PAX1 methylation as a robust predictor: developing and validating a nomogram for assessing endocervical curettage (ECC) necessity in human papillomavirus16/18-positive women undergoing colposcopy.

OBJECTIVE: The major challenge in routine endocervical curettage (ECC) among Human Papillomavirus (HPV) 16/18-positive patients is that only a small fraction benefit. Nevertheless, current reported models often overestimate the validity and necessity of ECC, making it difficult to improve benefits for patients. This research hypothesized that assessing paired boxed gene 1 methylation levels (PAX1m) and clinical characteristics could enhance the predictive accuracy of detecting additional high-grade squamous intraepithelial lesions or worse (HSIL +) through ECC that were not identified by colposcopy-directed biopsy (CDB). METHODS: Data from 134 women with HPV16/18 positivity undergoing CDB and ECC between April 2018 and April 2022 were collected and analyzed. Quantitative methylation-specific polymerase chain reaction (qMSP) was utilized to measure PAX1m, expressed as ΔCp. Univariate and multivariate regression analyses were conducted to screen variables and select predictive factors. A nomogram was constructed using multivariate logistic regression to predict additional HSIL + detected by ECC. The discrimination, calibration, and clinical utility of the nomogram were evaluated using receiver operating characteristic curves (ROC) and the calibration plot. RESULTS: Age (odds ratio [OR], 5.654; 95% confidence interval [CI], 1.131-37.700), cytology (OR, 24.978; 95% CI, 3.085-540.236), and PAX1 methylation levels by grade (PAX1m grade) (OR, 7.801; 95% CI, 1.548-44.828) were independent predictive factors for additional detection of HSIL + by ECC. In HPV16/18-positive women, the likelihood of additional detection of HSIL + through ECC increased with the severity of cytological abnormalities, peaking at 43.8% for high-grade cytological lesions. Moreover, when cytological findings indicated low-grade lesions, PAX1 methylation levels were positively correlated with the additional detection of HSIL + by ECC (P value < 0.001). A nomogram prediction model was developed (area under curve (AUC) = 0.946; 95% CI, 0.901-0.991), demonstrating high sensitivity (90.9%) and specificity (90.5%) at the optimal cutoff point of 107. Calibration analysis confirmed the model's strong agreement between predicted and observed probabilities. CONCLUSION: The clinical nomogram presented promising predictive performance for the additional detection of HSIL + through ECC among women with HPV16/18 infection. PAX1 methylation level could serve as a valuable tool in guiding individualized clinical decisions regarding ECC for patients with HPV 16/18 infection, particularly in cases of low-grade cytological findings.

Unravelling the molecular landscape of endometrial cancer subtypes: insights from multi-omics analysis.

BACKGROUND: Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multi-omics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes. METHODS: Two-sample Mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and non-endometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types. RESULTS: We identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and non-endometrioid EC, and 125 causal relationships between plasma proteins and non-endometrioid EC were observed. Substantial differences were observed between endometrioid and non-endometrioid histological types of EC at both the metabolite and protein levels. We identified 7 overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and 6 overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in non-endometrioid subtype and network analysis of above proteins and metabolites to identify coregulated nodes. CONCLUSIONS: Our findings observed substantial differences between endometrioid and non-endometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.

Treatment Options for Early Stage Inoperable Breast Cancer: Cryoablation or Radiotherapy?

Background: Surgical removal of the tumour is the gold standard treatment for early stage invasive breast cancer. However, with a global ageing population, a larger number of diagnoses are occurring in women with comorbidities that render them unsuitable for surgery. Hence, it is of interest to explore alternative treatment strategies for this group of women. Summary: Our narrative review aims to explore two such techniques, cryoablation and external beam radiotherapy, providing a brief summary of the evidence behind each technique. Following this, we discuss which groups of patients would gain the most benefit from each technique. Factors favouring the use of radiotherapy include patients with larger tumours, more superficial tumours, and those with less well-demarcated tumours where there is uncertainty regarding tumour extent. Meanwhile, patients who may benefit more from cryoablation include those who desire a smaller number of treatment sessions, have concerns regarding cosmesis and skin pigmentation, or who have relative contraindications to radiotherapy such as scleroderma, systemic lupus erythematosus, reduced lung function, or cardiac comorbidities. Key Messages: Continued advancements in both cryoablation and radiotherapy technologies are taking place, in tandem with imaging technologies enabling greater certainty in tumour detection and delineation. These factors will help increase local control rates in this group of non-operable early stage breast cancer patients. Through this review, we hope to aid in the clinical decision-making process regarding the selection and referral of patients for each treatment.

Population incidence and associated mortality of urinary tract infection in people living with dementia.

OBJECTIVES: Urinary tract infections (UTIs) frequently cause hospitalisation and death in people living with dementia (PLWD). We examine UTI incidence and associated mortality among PLWD relative to matched controls and people with diabetes and investigate whether delayed or withheld treatment further impacts mortality. METHODS: Data were extracted for n = 2,449,814 people aged ≥ 50 in Wales from 2000-2021, with groups matched by age, sex, and multimorbidity. Poisson regression was used to estimate incidences of UTI and mortality. Cox regression was used to study the effects of treatment timing. RESULTS: UTIs in dementia (HR=2.18, 95 %CI [1.88-2.53], p < .0) and diabetes (1.21[1.01-1.45], p = .035) were associated with high mortality, with the highest risk in individuals with diabetes and dementia (both) (2.83[2.40-3.34], p < .0) compared to matched individuals with neither dementia nor diabetes. 5.4 % of untreated PLWD died within 60 days of GP diagnosis-increasing to 5.9 % in PLWD with diabetes. CONCLUSIONS: Incidences of UTI and associated mortality are high in PLWD, especially in those with diabetes and dementia. Delayed treatment for UTI is further associated with high mortality.

Targeted non-invasive brain stimulation boosts attention and modulates contralesional brain networks following right hemisphere stroke.

Right hemisphere stroke patients frequently present with a combination of lateralised and non-lateralised attentional deficits characteristic of the neglect syndrome. Attentional deficits are associated with poor functional outcome and are challenging to treat, with non-lateralised deficits often persisting into the chronic stage and representing a common complaint among patients and families. In this study, we investigated the effects of non-invasive brain stimulation on non-lateralised attentional deficits in right-hemispheric stroke. In a randomised double-blind sham-controlled crossover study, twenty-two patients received real and sham transcranial Direct Current Stimulation (tDCS) whilst performing a non-lateralised attentional task. A high definition tDCS montage guided by stimulation modelling was employed to maximise current delivery over the right dorsolateral prefrontal cortex, a key node in the vigilance network. In a parallel study, we examined brain network response to this tDCS montage by carrying out concurrent fMRI during stimulation in healthy participants and patients. At the group level, stimulation improved target detection in patients, reducing overall error rate when compared with sham stimulation. TDCS boosted performance throughout the duration of the task, with its effects briefly outlasting stimulation cessation. Exploratory lesion analysis indicated that response to stimulation was related to lesion location rather than volume. In particular, reduced stimulation response was associated with damage to the thalamus and postcentral gyrus. Concurrent stimulation-fMRI revealed that tDCS did not affect local connectivity but influenced functional connectivity within large-scale networks in the contralesional hemisphere. This combined behavioural and functional imaging approach shows that brain stimulation targeted to surviving tissue in the ipsilesional hemisphere improves non-lateralised attentional deficits following stroke. This effect may be exerted via contralesional network effects.

ENIGMA's simple seven: Recommendations to enhance the reproducibility of resting-state fMRI in traumatic brain injury.

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field.

Triage method for endometrial biopsy in postmenopausal women: a multicenter retrospective cohort study.

OBJECTIVE: To identify the optimal triage procedure for endometrial biopsies in postmenopausal women. METHODS: The clinical information of 470 postmenopausal women with endometrial biopsy results and postmenopausal bleeding (PMB) and/or transvaginal ultrasonography (TVU) abnormalities were collected at the gynecology departments of four general hospitals from March 2021 to March 2022. In the validation cohort, 112 women with TVU abnormalities who underwent endometrial biopsy at Xiangya hospital between May 2022 and May 2023 were enrolled. The endpoint was the final diagnosis based on hysteroscopy reports and biopsy pathology results. The sensitivity, specificity, positive predictive value, and negative predictive value were compared among the three triage methods. A nomogram prediction model was developed and validated. RESULTS: Referring women with TVU abnormalities for endometrial biopsy identified 100% malignant/premalignant lesions despite low specificity (19.7%). Among women with measurable endometrial thickness (ET), we suggest that the ET cutoff value for biopsy referral should be ≥4 mm. The PMB (odds ratio [OR], 3.241; 95% confidence interval [CI], 1.073-9.789), diabetes (OR, 10.915; 95% CI, 3.389-35.156), and endometrial thickness (OR, 1.277; 95% CI, 1.156-1.409) were independent predictive factors for endometrial (pre)malignancy. A nomogram prediction model was constructed (area under curve [AUC] = 0.802, 95% CI: 0.715 to 0.889). The ideal cutoff point was 22.5, with a sensitivity of 100.0% and a specificity of 15.7%. The external validation achieved an AUC of 0.798 (95% CI, 0.685-0.911). CONCLUSIONS: It was possible to refer all postmenopausal women with TVU abnormity (ET ≥ 4 mm or other abnormal findings) for endometrial biopsy. Among women with TVU abnormalities, a nomogram was constructed, and a score greater than 22.5 suggested the need for referral for endometrial biopsy, while a score less than 22.5 suggested that regular follow-up was required, further improving the triage procedure.

Multicohort cross-sectional study of cognitive and behavioural digital biomarkers in neurodegeneration: the Living Lab Study protocol.

INTRODUCTION AND AIMS: Digital biomarkers can provide a cost-effective, objective and robust measure for neurological disease progression, changes in care needs and the effect of interventions. Motor function, physiology and behaviour can provide informative measures of neurological conditions and neurodegenerative decline. New digital technologies present an opportunity to provide remote, high-frequency monitoring of patients from within their homes. The purpose of the living lab study is to develop novel digital biomarkers of functional impairment in those living with neurodegenerative disease (NDD) and neurological conditions. METHODS AND ANALYSIS: The Living Lab study is a cross-sectional observational study of cognition and behaviour in people living with NDDs and other, non-degenerative neurological conditions. Patients (n≥25 for each patient group) with dementia, Parkinson's disease, amyotrophic lateral sclerosis, mild cognitive impairment, traumatic brain injury and stroke along with controls (n≥60) will be pragmatically recruited. Patients will carry out activities of daily living and functional assessments within the Living Lab. The Living Lab is an apartment-laboratory containing a functional kitchen, bathroom, bed and living area to provide a controlled environment to develop novel digital biomarkers. The Living Lab provides an important intermediary stage between the conventional laboratory and the home. Multiple passive environmental sensors, internet-enabled medical devices, wearables and electroencephalography (EEG) will be used to characterise functional impairments of NDDs and non-NDD conditions. We will also relate these digital technology measures to clinical and cognitive outcomes. ETHICS AND DISSEMINATION: Ethical approvals have been granted by the Imperial College Research Ethics Committee (reference number: 21IC6992). Results from the study will be disseminated at conferences and within peer-reviewed journals.

Using home monitoring technology to study the effects of traumatic brain injury in older multimorbid adults.

Internet of things (IOT) based in-home monitoring systems can passively collect high temporal resolution data in the community, offering valuable insight into the impact of health conditions on patients' day-to-day lives. We used this technology to monitor activity and sleep patterns in older adults recently discharged after traumatic brain injury (TBI). The demographics of TBI are changing, and it is now a leading cause of hospitalisation in older adults. However, research in this population is minimal. We present three cases, showcasing the potential of in-home monitoring systems in understanding and managing early recovery in older adults following TBI.

Psychiatric sequelae of traumatic brain injury - future directions in research.

Despite growing appreciation that traumatic brain injury (TBI) is an important public health burden, our understanding of the psychiatric and behavioural consequences of TBI remains limited. These changes are particularly detrimental to a person's sense of self, their relationships and their participation in the wider community, and they continue to have devastating individual and cumulative effects long after TBI. This Review relates specifically to TBIs that confer objective clinical or biomarker evidence of structural brain injury; symptomatic head injuries without such evidence are outside the scope of this article. Common psychiatric, affective and behavioural sequelae of TBI and their proposed underlying mechanisms are outlined, along with a brief overview of current treatments. Suggestions for how scientists and clinicians can work together in the future to address the chasms in clinical care and knowledge are discussed in depth.

Computerised cognitive assessment in patients with traumatic brain injury: an observational study of feasibility and sensitivity relative to established clinical scales.

Background: Online technology could potentially revolutionise how patients are cognitively assessed and monitored. However, it remains unclear whether assessments conducted remotely can match established pen-and-paper neuropsychological tests in terms of sensitivity and specificity. Methods: This observational study aimed to optimise an online cognitive assessment for use in traumatic brain injury (TBI) clinics. The tertiary referral clinic in which this tool has been clinically implemented typically sees patients a minimum of 6 months post-injury in the chronic phase. Between March and August 2019, we conducted a cross-group, cross-device and factor analyses at the St. Mary's Hospital TBI clinic and major trauma wards at Imperial College NHS trust and St. George's Hospital in London (UK), to identify a battery of tasks that assess aspects of cognition affected by TBI. Between September 2019 and February 2020, we evaluated the online battery against standard face-to-face neuropsychological tests at the Imperial College London research centre. Canonical Correlation Analysis (CCA) determined the shared variance between the online battery and standard neuropsychological tests. Finally, between October 2020 and December 2021, the tests were integrated into a framework that automatically generates a results report where patients' performance is compared to a large normative dataset. We piloted this as a practical tool to be used under supervised and unsupervised conditions at the St. Mary's Hospital TBI clinic in London (UK). Findings: The online assessment discriminated processing-speed, visual-attention, working-memory, and executive-function deficits in TBI. CCA identified two significant modes indicating shared variance with standard neuropsychological tests (r = 0.86, p < 0.001 and r = 0.81, p = 0.02). Sensitivity to cognitive deficits after TBI was evident in the TBI clinic setting under supervised and unsupervised conditions (F (15,555) = 3.99; p < 0.001). Interpretation: Online cognitive assessment of TBI patients is feasible, sensitive, and efficient. When combined with normative sociodemographic models and autogenerated reports, it has the potential to transform cognitive assessment in the healthcare setting. Funding: This work was funded by a National Institute for Health Research (NIHR) Invention for Innovation (i4i) grant awarded to DJS and AH (II-LB-0715-20006).

Investigating the characteristics and correlates of systemic inflammation after traumatic brain injury: the TBI-BraINFLAMM study.

INTRODUCTION: A significant environmental risk factor for neurodegenerative disease is traumatic brain injury (TBI). However, it is not clear how TBI results in ongoing chronic neurodegeneration. Animal studies show that systemic inflammation is signalled to the brain. This can result in sustained and aggressive microglial activation, which in turn is associated with widespread neurodegeneration. We aim to evaluate systemic inflammation as a mediator of ongoing neurodegeneration after TBI. METHODS AND ANALYSIS: TBI-braINFLAMM will combine data already collected from two large prospective TBI studies. The CREACTIVE study, a broad consortium which enrolled >8000 patients with TBI to have CT scans and blood samples in the hyperacute period, has data available from 854 patients. The BIO-AX-TBI study recruited 311 patients to have acute CT scans, longitudinal blood samples and longitudinal MRI brain scans. The BIO-AX-TBI study also has data from 102 healthy and 24 non-TBI trauma controls, comprising blood samples (both control groups) and MRI scans (healthy controls only). All blood samples from BIO-AX-TBI and CREACTIVE have already been tested for neuronal injury markers (GFAP, tau and NfL), and CREACTIVE blood samples have been tested for inflammatory cytokines. We will additionally test inflammatory cytokine levels from the already collected longitudinal blood samples in the BIO-AX-TBI study, as well as matched microdialysate and blood samples taken during the acute period from a subgroup of patients with TBI (n=18).We will use this unique dataset to characterise post-TBI systemic inflammation, and its relationships with injury severity and ongoing neurodegeneration. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (17/LO/2066). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of larger observational and experimental medicine studies assessing the role and management of post-TBI systemic inflammation.

Using home monitoring technology to study the effects of traumatic brain injury on older multimorbid adults: protocol for a feasibility study.

INTRODUCTION: The prevalence of traumatic brain injury (TBI) among older adults is increasing exponentially. The sequelae can be severe in older adults and interact with age-related conditions such as multimorbidity. Despite this, TBI research in older adults is sparse. Minder, an in-home monitoring system developed by the UK Dementia Research Institute Centre for Care Research and Technology, uses infrared sensors and a bed mat to passively collect sleep and activity data. Similar systems have been used to monitor the health of older adults living with dementia. We will assess the feasibility of using this system to study changes in the health status of older adults in the early period post-TBI. METHODS AND ANALYSIS: The study will recruit 15 inpatients (>60 years) with a moderate-severe TBI, who will have their daily activity and sleep patterns monitored using passive and wearable sensors over 6 months. Participants will report on their health during weekly calls, which will be used to validate sensor data. Physical, functional and cognitive assessments will be conducted across the duration of the study. Activity levels and sleep patterns derived from sensor data will be calculated and visualised using activity maps. Within-participant analysis will be performed to determine if participants are deviating from their own routines. We will apply machine learning approaches to activity and sleep data to assess whether the changes in these data can predict clinical events. Qualitative analysis of interviews conducted with participants, carers and clinical staff will assess acceptability and utility of the system. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (REC) (REC number: 17/LO/2066). Results will be submitted for publication in peer-reviewed journals, presented at conferences and inform the design of a larger trial assessing recovery after TBI.

Remote Monitoring of Physiology in People Living With Dementia: An Observational Cohort Study.

BACKGROUND: Internet of Things (IoT) technology enables physiological measurements to be recorded at home from people living with dementia and monitored remotely. However, measurements from people with dementia in this context have not been previously studied. We report on the distribution of physiological measurements from 82 people with dementia over approximately 2 years. OBJECTIVE: Our objective was to characterize the physiology of people with dementia when measured in the context of their own homes. We also wanted to explore the possible use of an alerts-based system for detecting health deterioration and discuss the potential applications and limitations of this kind of system. METHODS: We performed a longitudinal community-based cohort study of people with dementia using "Minder," our IoT remote monitoring platform. All people with dementia received a blood pressure machine for systolic and diastolic blood pressure, a pulse oximeter measuring oxygen saturation and heart rate, body weight scales, and a thermometer, and were asked to use each device once a day at any time. Timings, distributions, and abnormalities in measurements were examined, including the rate of significant abnormalities ("alerts") defined by various standardized criteria. We used our own study criteria for alerts and compared them with the National Early Warning Score 2 criteria. RESULTS: A total of 82 people with dementia, with a mean age of 80.4 (SD 7.8) years, recorded 147,203 measurements over 958,000 participant-hours. The median percentage of days when any participant took any measurements (ie, any device) was 56.2% (IQR 33.2%-83.7%, range 2.3%-100%). Reassuringly, engagement of people with dementia with the system did not wane with time, reflected in there being no change in the weekly number of measurements with respect to time (1-sample t-test on slopes of linear fit, P=.45). A total of 45% of people with dementia met criteria for hypertension. People with dementia with α-synuclein-related dementia had lower systolic blood pressure; 30% had clinically significant weight loss. Depending on the criteria used, 3.03%-9.46% of measurements generated alerts, at 0.066-0.233 per day per person with dementia. We also report 4 case studies, highlighting the potential benefits and challenges of remote physiological monitoring in people with dementia. These include case studies of people with dementia developing acute infections and one of a person with dementia developing symptomatic bradycardia while taking donepezil. CONCLUSIONS: We present findings from a study of the physiology of people with dementia recorded remotely on a large scale. People with dementia and their carers showed acceptable compliance throughout, supporting the feasibility of the system. Our findings inform the development of technologies, care pathways, and policies for IoT-based remote monitoring. We show how IoT-based monitoring could improve the management of acute and chronic comorbidities in this clinically vulnerable group. Future randomized trials are required to establish if a system like this has measurable long-term benefits on health and quality of life outcomes.

Autonomic dysfunction after moderate-to-severe traumatic brain injury: symptom spectrum and clinical testing outcomes.

Background: Survivors of moderate-to-severe traumatic brain injury (msTBI) frequently experience troublesome unexplained somatic symptoms. Autonomic dysfunction may contribute to these symptoms. However, there is no previous study of clinical subjective and objective autonomic dysfunction in msTBI. Methods: We present results from two groups of patients with msTBI. The first, a case-control comparative study, comprises prospectively recruited msTBI outpatients, in whom we measured burden of autonomic symptoms using the Composite Autonomic Symptom Score (COMPASS31) questionnaire. The second, a descriptive case series, comprises retrospectively identified msTBI outpatients who had formal clinical autonomic function testing at a national referral autonomics unit. Results: Group 1 comprises 39 patients with msTBI (10F:20M, median age 40 years, range 19-76), median time from injury 19 months (range 6-299) and 44 controls (22F:22M, median age 45, range 25-71). Patients had significantly higher mean weighted total COMPASS-31 score than controls (p<0.001), and higher gastrointestinal, orthostatic and secretomotor subscores (corrected p<0.05). Total COMPASS31 score inversely correlated with subjective rating of general health (p<0.001, rs=-0.84). Group 2 comprises 18 patients with msTBI (7F:11M, median age 44 years, range 21-64), median time from injury 57.5 months (range 2-416). Clinical autonomic function testing revealed a broad spectrum of autonomic dysfunction in 13/18 patients. Conclusions: There is clinically relevant autonomic dysfunction after msTBI, even at the chronic stage. We advocate for routine enquiry about potential autonomic symptoms, and demonstrate the utility of formal autonomic testing in providing diagnoses. Larger prospective studies are warranted, which should explore the causes and clinical correlates of post-TBI autonomic dysfunction.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

Conferences in the time of COVID: notes on organizing and delivering the first Brain Conference.

To further fulfil their missions of promoting teaching, education and research in neurology and related clinical-academic disciplines, the Guarantors of Brain and the Brain journal family invited delegates to the first Brain Conference in Spring of this year. This event aimed to deliver excellent teaching and scientific presentations across a broad spectrum of neuroscience fields, with the key aim of making the content as accessible as possible. We hoped to capitalize on the benefits of an online format, whilst trying to capture a little of the joy of the in-person meeting. This article reports on the approach and practical choices made to achieve these goals, and we hope this will provide some guidance and advice to others organizing their own online conference.

Investigating the interaction between white matter and brain state on tDCS-induced changes in brain network activity.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation whose potential as a cognitive therapy is hindered by our limited understanding of how participant and experimental factors influence its effects. Using functional MRI to study brain networks, we have previously shown in healthy controls that the physiological effects of tDCS are strongly influenced by brain state. We have additionally shown, in both healthy and traumatic brain injury (TBI) populations, that the behavioral effects of tDCS are positively correlated with white matter (WM) structure. OBJECTIVES: In this study we investigate how these two factors, WM structure and brain state, interact to shape the effect of tDCS on brain network activity. METHODS: We applied anodal, cathodal and sham tDCS to the right inferior frontal gyrus (rIFG) of healthy (n = 22) and TBI participants (n = 34). We used the Choice Reaction Task (CRT) performance to manipulate brain state during tDCS. We acquired simultaneous fMRI to assess activity of cognitive brain networks and used Fractional Anisotropy (FA) as a measure of WM structure. RESULTS: We find that the effects of tDCS on brain network activity in TBI participants are highly dependent on brain state, replicating findings from our previous healthy control study in a separate, patient cohort. We then show that WM structure further modulates the brain-state dependent effects of tDCS on brain network activity. These effects are not unidirectional - in the absence of task with anodal and cathodal tDCS, FA is positively correlated with brain activity in several regions of the default mode network. Conversely, with cathodal tDCS during CRT performance, FA is negatively correlated with brain activity in a salience network region. CONCLUSIONS: Our results show that experimental and participant factors interact to have unexpected effects on brain network activity, and that these effects are not fully predictable by studying the factors in isolation.

Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree.

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.