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Over a decade since its discovery, piscine myocarditis virus (PMCV) remains a significant pathogen in Atlantic salmon aquaculture. Despite this significant impact, the genomic landscape, evolutionary dynamics, and virulence factors of PMCV are poorly understood. This study enhances the existing PMCV sequence dataset by adding 34 genome sequences and 202 new ORF3 sequences from clinical cardiomyopathy syndrome (CMS) cases in Norwegian aquaculture. Phylogenetic analyses, also including sequences from the Faroe Islands and Ireland revealed that PMCV sequences are highly conserved with distinct clustering by country of origin. Still, single CMS outbreaks display multiple PMCV variants, and although some clustering was seen by case origin, occasional grouping of sequences from different cases was also apparent. Temporal data from selected cases indicated increased sequence diversity in the population. We hypothesize that multiple bottlenecks and changing infection dynamics in the host population, with transfer to naïve individuals over time, represent a continuous selection pressure on the virus populations. No clear relation was found between PMCV variants and the severity of heart pathology. However, specific non-synonymous and synonymous mutations that might impact protein function and gene expression efficiency were identified. An additional factor that may impact PMCV replication is the presence of defective viral genomes, a novel finding for viruses of the order Ghabrivirales . This study provides new insights into PMCV genomic characteristics and evolutionary dynamics, highlighting the complex interplay of genetic diversity, virulence markers, and host-pathogen interactions, underscoring the epidemiological complexity of the virus. Keywords: piscine myocarditis virus; evolutionary dynamics; diversity; phylogeny; genomic sequencing; defective viral genomes., Competing Interests: M.L. was affiliated by the diagnostic service company PatoGen AS, which offers PMCV screening, when the analyses were performed. F.M. is affiliated by the aquaculture production company Mowi ASA., (© The Author(s) 2024. Published by Oxford University Press.)

The present study was undertaken to address the recent spate of pasteurellosis outbreaks among sea-farmed Atlantic salmon ( Salmo salar ) in Norway and Scotland, coinciding with sporadic disease episodes in lumpfish ( Cyclopterus lumpus ) used for delousing purposes in salmon farms. Genome assemblies from 86 bacterial isolates cultured from diseased salmon or lumpfish confirmed them all as bona fide members of the Pasteurellaceae family, with phylogenetic reconstruction dividing them into two distinct branches sharing <88% average nucleotide identity. These branches therefore constitute two separate species, namely Pasteurella skyensis and the as-yet invalidly named " Pasteurella atlantica ". Both species further stratify into multiple discrete genomovars (gv.) and/or lineages, each being nearly or fully exclusive to a particular host, geographic region, and/or time period. Pasteurellosis in lumpfish is, irrespective of spatiotemporal origin, linked almost exclusively to the highly conserved " P. atlantica gv. cyclopteri " (Pac). In contrast, pasteurellosis in Norwegian sea-farmed salmon, dominated since the late-1980s by " P. atlantica gv. salmonicida " (Pas), first saw three specific lineages (Pas-1, -2, and -3) causing separate, geographically restricted, and short-lived outbreaks, before a fourth (Pas-4) emerged recently and became more widely disseminated. A similar situation involving P. skyensis (Ps) has apparently been unfolding in Scottish salmon farming since the mid-1990s, where two historic (Ps-1 and -2) and one contemporary (Ps-3) lineages have been recorded. While the epidemiology underlying all these outbreaks/epizootics remains unclear, repeated detection of 16S rRNA gene amplicons very closely related to P. skyensis and " P. atlantica " from at least five cetacean species worldwide raises the question as to whether marine mammals may play a part, possibly as reservoirs. In fact, the close relationship between the studied isolates and Phocoenobacter uteri associated with harbor porpoise ( Phocoena phocoena ), and their relatively distant relationship with other members of the genus Pasteurella , suggests that both P. skyensis and " P. atlantica " should be moved to the genus Phocoenobacter ., Competing Interests: CÅ was employed by Pharmaq Analytiq. FM was employed by Mowi Norway AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gulla, Colquhoun, Olsen, Spilsberg, Lagesen, Åkesson, Strøm, Manji, Birkbeck and Nilsen.)

Exportin-1 (XPO1) is a key player in the nuclear export pathway and is overexpressed in almost all cancers. This is especially relevant for non-Hodgkin lymphoma (NHL), where high XPO1 expression is associated with poor prognosis due to its oncogenic role in exporting proteins and RNA that are involved in cancer progression and treatment resistance. Here, we discuss the proteins and RNA transcripts that have been identified as XPO1 cargo in NHL lymphoma including tumour suppressors, immune modulators, and transcription factors, and their implications for oncogenesis. We then highlight the research to date on XPO1 inhibitors such as selinexor and other selective inhibitors of nuclear export (SINEs), which are used to treat some cases of non-Hodgkin lymphoma. In vitro, in vivo, and clinical studies investigating the anti-cancer effects of SINEs from bench to bedside, both as a single agent and in combination, are also reported. Finally, we discuss the limitations of the current research landscape and future directions to better understand and improve the clinical utility of SINE compounds in NHL.

Assessment of immune competence of farmed Atlantic salmon is especially important during smoltification and the first several months in the sea. Recently developed tools were applied to salmon raised in a traditional flow-through facility (FT, cohort 1) and in a recirculation aquaculture system (RAS, cohort 2). Fish were sampled at four time-points: parr, smolt, and at three weeks and three months after seawater transfer (SWT); expression of 85 selected immune and stress genes, IgM transcripts (Ig-seq), and circulating antibodies were analyzed. A steady increase in gene expression was seen over time in gill and spleen in both cohorts, and especially in antiviral and inflammatory genes in the gill. Differences between the cohorts were greatest in the dorsal fin but later leveled off. Comparison with a gill reference dataset found a deviation in only three of 85 fish, suggesting a good immune status in both cohorts. Levels of both specific and nonspecific antibodies were higher in cohort 2 in smolts and in growers three weeks after SWT; however, levels evened out after three months in the sea. Ig-seq indicated association between antibody production, expansion of the largest clonotypes, and massive migration of B cells from spleen to gill in smolts. The results suggested greater agitation and higher reactivity of the immune system in RAS-produced salmon, but the difference between the cohorts leveled off over time.

Case reports have discussed coronavirus disease of 2019 (COVID-19) patients presenting with hemolytic anemia, specifically with a positive direct antiglobulin test. However, Coombs-negative hemolytic anemia in COVID-19 patients has been rarely reported. We present an unusual case of Coombs-negative hemolytic anemia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which responded with evidence-based COVID-19 treatments. We demonstrate the importance of considering SARS-CoV-2 as a cause of Coombs-negative hemolytic anemia, and we illustrate how treatment of the underlying COVID-19 illness, even if it is just supportive care, will help resolve the associated hemolysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Neerukonda et al.)

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening autoimmune or hereditary thrombotic microangiopathy (TMA) that may be difficult to recognize given the wide spectrum of presenting symptoms. The clinical diagnosis of TTP is based on thrombocytopenia, microangiopathic hemolytic anemia and is confirmed by a disintegrin-like and metalloproteinase with thrombospondin type one motif, member 13 (ADAMTS13) <10%. However, the latter confirmation is not rapidly available, and treatment is typically initiated based on the degree of clinical suspicion. The PLASMIC score was recently developed to distinguish between TMA patients with and without severe ADAMTS13 deficiency and used as an adjunct in the diagnosis of TTP when the clinical picture is not clear.  Here we present the case of a completely asymptomatic female with no past medical history diagnosed with TTP after evaluation for thrombocytopenia found on a routine wellness visit. A high PLASMIC score was crucial in the decision to initiate treatment given an unusual asymptomatic presentation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Pisklakova et al.)

Multiple myeloma is a hematological malignancy characterized by an abnormal proliferation of monoclonal plasma cells. In some occurrences, plasma cell proliferation results in a solitary lesion (solitary bone plasmacytoma or extramedullary plasmacytoma with minimal bone marrow involvement). Approximately 50% of patients with solitary plasmacytoma develop multiple myeloma within 10 years after the initial diagnosis. While back pain and compression fractures are commonly described presentations of multiple myeloma and plasmacytoma, cauda equina syndrome related to plasma cell infiltration is rare and clinical guidelines are limited. Herein, we present a rare case of a woman with acute cauda equina syndrome (CES) secondary to solitary bone plasmacytoma and multiple myeloma., Competing Interests: This research was supported in part by HCA Healthcare and/or an HCA Healthcare-affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities., (Copyright © 2021, Pisklakova et al.)

Background: Epidemiological data from countries worldwide show a consistent pattern implying that a fraction of around 10% of those over 40-50 years in all populations will exhibit severe periodontitis with the potential risk of losing teeth during their life-time. The subgingival microbiota shows striking similarities between populations irrespective of disease severity and can only marginally explain the clinical pattern. It is also difficult to explain this pattern by genetic and acquired risk factors such as systemic disease (e.g. diabetes) or habits (e.g. smoking) even if they may have a confounding effect on the disease., Main Text: Inflammation of the gingiva appears to be a normal and physiological response to the presence of commensal bacteria along the gingival crevice and in the dental biofilm. Over many years of exposure to the dental biofilm, the chronic inflammation in the gingiva gradually results in a loss of attachment and bone loss. Numerous laboratory and clinical studies have provided insight into the potential role of determinants that are associated with periodontitis. However, it has been difficult to relate the findings to the pattern of the distribution of the disease observed in epidemiological studies. We propose a simple and parsimonious model that considers all the multitude of potential determinants as creating effectively random noise within the dental biofilm to which the tissues react by accumulating the effects of this noise., Conclusions: We suggest that such a model can explain many of the epidemiological features of periodontal breakdown over time, and we discuss its clinical implications.

Background: Mucormycosis is a group of rare but life threatening angioinvasive infections caused by fungi of the order Mucorales that often occurs in immunocompromised patients and individuals with poorly controlled diabetes. Rhinocerebral mucormycosis can mimic sinusitis but can rapidly progress to deeper disease and cause facial necrosis. Facial vascular thrombosis is a rare complication of mucormycosis and can confound diagnosis of the disease., Case Presentation: We report the case of a 25-year-old female with poorly controlled type 1 diabetes mellitus who initially presented with symptoms of sinusitis but rapidly progressed with signs of left-sided facial necrosis due to occlusion of the left internal maxillary artery. Early surgical debridement did not yield a microbiological diagnosis. Deeper surgical debridements ultimately revealed angioinvasive fungal disease consistent with mucormycosis. The patient recovered after repeated surgical intervention and aggressive parenteral antifungal therapy., Conclusion: This case illustrates an atypical complication of mucormycosis, and emphasizes that a high index of suspicion in vulnerable patient populations aids in the diagnosis of this life-threatening infection.

Malignancy associated lactic acidosis is a rare metabolic complication that may accompany various types of malignancies. To date, most cases that have been reported are associated with hematologic malignancies (lymphoma and leukemia). Many theories have been proposed to explain the pathophysiology of lactic acidosis in malignancies. We are reporting an unusual case of a 62-year-old female who presented with a complaint of generalized weakness. Patient was found to have pancytopenia and metabolic acidosis with an anion gap secondary to lactic acid in addition to non-anion gap acidosis (NAGA). The lactic acidosis resolved only after initiation of chemotherapy as she was diagnosed with B-cell acute lymphoblastic leukemia. Our patient also had a coexistent Renal Tubular Acidosis (RTA) with large kidneys. The kidney size also decreased with chemotherapy. Our case is unique as evidenced by aleukemic leukemia combined with anion gap acidosis and non-anion gap acidosis. Lactic acidosis has many different causes; although rare, hematologic malignancies should be included in the differential diagnosis regardless of cell counts or tumor burden.

Background: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory condition that can result from infections, autoimmune diseases and malignancies. It is a rarely reported life threatening complication of an acute HIV infection, with only ten documented case reports per our literature search. We present a case of HLH secondary to acute HIV infection with a negative HIV antibody-based assay and high plasma viral load., Case Presentation: A 45 year old male with a past medical history of well controlled hypertension presented with fever, dizziness and non-bloody diarrhea. Initial lab work revealed a new thrombocytopenia, marked renal failure and an elevated creatine kinase, ferritin, lactate dehydrogenase and D-dimer. A bone marrow biopsy revealed HLH. As part of the work up for thrombocytopenia, a rapid HIV antibody based assay was done and was negative. The sample was later routinely tested with a fourth generation antigen/antibody assay as per local protocol and was strongly positive. The plasma RNA viral load was >10,000,000 copies /mL confirming the diagnosis of an acute HIV infection. The patient was urgently started on antiretroviral therapy and recovered., Conclusion: This case illustrates a diagnostic approach to HLH which is an uncommon but life threatening multisystem disease, requiring the involvement of a multidisciplinary team of experts. Following any diagnosis of HLH, rapid identification and treatment of the underlying condition is critical. A negative rapid HIV antibody test can be misleading in the context of early HIV infection and the additional use of fourth generation antigen/antibody test or plasma RNA viral load may be required within the right clinical context for diagnosis.

Background: Dual antiplatelet (Plt) therapy with aspirin and clopidogrel is recommended for up to 1 year following acute coronary syndrome. Many of these cardiac patients are also on anithrombotic therapy like warfarin. Lower gastrointestinal bleeding (LGIB) is the main adverse event of this treatment., Aims: The main purpose of this study was to analyze the relationship of dual anti-Plt therapy and the risk of LGIB., Methods: Patients' electronic charts were reviewed to include a total of 19 variables, which included age, sex, ethnicity, daily use aspirin of any dose, daily use of clopidogrel, use of nonsteroidal anti-inflammatory drugs (NSAIDs) at least twice in the last week prior to admission and the daily use of anticoagulants (warfarin, heparin), and were obtained from history and physical examination reports, lab transcripts and procedural reports., Settings/design: A retrospective cohort study of the records of 3436 patients admitted to our hospital from January 1, 2009, to December 31, 2011, was evaluated. All the patients included were admitted through the emergency department with complaints of or relating to LGIB. The primary outcome studied was severe LGIB as defined by the requirement of at least two units of packed red blood cells and/or a decrease in the hematocrit of 20% or more or recurrent bleeding after 24 h of clinical stability with additional transfusions required. Other outcomes included surgical intervention., Statistical Methods/analysis: Univariate analysis using t -test on continuous variables and Chi-square test on categorical variables were done before carrying out logistic regression analysis. Logistic regression analyses were conducted to measures of association between the variables and LGIB. Logistic regression analysis was not carried for surgical intervention and death because none of the variables was significant from univariate tests., Results: A total of 511 patients were found to have true LGIB. Among these subjects, 61 were shown to be on dual or multiple antithrombotic therapies. Further exploration revealed that while the use of multiple blood thinning agents may, in fact, pose a significant risk to overall LGIB, it did not significantly increase the risk for severe bleeding as outlined above., Conclusion: The use of multiple blood thinning agents does not significantly increase the risk for severe LGIB., Competing Interests: There are no conflicts of interest.

Background: Preprocedural assessments are used by anesthesia providers to optimize perioperative care for patients undergoing invasive procedures. When these assessments are performed in advance by providers who are not caring for the patient during the procedure, there is an additional layer of complexity in ensuring that the workup meets the needs of the primary anesthesia care team. In this study, anesthesia providers were asked to rate the quality of preprocedural assessments prepared by other providers to evaluate anesthesia care team satisfaction., Methods: Quality ratings for preprocedural assessments were collected from anesthesia providers on the day of surgery using an electronic quality assurance tool from January 9, 2014 to October 21, 2014. Users could rate assessments as "exemplary," "satisfactory," or "unsatisfactory." Free text comments could be entered for any of the quality ratings chosen. A reviewer trained in clinical anesthesia categorized all comments as "positive," "constructive," or "neutral" and conducted in-depth chart reviews triggered by 67 "constructive" comments submitted during the first 3 months of data collection to further subcategorize perceived deficiencies in the preprocedural assessments. In May 2014, providers were asked to participate in a midpoint survey and provide general feedback about the preprocedural process and evaluations., Results: 37,611 procedures requiring anesthesia were analyzed. Of the 17,522 (46.6%) cases with a rated preprocedural assessment, anesthesia providers rated 3828 (21.8%) as "exemplary," 13,454 (76.8%) as "satisfactory," and 240 (1.4%) as "unsatisfactory." The monthly proportion of "unsatisfactory" ratings ranged from 3.1% to 0% over the study period, whereas the midpoint survey showed that anesthesia providers estimated that the number of unsatisfactory evaluations was 11.5%. Preprocedural evaluations performed on inpatients received significantly better ratings than evaluations performed on outpatients by the preadmission testing clinic or phone program (P < .0001). The most common reason given for "unsatisfactory" ratings was a perception of "missing information" (49.2%). Chart reviews revealed that inadequate documentation was in reality the most common deficiency in preprocedural evaluations (35 of 67 reviews, 52.2%)., Conclusions: The overwhelming majority of preprocedural assessments performed at our institution were considered satisfactory or exemplary by day-of-surgery anesthesia providers. This was demonstrated by both the case-by-case ratings and midpoint survey. However, the perceived frequency of "unsatisfactory" evaluations was worse when providers were asked to reflect on the quality of preprocedural evaluations generally versus rate them individually. Analysis of comments left by providers allowed us to identify specific and actionable areas for improvement. This method can be used by other institutions to identify systemic deficiencies in the preprocedural evaluation process.

Methylene blue is a phenothiazine-related heterocyclic aromatic molecule presently used in the treatment of methemoglobinemia. Recently, it has been implicated in the treatment of severe refractory vasoplegic shock caused by anaphylaxis, sepsis, or postcardiopulmonary bypass. We present a case of a 27-year-old male with profound vasoplegic shock of unknown etiology which was refractory to vasopressors who responded within hours to a single dose of methylene blue. Additionally, we review the evidence of methylene blue's role in the treatment of shock. This case illustrates a diagnostic approach and treatment options in the setting of undifferentiated vasodilatory shock and outlines a new and emerging role for methylene blue in this clinical setting.

Background: Dual energy subtraction (DES) radiography is a powerful but underutilized technique which aims to improve the diagnostic value of an X-ray by separating soft tissue from bones, producing two different images. Compared to traditional chest X-rays, DES requires exposure to higher doses of radiation but may achieve higher accuracy. The objective of this study was to assess the clinical benefits of DES radiography by comparing the speed and accuracy of diagnosis of pulmonary nodules with DES versus traditional chest X-rays., Methods: Five radiologists and five radiology residents read the DES and traditional chest X-rays of 51 patients, 34 with pulmonary nodules and 17 without. Their accuracy and speed in the detection of nodules were measured using specialized image display software., Results: DES radiography reduced reading time from 13 to 10 sec (P<0.0001) in staff and from 21 to 15 sec in residents (P<0.0001). There was also a small increase in sensitivity 0.58 to 0.67 overall (P<0.10) with no change in specificity (0.85 overall)., Conclusions: By eliminating rib shadows in soft tissue images, DES improved the speed and accuracy of radiologists in the diagnosis of pulmonary nodules.

Background. Surgery for GI dysmotility is limited to those with severe refractory disease. Though effective, use of serotonergic promotility drugs has been restricted in Canada due to adverse events. We aimed to investigate utilization of promotility serotonergic drugs in patients under consideration for surgical management. Methods. A retrospective cohort study was conducted using prospectively collected data. The study population included consecutive patients referred to a motility clinic for consideration of bowel resection at a Canadian tertiary hospital (1996-2011). Univariable tests and multivariable logistic regression analyses were used to assess predictors of serotonergic drug use. Results. Of 128 patients, the majority (n = 98, 76.6%) had constipation-dominant symptoms. Only 25% (n = 32) had tried serotonergic promotility drugs. There was no association between use of these drugs and severity of constipation nor was there an association between serotonergic drug use and presence of diffuse dysmotility (all p > 0.05). The majority of patients (n = 97, 75.8%) underwent some type of surgical resection, which was associated with considerable morbidity (n = 13, 13.4%). Conclusions. Surgical management of GI dysmotility results in serious morbidity. Serotonergic promotility drugs may allow patients to avoid surgery but disease severity does not predict use of these drugs.

Irritable bowel syndrome (IBS) is the most common of the functional gastrointestinal disorders (FGIDs). Despite its prevalence and health-care costs, there are few effective therapies for patients with severe symptoms. Our objective was to determine whether surgical management would improve health-related quality of life (HRQOL) in severe refractory constipation-dominant FGIDs. From 2003 to 2005, 6 patients underwent total colectomy with end ileostomy or primary anastomosis. They completed Short Form 36 (SF-36) and IBS-36 questionnaires preoperatively and postoperatively. HRQOL was compared with age- and sex-matched Canadian norms using Welch's unpaired t test. Preoperative SF-36 physical and mental health summary scores were significantly lower than Canadian norms (P < 0.0001), while postoperative scores were not significantly different than Canadian norms (P = 0.50 and P = 0.57, respectively). After surgical management, HRQOL in patients with severe constipation-dominant IBS improved from drastically below that of Canadian norms to a comparable level. This finding questions the convention of avoiding operations in IBS patients and demonstrates that surgical management may be suitable for the appropriately screened patient.