Myogenin and class II HDACs control neurogenic muscle atrophy by inducing E3 ubiquitin ligases.

Maintenance of skeletal muscle structure and function requires innervation by motor neurons, such that denervation causes muscle atrophy. We show that myogenin, an essential regulator of muscle development, controls neurogenic atrophy. Myogenin is upregulated in skeletal muscle following denervation and regulates expression of the E3 ubiquitin ligases MuRF1 and atrogin-1, which promote muscle proteolysis and atrophy. Deletion of myogenin from adult mice diminishes expression of MuRF1 and atrogin-1 in denervated muscle and confers resistance to atrophy. Mice lacking histone deacetylases (HDACs) 4 and 5 in skeletal muscle fail to upregulate myogenin and also preserve muscle mass following denervation. Conversely, forced expression of myogenin in skeletal muscle of HDAC mutant mice restores muscle atrophy following denervation. Thus, myogenin plays a dual role as both a regulator of muscle development and an inducer of neurogenic atrophy. These findings reveal a specific pathway for muscle wasting and potential therapeutic targets for this disorder.

Cardiovascular Disease Risk Factor Control in People With and Without HIV.

BACKGROUND: Management of hypertension, dyslipidemia, diabetes and other modifiable factors may mitigate the cardiovascular disease (CVD) risk in people with human immunodeficiency virus (HIV, PWH) compared with people without HIV (PWoH). METHODS: This was a retrospective cohort study of 8285 PWH and 170 517 PWoH from an integrated health system. Risk factor control was measured using a novel disease management index (DMI) accounting for amount/duration above treatment goals (0% to 100% [perfect control]), including 2 DMIs for hypertension (diastolic and systolic blood pressure), 3 for dyslipidemia (low-density lipoprotein, total cholesterol, triglycerides), and 1 for diabetes (HbA1c). CVD risk by HIV status was evaluated overall and in subgroups defined by DMIs, smoking, alcohol use, and overweight/obesity in adjusted Cox proportional hazards models. RESULTS: PWH and PWoH had similar DMIs (80%-100%) except for triglycerides (worse for PWH) and HbA1c (better for PWH). In adjusted models, PWH had an elevated risk of CVD compared with PWoH (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.07-1.31). This association was attenuated in subgroups with controlled dyslipidemia and diabetes but remained elevated for PWH with controlled hypertension or higher total cholesterol. The strongest HIV status association with CVD was seen in the subgroup with frequent unhealthy alcohol use (HR, 2.13; 95% CI, 1.04-4.34). CONCLUSIONS: Control of dyslipidemia and diabetes, but not hypertension, attenuated the HIV status association with CVD. The strong association of HIV and CVD with frequent unhealthy alcohol use suggests enhanced screening and treatment of alcohol problems in PWH is warranted.

Probiotic Bacillus spp. enhance TLR3-mediated TNF signalling in macrophages.

Probiotics have been reported to have immunomodulatory properties in the context of infectious disease and inflammation, although the underlying mechanisms are not fully understood. Here, we aimed to determine how different probiotic bacterial strains modulated macrophage function during TLR3 stimulation mimicking viral infection. We screened 14 different strains for their ability to modulate TNF-α, IL-6 IL-10, IFN-α, IFN-ß and IFN-γ secretion in RAW 264.7 macrophages with or without poly(I:C) stimulation. Seven strains were selected for further analysis using primary porcine alveolar macrophages. In-depth transcriptomic analysis on alveolar macrophages was conducted for two strains. Most strains induced a synergistic effect when co-incubated with poly(I:C) resulting in increased levels of IL-6 and TNF-α secretion from RAW 264.7 cells. This synergistic effect was found to be TLR2 independent. Only strains of Bacillus spp. could induce this effect in alveolar macrophages. Transcriptomic analysis indicated that the increased TNF-α secretion in alveolar macrophages after co-incubation with poly(I:C) correlated with significant upregulation of TNF and IL23A-related pathways. Collectively, our data show that probiotic bacteria possess strain-dependent immunomodulatory properties that may be harnessed to enhance innate immune responses to pathogens.

Unlocking the Power of Transcriptomic Biomarkers in Qualitative and Quantitative Genotoxicity Assessment of Chemicals.

To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known in vivo genotoxicants and two in vivo nongenotoxicants). Gene expression data were generated using the TempO-Seq technology. We found a prediction performance of 100%, confirming the applicability of GENOMARK to TempO-Seq. Classification using TGx-DDI was then compared to GENOMARK. For the chemicals identified as genotoxic, benchmark concentration modeling was conducted to perform potency ranking. The high concordance observed for both hazard classification and potency ranking by GENOMARK and TGx-DDI highlights the value of integrating these NAMs in a weight of evidence evaluation of genotoxicity.

Empirical Characterization of False Discovery Rates of Differentially Expressed Genes and Transcriptomic Benchmark Concentrations in Zebrafish Embryos.

High-throughput transcriptomics (HTTr) is increasingly applied to zebrafish embryos to survey the toxicological effects of environmental chemicals. Before the adoption of this approach in regulatory testing, it is essential to characterize background noise in order to guide experimental designs. We thus empirically quantified the HTTr false discovery rate (FDR) across different embryo pool sizes, sample sizes, and concentration groups for toxicology studies. We exposed zebrafish embryos to 0.1% dimethyl sulfoxide (DMSO) for 5 days. Pools of 1, 5, 10, and 20 embryos were created (n = 24 samples for each pool size). Samples were sequenced on the TempO-Seq platform and then randomly assigned to mock treatment groups before differentially expressed gene (DEG), pathway, and benchmark concentration (BMC) analyses. Given that all samples were treated with DMSO, any significant DEGs, pathways, or BMCs are false positives. As expected, we found decreasing FDRs for DEG and pathway analyses with increasing pool and sample sizes. Similarly, FDRs for BMC analyses decreased with increasing pool size and concentration groups, with more stringent BMC premodel filtering reducing BMC FDRs. Our study provides foundational data for determining appropriate experiment designs for regulatory toxicity testing with HTTr in zebrafish embryos.

Impact of temperature on physical and cognitive performance in elite female football players during intermittent exercise.

There is limited research on female football players, especially related to their physical and cognitive performance under different climactic conditions. We analyzed the impact of a hot environmental temperature on physical performance and anticipation in elite female football players during a fatigue-inducing intermittent protocol. Elite female players (n = 21) performed the countermovement jump (CMJ) and responded to filmed sequences of offensive play under two distinct environmental temperatures (i.e., mild environment temperature- 20°C and 30% rh versus hot environment temperature- 38°C and 80% rh), interspersed by 1-week interval. Linear mixed models were used. CMJ performance declined following the intermittent protocol on both temperature conditions (p < 0.05). Moreover, there were significant main effects for protocol on CMJ speed (m/s) (p = 0.001; ηp 2 = 0.12), CMJ power (p = 0.002; ηp 2 = 0.11), and CMJ Heightmax (p = 0.002; ηp 2 = 0.12). After performing the intermittent protocol, exposure to a hot temperature caused a greater decline in anticipation accuracy (mild temperature = 64.41% vs. hot temperature = 53.44%; p < 0.001). Our study shows impaired performance in elite female football players following an intermittent protocol under hot compared with mild environmental conditions. We report decreased performance in both CMJ and anticipation performance under hotter conditions. The results reveal that exposure to hot temperatures had a negative effect on the accuracy of their anticipatory behaviors. We consider the implication of the work for research and training interventions.

Social Determinants of Health and Limitation of Life-Sustaining Therapy in Neurocritical Care: A CHoRUS Pilot Project.

BACKGROUND: Social determinants of health (SDOH) have been linked to neurocritical care outcomes. We sought to examine the extent to which SDOH explain differences in decisions regarding life-sustaining therapy, a key outcome determinant. We specifically investigated the association of a patient's home geography, individual-level SDOH, and neighborhood-level SDOH with subsequent early limitation of life-sustaining therapy (eLLST) and early withdrawal of life-sustaining therapy (eWLST), adjusting for admission severity. METHODS: We developed unique methods within the Bridge to Artificial Intelligence for Clinical Care (Bridge2AI for Clinical Care) Collaborative Hospital Repository Uniting Standards for Equitable Artificial Intelligence (CHoRUS) program to extract individual-level SDOH from electronic health records and neighborhood-level SDOH from privacy-preserving geomapping. We piloted these methods to a 7 years retrospective cohort of consecutive neuroscience intensive care unit admissions (2016-2022) at two large academic medical centers within an eastern Massachusetts health care system, examining associations between home census tract and subsequent occurrence of eLLST and eWLST. We matched contextual neighborhood-level SDOH information to each census tract using public data sets, quantifying Social Vulnerability Index overall scores and subscores. We examined the association of individual-level SDOH and neighborhood-level SDOH with subsequent eLLST and eWLST through geographic, logistic, and machine learning models, adjusting for admission severity using admission Glasgow Coma Scale scores and disorders of consciousness grades. RESULTS: Among 20,660 neuroscience intensive care unit admissions (18,780 unique patients), eLLST and eWLST varied geographically and were independently associated with individual-level SDOH and neighborhood-level SDOH across diagnoses. Individual-level SDOH factors (age, marital status, and race) were strongly associated with eLLST, predicting eLLST more strongly than admission severity. Individual-level SDOH were more strongly predictive of eLLST than neighborhood-level SDOH. CONCLUSIONS: Across diagnoses, eLLST varied by home geography and was predicted by individual-level SDOH and neighborhood-level SDOH more so than by admission severity. Structured shared decision-making tools may therefore represent tools for health equity. Additionally, these findings provide a major warning: prognostic and artificial intelligence models seeking to predict outcomes such as mortality or emergence from disorders of consciousness may be encoded with self-fulfilling biases of geography and demographics.

Dietary non-starch polysaccharides impair immunity to enteric nematode infection.

BACKGROUND: The influence of diet on immune function and resistance to enteric infection and disease is becoming ever more established. Highly processed, refined diets can lead to inflammation and gut microbiome dysbiosis, whilst health-promoting dietary components such as phytonutrients and fermentable fibres are thought to promote a healthy microbiome and balanced mucosal immunity. Chicory (Cichorium intybus) is a leafy green vegetable rich in fibres and bioactive compounds that may promote gut health. RESULTS: Unexpectedly, we here show that incorporation of chicory into semisynthetic AIN93G diets renders mice susceptible to infection with enteric helminths. Mice fed a high level of chicory leaves (10% dry matter) had a more diverse gut microbiota, but a diminished type-2 immune response to infection with the intestinal roundworm Heligmosomoides polygyrus. Furthermore, the chicory-supplemented diet significantly increased burdens of the caecum-dwelling whipworm Trichuris muris, concomitant with a highly skewed type-1 immune environment in caecal tissue. The chicory-supplemented diet was rich in non-starch polysaccharides, particularly uronic acids (the monomeric constituents of pectin). In accordance, mice fed pectin-supplemented AIN93G diets had higher T. muris burdens and reduced IgE production and expression of genes involved in type-2 immunity. Importantly, treatment of pectin-fed mice with exogenous IL-25 restored type-2 responses and was sufficient to allow T. muris expulsion. CONCLUSIONS: Collectively, our data suggest that increasing levels of fermentable, non-starch polysaccharides in refined diets compromises immunity to helminth infection in mice. This diet-infection interaction may inform new strategies for manipulating the gut environment to promote resistance to enteric parasites.

Frequency of Persistent Opioid Use 6 Months After Exposure to IV Opioids in the Emergency Department: A Prospective Cohort Study.

BACKGROUND: As rates of opioid use disorder in the general population have increased, some have questioned whether IV opioids should be used routinely for treatment of acute severe pain in the emergency department (ED). OBJECTIVES: We determined the incidence of persistent opioid use among opioid-naïve patients exposed to IV opioids in the ED. METHODS: This was a prospective observational cohort study conducted in two EDs in the Bronx, NY. Opioid-naïve adults with severe pain who received IV opioids in the ED were followed-up 6 months later by telephone interview and review of the state opioid prescription database. We defined persistent opioid use as filling 6 or more prescriptions for opioids in the 6 months following the ED visit or an average of one prescription per month. RESULTS: We screened 1555 patients. Of these, 506 patients met entry criteria and provided analyzable data. Morphine was the IV opioid most frequently administered in the ED (478, 94%), followed by hydromorphone (20, 4%). Of the 506, 8 (2%) received both IV morphine and hydromorphone and 63 (12%) participants were prescribed an opioid for use after the ED visit. One patient/506 (0%) met our apriori criteria for persistent opioid use within 6 months. CONCLUSION: Among 506 opioid naïve ED patients administered IV opioids for acute severe pain, only one used opioids persistently during the subsequent 6 months.

Whipworm Infection in Mice Increases Coinfection of Enteric Pathogens but Promotes Clearance of Ascaris Larvae From the Lungs.

Infection with intestinal whipworms (Trichuris spp.) causes widespread morbidity and may alter responses to enteric and extraintestinal coinfections. Here, we show that Trichuris muris infection in mice increases coinfection with 2 evolutionary divergent enteric pathogens, the bacterium Citrobacter rodentium and the helminth Heligmosomoides polygyrus. Coinfection caused reduced weight gain and promoted type 1-biased inflammation. In contrast, T. muris-infected mice were more resistant to migrating Ascaris suum larvae in the lungs. Our results highlight the divergent nature of pathogen interactions and suggest that whipworm infection is a risk factor for coinfections with other pathogens within the gastrointestinal tract.

Modulation of insulin signaling pathway genes by ozone inhalation and the role of glucocorticoids: A multi-tissue analysis.

Air pollution is associated with increased risk of metabolic diseases including type 2 diabetes, of which dysregulation of the insulin-signaling pathway is a feature. While studies suggest pollutant exposure alters insulin signaling in certain tissues, there is a lack of comparison across multiple tissues needed for a holistic assessment of metabolic effects, and underlying mechanisms remain unclear. Air pollution increases plasma levels of glucocorticoids, systemic regulators of metabolic function. The objectives of this study were to 1) determine effects of ozone on insulin-signaling genes in major metabolic tissues, and 2) elucidate the role of glucocorticoids. Male Fischer-344 rats were treated with metyrapone, a glucocorticoid synthesis inhibitor, and exposed to 0.8 ppm ozone or clean air for 4 h, with tissue collected immediately or 24 h post exposure. Ozone inhalation resulted in distinct mRNA profiles in the liver, brown adipose, white adipose and skeletal muscle tissues, including effects on insulin-signaling cascade genes (Pik3r1, Irs1, Irs2) and targets involved in glucose metabolism (Hk2, Pgk1, Slc2a1), cell survival (Bcl2l1), and genes associated with diabetes and obesity (Serpine1, Retn, Lep). Glucocorticoid-dependent regulation was observed in the liver and brown and white adipose tissues, while effects in skeletal muscle were largely unaffected by metyrapone treatment. Gene expression changes were accompanied by altered phosphorylation states of insulin-signaling proteins (BAD, GSK, IR-ß, IRS-1) in the liver. The results show that systemic effects of ozone inhalation include tissue-specific regulation of insulin-signaling pathway genes via both glucocorticoid-dependent and independent mechanisms, providing insight into mechanisms underlying adverse effects of pollutants.

Dietary proanthocyanidins promote localized antioxidant responses in porcine pulmonary and gastrointestinal tissues during Ascaris suum-induced type 2 inflammation.

Proanthocyanidins (PAC) are dietary polyphenols with putative anti-inflammatory and immunomodulatory effects. However, whether dietary PAC can regulate type-2 immune function and inflammation at mucosal surfaces remains unclear. Here, we investigated if diets supplemented with purified PAC modulated pulmonary and intestinal mucosal immune responses during infection with the helminth parasite Ascaris suum in pigs. A. suum infection induced a type-2 biased immune response in lung and intestinal tissues, characterized by pulmonary granulocytosis, increased Th2/Th1 T cell ratios in tracheal-bronchial lymph nodes, intestinal eosinophilia, and modulation of genes involved in mucosal barrier function and immunity. Whilst PAC had only minor effects on pulmonary immune responses, RNA-sequencing of intestinal tissues revealed that dietary PAC significantly enhanced transcriptional responses related to immune function and antioxidant responses in the gut of both naïve and A. suum-infected animals. A. suum infection and dietary PAC induced distinct changes in gut microbiota composition, primarily in the jejunum and colon, respectively. Notably, PAC consumption substantially increased the abundance of Limosilactobacillus reuteri. In vitro experiments with porcine macrophages and intestinal epithelial cells supported a role for both PAC polymers and PAC-derived microbial metabolites in regulating oxidative stress responses in host tissues. Thus, dietary PAC may have distinct beneficial effects on intestinal health during infection with mucosal pathogens, while having a limited activity to modulate naturally-induced type-2 pulmonary inflammation. Our results shed further light on the mechanisms underlying the health-promoting properties of PAC-rich foods, and may aid in the design of novel dietary supplements to regulate mucosal inflammatory responses in the gastrointestinal tract.

Diet-microbiota crosstalk and immunity to helminth infection.

Helminths are large multicellular parasites responsible for widespread chronic disease in humans and animals. Intestinal helminths live in close proximity with the host gut microbiota and mucosal immune network, resulting in reciprocal interactions that closely influence the course of infections. Diet composition may strongly regulate gut microbiota composition and intestinal immune function and therefore may play a key role in modulating anti-helminth immune responses. Characterizing the multitude of interactions that exist between different dietary components (e.g., dietary fibres), immune cells, and the microbiota, may shed new light on regulation of helminth-specific immunity. This review focuses on the current knowledge of how metabolism of dietary components shapes immune response during helminth infection, and how this information may be potentially harnessed to design new therapeutics to manage parasitic infections and associated diseases.

Oral administration of helminth fluid modulates distinct tuft cell and immune-metabolic cues linked to reduced body fat.

Intestinal tuft cells have been shown to induce type 2 immune responses during viable parasite infections, but whether oral supplementation with a parasitic exudate is able to promote type 2 immune responses that have been shown to positively regulate obesogenic metabolic processes is yet unresolved. High-fat fed mice were gavaged with pseudocoelomic fluid (PCF) derived from the helminth Ascaris suum or saline thrice a week during weeks 5-9, followed by examination of intestinal tuft cell activity, immune, and metabolic parameters. Helminth PCF upregulated expression of distinct genes in small intestinal tuft cells, including genes involved in regulation of RUNX1 and organic cation transporters. Helminth PCF also enhanced levels of innate lymphoid cells in the ileum, and eosinophils in epididymal white adipose tissue (eWAT). Network analyses revealed two distinct immunometabolic cues affected by oral helminth PCF in high-fat fed mice: one coupling the small intestinal tuft cell responses to the fat-to-lean mass ratio and a second coupling eosinophils in eWAT to general regulation of body fat mass. Our findings point to specific mechanisms by which oral supplementation with helminth PCF may translate into systems-wide effects linking to reduced body and fat mass gain in mice during high-fat feeding.

Total pelvic floor ultrasound can reliably predict long-term treatment outcomes for patients with pelvic floor defaecatory dysfunction.

AIM: Integrated total pelvic floor ultrasound (TPFUS) may provide an alternative to defaecation proctography (DP) in decision making and treatment planning for patients with pelvic floor defaecatory dysfunction (PFDD). This study evaluates the use of TPUS as a screening tool, and its likelihood to predict long-term treatment outcomes. METHODS: Two blinded clinicians reviewed 100 women who had historically presented to a tertiary referral colorectal unit with PFDD from October 2014 to April 2015. The clinical history of the patients together with TPFUS or DP results were used to decide on main impression, treatment plan, likelihood of surgery and certainty of plan. These were compared to the actual treatment received six months later and again after a median follow-up of 68 months (range 48-84). RESULTS: A total of 82 patients were treated with biofeedback only and 18 also underwent surgery. There were no complications in any of the patients who had surgery. When compared with the actual treatment received, 99 of the 100 of the TPFUS group would have been treated appropriately. The number of false positives for surgical treatment was lower with TPFUS compared to DP. Clinician confidence in the overall decision was significantly higher after review with DP. CONCLUSIONS: TPFUS is a reliable assessment tool for PFDD. It can identify patients who can go straight to biofeedback and is just as good as DP at predicting likelihood of surgery. We might be able to rely on TPFUS more significantly in the future, even for surgical planning.

Pelvic floor investigations for anal incontinence: Are they useful to predict outcomes from conservative treatment?

AIMS: There are several options for treating anal incontinence (AI), with limited success rate in long-term follow-up. Patients' selection is important to avoid unnecessary investigations and therapies. The aim of this review is to assess the utility of pelvic floor investigations to predict success from conservative treatment in AI. METHODS: Baseline demographics, severity scores, and pelvic floor investigations of 490 patients with AI symptoms were retrospectively reviewed. Patient-reported outcomes were used to define success of conservative treatment. RESULTS: Bivariate analysis showed that gender, St Mark's incontinence score, Bowel continence and quality of life domains of International Consultation on Incontinence Modular Questionnaire-Bowel symptoms score, Bristol stool chart, anal squeeze pressure, enterocoele, leak of contrast at rest, and dyssynergia in defecography were associated with patient's outcomes from conservative treatment (p < 0.05). Multivariate analysis showed that only the Bowel continence score was an independent predictor of patient's success with treatment. CONCLUSIONS: Pelvic floor investigations are of limited value to predict success of conservative treatment and they should be reserved for patients who fail noninvasive management and might require surgical intervention.

Patient pathway in a tertiary referral pelvic floor unit: Telephone triage assessment clinic.

BACKGROUND: To meet the increasing demands for colorectal pelvic floor services, a dedicated telephone triage assessment clinic (TTAC) was set up to establish a more efficient pathway, and reduce waiting times and patient's visits to the hospital. The primary aim of this study was to review TTAC in patients suffering from pelvic floor dysfunction and assess its feasibility. Secondary aims include measurement of waiting times for TTAC, main presenting complaints, and main treatment outcomes, including the need for review by a consultant surgeon. METHODS: Review of data collected retrospectively in a single tertiary referral center collected from an institutional database. KEY RESULTS: Between January 2016 and October 2017, 1192 patients referred to our pelvic floor unit were suitable for TTAC. Of these, 694 patients had complete records. There were 66 without follow-up after the initial TTAC, leaving 628 patients for analysis. In all, 86% were females and 14% were males, with a mean age of 52 years (range: 18-89). The median waiting time for TTAC was 31 days (range: 0-184). The main presenting complaint during the TTAC was obstructive defecation in 69.4%, fecal incontinence in 28.5%, and rectal prolapse in 2.1%. In our study, 611 patients had conservative management (97.3%), with a median of three sessions per patient (range: 1-16), while 82 patients (13.1%) needed a surgical intervention. Only 223 patients (35.5%) were reviewed by a consultant at some stage during the study period. CONCLUSIONS AND INFERENCES: To optimize resources, an adequate triage system allowed us to streamline the pathway for each individual patient with pelvic floor dysfunction according to their symptoms and/or test results with the aim of reducing waiting times and expediting treatment.

The association between levator plate integrity and pelvic floor defaecatory dysfunction.

AIMS: Levator ani deficiency has been implicated in anterior pelvic floor pathology but its association with pelvic floor defaecatory dysfunction is less clear. The aim was to examine the relationship of levator ani deficiency with anatomical abnormalities (rectocoele, intussusception, enterocoele, perineal descent) and patient symptoms (bowel, vagina) in patients with pelvic floor defaecatory dysfunction. METHODS: The prospective observational case series of 223 women presenting to a tertiary colorectal pelvic floor unit with defaecatory dysfunction. Each underwent assessment with symptom severity and quality of life (QoL) scores, integrated total pelvic floor ultrasound (PFUS) (transvaginal, transperineal) and defaecation proctography (DP). Rectocoele, intussusception, enterocoele and perineal descent were assessed on both. Levator ani deficiency was scored using endovaginal ultrasound (score 0-18; mild [0-6], moderate [>6-12], severe [>12-18]). RESULTS: The proportion of patients with rectocoele, enterocoele, and intussusception increased with increasing levator ani damage (mild, moderate, severe). There was a weakly positive correlation between size of rectocoele and levator ani deficiency. On PFUS, there was a weakly positive correlation between severity of intussusception and enterocoele with levator ani deficiency. On DP, there was a weakly positive correlation between perineal descent and levator ani deficiency. There was no association between bowel symptom and QoL scores and levator ani deficiency. Vaginal symptoms were associated with levator ani deficiency. CONCLUSIONS: Anatomical abnormalities which are implicated in pelvic floor defaecatory dysfunction (rectocoele, intussusception, enterocoele, perineal descent) were associated with worsening levator ani deficiency. There was no association between bowel symptoms and levator ani deficiency. Vaginal symptoms were associated with levator ani deficiency.

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.

Representing and utilizing clinical textual data for real world studies: An OHDSI approach.

Clinical documentation in electronic health records contains crucial narratives and details about patients and their care. Natural language processing (NLP) can unlock the information conveyed in clinical notes and reports, and thus plays a critical role in real-world studies. The NLP Working Group at the Observational Health Data Sciences and Informatics (OHDSI) consortium was established to develop methods and tools to promote the use of textual data and NLP in real-world observational studies. In this paper, we describe a framework for representing and utilizing textual data in real-world evidence generation, including representations of information from clinical text in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM), the workflow and tools that were developed to extract, transform and load (ETL) data from clinical notes into tables in OMOP CDM, as well as current applications and specific use cases of the proposed OHDSI NLP solution at large consortia and individual institutions with English textual data. Challenges faced and lessons learned during the process are also discussed to provide valuable insights for researchers who are planning to implement NLP solutions in real-world studies.