Severe B12 Deficiency Causing a Maturation Defect Mimicking Myelodysplastic Syndrome With Excess Blasts.

Vitamin B12 deficiency is a common condition that is often asymptomatic, though in severe cases may cause megaloblastic anemia and even neurologic symptoms. Occasionally, the clinical presentation can include pancytopenia and thus mimic a more concerning myelodysplastic syndrome (MDS) until corrected by B12 supplementation. In this unusual case, we present a patient with B12 deficiency who presents with severe macrocytic anemia, neutropenia, lymphocytosis, and a bone marrow morphology consistent with MDS.

Intracerebral Hemorrhage in a Patient With Newly Diagnosed Immune Thrombocytopenic Purpura Precipitated by a Viral Illness.

Intracerebral hemorrhage (ICH) is a rare and severe complication of immune thrombocytopenic purpura (ITP) that can be spontaneous. Viral illnesses, other infections, autoimmune disorders, and medications can cause ITP. ITP causes a significant decrease in platelet levels, increasing bleeding risk. ITP can be treated by steroids, intravenous immunoglobulin, plasmapheresis, platelet transfusion, biological agents, and splenectomy. ICH treatment involves the treatment of underlying ITP, as well as any neuro-interventional procedures needed. In this case report, we look at the presenting symptoms and treatment course of an interesting case of ICH in a patient who developed ITP after a viral upper respiratory infection.

New-Onset Monosomy 7-Induced Pancytopenia in a 66-Year-Old Woman.

Myelodysplastic syndrome (MDS) is characterized by failure to initiate hematopoiesis or impaired maturation of cells, often presenting with pancytopenias with or without associated fatigue, infections, or inappropriate bleeding and bruising. Karyotype analyses of MDS patients commonly show deletion of the q arm of chromosome 7, suggesting loss of this region is likely implicated in the insufficient hematopoiesis seen in MDS. The predisposition to deletion of 7q is commonly inherited, with clinical presentation in early childhood associated with pancytopenia or hematological malignancy. In this case, we present a 66-year-old female who was incidentally found to be pancytopenic in the emergency department while being evaluated for dyspnea, with a bone marrow biopsy later confirming a diagnosis of MDS with monosomy 7. Sporadic loss of 7q can occur at any stage in life without any family history of hematological disease. Our patient has no known personal or family history of MDS, with normal blood counts during hospitalization three years prior, suggesting de novo loss of 7q occurring at greater than 60 years of age.

Waldenstrom Macroglobulinemia: Clinical Presentation, Diagnosis, and Management in an Elderly Male.

Waldenstrom macroglobulinemia (WM) is a rare lymphoproliferative disease that can have an ambiguous clinical presentation. A key component of the pathophysiology of WM is bone marrow infiltration, which most commonly presents as anemia. Other symptoms of WM tend to be generalized and non-specific, which presents a diagnostic challenge. This was the case with our patient as well, when he presented to our outpatient clinic with non-specific symptoms. We present a 79-year-old male with longstanding pancytopenia, polyarthralgia, bilateral pedal edema, decreased appetite, and increased bleeding from wounds. The patient had a complete blood count (CBC) and complete metabolic panel (CMP) done, confirming present anemia, which prompted inpatient treatment and an oncology workup, confirming WM. The patient began a zanubrutinib monotherapy regimen, showing improvement in his pancytopenia, polyarthralgia, and overall symptoms.

Incidental Metastatic Lung Cancer in a Patient Being Treated for Community-Acquired Pneumonia: The Case for Lung Cancer Screening in Rural America.

Lung cancer is the leading cause of cancer deaths in the United States. Efforts to decrease the number of deaths over the last decade have included the publication of guidelines by the United States Preventive Services Task Force (USPSTF) recommending annual low-dose computed tomography (LDCT) scanning in patients meeting specific criteria in order to facilitate the detection and classification of potential cancers, allowing for earlier and possibly curative intervention. Unfortunately, not every patient who meets these criteria will receive LDCT surveillance due to low socioeconomic status, geographic barriers, and limited access to healthcare related to the growing shortage of primary care physicians. We describe a case in which a patient located in a rural southeastern region of the United States presented to the emergency room with a one-week history of fevers, cough, and shortness of breath. Chest imaging revealed findings consistent with community-acquired pneumonia (CAP). He had over a 30-pack-year history of smoking cigarettes and fit the additional criteria within the USPSTF recommendations for annual LDCT scans for lung cancer screening though no screening records were found. While being treated for CAP as an inpatient, the decision was made to perform additional imaging of the patient's left hip, as he had been having increasing pain during the hospital stay. A mass lesion was seen on computed tomography (CT) scan in the posterior acetabular roof, prompting additional imaging and biopsy, which led to findings consistent with stage IV metastatic pulmonary adenocarcinoma. While improvements in both imaging and classification of potentially malignant pulmonary nodules and masses have been observed since the USPSTF recommendations were first released in 2013 and with the 2021 update, rural populations with high-risk patients who fit the criteria for LDCT scanning remain vulnerable to non-screening. This patient may have benefitted from annual LDCT screening for lung cancer. Encouraging primary care physicians to not only screen for current tobacco use but also to have necessary resources on hand in clinics to arrange for timely and appropriate screening appointments and follow-up visits is integral to improving the detection and early management of lung cancer. System-wide implementation of actions that may be carried out on multiple levels of care might provide both practitioners and patients with additional tools needed in a rural setting to decrease the number of lung cancer deaths.

Predictors of Discharge Home Without Opioids After Cardiac Surgery: A Multicenter Analysis.

BACKGROUND: Whether all patients will require an opioid prescription after cardiac surgery is unknown. We performed a multicenter analysis to identify patient predictors of not receiving an opioid prescription at the time of discharge home after cardiac surgery. METHODS: Opioid-naïve patients undergoing coronary artery bypass grafting and/or valve surgery through a sternotomy at 10 centers from January to December 2019 were identified retrospectively from a prospectively maintained data set. Opioid-naïve was defined as not taking opioids at the time of admission. The primary outcome was discharge without an opioid prescription. Mixed-effects logistic regression was performed to identify predictors of discharge without an opioid prescription, and postdischarge opioid prescribing was monitored to assess patient tolerance of discharge without an opioid prescription. RESULTS: Among 1924 eligible opioid-naïve patients, mean age was 64 ± 11 years, and 25% were women. In total, 28% of all patients were discharged without an opioid prescription. On multivariable analysis, older age, longer length of hospital stay, and undergoing surgery during the last 3 months of the study were independent predictors of discharge without an opioid prescription, whereas depression, non-Black and non-White race, and using more opioid pills on the day before discharge were independent predictors of receiving an opioid prescription. Among patients discharged without an opioid prescription, 1.8% (10 of 547) were subsequently prescribed an opioid. CONCLUSIONS: Discharging select patients without an opioid prescription after cardiac surgery appears well tolerated, with a low incidence of postdischarge opioid prescriptions. Increasing the number of patients discharged without an opioid prescription may be an area for quality improvement.

Large Mucocele of the Appendix Discovered in a 48-Year-Old Male Presenting With Appendicitis: A Case Report.

The appendix is a vermiform-like organ that extends from the cecum and has been thought of as having a rudimentary immunologic function. However, the appendix can become distended and mucus-filled, classifying it as a mucocele appendix. Mucoceles can be found in various locations in the body, including the colon and the appendix, and have malignancy potential. We report a case of a 48-year-old male that presented to the ED with a history of two days of abdominal pain. Upon arriving at the ED, he had a CT scan showing a 9.5 x 4.2 x 6.4 cm fluid collection in the right lower quadrant (RLQ) juxtaposed to the cecum, suggesting appendicitis or an abscess. Initially, a laparoscopic approach was taken, which was then converted to an open laparotomy. The mass was excised and a right hemicolectomy was performed along with an ileocolonic anastomosis due to extensive involvement of the large intestine. Pathology reported a low-grade appendiceal mucinous neoplasm resected with negative margins and 16 negative lymph nodes.

Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro.

Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.

Establishment and Implementation of Evidence-Based Opioid Prescribing Guidelines in Cardiac Surgery.

BACKGROUND: Despite the risk of new persistent opioid use after cardiac surgery, postdischarge opioid use has not been quantified and evidence-based prescribing guidelines have not been established. METHODS: Opioid-naive patients undergoing primary cardiac surgery via median sternotomy between January and December 2019 at 10 hospitals participating in a statewide collaborative were selected. Clinical data were linked to patient-reported outcomes collected at 30-day follow-up. An opioid prescribing recommendation stratified by inpatient opioid use on the day before discharge (0, 1-3, or ≥4 pills) was implemented in July 2019. Interrupted time-series analyses were performed for prescription size and postdischarge opioid use before (January to June) and after (July to December) guideline implementation. RESULTS: Among 1495 patients (729 prerecommendation and 766 postrecommendation), median prescription size decreased from 20 pills to 12 pills after recommendation release (P < .001), while opioid use decreased from 3 pills to 0 pills (P < .001). Change in prescription size over time was +0.6 pill/month before and -0.8 pill/month after the recommendation (difference = -1.4 pills/month; P = .036). Change in patient use was +0.6 pill/month before and -0.4 pill/month after the recommendation (difference = -1.0 pills/month; P = .017). Pain levels during the first week after surgery and refills were unchanged. Patients using 0 pills before discharge (n = 710) were prescribed a median of 0 pills and used 0 pills, while those using 1 to 3 pills (n = 536) were prescribed 20 pills and used 7 pills, and those using greater than or equal to 4 pills (n = 249) were prescribed 32 pills and used 24 pills. CONCLUSIONS: An opioid prescribing recommendation was effective, and prescribing after cardiac surgery should be guided by inpatient use.

Resistance to Second-Generation HIV-1 Maturation Inhibitors.

A betulinic acid-based compound, bevirimat (BVM), inhibits HIV-1 maturation by blocking a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. Previous studies showed that mutations conferring resistance to BVM cluster around the CA-SP1 cleavage site. Single amino acid polymorphisms in the SP1 region of Gag and the C terminus of CA reduced HIV-1 susceptibility to BVM, leading to the discontinuation of BVM's clinical development. We recently reported a series of "second-generation" BVM analogs that display markedly improved potency and breadth of activity relative to the parent molecule. Here, we demonstrate that viral clones bearing BVM resistance mutations near the C terminus of CA are potently inhibited by second-generation BVM analogs. We performed de novo selection experiments to identify mutations that confer resistance to these novel compounds. Selection experiments with subtype B HIV-1 identified an Ala-to-Val mutation at SP1 residue 1 and a Pro-to-Ala mutation at CA residue 157 within the major homology region (MHR). In selection experiments with subtype C HIV-1, we identified mutations at CA residue 230 (CA-V230M) and SP1 residue 1 (SP1-A1V), residue 5 (SP1-S5N), and residue 10 (SP1-G10R). The positions at which resistance mutations arose are highly conserved across multiple subtypes of HIV-1. We demonstrate that the mutations confer modest to high-level maturation inhibitor resistance. In most cases, resistance was not associated with a detectable increase in the kinetics of CA-SP1 processing. These results identify mutations that confer resistance to second-generation maturation inhibitors and provide novel insights into the mechanism of resistance.IMPORTANCE HIV-1 maturation inhibitors are a class of small-molecule compounds that block a late step in the viral protease-mediated processing of the Gag polyprotein precursor, the viral protein responsible for the formation of virus particles. The first-in-class HIV-1 maturation inhibitor bevirimat was highly effective in blocking HIV-1 replication, but its activity was compromised by naturally occurring sequence polymorphisms within Gag. Recently developed bevirimat analogs, referred to as "second-generation" maturation inhibitors, overcome this issue. To understand more about how these second-generation compounds block HIV-1 maturation, here we selected for HIV-1 mutants that are resistant to these compounds. Selections were performed in the context of two different subtypes of HIV-1. We identified a small set of mutations at highly conserved positions within the capsid and spacer peptide 1 domains of Gag that confer resistance. Identification and analysis of these maturation inhibitor-resistant mutants provide insights into the mechanisms of resistance to these compounds.

Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors.

Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1.

The left atrial "Medusa myxoma".

Although myxomas are the most commonly seen primary cardiac tumors, encompassing 30% to 50% of all primary tumors of the heart, they remain a rare finding with an annual reported incidence of 0.5 per million. The presenting symptoms of an atrial myxoma are widely varied as are the clinical consequences. Regardless of presentation, once a diagnosis is made prompt surgical excision is recommended to minimize the potential complications of obstruction or embolization. We present the "Medusa myxoma," an arborizing 4-fingered left atrial myxoma extending from the fossa ovalis across the left atrium.

Maturation inhibitors: a new therapeutic class targets the virus structure.

The current standard of care for HIV/AIDS in the developed world is HAART therapy, usually a combination of two reverse transcriptase inhibitors and a protease inhibitor. Despite the success of this regimen, there is a continuing need for new drug options to overcome problems with tolerability and the emergence of viral resistance. In this review we discuss the discovery of a potential new class of antiretroviral therapeutics, known as maturation inhibitors, and the development of the first-in-class compound, bevirimat. Bevirimat is distinguished from the currently available antiretrovirals by its unique target and mode of action. While the specific interactions responsible for activity have yet to be fully characterized, it is clear that the target for bevirimat is the Gag polyprotein precursor, the main structural protein responsible for assembly and budding of virion particles. As basic research continues on the precise mechanism of action of bevirimat, clinical development is progressing, with demonstration of both safety and efficacy in early-stage trials. These encouraging results, coupled with the discovery and development of future generations of maturation inhibitors, suggest that maturation inhibitors may be added to the growing set of tools available to control HIV/AIDS.

Determinants of activity of the HIV-1 maturation inhibitor PA-457.

3-O-(3',3'-dimethylsuccinyl) betulinic acid, also termed PA-457 or DSB, is a novel HIV-1 inhibitor that blocks virus maturation by disrupting cleavage of the capsid precursor, CA-SP1. To better define the molecular target for PA-457, we prepared a panel of mutant viruses with point deletions spanning the CA-SP1 cleavage domain and characterized each of these viruses for PA-457 sensitivity. Our results indicate that amino acid residues in the N-terminal half of SP1 serve as determinants of PA-457 activity, while residues in the C-terminal half of SP1 were not involved in compound activity. These findings support and extend previous observations that PA-457 is a specific inhibitor of CA-SP1 cleavage and identify the CA-SP1 domain as the primary viral determinant for this novel inhibitor of HIV-1 replication.

Effects of exposure to a 50 Hz electric field on plasma levels of lactate, glucose, free Fatty acids, triglycerides and creatine phosphokinase activity in hind-limb ischemic rats.

We previously reported that extremely low frequency electric fields (ELF-EFs) affect energy metabolism in stressed conditions. To further confirm this, the effect of exposure to ELF-EFs on the experimental ischemic rat was examined. The test was based on a comparison of rats treated with EF alone, ischemic surgery alone, the combination of EF with ischemic surgery, or no treatment (double sham). The EF condition used in this study was an alternating current of 50 Hz EF at 17 500 V/m intensity for 15 min per day. The exposure to EF in ischemic rats significantly decreased plasma levels of free fatty acids and triglycerides, compared to those of the no treatment or EF alone group. The plasma lactate levels of two ischemic groups peaked on experimental day-4 and gradually decreased until the end of the study. The changes in the lactate levels induced by ischemia did not show any difference between rats treated with ischemia alone or a combination of ischemia with an EF. Any changes in plasma levels of glucose and creatine phosphokinase activity were not influenced by EF treatment. These results indicate that the EF effect on glycolysis parameters, plasma lactate or glucose levels, does not appear in a highly stressed condition and that EF effects varied dependent on the condition of organism but ELF-EF used in this study have impact on lipid metabolism parameter in a hind-limb ischemic rat. However, further studies are needed to elucidate the association of ELF-EF with the lipid metabolism system.

Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression, fibrinogen binding, and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist.

The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed. P-selectin expression and fibrinogen binding of single platelets were unchanged at any of the dosing intervals compared to the pre-dose values, whereas microaggregate formation was reduced. Blood was also collected in hirudin to maintain physiological calcium concentrations and stimulated with platelet agonists to test whether GP IIb/IIIa antagonists lower the threshold for platelet activation. After stimulation with a concentration range of ADP and TRAP, P-selectin expression was not altered by Roxifiban administration compared to pre-dose levels. Fibrinogen binding and microaggregate formation were reduced by Roxifiban dosing in a dose-dependent manner. Inhibition of both parameters was retained at trough and no increase above pre-dose values was observed at any time. This study provides evidence for a dose-dependent inhibition of platelet functions by an orally active GP IIb/IIIa antagonist and does not detect paradoxical activation of platelets by a GP IIb/IIIa antagonist in humans.