Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

Exploitation of the host exocyst complex by bacterial pathogens.

Intracellular bacterial pathogens remodel the plasma membrane of eukaryotic cells in order to establish infection. A common and well-studied mechanism of plasma membrane remodelling involves bacterial stimulation of polymerization of the host actin cytoskeleton. Here, we discuss recent results showing that several bacterial pathogens also exploit the host vesicular trafficking pathway of 'polarized exocytosis' to expand and reshape specific regions in the plasma membrane during infection. Polarized exocytosis is mediated by an evolutionarily conserved octameric protein complex termed the exocyst. We describe examples in which the bacteria Listeria monocytogenes, Salmonella enterica serovar Typhimurium, and Shigella flexneri co-opt the exocyst to promote internalization into human cells or intercellular spread within host tissues. We also discuss results showing that Legionella pneumophila or S. flexneri manipulate exocyst components to modify membrane vacuoles to favour intracellular replication or motility of bacteria. Finally, we propose potential ways that pathogens manipulate exocyst function, discuss how polarized exocytosis might promote infection and highlight the importance of future studies to determine how actin polymerization and polarized exocytosis are coordinated to achieve optimal bacterial infection.

Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

DISCO: a database of Deeply Integrated human Single-Cell Omics data.

The ability to study cellular heterogeneity at single cell resolution is making single-cell sequencing increasingly popular. However, there is no publicly available resource that offers an integrated cell atlas with harmonized metadata that users can integrate new data with. Here, we present DISCO (https://www.immunesinglecell.org/), a database of Deeply Integrated Single-Cell Omics data. The current release of DISCO integrates more than 18 million cells from 4593 samples, covering 107 tissues/cell lines/organoids, 158 diseases, and 20 platforms. We standardized the associated metadata with a controlled vocabulary and ontology system. To allow large scale integration of single-cell data, we developed FastIntegration, a fast and high-capacity version of Seurat Integration. We also developed CELLiD, an atlas guided automatic cell type identification tool. Employing these two tools on the assembled data, we constructed one global atlas and 27 sub-atlases for different tissues, diseases, and cell types. DISCO provides three online tools, namely Online FastIntegration, Online CELLiD, and CellMapper, for users to integrate, annotate, and project uploaded single-cell RNA-seq data onto a selected atlas. Collectively, DISCO is a versatile platform for users to explore published single-cell data and efficiently perform integrated analysis with their own data.

The Role of Human Voice in Direct-To-Consumer Health Communication.

Despite overall positive perceptions, many customers distrust direct-to-consumer genetic testing companies in regard to privacy and aftercare. Prior research suggests companies can assuage mistrust by personalizing communication when discussing sensitive health information. This content analysis of customer e-mails (N = 338) investigates the purpose, personalization, and use of the human voice strategy by direct-to-consumer genetic testing companies to gain trust. Results reveal that companies rarely use human voice when communicating with customers, most of the information provided is promotional, and they invite dialogue less over time. Theoretical and practical implications are provided.

Can We Screen for Limb Length Discrepancy on Spinal Radiographs of Patients With Adolescent Idiopathic Scoliosis?

BACKGROUND: The aim of this study was to determine whether height differences in the levels of the iliac crests and femoral heads on erect spinal radiographs can be used as indirect measurements for the screening and surveillance of limb length discrepancy (LLD) in patients with scoliosis. METHODS: Whole body posteroanterior (PA) and lateral erect radiographs of patients with adolescent idiopathic scoliosis (AIS) were retrospectively reviewed. Patients with congenital, syndromic, and neuromuscular scoliosis were excluded. A direct measurement of each limb was taken from the highest point of the femoral head to the middle of the tibial plafond; any difference between the sides was recorded as the LLD. In addition, the PACS Software tool was used to measure femoral head height difference (FHHD) and iliac crest height difference (ICHD). Pearson's correlation, linear regression, and Bland-Altman plots were used to determine the relationships between LLD and FHHD, and LLD and ICHD. RESULTS: Radiographs of 141 patients (92 women, 49 men) with an average age of 12.0±2.65 years were analyzed. A strong correlation (r=0.730, P<0.001) was found between LLD and FHHD; the correlation between LLD and ICHD was weaker (r=0.585, P<0.001). The Bland-Altman analysis showed good agreements of LLD with FHHD and ICHD. Linear regression analysis predicted an LLD of ≤10 mm based on an FHHD of ≤11.5 mm or an ICHD of ≤15.3 mm. CONCLUSIONS: FHHD and ICHD on spinal PA radiographs can be used for the screening and monitoring of LLD in patients with AIS with FHHD being the preferred indirect measurement. These measurements are readily learned and quick to perform. The FHHD and ICHD can be measured on any erect scoliosis PA radiograph. Therefore, these proxy measurements can be used to screen and monitor for LLD in patients with AIS. LEVEL OF EVIDENCE: Level III.

Can the Lower Extremity Functional Scale Be Used in Children and Adolescents? A Validation Study.

BACKGROUND: The lower extremity functional scale (LEFS) is a patient-reported outcome measure for assessment of lower extremity function. It has been validated in adults but not in children or adolescents. METHODS: Patients 8 to 18 years of age who were treated for a lower limb fracture, injury, or other conditions were invited to join the study. LEFS and Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) were administered. Reliability and validity of the LEFS were determined for the entire cohort and for 2 age groups (children: 8 to 12 years; adolescents 13 to 18 years) using PedsQL as comparison. RESULTS: A total of 178 patients were recruited into this study. In the entire cohort, internal consistency of LEFS was excellent (0. 972) with acceptable floor (0%) and ceiling (12%) effects. Correlation between LEFS and PedsQL physical functioning component was high ( r =0.859). Construct validity was acceptable, with all 8 hypotheses demonstrating statistical significance. Factor analysis showed that item 15 (sitting for 1 hour) may contribute to measurement error in the pediatric population. Results remained similar when comparing the 2 age groups. CONCLUSIONS: The LEFS is overall an acceptable patient-reported outcome assessment of children and adolescents with various lower limbs disorders. LEVEL OF EVIDENCE: Level II.

Improved Comfortability and Satisfaction of Hybrid-mesh Casts in the Conservative Management of Pediatric Supracondylar Humeral Fractures: A Randomized Controlled Trial.

BACKGROUND: Cast immobilization is the mainstay of treatment for stable pediatric supracondylar humeral fractures (SCHFs). In recent years, a waterproof and breathable hybrid-mesh (HM) cast has emerged and been marketed to address common complaints such as itch, skin irritation, and malodor. Hence, this randomized controlled trial seeks to assess the overall satisfaction, comfort, and clinical outcomes of using HM casts in the conservative treatment of stable pediatric SCHF. METHODS: Seventy-nine patients (age range: 1 to 10 y) with modified Gartland's classification Type I and Type IIa SCHF were recruited and randomized for immobilization with either fiberglass or HM long-arm cast for 3 weeks. During follow-up visits, patients were assessed for any loss of reduction and skin rash. The weight of casts, the presence of cast breakage, the duration of cast application, and removal were recorded. A self-reported patient comfort and satisfaction questionnaire was also administered during the same visit. RESULTS: The final analysis included 38 patients immobilized with fiberglass casts and 39 patients with HM casts. Despite the significantly longer duration required for HM cast removal (4.18±1.25 min vs. 2.25±0.55 min, P <0.001), the HM cast was significantly lighter than its fiberglass counterpart (162.82±23.94 g vs. 203.95±36.52 g, P <0.001). The HM casts have better comfort (4.05±0.887 vs. 3.47±0.951, P =0.007) and satisfaction (3.69±1.055 vs. 3.11±0.953, P =0.012) scores as compared to fiberglass casts for immobilizing pediatric SCHF without compromising clinical outcome. CONCLUSIONS: HM casts have better comfort and overall satisfaction as compared to conventional fiberglass casts for immobilizing pediatric SCHF without compromising clinical outcomes. LEVEL OF EVIDENCE: Level II-therapeutic studies-investigating the results of treatment.

A pilot study on the "ScoliBrace" in the treatment of adolescent idiopathic scoliosis.

PURPOSE: Bracing for adolescents with idiopathic scoliosis (AIS) is a treatment option to prevent curve progression to surgical level. This study aimed to assess the efficacy of a 3D fully customized over corrective brace, "ScoliBrace," an orthosis treatment for AIS. METHODS: This was a prospective pilot study of AIS female patients with inclusion criteria followed recommended Scoliosis Research Society (SRS) Guidelines. Cobb angles measured at: baseline (T0), 21 months (T5-2), skeletal maturity (T6), 6 months post-brace (T7), along with hours of brace wear using a thermal sensor and health-related quality of life (HRQoL) using the SRS-22r questionnaire. RESULTS: A total of 30 female AIS patients with mean age 11.85 ± 0.68 years, predominantly Risser 0 (70%), and median Cobb angle 29° were recruited; 21 patients were included for the final analysis. Results showed significant difference in Cobb angle between T0 and T5-2 (median = 22.5° vs. 28.5°, p = 0.0082). 57.14% had reduction in Cobb angle by ≥ 5° at skeletal maturity. Cobb angle reduced 0.794° for each additional hour of dosage (p = 0.036, 95% CI = - 1.532°, - 0.056°). Although pain level was increased at T6 (4.37 ± 0.51vs.4.70 ± 0.41, p = 0.014), patients reported significantly greater satisfaction with management of their condition (3.90 ± 0.90vs.3.29 ± 0.88, p = 0.020). CONCLUSION: Results show similar findings to the BRAIST study, whereby curves remained under surgical threshold and showed improvement. More than half had curve reduction of ≥ 5° at skeletal maturity. Increased dose was also associated with improved outcomes. Using "ScoliBrace" as a non-surgical treatment, maintained curves below surgical threshold and showed curve reduction, improving patient satisfaction with management.

Gunther Tulip Filter Strut Penetration: Benign Long-Term Follow-up.

PURPOSE: To describe the natural history of Gunther Tulip filter (GTF) strut penetration based on the computed tomography (CT)-documented distance penetrated over time and any clinical manifestations. MATERIALS AND METHODS: The records of 203 patients (mean age, 59.1 years; 59.4% men) who had had an infrarenal GTF placed for venous thromboembolism (84.2%) with contraindications to anticoagulation (95.1%) and had CT follow-up were reviewed retrospectively for clinical or imaging evidence of complications. Filter strut penetration was measured on axial images from the outer caval wall to the inner edge of the distal end of each strut. Filter strut behavior over time was modeled using a linear mixed model. RESULTS: The extent of penetration correlated positively with filter dwell time (P < .001) but plateaued at 3.3 mm at 10-year follow-up. At median 4.7-year follow-up 79.3% of patients had at least 1 strut that was >0.2 mm and 31% had a strut >3 mm from the inferior vena caval wall. The extent of strut penetration was greater at all time points for women (P = .002). Abutment or entry into an adjacent structure was identified in 183 struts of 105 (52.7%) filters; of the 80 filters with CT follow-up, 47% showed progression and 19% regressed. There were no symptoms referable to filter strut penetration. CONCLUSIONS: GTF struts often penetrate the inferior vena cava progressively; however, this tends to plateau by 10 years. The limited long-term progression and a very low incidence of symptomatic complications together support a noninterventional approach to the finding of an asymptomatic GTF strut penetration.

An international RAND/UCLA expert panel to determine the optimal diagnosis and management of burn inhalation injury.

BACKGROUND: Burn inhalation injury (BII) is a major cause of burn-related mortality and morbidity. Despite published practice guidelines, no consensus exists for the best strategies regarding diagnosis and management of BII. A modified DELPHI study using the RAND/UCLA (University of California, Los Angeles) Appropriateness Method (RAM) systematically analysed the opinions of an expert panel. Expert opinion was combined with available evidence to determine what constitutes appropriate and inappropriate judgement in the diagnosis and management of BII. METHODS: A 15-person multidisciplinary panel comprised anaesthetists, intensivists and plastic surgeons involved in the clinical management of major burn patients adopted a modified Delphi approach using the RAM method. They rated the appropriateness of statements describing diagnostic and management options for BII on a Likert scale. A modified final survey comprising 140 statements was completed, subdivided into history and physical examination (20), investigations (39), airway management (5), systemic toxicity (23), invasive mechanical ventilation (29) and pharmacotherapy (24). Median appropriateness ratings and the disagreement index (DI) were calculated to classify statements as appropriate, uncertain, or inappropriate. RESULTS: Of 140 statements, 74 were rated as appropriate, 40 as uncertain and 26 as inappropriate. Initial intubation with ≥ 8.0 mm endotracheal tubes, lung protective ventilatory strategies, initial bronchoscopic lavage, serial bronchoscopic lavage for severe BII, nebulised heparin and salbutamol administration for moderate-severe BII and N-acetylcysteine for moderate BII were rated appropriate. Non-protective ventilatory strategies, high-frequency oscillatory ventilation, high-frequency percussive ventilation, prophylactic systemic antibiotics and corticosteroids were rated inappropriate. Experts disagreed (DI ≥ 1) on six statements, classified uncertain: the use of flexible fiberoptic bronchoscopy to guide fluid requirements (DI = 1.52), intubation with endotracheal tubes of internal diameter < 8.0 mm (DI = 1.19), use of airway pressure release ventilation modality (DI = 1.19) and nebulised 5000IU heparin, N-acetylcysteine and salbutamol for mild BII (DI = 1.52, 1.70, 1.36, respectively). CONCLUSIONS: Burns experts mostly agreed on appropriate and inappropriate diagnostic and management criteria of BII as in published guidance. Uncertainty exists as to the optimal diagnosis and management of differing grades of severity of BII. Future research should investigate the accuracy of bronchoscopic grading of BII, the value of bronchial lavage in differing severity groups and the effectiveness of nebulised therapies in different severities of BII.

Study protocol of the Our Futures Vaping Trial: a cluster randomised controlled trial of a school-based eHealth intervention to prevent e-cigarette use among adolescents.

BACKGROUND: Effective and scalable prevention approaches are urgently needed to address the rapidly increasing rates of e-cigarette use among adolescents. School-based eHealth interventions can be an efficient, effective, and economical approach, yet there are none targeting e-cigarettes within Australia. This paper describes the protocol of the OurFutures Vaping Trial which aims to evaluate the efficacy and cost-effectiveness of the first school-based eHealth intervention targeting e-cigarettes in Australia. METHODS: A two-arm cluster randomised controlled trial will be conducted among Year 7 and 8 students (aged 12-14 years) in 42 secondary schools across New South Wales, Western Australia and Queensland, Australia. Using stratified block randomisation, schools will be assigned to either the OurFutures Vaping Program intervention group or an active control group (health education as usual). The intervention consists of four web-based cartoon lessons and accompanying activities delivered during health education over a four-week period. Whilst primarily focused on e-cigarette use, the program simultaneously addresses tobacco cigarette use. Students will complete online self-report surveys at baseline, post-intervention, 6-, 12-, 24-, and 36-months after baseline. The primary outcome is the uptake of e-cigarette use at 12-month follow-up. Secondary outcomes include the uptake of tobacco smoking, frequency/quantity of e-cigarettes use and tobacco smoking, intentions to use e-cigarettes/tobacco cigarettes, knowledge about e-cigarettes/tobacco cigarettes, motives and attitudes relating to e-cigarettes, self-efficacy to resist peer pressure and refuse e-cigarettes, mental health, quality of life, and resource utilisation. Generalized mixed effects regression will investigate whether receiving the intervention reduces the likelihood of primary and secondary outcomes. Cost-effectiveness and the effect on primary and secondary outcomes will also be examined over the longer-term. DISCUSSION: If effective, the intervention will be readily accessible to schools via the OurFutures platform and has the potential to make substantial health and economic impact. Without such intervention, young Australians will be the first generation to use nicotine at higher rates than previous generations, thereby undoing decades of effective tobacco control. TRIAL REGISTRATION: The trial has been prospectively registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12623000022662; date registered: 10/01/2023).

The machine-vision image guided surgery system reduces fluoroscopy time, ionizing radiation and intraoperative blood loss in posterior spinal fusion for scoliosis.

PURPOSE: To determine if the novel 3D Machine-Vision Image Guided Surgery (MvIGS) (FLASH™) system can reduce intraoperative radiation exposure, while improving surgical outcomes when compared to 2D fluoroscopic navigation. METHODS: Clinical and radiographic records of 128 patients (≤ 18 years of age) who underwent posterior spinal fusion (PSF), utilising either MvIGS or 2D fluoroscopy, for severe idiopathic scoliosis were retrospectively reviewed. Operative time was analysed using the cumulative sum (CUSUM) method to evaluate the learning curve for MvIGS. RESULTS: Between 2017 and 2021, 64 patients underwent PSF using pedicle screws with 2D fluoroscopy and another 64 with the MvIGS. Age, gender, BMI, and scoliosis aetiology were comparable between the two groups. The CUSUM method estimated that the MvIGS learning curve with respect to operative time was 9 cases. This curve consisted of 2 phases: Phase 1 comprises the first 9 cases and Phase 2 the remaining 55 cases. Compared to 2D fluoroscopy, MvIGS reduced intraoperative fluoroscopy time, radiation exposure, estimated blood loss and length of stay by 53%, 62% 44%, and 21% respectively. Scoliosis curve correction was 4% higher in the MvIGS group, without any increase in operative time. CONCLUSION: MvIGS for screw insertion in PSF contributed to a significant reduction in intraoperative radiation exposure and fluoroscopy time, as well as blood loss and length of stay. The real-time feedback and ability to visualize the pedicle in 3D with MvIGS enabled greater curve correction without increasing the operative time.

'We don't live in a harm reduction world, we live in a prohibition world': tensions arising in the design of drug alerts.

BACKGROUND: Drug alerts designed for health and community workforces have potential to avert acute harms associated with unpredictable illicit drug markets, by preparing workers to respond to unusual drug-related events, and distribute information to service users. However, the design of such alerts is complicated by diverse needs of individuals, and broader socio-political contexts. Here, we discuss the tensions that arose in the process of co-designing drug alert templates with health and community workers. METHODS: We conducted five in-depth digital co-design workshops with 31 workers employed in alcohol and other drug and urgent care settings. Our approach to analysis was informed by Iterative Categorisation and reflexive thematic analysis methods. RESULTS: We identified five key tensions. First, there is a need to provide comprehensive information to meet the information needs of a diverse group of workers with varying knowledge levels, while also designing alerts to be clear, concise, and relevant to the work of individuals. Second, it is important that alerts do not create 'information overload'; however, it is also important that information should be available to those who want it. Third, alert design and dissemination must be perceived to be credible, to avoid 'alert scepticism'; however, credibility is challenging to develop in a broader context of criminalisation, stigmatisation, and sensationalism. Fourth, alerts must be carefully designed to achieve 'intended effects' and avoid unintended effects, while acknowledging that it is impossible to control all potential effects. Finally, while alerts may be intended for an audience of health and community workers, people who use drugs are the end-users and must be kept front of mind in the design process. CONCLUSIONS: The co-design process revealed complexities in designing drug alerts, particularly in the context of stigmatised illicit drug use, workforce diversity, and dissemination strategies. This study has highlighted the value of developing these important risk communication tools with their target audiences to ensure that they are relevant, useful, and impactful. The findings have informed the development of our drug alert prototypes and provide local context to complement existing best-practice risk-communications literature.

Co-designing drug alerts for health and community workers for an emerging early warning system in Victoria, Australia.

BACKGROUND: Alerts about changes in unregulated drug markets may be useful for supporting health and community workers to anticipate, prevent, and respond to unexpected adverse drug events. This study aimed to establish factors influencing the successful design and implementation of drug alerts for use in clinical and community service settings in Victoria, Australia. METHODS: An iterative mixed methods design was used to co-produce drug alert prototypes with practitioners and managers working across various alcohol and other drug services and emergency medicine settings. A quantitative needs-analysis survey (n = 184) informed five qualitative co-design workshops (n = 31). Alert prototypes were drafted based on findings and tested for utility and acceptability. Applicable constructs from the Consolidated Framework for Implementation Research helped to conceptualise factors that impact successful alert system design. RESULTS: Timely and reliable alerts about unexpected drug market changes were important to nearly all workers (98%) yet many reported insufficient access to this kind of information (64%). Workers considered themselves 'conduits' for information-sharing and valued alerts for increasing exposure to drug market intelligence; facilitating communication about potential threats and trends; and improving capacity for effective responding to drug-related harm. Alerts should be 'shareable' across a range of clinical and community settings and audiences. To maximise engagement and impact, alerts must command attention, be easily recognisable, be available on multiple platforms (electronic and printable formats) in varying levels of detail, and be disseminated via appropriate notification mechanisms to meet the needs of diverse stakeholder groups. Three drug alert prototypes (SMS prompt, summary flyer, and a detailed poster) were endorsed by workers as useful for supporting their work responding to unexpected drug-related harms. DISCUSSION: Alerts informed by coordinated early warning networks that offer close to real-time detection of unexpected substances can provide rapid, evidence-based drug market intelligence to inform preventive and responsive action to drug-related harm. The success of alert systems requires adequate planning and resourcing to support design, implementation, and evaluation, which includes consultation with all relevant audiences to understand how to maximise engagement with information, recommendations, and advice. Our findings about factors impacting successful alert design have utility to inform the development of local early warning systems.

Accurate genome-wide genotyping from archival tissue to explore the contribution of common genetic variants to pre-cancer outcomes.

PURPOSE: The contribution of common genetic variants to pre-cancer progression is understudied due to long follow-up time, rarity of poor outcomes and lack of available germline DNA collection. Alternatively, DNA from diagnostic archival tissue is available, but its somatic nature, limited quantity and suboptimal quality would require an accurate cost-effective genome-wide germline genotyping methodology. EXPERIMENTAL DESIGN: Blood and tissue DNA from 10 individuals were used to benchmark the accuracy of Single Nucleotide Polymorphisms (SNP) genotypes, Polygenic Risk Scores (PRS) or HLA haplotypes using low-coverage whole-genome sequencing (lc-WGS) and genotype imputation. Tissue-derived PRS were further evaluated for 36 breast cancer patients (11.7 years median follow-up time) diagnosed with DCIS and used to model the risk of Breast Cancer Subsequent Events (BCSE). RESULTS: Tissue-derived germline DNA profiling resulted in accurate genotypes at common SNPs (blood correlation r2 > 0.94) and across 22 disease-related polygenic risk scores (PRS, mean correlation r = 0.93). Imputed Class I and II HLA haplotypes were 96.7% and 82.5% concordant with clinical-grade blood HLA haplotypes, respectively. In DCIS patients, tissue-derived PRS was significantly associated with BCSE (HR = 2, 95% CI 1.2-3.8). The top and bottom decile patients had an estimated 28% and 5% chance of BCSE at 10 years, respectively. CONCLUSIONS: Archival tissue DNA germline profiling using lc-WGS and imputation, represents a cost and resource-effective alternative in the retrospective design of long-term disease genetic studies. Initial results in breast cancer suggest that common risk variants contribute to pre-cancer progression.

Shigellosis Cases With Bacterial Sexually Transmitted Infections: Population-Based Data From 6 US Jurisdictions, 2007 to 2016.

BACKGROUND: Shigella species, which cause acute diarrheal disease, are transmitted via fecal-oral and sexual contact. To better understand the overlapping populations affected by Shigella infections and sexually transmitted infections (STIs) in the United States, we examined the occurrence of reported STIs within 24 months among shigellosis case-patients. METHODS: Culture-confirmed Shigella cases diagnosed from 2007 to 2016 among residents of 6 US jurisdictions were matched to reports of STIs (chlamydia, gonorrhea, and all stages of syphilis) diagnosed 12 months before or after the shigellosis case. We examined epidemiologic characteristics and reported temporal trends of Shigella cases by sex and species. RESULTS: From 2007 to 2016, 10,430 shigellosis cases were reported. The annual number of reported shigellosis cases across jurisdictions increased 70%, from 821 cases in 2007 to 1398 cases in 2016; males saw a larger increase compared with females. Twenty percent of male shigellosis case-patients had an STI reported in the reference period versus 4% of female case-patients. The percentage of male shigellosis case-patients with an STI increased from 11% (2007) to 28% (2016); the overall percentage among females remained low. CONCLUSIONS: We highlight the substantial proportion of males with shigellosis who were diagnosed with STIs within 24 months and the benefit of matching data across programs. Sexually transmitted infection screening may be warranted for male shigellosis case-patients.

Chylous ascites in the setting of internal hernia: a reassuring sign.

BACKGROUND: Chylous ascites is often reported in cases with lymphatic obstruction or after lymphatic injuries such as intraabdominal malignancies or lymphadenectomies. However, chylous ascites is also frequently encountered in operations for internal hernias. We sought to characterize the frequency and conditions when chylous ascites is encountered in general surgery patients. METHODS: Data from patients who underwent operations for CPT codes related to open and laparoscopic abdominal and gastrointestinal surgery in our tertiary hospital from 2010 to 2019 were reviewed. Patients with the postoperative diagnosis of internal hernia were identified and categorized into three groups: Internal Hernia with chylous ascites, non-chylous ascites, and no ascites. Demographics, prior surgical history, CT findings, source of internal hernia, open or laparoscopic surgery, and preoperative labs were recorded and compared. RESULTS: Fifty-six patients were found to have internal hernias and were included in our study. 80.3% were female and 86% had a previous Roux-en-Y gastric bypass procedure (RYGBP). Laparoscopy was the main approach for all groups. Ascites was present in 46% of the cases. Specifically, chylous ascites was observed in 27% of the total operations and was exclusively (100%) found in patients with gastric-bypass history. Furthermore, it was more commonly associated with Petersen's defect (p < 0.001), while the non-chylous fluid group was associated with herniation through the mesenteric defect (p < 0.001). CONCLUSIONS: Chylous ascites is a common finding during internal hernia operations. Unlike other more morbid conditions, identification of chylous ascites during an internal hernia operation appears innocuous. However, in the context of a patient with a history of RYGBP, the presence of chylous fluid signifies the associated small bowel obstruction is likely related to an internal hernia through a patent Petersen's defect.

Mechanical Response of Mouse Cervices Lacking Decorin and Biglycan During Pregnancy.

Cervical remodeling is critical for a healthy pregnancy. The proper regulation of extracellular matrix (ECM) turnover leads to remodeling throughout gestation, transforming the tissue from a stiff material to a compliant, extensible, viscoelastic tissue prepared for delivery. Small leucine-rich proteoglycans (SLRPs) regulate structural fiber assembly in the cervical ECM and overall tissue material properties. To quantify the SLRPs' mechanical role in the cervix, whole cervix specimens from nonpregnant and late pregnant knockout mice of SLRPs, decorin and biglycan, were subjected to cyclic load-unload, ramp-hold, and load-to-failure mechanical tests. Further, a fiber composite material model, accounting for collagen fiber bundle waviness, was developed to describe the cervix's three-dimensional large deformation equilibrium behavior. In nonpregnant tissue, SLRP knockout cervices have the same equilibrium material properties as wild-type tissue. In contrast, the load-to-failure and ramp-hold tests reveal SLRPs impact rupture and time-dependent relaxation behavior. Loss of decorin in nonpregnant (NP) cervices results in inferior rupture properties. After extensive remodeling, cervical strength is similar between all genotypes, but the SLRP-deficient tissue has a diminished ability to dissipate stress during a ramp-hold. In mice with a combined loss of decorin and biglycan, the pregnant cervix loses its extensibility, compliance, and viscoelasticity. These results suggest that decorin and biglycan are necessary for crucial extensibility and viscoelastic material properties of a healthy, remodeled pregnant cervix.

School and learning contexts during the COVID-19 pandemic: Implications for child and youth mental health.

Despite significant disruption to school during the COVID-19 pandemic, research on the impact on children is sparse. This study examines in-person and virtual learning contexts and the impact of school format on mental health (MH). Children and adolescents were recruited from community and clinical settings. Parents and children completed prospective online surveys about school experiences (November 2020) and MH symptoms (February/March 2021), including school format and activities. Standardized measures of depression, anxiety, inattention, and hyperactivity were collected. Hierarchical regression analyses tested associations between school format and MH. Children (N = 1011; aged 6-18 years) attending school in-person (n = 549) engaged in high levels of participation in COVID-19 health measures and low levels of social learning activities. Learning online in high school was associated with greater MH symptoms (B = -2.22, CI[-4.32,-.12] to B = -8.18, CI[-15.59,-.77]). Children with no previous MH condition that attended school virtually experienced a similar magnitude of MH symptoms as those with previous MH conditions. However, children who attended school in a hybrid in-person format, with no previous MH condition, experienced less hyperactivity as same-age peers with prior MH problems (B = -8.08, CI[1.58,14.58]). Children's learning environments looked very different compared to before the pandemic. Removing children from school environments and limiting opportunities that support their MH, such as social learning activities, is problematic. Efforts to address the learning contexts to protect the mental health of children are needed.