Incidence of Thrombosis in COVID-19 Patients Compared to Non-COVID-19 Sepsis Patients in the Intensive Care Unit.

Background/Objectives: The hypercoagulable state associated with COVID-19 infection is associated with adverse outcomes and mortality. Studies have also demonstrated high rates of venous thromboembolism (VTE) events among patients with sepsis. We aimed to evaluate how the increase in thrombotic events in critically ill patients with COVID-19 infection compares to that of critically ill patients with non-COVID-19 sepsis. Methods: A chart review was performed of patients 18 years or older admitted to the intensive care unit (ICU) at Tampa General Hospital between 1 January 2020 and 31 December 2020 diagnosed with COVID-19 or sepsis secondary to other pathogens. Non-COVID-19 sepsis patients and COVID-19 patients were propensity-matched 3:1 on the Charlson Comorbidity Index. Multivariate analyses adjusting for confounding were conducted to report odds ratio (OR) and 95% confidence intervals (95% CIs) of predictors for thrombotic events and overall mortality. Results: After propensity score matching, 492 sepsis patients and 164 COVID-19 patients were included in the analysis. COVID-19 patients were significantly older (p = 0.021) and showed higher BMI (p < 0.001) than sepsis patients. COVID-19 patients did not show significantly higher odds of thrombosis after adjustment for confounders (OR 0.85, 95% CI 0.42-1.72), but had significantly lower odds of mortality than sepsis patients (OR 0.33, 95% CI 0.16-0.66). Conclusions: Our results suggest that further study is required to lower the rate of VTE in COVID-19 and non-COVID-19 sepsis patients admitted to the ICU; it is also reasonable to consider similar thromboembolism practices between these two patient groups.

Survivors Overcoming and Achieving Resiliency (SOAR): Mindful Eating Practice for Breast Cancer Survivors in a Virtual Teaching Kitchen.

The practice of mindful eating brings awareness to food choices, brings attention to the eating experience, and encourages selecting and preparing food that is both satisfying and nourishing. We examined mindful eating in breast cancer survivors following a 9-week, multidisciplinary virtual teaching kitchen intervention called Survivors Overcoming and Achieving Resiliency (SOAR). SOAR engaged participants through weekly cooking classes that also taught multiple domains of mindfulness. Participants (n = 102) were breast cancer survivors and completed the Mindful Eating Questionnaire (MEQ) prior to and after completion of the intervention. Linear regression analyses examined relationships between the aspects of mindful eating and body mass index (BMI). Wilcoxon (paired) rank sum tests evaluated the significance of the change in the MEQ total sum and subscales scores. A total of 102 participants completed both the pre- and post-intervention surveys. The mean change between the pre- and post-SOAR MEQ summary scores was 0.12 (sd = 0.30; Wilcoxon p-value = 0.0003). All MEQ subscale scores significantly increased with the exception of the distraction subscale. The MEQ summary scores increased for participants across both BMI stratifications. The SOAR teaching kitchen represents one of the first interventions that is tailored for breast cancer survivors and combines behavioral strategies from mindful eating training to nutritional knowledge and culinary medicine pedagogy in a virtual teaching kitchen. Further research is needed to examine whether mindful eating practices among cancer survivors result in sustainable healthy eating behaviors and food choices consistent with the cancer risk reduction guidelines.

Urgent Revascularization of the Left Proximal Circumflex Following Cessation of Cangrelor Within Six Hours of Procedure.

Patients undergoing procedures are often transitioned off anticoagulants using anti-platelet agents with short half-lives as a "bridge." We present the case of a patient with a history of in-stent thromboses who experienced a thrombotic event following a literature-guided bridging protocol. This case is one of the first to show that stopping cangrelor within six hours led to a need for urgent revascularization and suggests that the timing for discontinuing bridging agents should be customized based on the patient's history of increased blood clotting.

A Novel Case of Acute Respiratory Distress Syndrome Following Radiofrequency Ablation for Atrial Fibrillation.

Radiofrequency ablation (RFA) is a minimally invasive cardiac catheterization procedure employed in patients whose atrial fibrillation (AF) is not well-controlled on medical therapy. While serious complications after the RFA are uncommon, we present the unique case of a 71-year-old male who suffered from acute respiratory distress syndrome (ARDS) and pneumomediastinum post-procedure. He presented to the ED with dyspnea, non-massive hemoptysis, and fever three days following RFA. Admission CT thorax demonstrated patchy ground glass opacities (GGOs) and stable fibrotic changes. He was admitted for suspected pneumonia, however, he failed to significantly improve on broad-spectrum antibiotics. Bronchoscopy found blood in proximal airways, however, lavage with serial aliquots were without worsening hemorrhage, ruling out suspected diffuse alveolar hemorrhage. Cytology resulted in rare iron polymorphonuclear neutrophils and no malignant cells. With worsening clinical status, the patient was eventually intubated. Repeat CT thorax showed new moderate pneumopericardium, small pneumomediastinum, and progressed GGOs. The respiratory course continued to worsen, and the patient passed away approximately one month after admission. We also present a brief literature review with the aim of identifying prognostic risk factors regarding post-RFA ARDS development. Additionally, this case identifies a novel complication of RFA, as post-procedural pneumomediastinum has not been previously described.

Rapid Improvement Following Receipt of Infliximab in Steroid-refractory Durvalumab-Associated Grade 3 Pneumonitis.

Immune checkpoint inhibitors (ICIs) are important novel agents used in advanced non-small cell lung cancer (NSCLC) standard regimens; however, their use increases the risk of immune-related adverse effects (IRAEs). The incidence of IRAE pneumonitis is well documented in ICI use. Corticosteroids continue to be the mainstay of treatment for IRAEs. Here we report one of the first cases of using infliximab to treat durvalumab-associated pneumonitis.

Transcriptional repression by ApiAP2 factors is central to chronic toxoplasmosis.

Tachyzoite to bradyzoite development in Toxoplasma is marked by major changes in gene expression resulting in a parasite that expresses a new repertoire of surface antigens hidden inside a modified parasitophorous vacuole called the tissue cyst. The factors that control this important life cycle transition are not well understood. Here we describe an important transcriptional repressor mechanism controlling bradyzoite differentiation that operates in the tachyzoite stage. The ApiAP2 factor, AP2IV-4, is a nuclear factor dynamically expressed in late S phase through mitosis/cytokinesis of the tachyzoite cell cycle. Remarkably, deletion of the AP2IV-4 locus resulted in the expression of a subset of bradyzoite-specific proteins in replicating tachyzoites that included tissue cyst wall components BPK1, MCP4, CST1 and the surface antigen SRS9. In the murine animal model, the mis-timing of bradyzoite antigens in tachyzoites lacking AP2IV-4 caused a potent inflammatory monocyte immune response that effectively eliminated this parasite and prevented tissue cyst formation in mouse brain tissue. Altogether, these results indicate that suppression of bradyzoite antigens by AP2IV-4 during acute infection is required for Toxoplasma to successfully establish a chronic infection in the immune-competent host.

Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through ß-TrCP-mediated proteasome degradation.

Overexpression of the GLI1 gene has frequently been found in various cancer types, particularly in brain tumors, in which aberrant GLI1 induction promotes cancer cell growth. Therefore, identifying the molecular players controlling GLI1 expression is of clinical importance. Previously, we reported that AMPK directly phosphorylated and destabilized GLI1, resulting in the suppression of the Hedgehog signaling pathway. The current study not only demonstrates that AMPK inhibits GLI1 nuclear localization, but further reveals that ß-TrCP plays an essential role in AMPK-induced GLI1 degradation. We found that activation of AMPK promotes the interaction between ß-TrCP and GLI1, and induces ß-TrCP-mediated GLI1-ubiquitination and degradation. Inhibiting AMPK activity results in the dissociation of the ß-TrCP and GLI1 interaction, and diminishes ß-TrCP-mediated-GLI1 ubiquitination and degradation. On GLI1, substitution of AMPK phosphorylation sites to aspartic acid (GLI13E) results in stronger binding affinity of GLI1 with ß-TrCP, accompanied by enhanced GLI1 ubiquitination and later degradation. In contrast, the GLI1 alanine mutant (GLI13A) shows weaker binding with ß-TrCP, which is accompanied by reduced ß-TrCP-mediated ubiquitination and degradation. Together, these results demonstrate that AMPK regulates GLI1 interaction with ß-TrCP by phosphorylating GLI1 and thus both post-translational modifications by AMPK and ß-TrCP ultimately impact GLI1 degradation.

Toxoplasma gondii AP2IX-4 Regulates Gene Expression during Bradyzoite Development.

Toxoplasma gondii is a protozoan parasite of great importance to human and animal health. In the host, this obligate intracellular parasite persists as a tissue cyst that is imperceptible to the immune response and unaffected by current therapies. The tissue cysts facilitate transmission through predation and give rise to chronic cycles of toxoplasmosis in immunocompromised patients. Transcriptional changes accompany conversion of the rapidly replicating tachyzoites into the encysted bradyzoites, and yet the mechanisms underlying these alterations in gene expression are not well defined. Here we show that AP2IX-4 is a nuclear protein exclusively expressed in tachyzoites and bradyzoites undergoing division. Knockout of AP2IX-4 had no discernible effect on tachyzoite replication but resulted in a reduced frequency of tissue cyst formation following alkaline stress induction-a defect that is reversible by complementation. AP2IX-4 has a complex role in regulating bradyzoite gene expression, as the levels of many bradyzoite mRNAs dramatically increased beyond those seen under conditions of normal stress induction in AP2IX-4 knockout parasites exposed to alkaline media. The loss of AP2IX-4 also resulted in a modest virulence defect and reduced cyst burden in chronically infected mice, which was reversed by complementation. These findings illustrate that the transcriptional mechanisms responsible for tissue cyst development operate across the intermediate life cycle from the dividing tachyzoite to the dormant bradyzoite. IMPORTANCEToxoplasma gondii is a single-celled parasite that persists in its host as a transmissible tissue cyst. How the parasite converts from its replicative form to the bradyzoites housed in tissue cysts is not well understood, but the process clearly involves changes in gene expression. Here we report that parasites lacking a cell cycle-regulated transcription factor called AP2IX-4 display reduced frequencies of tissue cyst formation in culture and in a mouse model of infection. Parasites missing AP2IX-4 lose the ability to regulate bradyzoite genes during tissue cyst development. Expressed in developing bradyzoites still undergoing division, AP2IX-4 may serve as a useful marker in the study of transitional forms of the parasite.

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development.

Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As "readers" of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.

Targeting the Hedgehog Pathway in Pediatric Medulloblastoma.

Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%-80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical.

Algoriphagus machipongonensis sp. nov., co-isolated with a colonial choanoflagellate.

A Gram-negative, non-motile, non-spore-forming bacterial strain, PR1(T), was isolated from a mud core sample containing colonial choanoflagellates near Hog Island, Virginia, USA. Strain PR1(T) grew optimally at 30 °C and with 3 % (w/v) NaCl. Strain PR1(T) contained MK-7 as the major menaquinone as well as carotenoids but lacked pigments of the flexirubin-type. The predominant fatty acids were iso-C(15 : 0) (29.4 %), iso-C(17 : 1)ω9c (18.5 %) and summed feature 3 (C(16 : 1)ω6c and/or C(16 : 1)ω7c; 11.3 %). The major polar lipids detected in strain PR1(T) were phosphatidylethanolamine, an unknown phospholipid, an aminophospholipid, an aminolipid and two lipids of unknown character. The DNA G+C content was 38.7 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain PR1(T) fell within the cluster comprising the genus Algoriphagus and was most closely related to Algoriphagus halophilus JC 2051(T) (95.4 % sequence similarity) and Algoriphagus lutimaris S1-3(T) (95.3 % sequence similarity). The 16S rRNA gene sequence similarity between strain PR1(T) and the type strains of other species of the genus Algoriphagus were in the range 91-95 %. Differential phenotypic properties and phylogenetic and genetic distinctiveness of strain PR1(T) demonstrated that this strain was distinct from other members of the genus Algoriphagus, including its closest relative, A. halophilus. Based on phenotypic, chemotaxonomic, phylogenetic and genomic data, strain PR1(T) should be placed in the genus Algoriphagus as a representative of a novel species, for which the name Algoriphagus machipongonensis sp. nov. is proposed. The type strain is PR1(T) (= ATCC BAA-2233(T) = DSM 24695(T)).