Image quality in whole-body MRI using the MY-RADS protocol in a prospective multi-centre multiple myeloma study.

BACKGROUND: The Myeloma Response Assessment and Diagnosis System (MY-RADS) guidelines establish a standardised acquisition and analysis pipeline for whole-body MRI (WB-MRI) in patients with myeloma. This is the first study to assess image quality in a multi-centre prospective trial using MY-RADS. METHODS: The cohort consisted of 121 examinations acquired across ten sites with a range of prior WB-MRI experience, three scanner manufacturers and two field strengths. Image quality was evaluated qualitatively by a radiologist and quantitatively using a semi-automated pipeline to quantify common artefacts and image quality issues. The intra- and inter-rater repeatability of qualitative and quantitative scoring was also assessed. RESULTS: Qualitative radiological scoring found that the image quality was generally good, with 94% of examinations rated as good or excellent and only one examination rated as non-diagnostic. There was a significant correlation between radiological and quantitative scoring for most measures, and intra- and inter-rater repeatability were generally good. When the quality of an overall examination was low, this was often due to low quality diffusion-weighted imaging (DWI), where signal to noise ratio (SNR), anterior thoracic signal loss and brain geometric distortion were found as significant predictors of examination quality. CONCLUSIONS: It is possible to successfully deliver a multi-centre WB-MRI study using the MY-RADS protocol involving scanners with a range of manufacturers, models and field strengths. Quantitative measures of image quality were developed and shown to be significantly correlated with radiological assessment. The SNR of DW images was identified as a significant factor affecting overall examination quality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03188172 , Registered on 15 June 2017. CRITICAL RELEVANCE STATEMENT: Good overall image quality, assessed both qualitatively and quantitatively, can be achieved in a multi-centre whole-body MRI study using the MY-RADS guidelines. KEY POINTS: • A prospective multi-centre WB-MRI study using MY-RADS can be successfully delivered. • Quantitative image quality metrics were developed and correlated with radiological assessment. • SNR in DWI was identified as a significant predictor of quality, allowing for rapid quality adjustment.

Microbiota Predict Infections and Acute Graft-Versus-Host Disease After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Despite preventive measures, infections continue to pose significant risks to pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The gut microbiota has been linked to clinical outcomes following adult allo-HCT. This study evaluated whether similar disruptions or differing microbiota patterns were associated with infection risk in pediatric allo-HCT. METHODS: In a prospective observational study, fecal samples were obtained from 74 children before conditioning and upon neutrophil recovery. Microbiome signatures identified through sequencing were examined for their associations with infections or acute graft-versus-host disease (aGVHD) in the first-year post-HCT using Cox proportional hazards analysis. RESULTS: Microbiome disruption in adults, did not predict infection risk in pediatric allo-HCT. Unique microbiota signatures were associated with different infections or aGVHD. A ratio of strict and facultative anaerobes (eg, Lachnoclostridium, Parabacteroides) prior to conditioning predicted bacteremia risk (Cox hazard ratio [HR], 3.89). A distinct ratio of oral (eg, Rothia, Veillonella) to intestinal anaerobes (eg, Anaerobutyricum, Romboutsia) at neutrophil recovery predicted likelihood of bacterial infections (Cox HR, 1.81) and viral enterocolitis (Cox HR, 1.96). CONCLUSIONS: Interactions between medical interventions, pediatric hosts, and microbial communities contribute to microbiota signatures that predict infections. Further multicenter study is necessary to validate the generalizability of these ratios as biomarkers.

Implementation of Whole-Body MRI (MY-RADS) within the OPTIMUM/MUKnine multi-centre clinical trial for patients with myeloma.

BACKGROUND: Whole-body (WB) MRI, which includes diffusion-weighted imaging (DWI) and T1-w Dixon, permits sensitive detection of marrow disease in addition to qualitative and quantitative measurements of disease and response to treatment of bone marrow. We report on the first study to embed standardised WB-MRI within a prospective, multi-centre myeloma clinical trial (IMAGIMM trial, sub-study of OPTIMUM/MUKnine) to explore the use of WB-MRI to detect minimal residual disease after treatment. METHODS: The standardised MY-RADS WB-MRI protocol was set up on a local 1.5 T scanner. An imaging manual describing the MR protocol, quality assurance/control procedures and data transfer was produced and provided to sites. For non-identical scanners (different vendor or magnet strength), site visits from our physics team were organised to support protocol optimisation. The site qualification process included review of phantom and volunteer data acquired at each site and a teleconference to brief the multidisciplinary team. Image quality of initial patients at each site was assessed. RESULTS: WB-MRI was successfully set up at 12 UK sites involving 3 vendor systems and two field strengths. Four main protocols (1.5 T Siemens, 3 T Siemens, 1.5 T Philips and 3 T GE scanners) were generated. Scanner limitations (hardware and software) and scanning time constraint required protocol modifications for 4 sites. Nevertheless, shared methodology and imaging protocols enabled other centres to obtain images suitable for qualitative and quantitative analysis. CONCLUSIONS: Standardised WB-MRI protocols can be implemented and supported in prospective multi-centre clinical trials. Trial registration NCT03188172 clinicaltrials.gov; registration date 15th June 2017 https://clinicaltrials.gov/ct2/show/study/NCT03188172.

Human Astroviruses: A Tale of Two Strains.

Since the 1970s, eight closely related serotypes of classical human astroviruses (HAstV) have been associated with gastrointestinal illness worldwide. In the late 2000s, three genetically unique human astrovirus clades, VA1-VA3, VA2-VA4, and MLB, were described. While the exact disease associated with these clades remains to be defined, VA1 has been associated with central nervous system infections. The discovery that VA1 could be grown in cell culture, supports exciting new studies aimed at understanding viral pathogenesis. Given the association of VA1 with often lethal CNS infections, we tested its susceptibility to the antimicrobial drug, nitazoxanide (NTZ), which we showed could inhibit classical HAstV infections. Our studies demonstrate that NTZ inhibited VA1 replication in Caco2 cells even when added at 12 h post-infection, which is later than in HAstV-1 infection. These data led us to further probe VA1 replication kinetics and cellular responses to infection in Caco-2 cells in comparison to the well-studied HAstV-1 strain. Overall, our studies highlight that VA1 replicates more slowly than HAstV-1 and elicits significantly different cellular responses, including the inability to disrupt cellular junctions and barrier permeability.

Deep Sleep and Beeps: Sleep Quality Improvement Project in General Surgery Patients.

BACKGROUND: Poor sleep leads to poor health outcomes. Inpatient sleep disturbance has been studied primarily in the ICU. Minimal research exists on sleep in surgical populations. METHODS: We recruited patients undergoing elective, inpatient general surgery procedures. Participants wore Fitbit trackers while inpatient to measure total sleep time (CDC recommendation is 7 or more hours per night). At discharge, patients completed the Richards-Campbell Sleep Questionnaire (RCSQ) to measure inpatient sleep quality. The RCSQ combines 5 domains into a cumulative score (0 to 100); a higher score means better sleep quality. Patients also completed the outpatient Pittsburgh Sleep Quality Index preoperatively and postoperatively. The primary end point was percentage of patients with total sleep score ≥ 50. Secondary outcomes included mean RCSQ domain scores, Fitbit total sleep time, and percentage with Pittsburgh Sleep Quality Index Score indicating poor sleep. RESULTS: We included 64 patients (mean ± SD age 55.0 ± 14.1 years). Mean ± SD RCSQ total sleep score was 49 ± 20.5 and 53.1% with total sleep score < 50. Mean ± SD RCSQ domain scores were Awakenings: 40.4 ± 22.8, Sleep Quality: 49.1 ± 27.9, Sleep Latency: 49.2 ± 25.3, Sleep Depth: 50.2 ± 26.5, Returning to Sleep: 55.9 ± 28.1, and Noise Disturbance: 59.1 ± 27.9. On night one, 25 devices (40%) had recorded sleep data due to enough sleep. Mean ± SD total sleep time on night 1 was 4.7 ± 2.8 hours. Mean total sleep time for nights 2, 3, and 4 remained fewer than 7 hours. Percentages for each night that achieved the CDC goal of 7 or more hours were as follows: night one 10.9%, night two 32.8%, night three 35.3%, and night four 27.6%. Per the Pittsburgh Sleep Quality Index, 88.1% of patients were poor sleepers preoperatively and 84.5% were poor sleepers at follow-up (p = 0.6). CONCLUSIONS: Elective general surgery patients experience a severe inpatient sleep disturbance, worse than in similarly studied ICU cohorts. This disturbance is driven primarily by nighttime awakenings.

Top Ten Tips Palliative Care Clinicians Should Know About Opioid Use Disorder.

Since the prevalence of substance use disorders, and opioid use disorder (OUD) specifically, remains high and represents a public health crisis, it is critical that palliative care (PC) providers have a broad understanding of this class of chronic, yet treatable, diseases. Conceptualizing stigma associated with OUD, treatment modalities available, and educational opportunities are key factors in providing patient-centered care. A solid foundation of knowledge about OUD in the setting of serious illness is also crucial as PC providers often recommend or prescribe opioids for symptom management in patients who also have OUD. Furthermore, the PC interdisciplinary team is particularly well poised to care for patients suffering from OUD due to the inherently holistic approach already present in the specialty of PC. This article offers PC teams a framework for understanding the diagnosis and treatment of OUD, methods for performing risk stratification and monitoring, and an overview of opportunities to enhance our care of PC patients with OUD.

Astrovirus infects actively secreting goblet cells and alters the gut mucus barrier.

Astroviruses are a global cause of pediatric diarrhea, but they are largely understudied, and it is unclear how and where they replicate in the gut. Using an in vivo model, here we report that murine astrovirus preferentially infects actively secreting small intestinal goblet cells, specialized epithelial cells that maintain the mucus barrier. Consequently, virus infection alters mucus production, leading to an increase in mucus-associated bacteria and resistance to enteropathogenic E. coli colonization. These studies establish the main target cell type and region of the gut for productive murine astrovirus infection. They further define a mechanism by which an enteric virus can regulate the mucus barrier, induce functional changes to commensal microbial communities, and alter host susceptibility to pathogenic bacteria.

Neurological Complications of Sturge-Weber Syndrome: Current Status and Unmet Needs.

OBJECTIVE: We aimed to identify the current status and major unmet needs in the management of neurological complications in Sturge-Weber syndrome. METHODS: An expert panel consisting of neurologists convened during the Sturge-Weber Foundation Clinical Care Network conference in September 2018. Literature regarding current treatment strategies for neurological complications was reviewed. RESULTS: Although strong evidence-based standards are lacking, the implementation of consensus-based standards of care and outcome measures to be shared across all Sturge-Weber Foundation Clinical Care Network Centers are needed. Each patient with Sturge-Weber syndrome should have an individualized seizure action plan. There is a need to determine the appropriate abortive and preventive treatment of migraine headaches in Sturge-Weber syndrome. Likewise, a better understanding and better diagnostic modalities and treatments are needed for stroke-like episodes. As behavioral problems are common, the appropriate screening tools for mental illnesses and the timing for screening should be established. Brain magnetic resonance imaging (MRI) preferably done after age one year is the primary imaging modality of choice to establish the diagnosis, although advances in MRI techniques can improve presymptomatic diagnosis to identify patients eligible for preventive drug trials. CONCLUSION: We identified the unmet needs in the management of neurological complications in Sturge-Weber syndrome. We define a minimum standard brain MRI protocol to be used by Sturge-Weber syndrome centers. Future multicenter clinical trials on specific treatments of Sturge-Weber syndrome-associated neurological complications are needed. An improved national clinical database is critically needed to understand its natural course, and for retrospective and prospective measures of treatment efficacy.

RACCOON (PROCYON LOTOR) RESPONSE TO ONTARIO RABIES VACCINE BAITS (ONRAB) IN ST. LAWRENCE COUNTY, NEW YORK, USA.

Oral rabies vaccination (ORV) campaigns have been conducted annually in the US over the past two decades to prevent raccoon (Procyon lotor) rabies, which is enzootic along the eastern region of the country from southeastern Canada to Alabama. Because raccoon rabies has been eliminated from neighboring Canadian provinces, continued detection of the variant in the US is of concern due to the potential for infected raccoons to cross the border via the St. Lawrence River. Ontario Rabies Vaccine Baits (ONRAB) containing a live, recombinant human adenovirus expressing the rabies virus glycoprotein have been under experimental use in the US since 2011. We distributed ONRAB in St. Lawrence County, New York, from 2013 to 2015 as part of field trials to evaluate serologic responses in raccoons. Prior to ONRAB distribution, rabies virus neutralizing antibody (RVNA) seroprevalence in raccoons was 45.2% (183 of 405) and increased to 57.7% (165 of 286) after 3 yr of ONRAB baiting. Postbait RVNA seroprevalence increased each year, with a lower response observed in juvenile compared with adult raccoons. The pre-ONRAB seroprevalence detected in 2013 was relatively high and was likely impacted both by elevated rabies activity in the county and the use of ORV with a different vaccine bait for 14 consecutive years prior to our study. Tetracycline biomarker prevalence increased from 1.4% prior to ONRAB baiting to 51.3% from 2013 to 2015, demonstrating bait palatability to raccoons. These data complemented related field trials conducted in West Virginia and the northeastern US.

The Impact of Renal Tissue Procurement at Bedside on Specimen Adequacy and Best Practices.

Objectives: Renal biopsy is the gold standard for the diagnosis of both native and allograft renal diseases. We studied the impact of tissue procurement at bedside (TPB) omission on the adequacy of renal biopsies. Methods: We compared 120 renal biopsies collected during 2015 using TPB with 111 renal biopsies collected during 2016 when TPB was discontinued. Adequacy criteria were applied as follows: by light microscopy, 10 glomeruli and two arteries for allograft biopsies and seven glomeruli for native biopsies. At least one glomerulus was considered adequate for immunofluorescence and electron microscopy in both groups. Results: The rate of inadequacies in allograft biopsies increased significantly, from 12.50% to 21.61% (P < .05), when TPB was discontinued. Conclusions: Elimination of TPB service had a negative impact on allograft specimen adequacy. Repeat biopsies add cost and delay patient care. Institutions should take this into consideration when considering omission of TPB.

Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor With SDHC Germline Mutation and Bilateral Renal and Neck Cysts.

Gastrointestinal stromal tumors (GISTs) are rare in children. Succinate dehydrogenase (SDH)-deficient GISTs are wild type and lack KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A ( KIT or PDGFRA) mutations. These tumors result from germline SDH mutations, somatic SDH mutations, or SDH epimutants. Germline mutations in SDH genes ( SDHA, SDHB, SDHC, or SDHD) suggest Carney-Stratakis syndrome, a paraganglioma syndrome with predisposition for GIST. Negative immunohistochemistry for SDHB indicates dysfunction of the mitochondrial complex regardless of the subunit affected. We present an adolescent male with an SDH-deficient GIST and SDHC germline mutation who developed bilateral renal cysts and neck cysts, not previously described in children with this mutation. Germline testing is critical when SDH mutations are discovered due to treatment and surveillance implications. Further investigations are necessary to fully define the phenotypic expression of this mutation.

Armillaria mexicana, a newly described species from Mexico.

Armillaria mexicana (Agaricales, Physalacriaceae) is described as a new species based on morphology, DNA sequence data, and phylogenetic analyses. It clearly differs from previously reported Armillaria species in North, Central, and South America. It is characterized by the absence of fibulae in the basidioma, abundant cheilocystidia, and ellipsoidal, hyaline basidiospores that are apparently smooth under light microscope, but slightly to moderately rugulose under scanning electron microscope. It is differentiated from other Armillaria species by macromorphological characters, including annulus structure, pileus and stipe coloration, and other structures. DNA sequence data (nuc rDNA internal transcribed spacers [ITS1-5.8S-ITS2 = ITS], 28S D-domain, 3' end of 28S intergenic spacer 1, and translation elongation factor 1-α [TEF1]) show that A. mexicana sequences are quite distinct from sequences of analogous Armillaria species in GenBank. In addition, sequences of ITS of the A. mexicana ex-type culture reveal an ITS1 of 1299 bp and an ITS2 of 582 bp, the longest ITS regions reported thus far in fungi. Phylogenetic analysis based on TEF1 sequences place A. mexicana in a well-separated, monophyletic clade basal to the polyphyletic A. mellea complex.

Pediatric Testicular Hemangioma in a 10-Year-old: A Rare Entity That May Mimic Malignancy With Appraisal of the Literature.

Capillary hemangioma is a rare benign lesion in the testicle, particularly in pediatrics. It can mimic malignancy, leading to radical orchiectomy. We present a case of a testicular hemangioma in a child, and review the literature on testicular hemangiomas in this age group. A hypervascular testicular lesion without elevated tumor markers may warrant intraoperative biopsy to direct surgical management, which may include testis-sparing surgery if amenable.

TbSmee1 regulates hook complex morphology and the rate of flagellar pocket uptake in Trypanosoma brucei.

Trypanosoma brucei uses multiple mechanisms to evade detection by its insect and mammalian hosts. The flagellar pocket (FP) is the exclusive site of uptake from the environment in trypanosomes and shields receptors from exposure to the host. The FP neck is tightly associated with the flagellum via a series of cytoskeletal structures that include the hook complex (HC) and the centrin arm. These structures are implicated in facilitating macromolecule entry into the FP and nucleating the flagellum attachment zone (FAZ), which adheres the flagellum to the cell surface. TbSmee1 (Tb927.10.8820) is a component of the HC and a putative substrate of polo-like kinase (TbPLK), which is essential for centrin arm and FAZ duplication. We show that depletion of TbSmee1 in the insect-resident (procyclic) form of the parasite causes a 40% growth decrease and the appearance of multinucleated cells that result from defective cytokinesis. Cells lacking TbSmee1 contain HCs with aberrant morphology and show delayed uptake of both fluid-phase and membrane markers. TbPLK localization to the tip of the new FAZ is also blocked. These results argue that TbSmee1 is necessary for maintaining HC morphology, which is important for the parasite's ability to take up molecules from its environment.

Severe Diarrhea in the Setting of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICPIs) are novel therapeutic agents targeting a variety of cancers by enhanced T cell activation. Immune-related adverse events (irAEs) commonly occur with ICPI use and can affect multiple organ systems including the gastrointestinal tract. Due to irAEs, the use of ICPIs is limited in autoimmune diseases. We present a case of microscopic colitis diagnosed after the initiation of nivolumab and a case of ipilimumab colitis and Clostridium difficile in the setting of Crohn's colitis.

APOBEC3A efficiently deaminates methylated, but not TET-oxidized, cytosine bases in DNA.

AID/APOBEC family enzymes are best known for deaminating cytosine bases to uracil in single-stranded DNA, with characteristic sequence preferences that can produce mutational signatures in targets such as retroviral and cancer cell genomes. These deaminases have also been proposed to function in DNA demethylation via deamination of either 5-methylcytosine (mC) or TET-oxidized mC bases (ox-mCs), which include 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine. One specific family member, APOBEC3A (A3A), has been shown to readily deaminate mC, raising the prospect of broader activity on ox-mCs. To investigate this claim, we developed a novel assay that allows for parallel profiling of activity on all modified cytosines. Our steady-state kinetic analysis reveals that A3A discriminates against all ox-mCs by >3700-fold, arguing that ox-mC deamination does not contribute substantially to demethylation. A3A is, by contrast, highly proficient at C/mC deamination. Under conditions of excess enzyme, C/mC bases can be deaminated to completion in long DNA segments, regardless of sequence context. Interestingly, under limiting A3A, the sequence preferences observed with targeting unmodified cytosine are further exaggerated when deaminating mC. Our study informs how methylation, oxidation, and deamination can interplay in the genome and suggests A3A's potential utility as a biotechnological tool to discriminate between cytosine modification states.