Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.

Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.

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.

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.

Oncogene targeted therapy for metastatic primary scrotal melanoma.

Primary scrotal melanoma represents the rarest genitourinary malignancy. We describe the 25th reported case. The 79-year-old patient presented with a rapidly enlarging right cutaneous scrotal mass which after local excision demonstrated pT4b nodular malignant melanoma (BRAF V600E mutation positive). The patient underwent wide local excision of his hemiscrotum and inguinal lymph node dissection demonstrating nodes positive for melanoma (pN2b). Postoperatively, the patient developed a left sided malignant pleural effusion (M1b). Per American Joint Commission Cancer staging, BRAF mutant targeted therapy (dabrafenib) was initiated. This case documents the first instance in which metastatic scrotal melanoma will be treated with oncogene targeted therapy.

Strategies for Managing Risk due to Back Diffusion.

Back diffusion of contaminants from secondary sources may hamper site remediation if it is not properly addressed in the remedial design. A review of all reported technologies and strategies that have been or could be applied to address plume persistence due to back diffusion as published in the peer-reviewed literature is provided. We classify these into four major categories. The first category consists of those approaches that do not include active measures to specifically address contamination in the low permeable zones (LPZs) and can therefore be considered passive LPZ management approaches. A disadvantage of these approaches is the long duration that may be required to meet acceptable endpoints; however, this allows degradation to potentially play a significant part even at modest rates. The remaining three categories all use approaches to specifically address contaminants in the LPZ. The second category consists of strategies that promote contaminant destruction through the forward diffusion of amendments into the LPZ. A variety of laboratory tests indicate concentration or flux reductions range from no improvement, to reductions as high as four orders-of-magnitude depending on the evaluation metric. The third category consists of strategies that alter physical characteristics of the secondary source, and includes viscosity modification, fracturing, and soil mixing. Each of these offer unique advantages and are often used to deliver one or more amendments for contaminant treatment. The final category consists of thermal and electrokinetic remediation, both less susceptible to permeability contrast limitations. However, they are not routinely used for secondary-source treatment.

External Validation of Bladder Cancer Predictive Nomograms for Recurrence, Cancer-Free Survival and Overall Survival following Radical Cystectomy.

PURPOSE: We externally validated 3 previously published nomograms to predicting recurrence, and cancer specific and overall survival following radical cystectomy and pelvic lymph node dissection for urothelial carcinoma of the bladder. MATERIALS AND METHODS: Two surgeons from a single institution performed a total of 197 consecutive radical cystectomies and pelvic lymph node dissections for bladder cancer from January 2003 to September 2009. A total of 23 patients were excluded from analysis. Examined parameters were those used in the original nomograms, including patient age, gender, pathological T stage, N stage, tumor grade, presence of carcinoma in situ and lymphovascular invasion, neoadjuvant chemotherapy, adjuvant chemotherapy and adjuvant radiation therapy. Nomogram predictions were compared to actuarial outcomes and predictive accuracy was quantified using measures of discrimination and calibration. RESULTS: At the time of analysis 34 patients had experienced recurrence, of whom 28 died of disease and 6 were currently alive with disease. Discrimination at 2, 5 and 8 years was 0.776, 0.809 and 0.794 for recurrence, 0.822, 0.840 and 0.849 for cancer specific survival, and 0.812, 0.820 and 0.825, respectively, for overall survival. Calibration plots revealed nomogram overestimation of all 3 end points. CONCLUSIONS: Nomograms for bladder cancer recurrence, cancer specific survival and overall survival following radical cystectomy and pelvic lymph node dissection performed well in our series with accuracy comparable to that in the original series. The use of nomogram predictions should be further explored in clinical trials to assess the impact on patient care in clinical practice.

The malpractice liability of radiology reports: minimizing the risk.

The art and science of interpreting radiologic examinations, an ability that is acquired over years of training, is on display in every radiology report. It is vital that these reports be crafted so as to both reflect the radiologist's expertise and capability and eliminate any factors that might result in unintended harm to the patient. Unfortunately, a deficient report may result in legal action against the radiologist; thus, a thorough understanding of the litigious potential of the language used in radiology reports is crucial. It is important that ambiguous vocabulary, undefined modifiers, double negatives, and generalizations be avoided. Errors in radiology reports may result from inappropriate terminology, transcription mistakes, or deficient or inadequately documented communication. Critical findings that may have an immediate impact on patient management must be promptly communicated to the referring physician and such communication fully documented. A meticulous and well-written report is the best way for radiologists to care for their patients. In addition, a well-worded report can be the deciding factor in a successful defense against a malpractice claim. Understanding the legal implications of radiology reports will enable radiologists to develop strategies for avoiding malpractice suits.

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.

Celebrating a legacy, reflecting on the present, and safeguarding our future.

OBJECTIVE: During the 20th century, radiologists enjoyed relationships with clinicians and patients through daily face-to-face communication. As specialist consultants, radiologists were naturally integral members of the care team. CONCLUSION: The widespread availability of information technology, notably PACS, has disrupted the fundamental radiologist-clinician axis. New generations of radiologists must respond to this disturbing trend by (re)learning how to "add value" by rekindling personal professional relationships, developing global leadership skills, and becoming involved in health care system design and implementation.

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.

DiffusionCT: Latent Diffusion Model for CT Image Standardization.

Computed tomography (CT) is one of the modalities for effective lung cancer screening, diagnosis, treatment, and prognosis. The features extracted from CT images are now used to quantify spatial and temporal variations in tumors. However, CT images obtained from various scanners with customized acquisition protocols may introduce considerable variations in texture features, even for the same patient. This presents a fundamental challenge to downstream studies that require consistent and reliable feature analysis. Existing CT image harmonization models rely on GAN-based supervised or semi-supervised learning, with limited performance. This work addresses the issue of CT image harmonization using a new diffusion-based model, named DiffusionCT, to standardize CT images acquired from different vendors and protocols. DiffusionCT operates in the latent space by mapping a latent non-standard distribution into a standard one. DiffusionCT incorporates a U-Net-based encoder-decoder, augmented by a diffusion model integrated into the bottleneck part. The model is designed in two training phases. The encoder-decoder is first trained, without embedding the diffusion model, to learn the latent representation of the input data. The latent diffusion model is then trained in the next training phase while fixing the encoder-decoder. Finally, the decoder synthesizes a standardized image with the transformed latent representation. The experimental results demonstrate a significant improvement in the performance of the standardization task using DiffusionCT.

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.