The Tumor Suppressor Adenomatous Polyposis Coli (apc) Is Required for Neural Crest-Dependent Craniofacial Development in Zebrafish.

Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of NC induction, delamination, and migration. We report that a truncating mutation of the classical tumor suppressor Adenomatous Polyposis Coli (apc) disrupts craniofacial development in zebrafish larvae, with a marked reduction in the cranial neural crest (CNC) cells that contribute to mandibular and hyoid pharyngeal arches. While the mechanism is not yet clear, the altered expression of signaling molecules that guide CNC migration could underlie this phenotype. For example, apcmcr/mcr larvae express substantially higher levels of complement c3, which Mayor and colleagues showed impairs CNC cell migration when overexpressed. However, we also observe reduction in stroma-derived factor 1 (sdf1/cxcl12), which is required for CNC migration into the head. Consistent with our previous work showing that APC directly enhances the activity of glycogen synthase kinase 3 (GSK-3) and, independently, that GSK-3 phosphorylates multiple core mRNA splicing factors, we identify 340 mRNA splicing variations in apc mutant zebrafish, including a splice variant that deletes a conserved domain in semaphorin 3f (sema3f), an axonal guidance molecule and a known regulator of CNC migration. Here, we discuss potential roles for apc in CNC development in the context of some of the seminal findings of Mayor and colleagues.

Venetoclax ramp-up with concurrent voriconazole in a patient with chronic lymphocytic leukemia.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is commonly treated with the B-cell lymphoma 2 inhibitor (BCL-2) venetoclax. Venetoclax is associated with an increased risk of tumor lysis syndrome in this patient population. Because venetoclax undergoes CYP3A4 metabolism, strong CYP3A4 inhibitors are contraindicated during the ramp-up phase of venetoclax in patients with CLL. CASE REPORT: Our case report describes a 58 year old male initially diagnosed with CLL in 2013, whose first-line treatment consisted of ibrutinib. The patient developed a central nervous system (CNS) aspergillosis infection in 2018, and was initiated on voriconazole. He was subsequently under active surveillance until his disease progressed. The patient was started on venetoclax therapy, while on concomitant voriconazole, for management of his CLL. MANAGEMENT AND OUTCOME: The patient's initial venetoclax dose was 10 mg daily, and he received rasburicase on day 1 of therapy. He tolerated a modified ramp-up phase without complication. After receiving 9 days of inpatient therapy, the patient was discharged on 50 mg of venetoclax to continue outpatient dose escalation. His dose was ultimately escalated to 100 mg daily. DISCUSSION: Although this report describes the safe administration of venetoclax with voriconazole, extreme caution should be exercised when administering venetoclax with any strong CYP3A4 inhibitor during the ramp-up phase in patients with CLL.

COVID Toes: Concurrent Lower Limb Arterial and Venous Thromboembolism in a Patient with COVID-19 Pneumonitis Presenting with Foot Ischaemia.

We present a 74-year-old gentleman, who presented with foot ischaemia requiring bilateral amputation in the absence of radiological signs of occlusive peripheral arterial disease. He was found to have COVID-19 pneumonitis and concurrent arterial and venous thromboemboli despite no initial respiratory symptoms or signs, nor pre-existing risk factors for cardiovascular disease. Patients who present with foot ischaemia with or without respiratory symptoms or signs warrant a high index of suspicion for COVID-19 infection, particularly in those with no predisposing risk factors.

Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition.

The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-CoV, and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors, including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR-tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35-0.74], P = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type-dependent manner. Targeting GSK-3 may therefore provide an approach to treat COVID-19 and future coronavirus outbreaks.

Suggested Curricular Guidelines for Musculoskeletal and Sports Medicine in Physical Medicine and Rehabilitation Residency Training.

ABSTRACT: A sports medicine physician manages musculoskeletal (MSK) injuries and sport-related medical and MSK conditions of patients of all ages and abilities. Physical medicine and rehabilitation physicians (physiatrists) must be adequately trained to provide this care for all patients including, but not limited to, athletes participating in organized sports, the weekend warrior as well as athletes with disabilities. Accreditation Council of Graduate Medical Education core requirements and basic guidelines help physiatry residency training programs develop and implement residency curriculums. The goal of this article is to provide suggested curricular guidelines to optimize physiatrist training in MSK and sports medicine.

Assessment of the fetal thymus gland: Comparing MRI-acquired thymus volumes with 2D ultrasound measurements.

OBJECTIVES: The fetal thymus gland has been shown to involute in response to intrauterine infection, and therefore could be used as a non-invasive marker of fetal compartment infection. The objective of this study was to evaluate how accurately 2D ultrasound-derived measurements of the fetal thymus reflect the 3D volume of the gland derived from motion corrected MRI images. STUDY DESIGN: A retrospective study was performed using paired ultrasound and MRI datasets from the iFIND project (http://www.ifindproject.com). To obtain 3D volumetry of the thymus gland, T2-weighted single shot turbo spin echo (ssTSE) sequences of the fetal thorax were acquired. Thymus volumes were manually segmented from deformable slice-to-volume reconstructed images. To obtain 2D ultrasound measurements, previously stored fetal cine loops were used and measurements obtained at the 3-vessel-view (3VV) and 3-vessel-trachea view (3VT): anterior-posterior diameter (APD), intrathoracic diameter (ITD), transverse diameter (TD), perimeter and 3-vessel-edge (3VE). Inter-observer and intra-observer reliability (ICC) was calculated for both MRI and ultrasound measurements. Pearson correlation coefficients (PCC) were used to compare 2D-parameters with acceptable ICC to TV. RESULTS: 38 participants were identified. Adequate visualisation was possible on 37 MRI scans and 31 ultrasound scans. Of the 30 datasets where both MRI and ultrasound data were available, MRI had good interobserver reliability (ICC 0.964) and all ultrasound 3VV 2D-parameters and 3VT 3VE had acceptable ICC (>0.75). Four 2D parameters were reflective of the 3D thymus volume: 3VV TD r = 0.540 (P = 0.002); 3VV perimeter r = 0.446 (P = 0.013); 3VV APD r = 0.435 (P = 0.110) and 3VT TD r = 0.544 (P = 0.002). CONCLUSIONS: MRI appeared superior to ultrasound for visualization of the thymus gland and reproducibility of measurements. Three 2D US parameters, 3VV TD, perimeter and 3VT APD, correlated well with TV. Therefore, these represent a more accurate reflection of the true size of the gland than other 2D measurements, where MRI is not available.

Restoring two tumor suppressor pathways with one PAWI.

In this issue of Cell Chemical Biology, Cheng et al. (2021) identify a class of drugs that activate a mitotic stress-dependent signaling cascade, which culminates in p53 activation and Wnt pathway inhibition (PAWI). PAWI compounds may therefore be effective in cancers associated with loss of p53 and activation of Wnt signaling.

Musculoskeletal and Sports Medicine Curriculum Guidelines for Pediatric Residents.

ABSTRACT: Musculoskeletal (MSK) and sports-related conditions are relatively common in the pediatric population. Pediatric residencies should provide residents with the knowledge and skills to assess and manage both acute and chronic MSK and sports injuries and complaints. Residents should develop the competencies and attitudes to safeguard and promote a healthy and active lifestyle for youth. Programs can use a variety of educational tools, both in the clinic and on the field, to provide a well-rounded MSK curriculum throughout the residency years. This article provides a review of general pediatric sports medicine curriculum guidelines and suggested implementation strategies.

Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition.

The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome (MERS-CoV), and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35 - 0.74], p = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type dependent manner. Targeting GSK-3 may therefore provide a new approach to treat COVID-19 and future coronavirus outbreaks. SIGNIFICANCE: COVID-19 is taking a major toll on personal health, healthcare systems, and the global economy. With three betacoronavirus epidemics in less than 20 years, there is an urgent need for therapies to combat new and existing coronavirus outbreaks. Our analysis of clinical data from over 300,000 patients in three major health systems demonstrates a 50% reduced risk of COVID-19 in patients taking lithium, a direct inhibitor of glycogen synthase kinase-3 (GSK-3). We further show that GSK-3 is essential for phosphorylation of the SARS-CoV-2 nucleocapsid protein and that GSK-3 inhibition blocks SARS-CoV-2 infection in human lung epithelial cells. These findings suggest an antiviral strategy for COVID-19 and new coronaviruses that may arise in the future.

Citrobacter braakii CLABSI in a hematopoietic stem cell transplant patient.

INTRODUCTION: Citrobacter bacteria are gram-negative anaerobic bacilli commonly found in water, soil, food, and the intestinal tracts of animals and humans. Patients at highest risk of these nosocomial infections include neonates and adults who are ≥65 years of age, debilitated, or immunocompromised. Citrobacter braakii (C. braakii), specifically, has been reported to cause sepsis in immunocompromised patients. Herein, we describe a case of an allogeneic stem cell transplant (SCT) adult patient with C. braakii bloodstream infection. CASE REPORT: We report our experience managing a central line-associated bloodstream infection (CLABSI) due to C. braakii in an allogeneic SCT patient.Management and Outcomes: Our patient was initially managed with cefepime. The central venous catheter (CVC) was removed. Blood cultures cleared 24 hours after antibiotic initiation. Therapy was transitioned to oral levofloxacin once susceptibilities resulted. DISCUSSION: The course of this patient highlights the important relationship between an unusual pathogen, C. braakii, in an immunocompromised allogeneic SCT patient. In our case, the source of the bacteremia was most likely a CLABSI given the positive catheter tip cultures. Although this report describes the successful utilization of cefepime and levofloxacin in the treatment of C. braakii infection, caution should be exercised when choosing empiric antimicrobial therapy as AmpC resistance. This clinical scenario can aid health care providers in making informed treatment decisions when faced with patients diagnosed with this relatively uncommon pathogen. Further reports should be published to determine C. braakii bacteremia management in hematopoietic stem cell transplant patients.

Recommended Musculoskeletal and Sports Medicine Curriculum for Internal Medicine Residency Training.

ABSTRACT: Patients present to primary care physicians with musculoskeletal complaints more often than they do for upper respiratory infections, hypertension, or diabetes. Despite this, instruction in musculoskeletal medicine for internal medicine residents represents less than 1% of their total didactic and clinical education time. We recognize the immense breadth of knowledge and skill required to train residents in the practice of internal medicine. This curriculum guideline defines a recommended training strategy, and supplies relevant resources, to improve musculoskeletal education among internal medicine residents to optimize patient care. This curriculum guideline was created by internists who are sports medicine specialists. Sports medicine physicians promote overall health and well-being while providing expertise in acute and chronic musculoskeletal conditions, as well as how disease affects exercise and using exercise as medicine for people with chronic disease.

Recommended Musculoskeletal and Sports Medicine Model Curriculum for Emergency Medicine Residency Training.

ABSTRACT: Musculoskeletal and sports medicine conditions are common in the emergency department (ED). Emergency physicians may not be receiving adequate education to achieve clinical competency in musculoskeletal medicine during residency training. This article aims to provide a standardized musculoskeletal and sports medicine curriculum for emergency medicine training. Broad curriculum goals include proficiency in evaluating and managing patients presenting to the ED with acute and chronic musculoskeletal complaints and other medical conditions related to or affected by physical exertion, sports participation, or environmental exposure. Specific objectives focus on knowledge of these disorders, physical examination skills, procedural skills including musculoskeletal ultrasound, appropriate consultation and referral, and patient education for these conditions. Educational methods will consist of didactics; online self-directed learning modules; simulation; and supervised clinical experiences in the ED, primary care sports medicine clinics, and orthopedic clinics if available. Curriculum implementation is expected to vary across programs due to differences in residency program structure and resources.

Sexual violence in sport: American Medical Society for Sports Medicine Position Statement.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the Task Force used an iterative process and expert consensus to finalise the Position Statement. The objective of this Position Statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.

Gilteritinib administration in a hemodialysis patient.

INTRODUCTION: Gilteritinib is a multitargeted tyrosine kinase inhibitor (TKI) approved by the Food and Drug Administration (FDA) for acute myeloid leukemia (AML) with a FMS-related tyrosine kinase 3 (FLT3) mutation. The pharmacokinetics of gilteritinib in the setting of severe renal impairment (creatinine clearance [CrCl] 15-29 mL/min utilizing Cockcroft-Gault method) and end-stage renal disease are unknown. Gilteritinib is primarily metabolized by the liver through the CYP3A4 enzyme and is eliminated in both the feces and urine. Its excretion is primarily through the fecal route, accounting for 64.5% of the recovered dose. Only about 16.4% of the recovered dose has been detected in the urine of human subjects. CASE REPORT: We describe our patient case documenting the administration of gilteritinib in the setting of end-stage renal disease (ESRD) and hemodialysis (HD).Management and Outcomes: Our patient was initiated on single agent gilteritinib 120 mg by mouth once daily for relapse FLT3-TDK positive AML. Treatment course was complicated by pancytopenia, neutropenic fever, and staphylococcus lugdunensis bacteremia requiring temporary interruption of therapy. DISCUSSION: Given that gilteritinib is metabolized by the liver and eliminated primarily in the feces, one does not expect an increase in toxicity related to impaired renal function. Although this report describes the successful utilization of gilteritinib, caution should be exercised when administering in patient populations with end organ disease, and patient comorbidities should be taken into account.

Sexual Violence in Sport: American Medical Society for Sports Medicine Position Statement.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the position statement. The objective of this position statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.

Sexual Violence in Sport: American Medical Society for Sports Medicine Position Statement.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the Position Statement. The objective of this Position Statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.

Sexual Violence in Sport: American Medical Society for Sports Medicine Position Statement.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a position statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the position statement. The objective of this position statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.