Reduced IFNL1 and/or IFNL2, but not IFNL3 is associated with worse outcome in patients with COVID-19.

The recent pandemic was caused by the emergence of a new human pathogen, SARS-CoV-2. While the rapid development of many vaccines provided an end to the immediate crisis, there remains an urgent need to understand more about this new virus and what constitutes a beneficial immune response in terms of successful resolution of infection. Indeed, this is key for development of vaccines that provide long lasting protective immunity. The interferon lambda (IFNL) family of cytokines are produced early in response to infection and are generally considered anti-viral and beneficial. However, data regarding production of IFNL cytokines in COVID-19 patients is highly variable, and generally from underpowered studies. In this study, we measured all three IFNL1, IFNL2 and IFNL3 cytokines in plasma from a well characterised, large COVID-19 cohort (n=399) that included good representation from patients with a more indolent disease progression, and hence a beneficial immune response. While all three cytokines were produced, they differed in both the frequency of expression in patients, and the levels produced. IFNL3 was produced in almost all patients but neither protein level nor IFNL3/IFNL4 SNPs were associated with clinical outcome. In contrast, both IFNL1 and IFNL2 levels were significantly lower, or absent, in plasma of patients that had a more severe disease outcome. These data are consistent with the concept that early IFNL1 and IFNL2 cytokine production is protective against SARS-CoV-2 infection.

Obstructing colorectal cancer: a population-based review of colonic stenting in Queensland, Australia.

PURPOSE: Stenting is a useful treatment option for malignant colonic obstruction, but its role remains unclear. This study was designed to establish how stents have been used in Queensland, Australia, and to review outcomes. METHODS: Patients diagnosed with colorectal cancer in Queensland from January 1, 2008, to December 31, 2014, who underwent colonic stent insertion were reviewed. Primary outcomes of 5-year survival, 30-day mortality, and overall length of survival were calculated. The secondary outcomes included patient and tumor factors, and stoma rates. RESULTS: In total, 319 patients were included, and distant metastases were identified in 183 patients (57.4%). The 30-day mortality rate was 6.6% (n=21), and the 5-year survival was 11.9% (n=38). Median survival was 11 months (interquartile range, 4-27 months). A further operation (hazard ratio [HR], 0.19; P<0.001) and chemotherapy and/or radiotherapy (HR, 0.718; P=0.046) reduced the risk of 5-year mortality. The presence of distant metastases (HR, 2.052; P<0.001) and a comorbidity score of 3 or more (HR, 1.572; P=0.20) increased mortality. Surgery was associated with a reduced risk of mortality even in patients with metastatic disease (HR, 0.14; P<0.001). Twenty-two patients (6.9%) ended the study period with a stoma. CONCLUSION: Colorectal stenting was used in Queensland in several diverse scenarios, in both localized and metastatic disease. Surgery had a survival advantage, even in patients with metastatic disease. There was no survival difference according to whether patients were socioeconomically disadvantaged, diagnosed in a major city or not, or treated at private or public hospitals. Stenting proved a valid treatment option with low stoma rates.

A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate.

Nalbuphine (NAL) is a κ-agonist/µ-antagonist opioid being developed as an oral extended formulation (ER) for the treatment of chronic cough in idiopathic pulmonary fibrosis and itch in prurigo nodularis. NAL is extensively glucuronidated and likely undergoes enterohepatic recirculation (EHR). The purpose of this work is to develop pharmacokinetic models for NAL absorption and enterohepatic recirculation (EHR). Clinical pharmacokinetic (PK) data sets in healthy subjects from three trials that included IV, oral solution, and ER tablets in fed and fasted state and two published trials were used to parametrize a novel partial differential equation (PDE)-based model, termed "PDE-EHR" model. Experimental inputs included in vitro dissolution and permeability data. The model incorporates a continuous intestinal absorption framework, explicit liver and gall bladder compartments, and compartments for systemic drug disposition. The model was fully PDE-based with well-stirred compartments achieved by rapid diffusion. The PDE-EHR model accurately reproduces NAL concentration-time profiles for all clinical data sets. NAL disposition simulations required inclusion of both parent and glucuronide recirculation. Inclusion of intestinal P-glycoprotein efflux in the simulations suggests that NAL is not expected to be a victim or perpetrator of P-glycoprotein-mediated drug interactions. The PDE-EHR model is a novel tool to predict EHR and food/formulation effects on drug PK. The results strongly suggest that even intravenous dosing studies be conducted in fasted subjects when EHR is suspected. The modeling effort is expected to aid in improved prediction of dosing regimens and drug disposition in patient populations.

Graft Patency and Clinical Outcomes in Patients With Radial Artery Grafts Previously Instrumented for Cardiac Catheterization.

BACKGROUND: While transradial access is favored for cardiac catheterization, the radial artery (RA) is increasingly preferred for coronary artery bypass grafting. Whether the RA is suitable for use as a graft following instrumentation for transradial access remains uncertain. METHODS: Consecutive patients from 2015 to 2019 who underwent coronary artery bypass grafting using both the left and right RAs as grafts were included. Instrumented RAs underwent careful preoperative assessment for suitability. The clinical analysis was stratified by whether patients received an instrumented RA graft (instrumented versus noninstrumented groups). Eligible patients with both instrumented and noninstrumented RAs underwent computed tomography coronary angiography to evaluate graft patency. The primary outcome was a within-patient paired analysis of graft patency comparing instrumented to noninstrumented RA grafts. RESULTS: Of the 1123 patients who underwent coronary artery bypass grafting, 294 had both the left and right RAs used as grafts and were included. There were 126 and 168 patients in the instrumented and noninstrumented groups, respectively. Baseline characteristics and perioperative outcomes were comparable. The rate of major adverse cardiac events at 2 years following coronary artery bypass grafting was 2.4% in the instrumented group and 5.4% in the noninstrumented group (hazard ratio, 0.44 [95% CI, 0.12-1.61]; P=0.19). There were 50 patients included in the graft patency analysis. At a median follow-up of 4.3 (interquartile range, 3.7-4.5) years, 40/50 (80%) instrumented and 41/50 (82%) noninstrumented grafts were patent (odds ratio, 0.86 [95% CI, 0.29-2.52]; P>0.99). No significant differences were observed in the luminal diameter or cross-sectional area of the instrumented and noninstrumented RA grafts. CONCLUSIONS: There was no evidence found in this study that RA graft patency was affected by prior transradial access, and the use of an instrumented RA was not associated with worse outcomes in the exploratory clinical analysis. Although conduits must be carefully selected, prior transradial access should not be considered an absolute contraindication to the use of the RA as a bypass graft. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12621000257864.

Percutaneous coronary intervention outcomes based on American College of Cardiology/American Heart Association coronary lesion classification over 14 years - Melbourne interventional group (MIG) registry.

BACKGROUND: The American College of Cardiology / American Heart Association (ACC/AHA) introduced a coronary lesion classification in 1988 to stratify coronary lesions for probability of procedural success and complications after coronary angioplasty. Our aim is to assess the validity of the ACC/AHA lesion classification in predicting outcomes of percutaneous coronary intervention (PCI) in a contemporary cohort of patients. METHODS: Consecutive PCI procedures performed between 2005 and 2018, were divided into three periods. At each period, the ACC/AHA lesion classification (A, B1, B2, C) was analysed with respect to procedural characteristics, in-hospital and 30-day outcomes, as well as long-term mortality by linkage to the National Death Index (NDI). RESULTS: In total, 21,437 lesions were included with 7399 lesions (2005-2009), 6917 lesions (2010-2014) and 7121 lesions (2015-2018). There was a progressive increase in the number of complex lesions treated over time with ACC/AHA type C (15 %, 21 % and 26 %, p < 0.01). The rate of PCI procedural success decreased with increase in the complexity of lesions treated across all three periods (p < 0.01). Further, in-hospital and 30-day major adverse cardiovascular events (MACE), major adverse cardiac and cerebrovascular events (MACCE) increased across all three time periods (all p < 0.05). CONCLUSIONS: Our study validates the ACC/AHA lesion classification as a meaningful tool for prediction of PCI outcomes. Despite advances in PCI techniques and technology, complex lesion PCI defined by this classification continues to be associated with adverse outcomes.

Protocol for a home-based self-delivered prehabilitation intervention to proactively reduce fall risk in older adults: a pilot randomized controlled trial of transcranial direct current stimulation and motor imagery.

BACKGROUND: Several changes occur in the central nervous system with increasing age that contribute toward declines in mobility. Neurorehabilitation has proven effective in improving motor function though achieving sustained behavioral and neuroplastic adaptations is more challenging. While effective, rehabilitation usually follows adverse health outcomes, such as injurious falls. This reactive intervention approach may be less beneficial than prevention interventions. Therefore, we propose the development of a prehabilitation intervention approach to address mobility problems before they lead to adverse health outcomes. This protocol article describes a pilot study to examine the feasibility and acceptability of a home-based, self-delivered prehabilitation intervention that combines motor imagery (mentally rehearsing motor actions without physical movement) and neuromodulation (transcranial direct current stimulation, tDCS; to the frontal lobes). A secondary objective is to examine preliminary evidence of improved mobility following the intervention. METHODS: This pilot study has a double-blind randomized controlled design. Thirty-four participants aged 70-95 who self-report having experienced a fall within the prior 12 months or have a fear of falling will be recruited. Participants will be randomly assigned to either an active or sham tDCS group for the combined tDCS and motor imagery intervention. The intervention will include six 40-min sessions delivered every other day. Participants will simultaneously practice the motor imagery tasks while receiving tDCS. Those individuals assigned to the active group will receive 20 min of 2.0-mA direct current to frontal lobes, while those in the sham group will receive 30 s of stimulation to the frontal lobes. The motor imagery practice includes six instructional videos presenting different mobility tasks related to activities of daily living. Prior to and following the intervention, participants will undergo laboratory-based mobility and cognitive assessments, questionnaires, and free-living activity monitoring. DISCUSSION: Previous studies report that home-based, self-delivered tDCS is safe and feasible for various populations, including neurotypical older adults. Additionally, research indicates that motor imagery practice can augment motor learning and performance. By assessing the feasibility (specifically, screening rate (per month), recruitment rate (per month), randomization (screen eligible who enroll), retention rate, and compliance (percent of completed intervention sessions)) and acceptability of the home-based motor imagery and tDCS intervention, this study aims to provide preliminary data for planning larger studies. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov (NCT05583578). Registered October 13, 2022. https://www. CLINICALTRIALS: gov/study/NCT05583578.

The discovery of indazapyroxamet: a novel 3-pyridinyl insecticide targeting piercing/sucking insectsa.

In recent years, the registrations for a number of commercial insecticides utilized for piercing/sucking insects have been cancelled or restricted. To meet this growing need for new hemipteran controlling agrochemicals, we discovered a 2-(pyridin-3-yl)-thiazole compound, with limited insecticidal activity against cotton/melon aphid (Aphis gossypii). The 2-(pyridin-3-yl)-thiazole moiety offered us a basis to pursue the bicyclic 2-(pyridin-3-yl)-2H-indazole carboxamides. Evaluation of such 2-(pyridin-3-yl)-2H-indazole carboxamides revealed that even analogs containing only simple alkyl amides attached at the 4 or 5 positions possess promising insecticidal activity. Extensive optimization of this novel class of 2-(pyridin-3-yl)-2H-indazole carboxamides led to identifying indazapyroxamet for commercial development. © 2024 Society of Chemical Industry.

A Student-Driven Approach to Course Revitalization.

A first-year foundational science course grew beyond its scope. Revitalization of the course was driven by second and third-year medical students, who created new learning objectives and edited cases that were well-received by course facilitators and students. The students' role in the course revitalization is a novel approach.

Prevalence and outcomes of patients with SMuRF-less acute coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: There is increasing awareness that patients without standard modifiable risk factors (SMuRFs; diabetes, hypercholesterolaemia, hypertension and smoking) may represent a unique subset of patients with acute coronary syndrome (ACS). We aimed to investigate the prevalence and outcomes of patients with SMuRF-less ACS undergoing percutaneous coronary intervention (PCI) compared with those with SMuRFs. METHODS: We analysed data from the Melbourne Interventional Group PCI Registry. Patients with coronary artery disease were excluded. The primary outcome was 30-day mortality. Secondary outcomes included in-hospital and 30-day events. Long-term mortality was investigated using Cox-proportional hazards regression. RESULTS: From 1 January 2005 to 31 December 2020, 2727/18 988 (14.4%) patients were SMuRF less, with the proportion increasing over time. Mean age was similar for patients with and without SMuRFs (63 years), and fewer females were SMuRF-less (19.8% vs 25.4%, p<0.001). SMuRF-less patients were more likely to present with cardiac arrest (6.6% vs 3.9%, p<0.001) and ST-elevation myocardial infarction (59.1% vs 50.8%, p<0.001) and were more likely to experience postprocedural cardiogenic shock (4.5% vs 3.6%, p=0.019) and arrhythmia (11.2% vs 9.9%, p=0.029). At 30 days, mortality, myocardial infarction, revascularisation and major adverse cardiac and cerebrovascular events did not differ between the groups. During median follow-up of 7 years, SMuRF-less patients had an adjusted 13% decreased rate of mortality (HR 0.87 (95% CI 0.78 to 0.97)). CONCLUSIONS: The proportion of SMuRF-less patients increased over time. Presentation was more often a devastating cardiac event compared with those with SMuRFs. No difference in 30-day outcomes was observed and SMuRF-less patients had lower hazard for long-term mortality.

Successful remote treatment of a client with Hikikomori using internet-delivered cognitive therapy for social anxiety disorder: a case report.

Hikikomori (prolonged social withdrawal) has been discussed as a hidden worldwide epidemic and a significant social and healthcare issue. Social anxiety disorder is the most common psychiatric disorder preceding the onset of Hikikomori. Although studies exist suggesting the effectiveness of family-support interventions, little is known about psychotherapeutic approaches for Hikikomori individuals. Here, we present a case of Hikikomori wherein an internet-delivered cognitive therapy for social anxiety disorder (iCT-SAD) worked effectively in improving the client's social anxiety symptoms and social interaction behaviors. This case study demonstrates the principle that evidence-based psychological interventions focusing on social anxiety can be effective for clients with Hikikomori. Furthermore, the online mode of treatment delivery, along with a variety of relevant modules, may facilitate clients' engagement with treatment at home. The findings suggest that iCT-SAD might be a promising option for Hikikomori clients who have social anxiety problems, within the recommended stepped-intervention approach.

Ultrasound Guidance for Transradial Access in the Cardiac Catheterisation Laboratory: A Systematic Review of the Literature and Meta-Analysis.

BACKGROUND: Although ultrasound (US) guidance for vascular access has been widely adopted, its use for transradial access (TRA) in the cardiac catheterisation laboratory is rare. There is a perception that US guidance does not offer a clinically relevant benefit over traditional palpation-guided TRA, amplified by inconsistent findings of individual studies. METHOD: A systematic review of MEDLINE, EMBASE and the Cochrane Library identified studies comparing US to palpation-guided TRA for cardiac catheterisation. Studies evaluating radial artery (RA) cannulation for any other reason were excluded. Event rates and risk ratios (RRs) were pooled for meta-analysis. Access failure was the primary outcome. A random-effects model was used for analysis. RESULTS: Of the 977 records screened, four studies with a total of 1,718 patients (861 US-guided and 864 palpation-guided procedures) were included in the meta-analysis. Most procedures were elective. The pooled analysis showed US guidance significantly lowered the risk of access failure (RR 0.45; 95% confidence interval [CI] 0.21-0.97; p=0.04). Heterogeneity was moderate (I2=51.2%; p=0.105). There was a strong trend to improved first-pass success with US (RR 1.29; 95% CI 1.00-1.66; p=0.05; I2=83.8%), although no differences were found in rates of difficult access (RR 0.29; 95% CI 0.07-1.18; p=0.09; I2=88.3%). Salvage US guidance was successful in 30/41 (73.2%) patients following failed palpation-guided TRA. No differences were found in already low complication rates including RA spasm (RR 1.18; 95% CI 0.70-1.99; p=0.53; I2=0.0%) and bleeding (RR 1.32; 95% CI 0.46-3.80; p=0.60; I2=0.0%). CONCLUSIONS: US guidance was found to improve TRA success in the cardiac catheterisation laboratory. Further investigation is necessary to determine whether routine, selective, or salvage use of US confers the most RA protection, patient satisfaction, and overall clinical benefit. (PROSPERO registration: CRD42022332238).

Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

OBJECTIVE: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. CONCLUSION: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

Speed- and Endurance-Based Classifications of Community Ambulation Post-Stroke Revisited: The Importance of Location in Walking Performance Measurement.

BACKGROUND: Gait speed or 6-minute walk test are frequently used to project community ambulation abilities post-stroke by categorizing individuals as household ambulators, limited, or unlimited community ambulators. However, whether improved clinically-assessed gait outcomes truly translate into enhanced real-world community ambulation remains uncertain. OBJECTIVE: This cross-sectional study aimed to examine differences in home and community ambulation between established categories of speed- and endurance-based classification systems of community ambulation post-stroke and compare these with healthy controls. METHODS: Sixty stroke survivors and 18 healthy controls participated. Stroke survivors were categorized into low-speed, medium-speed, or high-speed groups based on speed-based classifications and into low-endurance, medium-endurance, or high-endurance groups based on the endurance-based classification. Home and community steps/day were quantified using Global Positioning System and accelerometer devices over 7 days. RESULTS: The low-speed groups exhibited fewer home and community steps/day than their medium- and high-speed counterparts (P < .05). The low-endurance group took fewer community steps/day than the high-endurance group (P < .05). Despite vast differences in clinical measures of gait speed and endurance, the medium-speed/endurance groups did not differ in their home and community steps/day from the high-speed/endurance groups, respectively. Stroke survivors took 48% fewer home steps/day and 77% fewer community steps/day than healthy controls. CONCLUSIONS: Clinical classification systems may only distinguish home ambulators from community ambulators, but not between levels of community ambulation, especially beyond certain thresholds of gait speed and endurance. Clinicians should use caution when predicting community ambulation status through clinical measures, due to the limited translation of these classification systems into the real world.

Resting state brain network segregation is associated with walking speed and working memory in older adults.

Older adults exhibit larger individual differences in walking ability and cognitive function than young adults. Characterizing intrinsic brain connectivity differences in older adults across a wide walking performance spectrum may provide insight into the mechanisms of functional decline in some older adults and resilience in others. Thus, the objectives of this study were to: (1) determine whether young adults and high- and low-functioning older adults show group differences in brain network segregation, and (2) determine whether network segregation is associated with working memory and walking function in these groups. The analysis included 21 young adults and 81 older adults. Older adults were further categorized according to their physical function using a standardized assessment; 54 older adults had low physical function while 27 were considered high functioning. Structural and functional resting state magnetic resonance images were collected using a Siemens Prisma 3T scanner. Working memory was assessed with the NIH Toolbox list sorting test. Walking speed was assessed with a 400 m-walk test at participants' self-selected speed. We found that network segregation in mobility-related networks (sensorimotor, vestibular, and visual networks) was higher in younger adults compared to older adults. There were no group differences in laterality effects on network segregation. We found multivariate associations between working memory and walking speed with network segregation scores. Higher right anterior cingulate cortex network segregation was associated with higher working memory function. Higher right sensorimotor, right vestibular, right anterior cingulate cortex, and lower left anterior cingulate cortex network segregation was associated with faster walking speed. These results are unique and significant because they demonstrate higher network segregation is largely related to higher physical function and not age alone.

Prefrontal cortical activity during uneven terrain walking in younger and older adults.

Introduction: Walking in complex environments increases the cognitive demand of locomotor control; however, our understanding of the neural mechanisms contributing to walking on uneven terrain is limited. We used a novel method for altering terrain unevenness on a treadmill to investigate the association between terrain unevenness and cortical activity in the prefrontal cortex, a region known to be involved in various cognitive functions. Methods: Prefrontal cortical activity was measured with functional near infrared spectroscopy while participants walked on a novel custom-made terrain treadmill surface across four different terrains: flat, low, medium, and high levels of unevenness. The assessments were conducted in younger adults, older adults with better mobility function and older adults with worse mobility function. Mobility function was assessed using the Short Physical Performance Battery. The primary hypothesis was that increasing the unevenness of the terrain would result in greater prefrontal cortical activation in all groups. Secondary hypotheses were that heightened prefrontal cortical activation would be observed in the older groups relative to the younger group, and that prefrontal cortical activation would plateau at higher levels of terrain unevenness for the older adults with worse mobility function, as predicted by the Compensation Related Utilization of Neural Circuits Hypothesis. Results: The results revealed a significant main effect of terrain, indicating a significant increase in prefrontal cortical activation with increasing terrain unevenness during walking in all groups. A significant main effect of group revealed that prefrontal cortical activation was higher in older adults with better mobility function compared to younger adults and older adults with worse mobility function in all pooled terrains, but there was no significant difference in prefrontal cortical activation between older adults with worse mobility function and younger adults. Contrary to our hypothesis, the older group with better mobility function displayed a sustained increase in activation but the other groups did not, suggestive of neural compensation. Additional findings were that task-related increases in prefrontal cortical activation during walking were lateralized to the right hemisphere in older adults with better mobility function but were bilateral in older adults with worse mobility function and younger adults. Discussion: These findings support that compared to walking on a flat surface, walking on uneven terrain surfaces increases demand on cognitive control resources as measured by prefrontal cortical activation.

Patient preference and acceptability of self-sampling for cervical screening in colposcopy clinic attenders: A cross-sectional semi-structured survey.

Low vaginal self-sampling has been pioneered as an important development to improve uptake of cervical screening globally. Limited research is available in specific patient groups in the UK exploring views around self-sampling to detect high-risk human papillomavirus (hrHPV) DNA. Therefore, we explored patient views to support development of a novel point-of-care self-sampling cervical cancer screening device, by undertaking a cross-sectional semi-structured questionnaire survey to explore preferences, acceptability, barriers and facilitators around self-sampling. Patients attending a colposcopy clinic, 25-64 years old, were invited to participate after having carried out a low vaginal self-sample using a regular flocked swab. Participants self-completed an anonymous 12-point questionnaire. Quantitative data were analysed in MS Excel and Graphpad Prism, and qualitative data with Nvivo. We recruited 274 patients with a questionnaire response rate of 76%. Acceptability of self-sampling was high (95%, n = 187/197; Cronbachs-α = 0.778). Participants were asked their choice of future screening method: a) low vaginal self-sampling, b) healthcare professional collected vaginal swab, c) cervical brush sample with healthcare professional speculum examination, or d) no preference. Preferences were: a) 37% (n = 74/198), b) 19% (n = 37/198); c) 9% (n = 17/198), and d) 35% (n = 70/198), showing no single option as a strong preference. Key motivators were: Test simplicity (90%, n = 170/190), speed (81%, n = 153/190) and less pain (65%, n = 123/190). Barriers included lack of confidence taking the sample (53%, n = 10/19), resulting in preference for a healthcare professional sample (47%, n = 9/19). Whilst self-sampling showed high acceptability, lack of strong preference for screening method may reflect that respondents attending colposcopy are already engaged with screening and have differing perception of cervical cancer risk. This group appear less likely to 'switch' to self-sampling, and it may be better targeted within primary and community care, focusing on under-screened populations. Any shift in this paradigm in the UK requires comprehensive education and support for patients and providers.

Examining chromatin heterogeneity through PacBio long-read sequencing of M.EcoGII methylated genomes: an m6A detection efficiency and calling bias correcting pipeline.

Recent studies have combined DNA methyltransferase footprinting of genomic DNA in nuclei with long-read sequencing, resulting in detailed chromatin maps for multi-kilobase stretches of genomic DNA from one cell. Theoretically, nucleosome footprints and nucleosome-depleted regions can be identified using M.EcoGII, which methylates adenines in any sequence context, providing a high-resolution map of accessible regions in each DNA molecule. Here, we report PacBio long-read sequence data for budding yeast nuclei treated with M.EcoGII and a bioinformatic pipeline which corrects for three key challenges undermining this promising method. First, detection of m6A in individual DNA molecules by the PacBio software is inefficient, resulting in false footprints predicted by random gaps of seemingly unmethylated adenines. Second, there is a strong bias against m6A base calling as AT content increases. Third, occasional methylation occurs within nucleosomes, breaking up their footprints. After correcting for these issues, our pipeline calculates a correlation coefficient-based score indicating the extent of chromatin heterogeneity within the cell population for every gene. Although the population average is consistent with that derived using other techniques, we observe a wide range of heterogeneity in nucleosome positions at the single-molecule level, probably reflecting cellular chromatin dynamics.

The future of psychological treatments: The Marburg Declaration.

Although psychological treatments are broadly recognized as evidence-based interventions for various mental disorders, challenges remain. For example, a substantial proportion of patients receiving such treatments do not fully recover, and many obstacles hinder the dissemination, implementation, and training of psychological treatments. These problems require those in our field to rethink some of our basic models of mental disorders and their treatments, and question how research and practice in clinical psychology should progress. To answer these questions, a group of experts of clinical psychology convened at a Think-Tank in Marburg, Germany, in August 2022 to review the evidence and analyze barriers for current and future developments. After this event, an overview of the current state-of-the-art was drafted and suggestions for improvements and specific recommendations for research and practice were integrated. Recommendations arising from our meeting cover further improving psychological interventions through translational approaches, improving clinical research methodology, bridging the gap between more nomothetic (group-oriented) studies and idiographic (person-centered) decisions, using network approaches in addition to selecting single mechanisms to embrace the complexity of clinical reality, making use of scalable digital options for assessments and interventions, improving the training and education of future psychotherapists, and accepting the societal responsibilities that clinical psychology has in improving national and global health care. The objective of the Marburg Declaration is to stimulate a significant change regarding our understanding of mental disorders and their treatments, with the aim to trigger a new era of evidence-based psychological interventions.

Evaluating patient factors, operative management and postoperative outcomes in trauma laparotomy patients worldwide: a protocol for a global observational multicentre trauma study.

INTRODUCTION: Trauma contributes to the greatest loss of disability-adjusted life-years for adolescents and young adults worldwide. In the context of global abdominal trauma, the trauma laparotomy is the most commonly performed operation. Variation likely exists in how these patients are managed and their subsequent outcomes, yet very little global data on the topic currently exists. The objective of the GOAL-Trauma study is to evaluate both patient and injury factors for those undergoing trauma laparotomy, their clinical management and postoperative outcomes. METHODS: We describe a planned prospective multicentre observational cohort study of patients undergoing trauma laparotomy. We will include patients of all ages who present to hospital with a blunt or penetrating injury and undergo a trauma laparotomy within 5 days of presentation to the treating centre. The study will collect system, patient, process and outcome data, following patients up until 30 days postoperatively (or until discharge or death, whichever is first). Our sample size calculation suggests we will need to recruit 552 patients from approximately 150 recruiting centres. DISCUSSION: The GOAL-Trauma study will provide a global snapshot of the current management and outcomes for patients undergoing a trauma laparotomy. It will also provide insight into the variation seen in the time delays for receiving care, the disease and patient factors present, and patient outcomes. For current standards of trauma care to be improved worldwide, a greater understanding of the current state of trauma laparotomy care is paramount if appropriate interventions and targets are to be identified and implemented.

Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.