Clinical outcomes and frequency of persistent infection among immunosuppressed patients treated with bebtelovimab for COVID-19 infection at an ambulatory cancer center.

BACKGROUND: There are limited data on clinical outcomes associated with the use of bebtelovimab for the treatment of coronavirus disease 2019 (COVID-19) among cancer patients. We aimed to define the clinical characteristics and outcomes among patients receiving bebtelovimab as part of the COVID-19 therapeutics program at our cancer center. METHODS: This is a retrospective cohort study of immunosuppressed adult patients who received bebtelovimab at Fred Hutchinson Cancer Center between March 2022, and November 2022. We reviewed medical records to capture the date of the first positive COVID-19 test, clinical characteristics, outcomes, and follow-up COVID-19 testing for 60 days after the first positive. Persistent infection was defined as a positive test beyond day 30; these patients were reviewed beyond day 60. RESULTS: Among 93 patients who received bebtelovimab, 64 (69%) had hematologic malignancy. Sixty-nine (74%) patients received bebtelovimab within 2 days after diagnosis. Two (2%) patients were hospitalized, none required ICU care, and one patient died on day 52; although it is unknown if death was directly related to COVID-19. Ten (11%) patients had persistent COVID-19 infection; of these, four received additional COVID-19 therapy with either nirmatrelvir/ritonavir or remdesivir, and five out of six patients with sequencing data available had spike protein mutations associated with bebtelovimab resistance. CONCLUSION: A coordinated systems-based approach led to prompt initiation of bebtelovimab within two days of testing positive in most patients. We observed few hospitalizations or deaths. Persistent infection was noted in 11% of patients with four requiring additional therapies, highlighting a need for novel strategies to manage immunosuppressed patients.

Curriculum mapping of accredited pharmacy programs in the United States.

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US). METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates. RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate. CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

Antibiotic prescribing knowledge: A brief survey of providers and staff at an ambulatory cancer center during Antibiotic Awareness Week 2019.

We surveyed healthcare professionals at a cancer center regarding their knowledge and perceptions of antibiotic use. Most knew the term "antimicrobial stewardship." Nurses and other staff were less likely than pharmacists or providers to answer knowledge-based questions correctly. Opportunities exist to improve antibiotic knowledge among cancer center staff.

CMV and HSV Pneumonia After Immunosuppressive Agents for Treatment of Cytokine Release Syndrome Due to Chimeric Antigen Receptor-modified T (CAR-T)-Cell Immunotherapy.

Pneumonia due to cytomegalovirus and herpes simplex virus-1 caused substantial morbidity after hematopoietic cell transplantation before the institution of preventative approaches. End-organ disease from herpesviruses is poorly described after chimeric antigen receptor-modified T-cell immunotherapy. We report 2 cases of cytomegalovirus pneumonia and 1 case of herpes simplex virus-1 gingivostomatitis, esophagitis, and pneumonia after chimeric antigen receptor-modified T-cell immunotherapy for the treatment of hematologic malignancies.

Clinical and Virologic Characteristics and Outcomes of Coronavirus Disease 2019 at a Cancer Center.

BACKGROUND: High morbidity and mortality have been observed in patients with cancer and coronavirus disease 2019 (COVID-19); however, there are limited data on antimicrobial use, coinfections, and viral shedding. METHODS: We conducted a retrospective cohort study of adult patients at the Seattle Cancer Care Alliance diagnosed with COVID-19 between February 28, 2020 and June 15, 2020 to characterize antimicrobial use, coinfections, viral shedding, and outcomes within 30 days after diagnosis. Cycle threshold values were used as a proxy for viral load. We determined viral clearance, defined as 2 consecutive negative results using severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction results through July 30, 2020. RESULTS: Seventy-one patients were included with a median age of 61 years; 59% had a solid tumor. Only 3 patients had documented respiratory bacterial coinfection. Empiric antibiotics for pneumonia were prescribed more frequently early in the study period (February 29-March 28, 2020; 12/34) compared to the later period (March 29-June 15, 2020; 2/36) (P = .002). The median number of days from symptom onset to viral clearance was 37 days with viral load rapidly declining in the first 7-10 days after symptom onset. Within 30 days of diagnosis, 29 (41%) patients were hospitalized and 12 (17%) died. Each additional comorbidity was associated with 45% lower odds of days alive and out of hospital in the month following diagnosis in adjusted models. CONCLUSIONS: Patients at a cancer center, particularly those with multiple comorbidities, are at increased risk of poor outcomes from COVID-19. Prolonged viral shedding is frequently observed among cancer patients, and its implications on transmission and treatment strategies warrant further study.

Social context-dependent singing alters molecular markers of synaptic plasticity signaling in finch basal ganglia Area X.

Vocal communication is a crucial skill required throughout life. However, there is a critical gap in our understanding of the underlying molecular brain mechanisms, thereby motivating our use of the zebra finch songbird model. Adult male zebra finches show differences in neural activity patterns in song-dedicated brain nuclei when they sing in two distinct social contexts: a male singing by himself (undirected, UD) and a male singing to a female (female-directed, FD). In our prior work, we showed that in song-dedicated basal ganglia Area X, protein levels of a N-methyl-D-aspartate receptor subtype 2B (NMDAR2B) increased with more UD song and decreased with more FD song. We hypothesized that molecules downstream of this receptor would show differential protein expression levels in Area X between UD and FD song. Specifically, we investigated calcium/calmodulin dependent protein kinase II beta (CaMKIIB), homer scaffold protein 1 (HOMER1), serine/threonine protein kinase (Akt), and mechanistic target of rapamycin kinase (mTOR) following singing and non-singing states in Area X. We show relationships between social context and protein levels. HOMER1 protein levels decreased with time spent singing FD song, and mTOR protein levels decreased with the amount of and time spent singing FD song. For both HOMER1 and mTOR, there were no differences with the amount of UD song. With time spent singing UD, CaMKIIB protein levels trended in a U-shaped curve whereas Akt protein levels trended down. Both molecules showed no change with FD song. Our results support differential involvement of molecules in synaptic plasticity pathways between UD and FD song behaviors.

Highly-selective µ-opioid receptor antagonism does not block L-DOPA-induced dyskinesia in a rodent model.

OBJECTIVES: Dopamine-replacement utilizing L-DOPA is still the mainstay treatment for Parkinson's disease (PD), but often leads to development of L-DOPA-induced dyskinesia (LID), which can be as debilitating as the motor deficits. There is currently no satisfactory pharmacological adjunct therapy. The endogenous opioid peptides enkephalin and dynorphin are important co-transmitters in the direct and indirect striatofugal pathways and have been implicated in genesis and expression of LID. Opioid receptor antagonists and agonists with different selectivity profiles have been investigated for anti-dyskinetic potential in preclinical models. In this study we investigated effects of the highly-selective µ-opioid receptor antagonist CTAP (> 1200-fold selectivity for µ- over δ-opioid receptors) and a novel glycopeptide congener (gCTAP5) that was glycosylated to increase stability, in the standard rat LID model. RESULTS: Intraperitoneal administration (i.p.) of either 0.5 mg/kg or 1 mg/kg CTAP and gCTAP5 completely blocked morphine's antinociceptive effect (10 mg/kg; i.p.) in the warm water tail-flick test, showing in vivo activity in rats after systemic injection. Neither treatment with CTAP (10 mg/kg; i.p.), nor gCTAP5 (5 mg/kg; i.p.) had any effect on L-DOPA-induced limb, axial, orolingual, or locomotor abnormal involuntary movements. The data indicate that highly-selective µ-opioid receptor antagonism alone might not be sufficient to be anti-dyskinetic.

Social context-dependent singing alters molecular markers of dopaminergic and glutamatergic signaling in finch basal ganglia Area X.

Dopamine (DA) is an important neuromodulator of motor control across species. In zebra finches, DA levels vary in song nucleus Area X depending upon social context. DA levels are high and song output is less variable when a male finch sings to a female (female directed, FD) compared to when he is singing by himself (undirected, UD). DA modulates glutamatergic input onto cortico-striatal synapses in Area X via N-methyl-d-aspartate (NMDA) and DA receptor mechanisms, but the relationship to UD vs. FD song output is unclear. Here, we investigate the expression of molecular markers of dopaminergic and glutamatergic synaptic transmission (tyrosine hydroxylase - TH, alpha-synuclein - α-syn) and plasticity (NMDA 2B receptor - GRIN2B) following singing (UD vs. FD) and non-singing states to understand the molecular mechanisms driving differences in song output. We identified relationships between protein levels for these biomarkers in Area X based on singing state and the amount of song, measured as the number of motifs and time spent singing. UD song amount drove increases in TH, α-syn, and NMDA 2B receptor protein levels. By contrast, the amount of FD song did not alter TH and NMDA 2B receptor expression. Levels of α-syn showed differential expression patterns based on UD vs. FD song, consistent with its role in modulating synaptic transmission. We propose a molecular pathway model to explain how social context and amount of song are important drivers of molecular changes required for synaptic transmission and plasticity.

Differential effects of the NMDA receptor antagonist MK-801 on dopamine receptor D1- and D2-induced abnormal involuntary movements in a preclinical model.

Dopamine-replacement therapy with l-DOPA is still the gold standard treatment for Parkinson's disease (PD). One drawback is the common development of l-DOPA-induced dyskinesia (LID) in patients, which can be as disabling as the disease itself. There is no satisfactory adjunct therapy available. Glutamatergic transmission in the basal ganglia circuitry has been shown to be an important player in the development of LID. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has previously been shown to reduce l-DOPA-induced abnormal involuntary movements (AIMs) in a rat preclinical model but only at concentrations that worsen parkinsonism. We investigated the contribution of the direct and indirect striatofugal pathways to these effects. In the direct pathway, dopamine D1 receptors (D1R) are expressed, whereas in the indirect pathway, dopamine D2 receptors (D2R) are expressed. We used the 6-hydroxydopamine-lesioned hemi-parkinsonian rat model initially primed with l-DOPA to induce dyskinesia. When the rats were then primed and probed with the D1R agonist SKF81297, co-injection of MK-801 worsened the D1R-induced limb, axial, and orolingual (LAO) AIMs by 18% (predominantly dystonic axial AIMs) but did not aggravate parkinsonian hypokinesia as reflected by a surrogate measure of ipsiversive rotations in this model. In contrast, when the rats were then primed and probed with the D2R agonist quinpirole, co-injection of MK-801 reduced D2R-induced LAO AIMs by 89% while inducing ipsiversive rotations. The data show that only inhibition of the indirect striatopallidal pathway is sufficient for the full anti-dyskinetic/pro-parkinsonian effects of the NMDA receptor antagonist MK-801, and that MK-801 modestly worsens dyskinesias that are due to activation of the direct striatonigral pathway alone. This differential activation of the glutamatergic systems in D1R- and D2R-mediated responses is relevant to current therapy for PD which generally includes a mixture of dopamine agonists and l-DOPA.