Correlates of intention-to-attend and confirmed cervical screening attendance during the COVID-19 pandemic in Australia: Findings from Compass-PLUS, a prospective cohort study.

Objective: The coronavirus pandemic impacted health-seeking behaviour and access to primary care in Australia. We investigated factors associated with intention-to-attend and attendance of cervical screening during the pandemic, mainly in Victoria, Australia. Methods: We used questionnaire and attendance data (Aug 2020-Nov 2022) from Compass-PLUS, a sub-study of the Compass randomized-controlled trial of Human Papillomavirus-based vs cytology-based screening. Data was restricted to the HPV-screening arm for comparability to the national program. We investigated associations overall and for younger (25-39 years) and older (≥40 years) cohorts, between intention-to-attend/attendance, and socio-demographics, anxiety-related scores, and agreement with beliefs about screening during the pandemic (e.g. importance of screening, increased workload, working from home, risk of infection). Results: Among 2,226 participants, positive intention to attend screening was more likely among those with a family history of cancer (p = 0.030) or living outside major cities (p = 0.024). Increased attendance was associated with increasing age (p < 0.001), prior regular cervical screening history [adjusted relative risk (aRR) for 2 screens in 6 years vs none: 1.23 (95 %CI 1.09,1.40); p < 0.001], and part-time employment or retirement compared to full-time employment [aRR:1.08 (1.02,1.14); aRR:1.12 (1.03, 1.22); respectively]. Lower attendance was related to increased agreement with statements indicating screening de-prioritisation (p-trend < 0.05) and higher recent anxiety, specifically in the older cohort (p-trend = 0.002). Conclusions: Reduced priority of screening and heightened recent anxiety may partly explain indications of lower-than-expected cervical screening rates during the pandemic. It is important that catch-up of missed HPV screens is performed to prevent a possible increase in cancer diagnoses in the long term.

Anorectal physiology and colonic motility in children with a history of tethered cord syndrome.

OBJECTIVES: The understanding of the impact of tethered cord syndrome (TCS) on the physiology of the colorectal area is limited. Our aim was to describe anorectal and colonic motility in children with TCS and compare the findings to those of children with functional constipation (FC). METHODS: We conducted a retrospective review of children with TCS who had an anorectal manometry (ARM) performed at our institution from January 2011 to September 2023. We recorded demographics, medical and surgical history, clinical symptoms, and treatment at time of ARM, ARM findings (resting pressure, push maneuver, rectal sensation, rectoanal inhibitory reflex [RAIR], and RAIR duration), and the final interpretation of colonic manometry (CM) if performed. We identified age and sex-matched control groups of children with FC. RESULTS: We included 24 children with TCS (50% female) who had ARM testing (median age at ARM 6.0 years, interquartile range 4.0-11.8 years). All children had constipation at time of ARM. Nineteen children had detethering surgery before ARM was performed. No significant differences in ARM parameters were found between children who had detethering surgery before ARM and children with FC. Among the 24 children, 14 also had a CM performed (13/14 after detethering surgery). No significant differences in colonic motility were found between children with a history of TCS and children with FC. CONCLUSIONS: Anorectal physiology and colonic motility are similar between children with a history of TCS and children with FC, suggesting that the underlying pathophysiology of defecatory disorders in children with and without history of TCS is similar.

Intracardiac vs Transesophageal Echocardiography for Left Atrial Appendage Occlusion: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Multiple studies continue to evaluate the use of intracardiac echocardiography (ICE) and transesophageal echocardiography (TEE) for guiding left atrial appendage occlusion (LAAO). OBJECTIVE: To conduct an updated meta-analysis comparing the effectiveness and safety outcomes of both imaging modalities. METHODS: PubMed, Cochrane, and Embase were searched for studies comparing ICE vs TEE to guide LAAO. Odds ratios (OR) with 95% confidence intervals (CI) were pooled using a random-effects model. The primary effectiveness endpoint was procedural success. The primary safety endpoint included the overall complications rate. Additional safety outcomes were assessed as secondary endpoints. Subgroup analysis of primary endpoints was conducted according to device type (Amulet, LAmbre, Watchman, Watchman FLX) and study region (American, Asia, Europe). We used R version 4.3.1 for all statistical analyses. RESULTS: Our meta-analysis included 19 observational studies encompassing 42,474 patients, of whom 4,415 (10.4%) underwent ICE-guided LAAO. Compared with TEE, ICE was associated with a marginally higher procedural success (OR 1.33; 95% CI: 1.01-1.76; p=0.04; I2=0%). There was no significant difference in the overall complications rate (OR 1.02; 95% CI: 0.77-1.36; p=0.89; I2=5%). However, ICE showed higher rates of pericardial effusion (OR 2.11; 95% CI: 1.47-3.03; p<0.001; I2=0%) and residual iatrogenic atrial septal defect (iASD) (OR 1.52; 95% CI: 1.15-2.03; p<0.004; I2=0%). Subgroup analysis revealed variations in procedural success within the ICE group across study regions (p=0.02). CONCLUSION: In this updated meta-analysis, the increasing adoption of ICE-guided LAAO demonstrated higher procedural success rates compared to TEE, although with limited statistical significance. Overall complication rates were similar; however, ICE showed higher rates of pericardial effusion and residual iASD.

Enhanced intratumoral delivery of immunomodulator MPLA via hyperbranched polyglycerol-coated biodegradable nanoparticles.

Immunomodulatory agents (IMA) have significant potential to enhance cancer treatment but have demonstrated limited efficacy beyond the preclinical setting due to poor pharmacokinetics and toxicity associated with systemic administration. On the other hand, when locally delivered, IMAs require repeated administration to optimize immune stimulation. To overcome these challenges, we encapsulated the toll-like receptor (TLR)4 agonist monophosphoryl lipid A (MPLA) within hyperbranched polyglycerol (HPG)-coated biodegradable nanoparticles (NP) engineered for gradual drug release from the nanoparticle core, resulting in a more persistent stimulation of anti-tumor immune responses while minimizing systemic side effects. In a model of malignant melanoma, we demonstrate that HPG-NP encapsulation significantly improves the antitumor efficacy of MPLA by enhancing its ability to remodel the tumor microenvironment (TME). Compared to free MPLA, HPG-NP-MPLA significantly increased the natural killer cell and cytotoxic T cell mediated antitumor immune response and tuned the tumor draining lymph nodes towards a T helper (Th)1 response. Furthermore, when combined with local delivery of a chemotherapeutic agent, HPG-NP-MPLA induces the conversion of an immunosuppressive TME to immunogenic TME and significantly improves survival.

Neuropsychological and behavioural outcomes in epilepsy involving the insula: A scoping review.

Objective: In patients with epilepsy, the insula has been increasingly recognized as a common site of seizures. There is growing interest in understanding the cognitive and psychological consequences of insular epilepsy to help provide clinical recommendations to support patient's cognitive and psychosocial functioning, and to help identify candidates for epilepsy resective surgery. The aim of this scoping review was to describe the cognitive and behavioural characteristics associated with insular epilepsy in children and adults. Method: A systematic search was completed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis -Extension for Scoping Reviews guidelines. Eligible studies reported on a neuropsychological or behavioural outcome, using standardized or research-based psychological measures, in individuals with insular epilepsy, (i.e. the seizure focus and/or surgical resection included the insula), and a comparison group. After duplicates were removed, 2,423 citations were identified from the search, and 39 studies were included in the scoping review. Results: Across the included studies, intellectual/global cognitive functioning and language were most often evaluated. Lower functioning was found across multiple cognitive and behavioural processes in pediatric and adult patients with insular epilepsy. Following resective surgery involving the insula, behavioural and cognitive outcomes are general stable. Conclusions: The results of this scoping review further neuropsychologists' knowledge of the cognitive and behavioural outcomes of insular seizures prior to and following surgical treatment. These results can aid in counselling patients of the potential cognitive dysfunctions, and aid with treatment planning.

The Role of Coenzyme Q10 in Skin Aging and Opportunities for Topical Intervention: A Review.

Background: Coenzyme Q10 (CoQ10) is a naturally produced, lipid-soluble molecule crucial for cellular energy production and antioxidant activity. It diminishes with age and under external stress factors in skin, leading to signs of aging. Beyond its role in cellular energy production within the mitochondria, CoQ10 is vital to skin's defense against oxidative stress, a key contributor to premature aging. Use of topical skincare products with CoQ10 can be effective to replenish levels of CoQ10 and reverse skin aging. Objective: This publication discusses the role of CoQ10 in skin aging along with the benefits of topical skincare products that incorporate CoQ10 as an ingredient. Methods: We searched the PubMed database using terms "Coenzyme Q10" and "skin" and "aging." Overall, the search yielded 80 results, but a limitation of 10 years was then applied to restrict publications to those with the most up-to-date science. Results: A total of 36 publications were identified and included as background for this article. These 36 publications encompassed both original research articles and review articles. Discussion: Applying topical skincare products with CoQ10 replenishes CoQ10 cellular levels, helping to normalize cellular energy homeostasis and providing antioxidative effects to support and repair cutaneous damage including signs of skin aging. In ex vivo and in vivo studies, application of CoQ10 increased CoQ10 levels both on the skin surface (i.e., stratum corneum) and even more in deeper levels of the skin. Clinically, topical application of CoQ10-formulated products reduces the depth of cutaneous wrinkles, a sign associated with aging. Conclusion: Aging and stressed skin are, in part, the result of alterations in cellular metabolic homeostasis, which can be reversed via the benefits of topical application of CoQ10-enriched formulations that stimulate cutaneous energy metabolism and reduce free radicals via antioxidant function. By restoring physiological homeostasis, topical skincare products with CoQ10 replenish the skin's antioxidant levels, increase cellular (energy) metabolism, and reduce the signs of skin aging.

Celiac disease in North America: What is the current practice of pediatric gastroenterology providers?

Objectives: While guidelines exist for the diagnosis and management of pediatric celiac disease (CeD), current practices in North America are not well-described. This study aimed to explore current practice patterns to identify gaps and direct future clinical, training and research initiatives. Methods: A 23-item survey designed by the Celiac Disease Special Interest Group was distributed electronically to its members. Questions explored four themes: (1) screening and diagnosis pre and post the coronavirus disease (COVID)-19 pandemic, (2) treatment and monitoring, (3) family screening and transition of care, and (4) CeD focused training. Results: The survey response rate was 10.8% (278/2552). Most respondents were from the United States (89.9%, n = 250) and Canada (8.6%, n = 24). While endoscopy remained the gold standard, serology-based diagnosis was accepted by 47.5% (132/278). In response to the COVID-19 pandemic, 37.4% of providers changed their diagnostic practice. Barriers to care included: lack of insurance coverage for dietitians, wait times, and lack of CeD focused training. During fellowship 69.1% (192/278) reported no focused CeD training. Conclusion: Survey results revealed practice variation regarding the diagnosis and management of CeD in North America including a substantial proportion accepting non-biopsy, serology-based diagnosis, which increased during the COVID-19 pandemic. Variations in screening, diagnosis, interval surveillance, and family screening were also identified. Dedicated CeD education in pediatric gastroenterology fellowship may be an opportunity for standardizing practice and advancing research. Future North American guidelines should take current care patterns into consideration and develop new initiatives to improve care of children with CeD.

A case of fungal peritonitis in a patient with paramalignant ascites.

Here, we present the case of a patient with a metastatic neuroendocrine tumor with cytologically negative ascites treated for spontaneous bacterial peritonitis (SBP). Ascitic cultures remained negative for bacterial growth but were positive for Candida albicans 8 days after SBP diagnosis. ß-D-glucan was only positive in ascites, while being negative in blood. Blood cultures remained negative throughout the whole admission. Fungal peritonitis presumably originated from an impending bowl perforation or an increasing vascular permeability caused by an increase in VEGF secondary to diffuse infiltration by the underlying malignant disease.

Nodal Response and Survival After Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive Breast Cancer: 20-Year Experience from a Single Institution.

INTRODUCTION: Axillary response to neoadjuvant endocrine therapy (NET) for the treatment of hormone receptor-positive breast cancer (HR+ BC) is not well-described. This study was designed to characterize nodal response after NET. METHODS: Patients receiving NET followed by curative intent surgery at a comprehensive cancer center from 1998 to 2022 in a prospectively collected registry were included. Patients with distant metastasis were excluded. Primary outcome was nodal pathologic complete response (pCR). Downstaging was defined as post-NET decrease in category. RESULTS: We included 123 patients; the majority were cT2 (n = 59) or cT3 (n = 35), and cN0 (n = 81). Median age was 70.0 years (interquartile range 62.1-76.0). Forty-two patients (34.1%) were clinically node-positive. After NET, 73 (59.8%) underwent breast-conserving surgery. All patients underwent sentinel lymph node biopsy, and 12 (9.8%) underwent completion axillary lymph node dissection. In-breast downstaging was achieved in 51 (41.5%) patients, 1 (0.8%) had breast pCR, and 14 (11.4%) had breast upstaging. Axillary downstaging was achieved in 10 (23.8%), 6 patients (14.3%) had nodal pCR, and 14 (33.3%) had axillary upstaging. At 10-year follow-up, local recurrence was 1% and distant recurrence was 14%, while disease-free survival was 82%. After adjusting for demographic and clinical factors, age was the only characteristic associated with mortality (hazard ratio 1.07, 95% confidence interval 1.01-1.13). CONCLUSIONS: In HR+ BC treated with NET, long-term disease-free survival is good, although nodal pCR is uncommon for cN+ patients. Future studies are needed to elucidate optimal neoadjuvant systemic therapy and to delineate oncologically safe strategies to deescalate axillary management for residual microscopic disease.

Structures of human PTP1B variants reveal allosteric sites to target for weight loss therapy.

Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of leptin signaling whose disruption protects against diet-induced obesity in mice. We investigated whether structural characterization of human PTP1B variant proteins might reveal precise mechanisms to target for weight loss therapy. We selected 12 rare variants for functional characterization from exomes from 997 people with persistent thinness and 200,000 people from UK Biobank. Seven of 12 variants impaired PTP1B function by increasing leptin-stimulated STAT3 phosphorylation in cells. Using room-temperature X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, and computational modeling, we determined that human variants modulate the 3-dimensional structure of PTP1B through distinct allosteric conduits that energetically link distal, highly ligandable structural regions to the active site. These studies inform the design of allosteric PTP1B inhibitors for the treatment of obesity.

Thiazine-derived compounds in inhibiting efflux pump in Staphylococcus aureus K2068, mepA gene expression, and membrane permeability alteration.

Staphylococcus aureus is a bacterium responsible for resistance to multiple drugs and the efflux system is widely studied among the resistance mechanisms developed by this species. The present study evaluates the inhibition of the MepA efflux pump by thiadiazine-derived compounds. For this purpose, thiadiazine-derived compounds (IJ-14 to IJ-20) were tested against S. aureus K2068 strains. Microdilution tests were initially conducted to assess the Minimum Inhibitory Concentration (MIC) of the compounds and their efflux pump inhibition activity. In addition, fluorimetry tests were performed using BrEt emission and tests were conducted to inhibit the expression of the mepA gene. This involved comparing the bacterial gene expression with the antibiotic alone to the gene expression after combining compounds (IJ-17 and IJ-20) with the antibiotic. Furthermore, membrane permeability assessment tests and in silico molecular docking tests were performed. It was observed that the IJ17 and IJ20 compounds exhibited direct activity against the tested strain. The IJ17 compound produced significant results in the gene inhibition tests, which was also evidenced through the membrane permeability alteration test. These findings suggest that thiadiazine-derived compounds have promising effects against one of the main resistance mechanisms, with the IJ17 compound presenting observable mechanisms of action.

Quality of life is impaired in myelin oligodendrocyte glycoprotein antibody associated disease.

Background: There is a paucity of studies examining quality of life (QoL) in people with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Methods: A cross-sectional, online, self-administered survey was distributed. Data elements included demographic and clinical characteristics, and QoL in Neurological Disorders (Neuro-QoL) short form questionnaires. Neuro-QoL domain scores were compared to reference populations, yielding standardized T-scores. Symptom severity was categorized as mild, moderate, or severe, using standard Neuro-QoL cut points. Results: A total of 259 participants completed the survey. Neuro-QoL domain impairment was present in a significant proportion of respondents (anxiety: 58.1%, depression: 30.7%, stigma 29.8%, cognition: 58.5%, social function: 57.7%). T-scores were significantly worse than the reference population for anxiety (p<0.001), stigma (p=0.005), cognitive function (p<0.001) and social interactions (p<0.001). There was no clear association between QoL domains and demographics, disease-modifying therapy class, or type of clinical presentation. A relapsing vs monophasic disease course was associated with worse anxiety, stigma, cognition, and social interactions (p<0.05). Conclusion: People with MOGAD may exhibit impairment in multiple domains of QoL. Practicing clinicians should be aware of this burden in MOGAD. Further research is needed to better understand factors associated with QoL impairment in MOGAD.

The genetic architecture of repeated local adaptation to climate in distantly related plants.

Closely related species often use the same genes to adapt to similar environments. However, we know little about why such genes possess increased adaptive potential and whether this is conserved across deeper evolutionary lineages. Adaptation to climate presents a natural laboratory to test these ideas, as even distantly related species must contend with similar stresses. Here, we re-analyse genomic data from thousands of individuals from 25 plant species as diverged as lodgepole pine and Arabidopsis (~300 Myr). We test for genetic repeatability based on within-species associations between allele frequencies in genes and variation in 21 climate variables. Our results demonstrate significant statistical evidence for genetic repeatability across deep time that is not expected under randomness, identifying a suite of 108 gene families (orthogroups) and gene functions that repeatedly drive local adaptation to climate. This set includes many orthogroups with well-known functions in abiotic stress response. Using gene co-expression networks to quantify pleiotropy, we find that orthogroups with stronger evidence for repeatability exhibit greater network centrality and broader expression across tissues (higher pleiotropy), contrary to the 'cost of complexity' theory. These gene families may be important in helping wild and crop species cope with future climate change, representing important candidates for future study.

Does Delaying Levodopa Prevent Motor Complications in Parkinson's Disease? A Meta-Analysis.

BACKGROUND: There has been a long debate whether delaying treatment with levodopa prevents motor complications in Parkinson's disease (PD). OBJECTIVES: We performed a meta-analysis on randomized clinical trials (RCTs) that compared early- versus delayed-start treatment with levodopa in PD. METHODS: A systematic review was conducted in PubMed, EMBASE, and Web of Science databases from inception to July 1, 2023. Only RCTs that compared early and delayed levodopa treatment in PD were included. Non-randomized comparisons from follow-up studies were included as well. Our primary outcomes were occurrence of overall motor complications, motor fluctuations, and dyskinesias. RESULTS: Seven studies with a total of 1149 patients (636 in the early-start group and 513 in the delayed-start) were included in our analysis. There was no difference between groups regarding motor complications (OR 1.39; 95% CI: 0.68-1.72; P = 0.37) or dyskinesias (OR 1.52; 95% CI: 0.90-2.57; P = 0.11). Motor fluctuations occurred less frequently in the early-start group (OR 0.70; 95% CI: 0.52-0.95; P = 0.02). Nonetheless, on subgroup analysis of dopamine agonists, rate of dyskinesias was smaller in the delayed-start group (OR 1.82; 95% CI: 1.08-3.07; P = 0.03). CONCLUSIONS: Delaying treatment with levodopa does not seem to prevent levodopa-related motor complications in PD. Adjunct treatment with dopamine agonists may reduce the need for higher doses of levodopa and thus reduce the risk for dyskinesias but this practice is often associated with a higher frequency of adverse effects related to dopamine agonists.

Fabricated devices for performing bacterial-fungal interaction experiments across scales.

Diverse and complex microbiomes are found in virtually every environment on Earth. Bacteria and fungi often co-dominate environmental microbiomes, and there is growing recognition that bacterial-fungal interactions (BFI) have significant impacts on the functioning of their associated microbiomes, environments, and hosts. Investigating BFI in vitro remains a challenge, particularly when attempting to examine interactions at multiple scales of system complexity. Fabricated devices can provide control over both biotic composition and abiotic factors within an experiment to enable the characterization of diverse BFI phenotypes such as modulation of growth rate, production of biomolecules, and alterations to physical movements. Engineered devices ranging from microfluidic chips to simulated rhizosphere systems have been and will continue to be invaluable to BFI research, and it is anticipated that such devices will continue to be developed for diverse applications in the field. This will allow researchers to address specific questions regarding the nature of BFI and how they impact larger microbiome and environmental processes such as biogeochemical cycles, plant productivity, and overall ecosystem resilience. Devices that are currently used for experimental investigations of bacteria, fungi, and BFI are discussed herein along with some of the associated challenges and several recommendations for future device design and applications.

Perspectives of Sexual and Gender Minority Youth on Anti-Vaping Messages in Social Media.

INTRODUCTION: Sexual and gender minority (SGM) youth have higher rates of nicotine vaping than other youth in the United States. While social media can be effective in reaching youth and discouraging vaping, informed cultural tailoring is necessary to ensure effective messaging to SGM youth. This study aimed to understand SGM youth perspectives on anti-vaping social media messages and tailoring approaches. METHODS: In-depth, qualitative videoconference interviews were conducted from February to July 2022 with 34 SGM youth recruited in the United States via social media ads. The interview guide addressed participants' beliefs about vaping, the context of vaping, perspectives on tailoring messages, and responses to examples of social media anti-vaping messages. Coding and thematic analysis followed a team-based approach. RESULTS: SGM youth perspectives fell into four categories - representation and diversity, facts and evidence, empowering messages, and source credibility. Participants stressed the importance of accurate, genuine representation of SGM youth in messages, but also noted that more overt representation may be seen as tokenizing. Participants recommended partnering with known LGBTQ+ influencers who can promote or share anti-vaping messages on social media platforms. They also recommended using culturally tailored language, including statistics specific to SGM youth, and invoking themes of empowerment to improve the relevance, reach, and effectiveness of anti-vaping campaigns. CONCLUSIONS: Findings can inform future efforts to develop anti-vaping messages for SGM youth with effective reach through social media. Nuanced perspectives on SGM representation in messages suggest a careful approach to tailoring. Concerns around inauthenticity may be minimized by ensuring SGM youth are included in message development and dissemination. IMPLICATIONS: This study describes the importance of being attentive to the tailoring preferences among the current generation of sexual and gender minority youth. Findings will inform social media-based messaging strategies that discourage nicotine vaping tailored for SGM youth in health campaign material design and evaluation, ensuring that tailored messages are designed in ways that avoid unintended consequences. The study also describes methods for effectively engaging SGM youth in research to improve the relevance of health education materials for this population and increase reach, which in turn can lead to reduction in vaping practices among SGM youth.

Experiencing Psychosis and Shame: A Systematic Review and Meta-analysis of the Strength and Patterns of Association.

BACKGROUND AND HYPOTHESIS: Shame has been linked to the experience of psychosis, with implications for clinical outcomes, however, a meta-analysis of the relationship has not yet been conducted. This systematic review and meta-analysis aimed to examine the strength of the association between shame and psychosis, and any variations between clinical and non-clinical populations and shame type (internal vs external shame). STUDY DESIGN: Searches were conducted in CINAHL, EMBASE, PsycInfo, PubMed, Scopus, and Web of Science from the inception of the e-databases until July 2023. For inclusion, studies reported a quantitative association between psychosis and shame, or data that could be used to identify a relationship. From 11 372 unique retrieved records, 40 articles met the inclusion criteria and 38 were included in the meta-analyses. STUDY RESULTS: A significant large pooled estimate of the psychosis-shame association was identified (Zr = 0.36, [95% CI: 0.28, 0.44], P < .001), indicating that higher levels of shame were associated with greater severity of psychotic symptoms. The strength of the association was similar across clinical and non-clinical populations, however, differed by type of shame and psychosis symptom measured. External shame was strongly associated with paranoia suggesting possible confounding. Only a minority of studies met the highest quality criteria. CONCLUSIONS: Shame is strongly associated with the severity of psychotic symptoms in clinical and non-clinical populations. Given the overlap with paranoia, measurement of external shame alone is not advised. Larger studies in clinical populations, with measures of a range of psychosis symptoms, are needed to better understand the relationship between shame and specific symptoms.

Receipt of the 5As intervention for smoking cessation among people with and without mental health disorders.

Brief interventions for smoking cessation, such as the 5As (ask, assess, advise, assist, arrange) are effective, but limited data are available regarding their delivery to smokers with mental health disorders (MHDs), and whether a disparity in care exists. This study explored the difference in the self-reported receipt of 5As between smokers with and without MHDs in a community setting. Baseline data from 1452 (1206 without and 246 with self-reported MHDs) Australian smokers who participated in a smoking cessation trial were analysed. Participants reported interactions with healthcare providers and receipt of the 5As over the past 12 months. Multivariate logistic regression analysis was employed to investigate the association between receipt of the 5As and MHD status. Smokers with MHDs were significantly more likely to be asked, assessed, advised, and assisted compared to those without MHDs, but arranging follow-up was very low in both groups (7.7% with MHDs and 4.1% without MHDs). This is particularly concerning for vulnerable population like smokers with MHDs, who may struggle more in their quit attempt. The findings highlight the need to enhance the implementation of the 'arrange follow-up' component to improve cessation outcomes and reduce health disparities.

Mirror-Image Random Nonstandard Peptide Integrated Discovery (MI-RaPID) Technology Yields Highly Stable and Selective Macrocyclic Peptide Inhibitors for Matrix Metallopeptidase 7.

Matrix metallopeptidase 7 (MMP7) plays a crucial role in cancer metastasis and progression, making it an attractive target for therapeutic development. However, the development of selective MMP7 inhibitors is challenging due to the conservation of active sites across various matrix metalloproteinases (MMPs). Here, we have developed mirror-image random nonstandard peptides integrated discovery (MI-RaPID) technology to discover innate protease-resistant macrocyclic peptides that specifically bind to and inhibit human MMP7. One identified macrocyclic peptide against D-MMP7, termed D20, was synthesized in its mirror-image form, D'20, consisting of 12 D-amino acids, one cyclic b-amino acid, and a thioether bond. Notably, it potently inhibited MMP7 with an IC50 value of 90 nM, and showed excellent selectivity over other MMPs with similar substrate specificity. Moreover, D'20 inhibited the migration of pancreatic cell line CFPAC-1, but had no effect on the cell proliferation and viability. D'20 exhibited excellent stability in human serum, as well as in simulated gastric and intestinal fluids. This study highlights that MI-RaPID technology can serve as a powerful tool to develop in vivo stable macrocyclic peptides for therapeutic applications.

RNA mis-splicing in children with myotonic dystrophy is associated with physical function.

Objectives: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Methods: 82 participants (42 DM1 adults & 40 CDM children) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL] inferred in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL] inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics. Results: Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL] inferred in our cohort of all DM1 individuals and when assessing CDM children independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL] inferred from select clinical outcome assessments alone in all subjects (adjusted R 2 = 0.6723) or exclusively in CDM children (adjusted R 2 = 0.5875). Interpretation: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL] inferred, in DM1. The strength of these correlations and the development of the predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.