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.

Probenecid Inhibits Influenza A(H5N1) and A(H7N9) Viruses In Vitro and in Mice.

Avian influenza (AI) viruses cause infection in birds and humans. Several H5N1 and H7N9 variants are highly pathogenic avian influenza (HPAI) viruses. H5N1 is a highly infectious bird virus infecting primarily poultry, but unlike other AIs, H5N1 also infects mammals and transmits to humans with a case fatality rate above 40%. Similarly, H7N9 can infect humans, with a case fatality rate of over 40%. Since 1996, there have been several HPAI outbreaks affecting humans, emphasizing the need for safe and effective antivirals. We show that probenecid potently inhibits H5N1 and H7N9 replication in prophylactically or therapeutically treated A549 cells and normal human broncho-epithelial (NHBE) cells, and H5N1 replication in VeroE6 cells and mice.

Antiviral Activity of Probenecid and Oseltamivir on Influenza Virus Replication.

Influenza can cause respiratory infections, leading to significant morbidity and mortality in humans. While current influenza vaccines offer varying levels of protection, there remains a pressing need for effective antiviral drugs to supplement vaccine efforts. Currently, the FDA-approved antiviral drugs for influenza include oseltamivir, zanamivir, peramivir, and baloxavir marboxil. These antivirals primarily target the virus, making them vulnerable to drug resistance. In this study, we evaluated the efficacy of the neuraminidase inhibitor, oseltamivir, against probenecid, which targets the host cells and is less likely to engender resistance. Our results show that probenecid has superior antiviral efficacy compared to oseltamivir in both in vitro replication assays and in vivo mouse models of influenza infection.

Screening Drugs for Broad-Spectrum, Host-Directed Antiviral Activity: Lessons from the Development of Probenecid for COVID-19.

In the early stages of drug discovery, researchers develop assays that are compatible with high throughput screening (HTS) and structure activity relationship (SAR) measurements. These assays are designed to evaluate the effectiveness of new and known molecular entities, typically targeting specific features within the virus. Drugs that inhibit virus replication by inhibiting a host gene or pathway are often missed because the goal is to identify active antiviral agents against known viral targets. Screening efforts should be sufficiently robust to identify all potential targets regardless of the antiviral mechanism to avoid misleading conclusions.

From Obscurity To Spotlight: Staphylococcus lugdunensis-Induced Infective Endocarditis, a Profound Case Unraveling.

Infective endocarditis (IE) represents a grave infection characterized by endocardial inflammation and valve impairment due to diverse pathogens. Staphylococcus lugdunensis, a coagulase-negative organism, has garnered increasing recognition as a significant etiological agent of IE. This bacterium is renowned for its aggressive tissue infections encompassing bone and joint, bloodstream, and IE sites. Particularly noteworthy is the rapid devastation and abscess formation it induces on heart valves, resulting in elevated mortality rates. The pathogen's affinity for von Willebrand factor facilitates its attachment to cardiac valves and blood vessels, thereby exacerbating its virulence. This abstract provides a comprehensive overview of S. lugdunensis-triggered IE. We present a compelling case involving a 66-year-old female afflicted by IE attributed to this microorganism, illuminating the clinical manifestations and challenges linked to the ailment. Moreover, we scrutinize previously reported instances of S. lugdunensis-related IE spanning from 1993 to 2022, accentuating the escalating importance of this pathogen in disease causality. The deleterious consequences of S. lugdunensis-induced IE emanate from its distinctive clinical attributes, necessitating tailored diagnostic strategies and treatment considerations. Given the gravity and swift progression of the infection, healthcare professionals play a pivotal role in administering timely and efficacious management for afflicted patients. Further research is imperative to enhance diagnostic modalities and explore therapeutic approaches aimed at effectively combating this formidable and life-threatening infection.

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.

Drug-Induced Thrombocytopenia: A Case Involving Vancomycin.

Drug-induced thrombocytopenia (DIT) is a rare adverse effect that occurs when administering various medications. The medications associated with this possible adverse effect include heparin, penicillin, furosemide, vancomycin, non-steroidal anti-inflammatory drugs, ranitidine, and many others. DIT causes a rapid decrease in platelet counts after drug administration and typically resolves once the offending agent has been discontinued. The induced thrombocytopenia increases the bleeding risk and possibility of adverse effects throughout a hospital course. In this case report, we look at the presenting symptoms and treatment course of an interesting case of DIT that occurred following the administration of vancomycin.

Oral Probenecid for Nonhospitalized Adults with Symptomatic Mild-to-Moderate COVID-19.

Probenecid is an orally bioavailable, uricosuric agent that was first approved in 1951 for the treatment of gout, but was later found to have potent, broad-spectrum antiviral activity against several respiratory viruses including SARS-CoV-2. We conducted a phase 2 randomized, placebo-controlled, single-blind, dose-range finding study in non-hospitalized patients with symptomatic, mild-to-moderate COVID-19. Patients were randomly assigned in a 1:1:1 ratio to receive either 500 mg of probenecid, 1000 mg of probenecid, or a matching placebo every 12 h for five days. The patients' COVID-19 viral load hospitalization, or death from any cause through day 28, as well as safety, were evaluated. COVID-19-related symptoms were assessed at baseline, and on days 3, 5, 10, 15, and 28. The primary endpoints of the study were time to first negative SARS-CoV-2 viral test (or viral clearance) and the proportion of patients that were symptom-free at day 5. A total of 75 patients were randomized, with 25 patients in each group. All of the patients completed the study as planned with no hospitalizations or deaths being reported. The median time to viral clearance was significantly shorter for the probenecid 1000 mg group than for placebo (7 days vs. 11 days, respectively; p < 0.0001), and for the probenecid 500 mg group versus placebo (9 days vs. 11 days, respectively; p < 0.0001). In addition, the median time to viral clearance was significantly shorter for the probenecid 1000 mg group than for the probenecid 500 mg group (7 days vs. 9 days, respectively; p < 0.0001). All patients reported at least one COVID-19-related symptom on days 3 and 5; however, on day 10, a significantly greater proportion of patients receiving probenecid 1000 mg reported the complete resolution of symptoms versus placebo (68% vs. 20%, respectively; p = 0.0006), as well as for those receiving probenecid 500 mg versus placebo (56% vs. 20%, respectively, p = 0.0087). The incidence of adverse events during treatment was similar across all groups for any adverse event, and was 12%. All events were mild with no serious adverse events reported and no discontinuations due to an adverse event. The treatment of patients with symptomatic, mild-to-moderate COVID-19 with probenecid resulted in a significant, dose-dependent decrease in the time to viral clearance and a significantly higher proportion of patients reporting complete symptom resolution by day 10. (Supported by TrippBio; ClinicalTrials.gov number, NCT05442983 and Clinical Trials Registry India number CTRI/2022/07/043726).

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.

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication.

RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.

Repurposing Probenecid to Inhibit SARS-CoV-2, Influenza Virus, and Respiratory Syncytial Virus (RSV) Replication.

Viral replication and transmissibility are the principal causes of endemic and pandemic disease threats. There remains a need for broad-spectrum antiviral agents. The most common respiratory viruses are endemic agents such as coronaviruses, respiratory syncytial viruses, and influenza viruses. Although vaccines are available for SARS-CoV-2 and some influenza viruses, there is a paucity of effective antiviral drugs, while for RSV there is no vaccine available, and therapeutic treatments are very limited. We have previously shown that probenecid is safe and effective in limiting influenza A virus replication and SARS-CoV-2 replication, along with strong evidence showing inhibition of RSV replication in vitro and in vivo. This review article will describe the antiviral activity profile of probenecid against these three viruses.

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.

Rapid deterioration of sediment surface habitats in Bellingham Bay, Washington State, as indicated by benthic foraminifera.

Foraminiferal assemblages in sediment grab samples were utilized to evaluate the impacts of anthropogenic activities on benthic habitats in Bellingham Bay, Washington State, U.S.A. Seventy-three samples taken in 1987, 1997, 2006 and 2010 yielded 35 species of foraminifera from 28 genera. Assemblage composition and diversity data indicate a marked deterioration between 1987 and 2010, contrary to the published Chemical Index, but analogous to the situation with macrobiota. Correlation of diversity with chemical pollutants and metals did not identify any significant correlations, however, an unrelated but highly relevant study of bottom water dissolved oxygen concentrations and pH in Bellingham Bay suggests eutrophication with accompanying hypoxia and acidification may be part of the cause. Thus, the metrics of contamination alone do not adequately characterize habitat viability, and benthic foraminiferal assemblages provide insight into the health of coastal ecosystems.

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.