local mental health services within a defined catchment area were included. Psychotic disorder diagnoses were determined using the SCID and symptom and functioning domains were measured using validated and reliable measures. RESULTS: From a cohort of 612 people, 21.1% were first-generation migrants and there was no difference in the demographic characteristics, diagnoses, symptoms or functioning between migrants and those born in the Republic of Ireland, except that migrants from Africa presented with less insight. Of those admitted, 48.6% of admissions for migrants were involuntary compared to 37.7% for the native-born population (p = 0.09). CONCLUSIONS: First-generation migrants now make up a significant proportion of people presenting with a FEP to an Irish EI for psychosis service. Broadly the demographic and clinical characteristics of migrants and those born in the Republic of Ireland are similar, except for less insight in migrants from Africa and a trend for a higher proportion of involuntary admissions in the total migrant group.

A treatment planning comparison of photon stereotactic ablative radiotherapy and proton beam therapy for the re-irradiation of pelvic cancer recurrence.

BACKGROUND: Patients who experience a pelvic cancer recurrence in or near a region that received initial radiotherapy, typically have few options for treatment. Organs at risk (OAR) have often reached their dose constraint limits leaving minimal dose remaining for standard re-irradiation (reRT). However, photon based stereotactic ablative radiotherapy (SABR) has been utilised for reRT with promising initial results although meeting OAR constraints can be challenging. Proton beam therapy (PBT) could offer an advantage. MATERIALS AND METHODS: SABR plans used for treatment for ten pelvic reRT patients were dosimetrically compared to PBT plans retrospectively planned using the same CT and contour data. PBT plans were created to match the CTV dose coverage of SABR treatment plans with V100% ≥95%. An 'as low as reasonably achievable' approach was taken to OAR tolerances with consideration of OAR dose from the initial radiation (using equivalent dose in 2 Gy fractions). RESULTS: Dosimetric comparison of relevant OAR statistics showed a decrease in OAR dose using PBT over SABR in all patients, with equivalent target coverage. The largest statistically significant reduction was seen for the colon D0.5 cm3 with a median reduction from 13.1 Gy to 5.9 Gy. There were statistically significant dose reductions in the median dose to small bowel, sacral plexus and cauda equina. CONCLUSION: PBT has the potential for significant dose reductions for OARs in the pelvic reRT setting compared to SABR. However, it remains unclear if the magnitude of these OAR dose reductions will translate into clinical benefit.

Sleep disturbance: a potential target to improve symptoms and quality of life in those living with psychosis.

Sleep has been shown to impact on both physical and mental health, and sleep problems present a considerable burden for individuals and society. There appears to be a complex bidirectional relationship between sleep disturbance and psychiatric symptoms, each potentially influencing the other. In particular, sleep disorders have been associated with more severe symptoms and are predictive of relapse in those with psychotic disorders. This article discusses the relationship between psychosis and insomnia, sleep apnoea, nightmares, circadian rhythm abnormalities and the impact of medications on these relationships. We also discuss the clinical implications of the relationship between sleep disturbance and psychotic disorders along with potential targets for intervention.

Psychotic-like experiences? Trajectories and typologies of hallucinations and delusions from early adolescence to early adulthood in a population-based sample of Irish youth.

OBJECTIVES: Hallucinations and delusions that occur in the absence of a psychotic disorder are common in children and adolescents. Longitudinal phenomenological studies exploring these experiences are notably lacking. The objective of the current paper was to explore the phenomenology and characteristics of hallucinations and delusions from early adolescence to early adulthood. METHODS: Participants were 17 young people aged 18-21 years from the general population, all of whom had a history of childhood hallucinations and/or delusions. Longitudinal data on the phenomenological characteristics and attributions of reported hallucinatory and delusional phenomena spanning nine years were explored using content analysis. RESULTS: Hallucinatory and delusional phenomena were transient for two-thirds of the sample. The remaining one-third reported reoccurring hallucinatory and delusional phenomena into early adulthood. In those, two typologies were identified: (1) Paranormal typology and (2) Pathological typology. The former was characterised by hallucinatory and delusional phenomena that were exclusively grounded in subcultural paranormal or spiritual belief systems and not a source of distress. The latter was characterised by delusion-like beliefs that were enmeshed with individuals' mood states and a source of distress. The perceived source, the subcultural context and how young people appraised and integrated their experiences differentiated the Paranormal and Pathological typologies. CONCLUSIONS: Not all hallucinatory and delusion-like experiences are psychotic-like in nature. To reliably differentiate between pathological and non-pathological hallucinations and delusions, assessments need to explore factors including the phenomenology of individuals' experiences, how people make sense and appraise them, and the subcultural contexts within which they are experienced.

White matter tracts that overlap with the thalamus and the putamen are protected against multiple sclerosis pathology.

BACKGROUND: The thalamus and the putamen are highly connected hubs implicated in multiple sclerosis (MS) pathology. It remains unclear if white matter (WM) tracts, which pass through them, have a different susceptibility to MS pathology, and if so, if their impact on disability predominates over that exerted by disease in other WM tracts. We hypothesized that WM tracts connected to and passing through these hubs (subsequently termed hub+ tracts) would be more susceptible to MS-related pathology than tracts that do not pass through them (hub- tracts) due to retrograde and anterograde distant degeneration. Thus, we compared the lesion load and neurite orientation dispersion and density imaging (NODDI) derived metrics between hub+ and hub- tracts and assessed the relationship between these MRI metrics and those of physical impairment. METHODS: Eighteen patients (mean age of 45.5 years, 12 females) had 3 Tesla MRI consisting of T1-weighted and T2-weighted Fluid Attenuated Inversion Recovery (FLAIR), and NODDI from which the orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (IVF) were derived. Forty-nine WM tracts, i.e., 12 hub+ and 37 hub- tracts, were segmented out. Exploratory analyses of the differences in lesion burden, whole tract and normal appearing WM (NAWM) NODDI metrics were carried out between the two types of tracts using a Mann-Whitney U test. Correlations with physical impairment, quantified using the expanded disability status scale (EDSS) and timed 25-foot walk (T25FW) test were assessed using Spearman correlation analyses. RESULTS: Hub- tracts had larger T1- (p<0.001) and T2-lesion (p<0.001) volumes; lower ODI (p<0.001), NDI (p<0.001) and higher IVF (p = 0.020) in comparison to hub+ tracts. Measures of tissue injury in hub+ tracts correlated with those of clinical disability, though less strongly than in hub- tracts. CONCLUSIONS: Contrary to our hypothesis, our exploratory pilot study results suggest that WM tracts that overlap with the thalamus and the putamen have a lower degree of lesional and non-lesional tissue injury, suggesting a protective role of the hubs against MS pathology or a higher degree of vulnerability of those not passing through hub stations. We also show a weaker association between disability impairment and hub+ pathology, compared to that in hub- tracts. Our findings point to a potential role of disease location in relation to hubs as guidance for treatment personalization in MS.

Phenomenological characteristics and explanations of unusual perceptual experiences, thoughts and beliefs in a population sample of early adolescents.

OBJECTIVES: Often referred to as psychotic experiences, unusual perceptual experiences, thoughts and beliefs (UPTBs) are not uncommon in youth populations. Phenomenological studies of these experiences are lacking. This study aimed to (1) describe the phenomenological characteristics of UPTBs in a sample of young adolescents and (2) explore how young people made sense of those experiences. METHODS: Participants were 53 young people aged 11-13 years from a population-based study of mental health. All met criteria for UPTBs following clinical interviews as part of the study. Documentary data on UPTBs in the form of transcribed notes, recorded during clinical interviews, were analysed using content analysis. Data on UPTBs were coded, organised into categorical themes and quantified using descriptive statistics. Qualitative themes on how participants made sense of their experiences were identified. RESULTS: Participants reported UPTBs across four domains: auditory verbal, auditory non-verbal, non-auditory perceptual experiences and unusual thoughts and beliefs. UPTBs were phenomenologically rich and diverse. Young people sought to make sense of their experiences in multiple ways: normalising them, externalising them by attributing them to paranormal entities and distancing them from psychiatric explanations. Uncertainty about the source of UPTBs was identified as a superordinate theme. CONCLUSION: Findings from this study offer new insights into the phenomenological qualities and characteristics of UPTBs in young adolescents. They also reveal that early adolescents may not make sense of their experiences within a psychiatric framework. These findings highlight the need to develop a more phenomenologically sensitive and nuanced approach to studying UPTBs in young people.

A protocol for the Development of Core Outcome Sets for Endodontic Treatment modalities (COSET): an international consensus process.

BACKGROUND: The outcome of endodontic treatment is generally assessed using a range of patient and clinician-centred, non-standardised clinical and radiographic outcome measures. This makes it difficult to synthesise evidence for systematic analysis of the literature and the development of clinical guidelines. Core outcome sets (COS) represent a standardised list of outcomes that should be measured and reported in all clinical studies in a particular field. Recently, clinical researchers and guideline developers have focussed on the need for the integration of a patient-reported COS with clinician-centred measures. This study aims to develop a COS that includes both patient-reported outcomes and clinician-centred measures for various endodontic treatment modalities to be used in clinical research and practice. METHODS: To identify reported outcomes (including when and how they are measured), systematic reviews and their included clinical studies, which focus on the outcome of endodontic treatment and were published between 1990 and 2020 will be screened. The COSs will be defined by a consensus process involving key stakeholders using semi-structured interviews and an online Delphi methodology followed by an interactive virtual consensus meeting. A heterogeneous group of key 'stakeholders' including patients, general dental practitioners, endodontists, endodontic teachers, clinical researchers, students and policy-makers will be invited to participate. Patients will establish, via interactive interviews, which outcomes they value and feel should be included in a COS. In the Delphi process, other stakeholders will be asked to prioritise outcomes identified from the literature and patient interviews and will have the opportunity at the end of the first round to add outcomes that are not included, but which they consider relevant. Feedback will be provided in the second round, when participants will be asked to prioritise the list again. If consensus is reached, the remaining outcomes will be discussed at an online meeting and agreement established via defined consensus rules of outcome inclusion. If consensus is not reached after the second round, a third round will be conducted with feedback, followed by the online meeting. Following the identification of a COS, we will proceed to identify how and when these outcomes are measured. DISCUSSION: Using a rigorous methodology, the proposed consensus process aims to develop a COS for endodontic treatment that will be relevant to stakeholders. The results of the study will be shared with participants and COS users. To increase COS uptake, it will also be actively shared with clinical guideline developers, research funders and the editors of general dental and endodontology journals. TRIAL REGISTRATION: COMET 1879. 21 May 2021.

Introduction of paediatric laparoscopic cholecystectomy in Scotland: a national review of incidence, outcomes and training implications.

BACKGROUND: We present a national data series to determine the incidence, outcomes and training opportunities for laparoscopic cholecystectomy among children <16yrs in Scotland as performed by paediatric surgeons. METHODS: A retrospective cohort study was performed reviewing laparoscopic cholecystectomy performed at the three children's hospitals in Scotland. Using the National Records Scotland Database mid-year population estimates; age and sex specific annual incidence rates of laparoscopic cholecystectomy were calculated between 1998-2015. Trends in the observed case mix were tested using univariate linear regression and students t-test. RESULTS: Between 1998-2015; 141 paediatric laparoscopic cholecystectomies were performed. The annual rate of cholecystectomy increased from 0.10/100,000 to 0.88/100,000 (p = 0.069). Sex specific incidences were identified; 0.00-0.90/100,000 (p = 0.098) in girls and 0.20-0.86/100,000 in boys (p = 0.28). Cholecystectomy was more frequent in girls (63%; p = 0.04). No major complications, defined as common bile duct injury or mortality were identified. Overall; 75% of cases were performed by consultants (n = 17 consultants, median = 5 cases, p < 0.05) and 25% by trainees. CONCLUSION: We have demonstrated that despite a low national case load (8 laparoscopic cholecystectomies per year) paediatric surgeons have been able to perform laparoscopic cholecystectomy safely without major morbidity.

Physical health among patients with common mental health disorders in primary care in Europe: a scoping review.

INTRODUCTION: Mental disorders are increasingly common among adults in both the developed and developing world and are predicted by the WHO to be the leading cause of disease burden by 2030. Many common physical conditions are more common among people who also have a common mental disorder. This scoping review aims to examine the current literature about the prevention, identification and treatment of physical problems among people with pre-existing mental health disorders in primary care in Europe. METHODS: The scoping review framework comprised a five-stage process developed by Arksey & O'Malley (2005). The search process was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Both quantitative and qualitative studies were included, with no restriction on study design. RESULTS: The initial search identified 299 studies, with a further 28 added from the hand-search (total n = 327) of which 19 were considered relevant to the review research question and included for full analysis. Depression was the mental health condition most commonly studied (nine studies), followed by depression and anxiety (seven studies), with three studies examining any mental disorder. Eleven studies examined the effects of various interventions to address physical and mental comorbidity, with the most commonly studied intervention being collaborative care. CONCLUSIONS: With just 19 studies meeting our criteria for inclusion, there is clearly a paucity of research in this area. Further research is essential in order to understand the pathophysiological mechanisms underlying the association between mental disorders and chronic conditions.