Examining site intervention efficacy and uncertainties with conceptual Bayesian networks: preventing offsite migration of DNAPL and contaminated groundwater.

For contaminated sites, conceptual site models (CSMs) guide the assessment and management of risks, including remediation strategies. Recent research has expanded diagrammatic CSMs with structural causal modeling to develop what are nominally called conceptual Bayesian networks (CBNs) for environmental risk assessment. These CBNs may also be useful for problems of controlling and preventing offsite contaminant migration, especially for sites containing dense nonaqueous phase liquids (DNAPLs). In particular, the CBNs provide greater clarity on the causal relationships between source term, onsite and offsite migration, and remediation effectiveness characterization for contaminated DNAPL sites compared to traditional CSMs. These ideas are demonstrated by the inclusion of modifying variables, causal pathway analysis, and interventions in CBNs. Additionally, several new extensions of the CBN concept are explored including the representation of measurement variables as lines of evidence and alignment with conventional pictorial CSMs for groundwater modeling. Taken as a whole, the CBNs provide a powerful and adaptable knowledge representation tool for remediating subsurface systems contaminated by DNAPL.

Ascorbic acid deficiency amongst spondylodiscitis patients.

BACKGROUND: Spondylodiscitis can be a disabling and life-threatening infection. Ascorbic Acid is crucial for neutrophil function and collagen formation. Its association and clinical relevance in spondylodiscitis has not been previously examined. AIMS: To determine the prevalence, characteristics, and clinical outcomes of spondylodiscitis patients with Ascorbic Acid deficiency. METHODS: Sixty-eight consecutive patients admitted with spondylodiscitis, between December 2021 and August 2023 were included. Clinical characteristics, Ascorbic Acid levels and clinical outcomes were evaluated. RESULTS: Thirty-seven patients had Ascorbic Acid levels taken during admission. The median initial Ascorbic Acid level was 15 µmol/L with an IQR 6.5-27 µmol/L. Depletion defined as <28 µmol/L was present in 78% of patients. Deficiency defined as ≤11 µmol/L was present in and 46% of patients. Patients with depletion were more likely to require Intensive Care Admission (absolute risk increase = 24.1%; 2.6%-45.7%). Fifteen patients had repeat serum levels taken during admission with median increase of 17 µmol/L and an IQR 0-26 µmol/L. Patients that received supplementation had a significantly greater increase in Ascorbic Acid levels compared with those that did not receive supplementation (P = 0.002). CONCLUSION: Ascorbic acid deficiency is highly prevalent amongst spondylodiscitis patients. Depletion was associated with worse outcomes. Replacement significantly increased serum levels in comparison to standard hospital diet. The clinical significance of replacement remains to be evaluated.

A Guide to Expanding the Use of Buprenorphine Beyond Standard Initiations for Opioid Use Disorder.

Buprenorphine has become an important medication in the context of the ongoing opioid epidemic. However, complex pharmacologic properties and varying government regulations create barriers to its use. This narrative review is intended to facilitate buprenorphine use-including non-traditional initiation methods-by providers ranging from primary care providers to addiction specialists. This article briefly discusses the opioid epidemic and the diagnosis and treatment of opioid use disorder (OUD). We then describe the basic and complex pharmacologic properties of buprenorphine, linking these properties to their clinical implications. We guide readers through the process of initiating buprenorphine in patients using full agonist opioids. As there is no single recommended approach for buprenorphine initiation, we discuss the details, advantages, and disadvantages of the standard, low-dose, bridging-strategy, and naloxone-facilitated initiation techniques. We consider the pharmacology of, and evidence base for, buprenorphine in the treatment of pain, in both OUD and non-OUD patients. Throughout, we address the use of buprenorphine in children and adolescent patients, and we finish with considerations related to the settings of pregnancy and breastfeeding.

Rheumatology nurses' perceptions of undertaking a postgraduate education programme: A phenomenological study.

BACKGROUND: The expansion of the role of the rheumatology nurse specialist led to the instigation, in 1999, of the first Masters programme in rheumatology nursing, with the aim of supporting clinical advancement with evidence-based practice. This study explored the experience of rheumatology nurses undertaking postgraduate study at Masters level. OBJECTIVES: (1) To explore the perceptions and experiences of clinical nurse specialists undertaking a Masters programme in Rheumatology Nursing, including perceptions of impact. (2) To identify future educational needs. METHODS: Ten rheumatology nurses who had completed a Masters degree in rheumatology nursing participated in a semi-structured video link or telephone interview conducted between 17th March 2021-17th May 2021. Interpretive phenomenological analysis was undertaken by two researchers and two public contributors. RESULTS: Four themes were identified: (i) Increased confidence and the development of new clinical skills. (ii) The perceived impact on the organisation; (iii) Benefits of face-to-face learning; and (iv) Continuing evolution of the rheumatology nurse specialist role. Participants reported increased confidence in clinical skills and felt that their learning had benefited their employing organisation. However, lack of time and insufficient managerial support could impede the implementation of new skills. Learning examination techniques, engagement in learning and peer support were seen as advantages of face-to-face learning. Future educational needs focused on diagnostic and prescribing skills. CONCLUSIONS: Participant learners perceived that completing a face-to-face Masters in rheumatology increased confidence in delivering new clinical skills and fostered peer networks, whilst also benefiting their employing organisations. There is a need for organisational support to apply learning to the clinical setting.

Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells.

OBJECTIVE: Brain organoids are miniaturized in vitro brain models generated from pluripotent stem cells, which resemble full-sized brain more closely than conventional two-dimensional cell cultures. Although brain organoids mimic the human brain's cell-to-cell network interactions, they generally fail to faithfully recapitulate cell-to-matrix interactions. Here, an engineered framework, called an engineered extracellular matrix (EECM), was developed to provide support and cell-to-matrix interactions to developing brain organoids. METHODS: We generated brain organoids using EECMs comprised of human fibrillar fibronectin supported by a highly porous polymer scaffold. The resultant brain organoids were characterized by immunofluorescence microscopy, transcriptomics, and proteomics of the cerebrospinal fluid (CSF) compartment. RESULTS: The interstitial matrix-mimicking EECM enhanced neurogenesis, glial maturation, and neuronal diversity from human embryonic stem cells versus conventional protein matrix (Matrigel). Additionally, EECMs supported long-term culture, which promoted large-volume organoids containing over 250 µL of CSF. Proteomics analysis of the CSF found it superseded previous brain organoids in protein diversity, as indicated by 280 proteins spanning 500 gene ontology pathways shared with adult CSF. INTERPRETATION: Engineered EECM matrices represent a major advancement in neural engineering as they have the potential to significantly enhance the structural, cellular, and functional diversity that can be achieved in advanced brain models.

Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms.

BACKGROUND: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. METHODS: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr-/-) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3-/-). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. RESULTS: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3-/- mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK. CONCLUSIONS: These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.

Inflammatory memory restrains intestinal stem cell regeneration.

Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures demonstrating the persistence of the maladaptive impact of an in vivo inflammatory encounter by the ISCs. Thus, inflammation from GI GVHD leaves a memory of its effects on ISCs that persist and are likely to affect their sensitivity to adapt to future stress or challenges.

Contaminant Back Diffusion from Low-Conductivity Matrices: Case Studies of Remedial Strategies.

Recalcitrant groundwater contamination is a common problem at hazardous waste sites worldwide. Groundwater contamination persists despite decades of remediation efforts at many sites because contaminants sorbed or dissolved within low-conductivity zones can back diffuse into high-conductivity zones, and therefore act as a continuing source of contamination to flowing groundwater. A review of the available literature on remediation of plume persistence due to back diffusion was conducted, and four sites were selected as case studies. Remediation at the sites included pump and treat, enhanced bioremediation, and thermal treatment. Our review highlights that a relatively small number of sites have been studied in sufficient detail to fully evaluate remediation of back diffusion; however, three general conclusions can be made based on the review. First, it is difficult to assess the significance of back diffusion without sufficient data to distinguish between multiple factors contributing to contaminant rebound and plume persistence. Second, high-resolution vertical samples are decidedly valuable for back diffusion assessment but are generally lacking in post-treatment assessments. Third, complete contaminant mass removal from back diffusion sources may not always be possible. Partial contaminant mass removal may nonetheless have potential benefits, similar to partial mass removal from primary DNAPL source zones.

Morbidity and mortality of multivisceral resection with radical nephrectomy for locally advanced renal cell carcinoma: An analysis of the National Surgical Quality Improvement Program (NSQIP) database.

INTRODUCTION: Locally advanced renal cell carcinoma (RCC) can rarely invade into adjacent abdominal viscera without clinical evidence of distant metastases. The role of multivisceral resection (MVR) of involved adjacent organs at the time of radical nephrectomy (RN) remains poorly described and quantified. Using a national database, we aimed to evaluate the association between RN+MVR and 30-day postoperative complications. METHODS AND MATERIALS: We conducted a retrospective cohort study of adult patients undergoing RN for RCC with and without MVR between 2005 and 2020 using the ACS-NSQIP database. The primary outcome was a composite of any of the following 30-day major postoperative complications: mortality, reoperation, cardiac event, and neurologic event. Secondary outcomes included individual components of the composite primary outcome, as well as infectious and venous thromboembolic complications, unplanned intubation and ventilation, transfusion, readmission, and prolonged length of stay (LOS). Groups were balanced using propensity score matching. Likelihood of complications was assessed by conditional logistic regression adjusted for unbalanced total operation time. Postoperative complications were compared by Fisher's exact test among subtypes of resection. RESULTS: A total of 12,417 patients were identified: 12,193 (98.2%) undergoing RN alone and 224 (1.8%) undergoing RN+MVR. Patients undergoing RN+MVR were more likely to experience major complications (odds ratio [OR] 2.46; 95% confidence interval [CI] 1.28-4.74). However, there was no significant association between RN+MVR and postoperative mortality (OR 2.49; 95% CI 0.89-7.01). RN+MVR was associated with higher rates of reoperation (OR 7.85; 95% CI 2.38-25.8), sepsis (OR 5.45; 95% CI 1.83-16.2), surgical site infection (OR 4.41; 95% CI 2.14-9.07), blood transfusion (OR 2.24; 95% CI 1.55-3.22), readmission (OR 1.78; 95% CI 1.11-2.84), infectious complications (OR 2.62; 95% CI 1.62-4.24), and longer hospital stay (5 days [IQR 3-8] vs. 4 days [IQR 3-7]; OR 2.31 [95% CI 2.13-3.03]).  There was no heterogeneity in the association between subtype of MVR and major complication rate. CONCLUSION: Undergoing RN+MVR is associated with an increased risk of 30-day postoperative morbidity, including infectious complications, reoperation, blood transfusion, prolonged LOS, and readmission.

Deep Learning Diagnosis and Classification of Rotator Cuff Tears on Shoulder MRI.

BACKGROUND: Detection of rotator cuff tears, a common cause of shoulder disability, can be time-consuming and subject to reader variability. Deep learning (DL) has the potential to increase radiologist accuracy and consistency. PURPOSE: The aim of this study was to develop a prototype DL model for detection and classification of rotator cuff tears on shoulder magnetic resonance imaging into no tear, partial-thickness tear, or full-thickness tear. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act-compliant, institutional review board-approved study included a total of 11,925 noncontrast shoulder magnetic resonance imaging scans from 2 institutions, with 11,405 for development and 520 dedicated for final testing. A DL ensemble algorithm was developed that used 4 series as input from each examination: fluid-sensitive sequences in 3 planes and a sagittal oblique T1-weighted sequence. Radiology reports served as ground truth for training with categories of no tear, partial tear, or full-thickness tear. A multireader study was conducted for the test set ground truth, which was determined by the majority vote of 3 readers per case. The ensemble comprised 4 parallel 3D ResNet50 convolutional neural network architectures trained via transfer learning and then adapted to the targeted domain. The final tear-type prediction was determined as the class with the highest probability, after averaging the class probabilities of the 4 individual models. RESULTS: The AUC overall for supraspinatus, infraspinatus, and subscapularis tendon tears was 0.93, 0.89, and 0.90, respectively. The model performed best for full-thickness supraspinatus, infraspinatus, and subscapularis tears with AUCs of 0.98, 0.99, and 0.95, respectively. Multisequence input demonstrated higher AUCs than single-sequence input for infraspinatus and subscapularis tendon tears, whereas coronal oblique fluid-sensitive and multisequence input showed similar AUCs for supraspinatus tendon tears. Model accuracy for tear types and overall accuracy were similar to that of the clinical readers. CONCLUSIONS: Deep learning diagnosis of rotator cuff tears is feasible with excellent diagnostic performance, particularly for full-thickness tears, with model accuracy similar to subspecialty-trained musculoskeletal radiologists.

Comparative real-world survival outcomes of metastatic papillary and clear cell renal cell carcinoma treated with immunotherapy, targeted therapy, and combination therapy.

INTRODUCTION: While there are a plethora of studies supporting novel treatment approaches in metastatic clear cell renal cell carcinoma (ccRCC), much of the data used to inform care of patients with metastatic papillary RCC (pRCC) is extrapolated from ccRCC. Several recent phase III trials have supported the use of immunotherapy (IO) and targeted therapy (TT)+IO in ccRCC, without corresponding data for pRCC. Using ccRCC as a comparison group, we sought to describe real-world trends in the utilization of systemic therapy and its impact on overall survival (OS) among patients with metastatic pRCC. METHODS: Using the National Cancer Database (NCDB), we identified cases of metastatic pRCC and ccRCC between 2015 and 2018. Patients were stratified into groups based on histology and first-line treatments (TT, IO, TT + IO). Differences in baseline characteristics were assessed using the Kruskal-Wallis test for continuous variables, and the Chi-square or Fisher's exact test for categorical variables. Survival analysis was performed using Kaplan-Meier estimates and multivariable Cox regression analyses. RESULTS: A total of 6,920 patients with a diagnosis of metastatic RCC were identified: 594 (8.6%) with pRCC and 6,326 (91.4%) with ccRCC. Overall, 4,710 patients received TT (455 pRCC and 4,255 ccRCC), 1,585 received IO (77 pRCC and 1,508 ccRCC), and 625 received TT+IO (62 pRCC and 563 ccRCC). Temporal trend between 2015 and 2018 revealed an increased utilization of IO and TT + IO for pRCC and ccRCC. In patients with metastatic pRCC, neither IO (HR 1.03; 95% CI 0.75-1.42) nor TT+IO (HR 0.90, 95% CI 0.63-1.28) were associated with better OS compared to TT alone. In contrast, both IO and combination TT and IO were associated with significantly better OS than TT for patients with metastatic ccRCC (IO group: hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.68-0.82; TT+IO group: HR 0.82, 95% CI 0.72-0.93). Cytoreductive nephrectomy was associated with better OS in both pRCC (HR 0.59, 95% CI 0.46-0.77) and ccRCC (HR 0.54, 95% CI 0.50-0.58). CONCLUSIONS: Although IO and TT + IO were associated with better OS among patients with metastatic ccRCC, this same effect was not observed among patients with pRCC.

Open vs. robot-assisted radical cystectomy with extracorporeal or intracorporeal urinary diversion for bladder cancer A pairwise meta-analysis of outcomes and a network meta-analysis of complications.

INTRODUCTION: There are no meta-analyses of randomized controlled trials (RCTs) comparing open radical cystectomy (OR C) with robot-assisted radical cystectomy (RARC), inclusive of both intracorporeal (iRARC) and extracorporeal (hybrid RARC, hRARC) urinary reconstruction. METHODS: MEDL INE, Embase, Scopus, the International Clinical Trials Registry Platform and ClinicalTrials.gov registries were searched in May 2022. Outcomes of interest included recurrence- or progression-free survival (RFS/PFS), margin status and lymph node yield, mean estimated blood loss (EBL) and operating room time (ORT ), hospital length of stay (LOS ), 90-day complications and readmissions, and quality of life (QoL). Pairwise meta-analyses and network meta-analyses were performed using random-effects models and Bayesian hierarchical random-effects models, respectively. RESULTS: We found no significant differences between RARC and OR C for oncological and most perioperative outcomes: RFS/PFS (hazard ratio [HR ] 0.91, 95% confidence interval [CI] 0.67-1.23); positive surgical margins (odds ratio [OR ] 1.05, 95% CI 0.60-1.85); lymph node yield (mean difference [MD ] -0.63, 95% CI -2.63-1.37); LOS (MD -0.22, 95% CI -1.10-0.65); overall complications (OR 0.81, 95% CI 0.61-1.07); major complications (OR 0.94, 95% CI 0.69-1.30); readmissions (OR 0.90, 95% CI 0.60-1.35); and QoL (standardized MD -0.02, 95% CI -0.17-0.14). We found significantly lower EBL for RARC compared to OR C (MD -312.61, 95% CI -447 to -178.22) at the expense of significantly prolonged ORT (MD 82.34 minutes, 95% CI 44.82-119.86). Network meta-analysis did not find significant differences in complications between hRARC and iRARC. CONCLUSIONS: This meta-analysis confirms the equivalence of RARC and OR C with respect to oncological outcomes.

The impact of primary and secondary processing steps on Campylobacter concentrations on chicken carcasses and portions.

Campylobacteriosis is the most commonly notified foodborne disease in New Zealand and poultry meat is the major source for human infection. Carcasses and portions were sampled from key points along primary and secondary processing chains of three New Zealand poultry processors to determine the impact of processing steps on Campylobacter concentrations. Primary processing reduced Campylobacter concentrations on carcasses by almost 6-log; the biggest reduction was achieved by the spinchill, followed by the scald step. Significant plant differences in the degree of Campylobacter reduction were also observed at these steps. The spinchill and final acidified sodium chlorite wash resulted in carcasses with low-to-no levels of Campylobacter regardless of concentrations at prior steps. A similar study was conducted at primary processing for one plant in 2013; significant improvements in Campylobacter mitigation since 2013 were noted. Campylobacter concentrations from final product from secondary processing were higher than concentrations at the end of primary processing. Drumsticks had lower Campylobacter concentrations than other portion types. Skin removal from product did not consistently result in product with lower Campylobacter concentrations. Results identify key areas to target for further reduction of Campylobacter on poultry meat, and provide a benchmark to compare the efficacy of future interventions.