Evaluation of pharmacokinetics of metoclopramide administered via subcutaneous bolus and intravenous constant rate infusion to adult horses.

OBJECTIVE: To determine the pharmacokinetics (PK) of metoclopramide administered via intravenous continuous rate infusion (IV CRI) and subcutaneous (SC) bolus and evaluate for gastrointestinal motility and adverse side effects. STUDY DESIGN: Experimental study; randomized, crossover design. ANIMALS: Six healthy adult horses. METHODS: Each horse received metoclopramide via IV CRI (0.04 mg/kg/h for 24 h) and SC bolus (0.08 mg/kg once), with ≥1 week washout period between. Plasma was analyzed by UPLC-MS/MS. Compartmental modeling was used to determine PK parameters for each treatment; nonparametric superposition was used to simulate multiple SC bolus regimens. Gastrointestinal motility and evidence of adverse effects were monitored. RESULTS: Tmax (h) for SC bolus was 0.583 ± 0.204 versus 17.3 ± 6.41 for IV CRI, while Cmax (ng/mL) was 27.7 ± 6.38 versus 43.6 ± 9.97, respectively. AUC (h × ng/mL) was calculated as 902 ± 189 for 24 h IV CRI versus 244 ± 37.4 simulated for 0.08 mg/kg SC bolus every 8 h. Simulations revealed similar exposure between groups with administration of 0.96 mg/kg/day SC bolus, divided into three, four, or six doses. SC bolus bioavailability was estimated as 110 ± 11.5%. No clear trends in motility alteration were identified. No adverse effects were noted. CONCLUSION: Repeated SC boluses of metoclopramide at 0.08 mg/kg would result in lower total drug exposure and Tmax than IV CRI administration but would be highly bioavailable. CLINICAL SIGNIFICANCE: Higher and/or more frequent SC bolus doses are needed to achieve a similar AUC to IV CRI. No adverse effects were noted; however, evaluation of alternative dosing strategies is warranted.

Reflective Engagement With a Digital Physical Activity Intervention Among People Living With and Beyond Breast Cancer: Mixed Methods Study.

BACKGROUND: People living with and beyond breast cancer can face internal barriers to physical activity (eg, fatigue and pain). Digital interventions that promote psychological acceptance and motivation may help this population navigate these barriers. The degree to which individuals (1) adhere to intervention protocols and (2) reflect on and internalize intervention content may predict intervention efficacy. OBJECTIVE: The objective of this study was to characterize the nature of reflective processes brought about by an 8-week acceptance- and mindfulness-based physical activity intervention for insufficiently active survivors of breast cancer (n=75). Furthermore, we explored the potential utility of a metric of reflective processes for predicting study outcomes. METHODS: Of the intervention's 8 weekly modules, 7 (88%) included an item that asked participants to reflect on what they found to be most useful. Two coders conducted directed content analysis on participants' written responses. They assessed each comment's depth of reflection using an existing framework (ranging from 0 to 4, with 0=simple description and 4=fundamental change with consideration of social and ethical issues). The coders identified themes within the various levels of reflection. We fit multiple linear regression models to evaluate whether participants' (1) intervention adherence (ie, number of modules completed) and (2) the mean level of the depth of reflection predicted study outcomes. RESULTS: Participants were aged on average 57.2 (SD 11.2) years, mostly non-Hispanic White (58/75, 77%), and mostly overweight or obese (54/75, 72%). Of the 407 responses to the item prompting personal reflection, 70 (17.2%) were rated as reflection level 0 (ie, description), 247 (60.7%) were level 1 (ie, reflective description), 74 (18.2%) were level 2 (ie, dialogic reflection), 14 (3.4%) were level 3 (ie, transformative reflection), and 2 (0.5%) were level 4 (ie, critical reflection). Lower levels of reflection were characterized by the acquisition of knowledge or expressing intentions. Higher levels were characterized by personal insight, commentary on behavior change processes, and a change of perspective. Intervention adherence was associated with increases in self-reported weekly bouts of muscle-strengthening exercise (B=0.26, SE 0.12, 95% CI 0.02-0.50) and decreases in sleep disturbance (B=-1.04, SE 0.50, 95% CI -0.06 to -2.02). The mean level of reflection was associated with increases in psychological acceptance (B=3.42, SE 1.70, 95% CI 0.09-6.75) and motivation for physical activity (ie, integrated regulation: B=0.55, SE 0.25, 95% CI 0.06-1.04). CONCLUSIONS: We identified a useful method for understanding the reflective processes that can occur during digital behavior change interventions serving people living with and beyond breast cancer. Intervention adherence and the depth of reflection each predicted changes in study outcomes. Deeper reflection on intervention content was associated with beneficial changes in the determinants of sustained behavior change. More research is needed to investigate the relations among digital behavior change intervention use, psychological processes, and intervention efficacy.

SARS-CoV-2 shedding and evolution in patients who were immunocompromised during the omicron period: a multicentre, prospective analysis.

BACKGROUND: Prolonged SARS-CoV-2 infections in people who are immunocompromised might predict or source the emergence of highly mutated variants. The types of immunosuppression placing patients at highest risk for prolonged infection have not been systematically investigated. We aimed to assess risk factors for prolonged SARS-CoV-2 infection and associated intrahost evolution. METHODS: In this multicentre, prospective analysis, participants were enrolled at five US medical centres. Eligible patients were aged 18 years or older, were SARS-CoV-2-positive in the previous 14 days, and had a moderately or severely immunocompromising condition or treatment. Nasal specimens were tested by real-time RT-PCR every 2-4 weeks until negative in consecutive specimens. Positive specimens underwent viral culture and whole genome sequencing. A Cox proportional hazards model was used to assess factors associated with duration of infection. FINDINGS: From April 11, 2022, to Oct 1, 2022, 156 patients began the enrolment process, of whom 150 were enrolled and included in the analyses. Participants had B-cell malignancy or anti-B-cell therapy (n=18), solid organ transplantation or haematopoietic stem-cell transplantation (HSCT; n=59), AIDS (n=5), non-B-cell malignancy (n=23), and autoimmune or autoinflammatory conditions (n=45). 38 (25%) participants were real-time RT-PCR-positive and 12 (8%) were culture-positive 21 days or longer after initial SARS-CoV-2 detection or illness onset. Compared with the group with autoimmune or autoinflammatory conditions, patients with B-cell dysfunction (adjusted hazard ratio 0·32 [95% CI 0·15-0·64]), solid organ transplantation or HSCT (0·60 [0·38-0·94]), and AIDS (0·28 [0·08-1·00]) had longer duration of infection, defined as time to last positive real-time RT-PCR test. There was no significant difference in the non-B-cell malignancy group (0·58 [0·31-1·09]). Consensus de novo spike mutations were identified in five individuals who were real-time RT-PCR-positive longer than 56 days; 14 (61%) of 23 were in the receptor-binding domain. Mutations shared by multiple individuals were rare (<5%) in global circulation. INTERPRETATION: In this cohort, prolonged replication-competent omicron SARS-CoV-2 infections were uncommon. Within-host evolutionary rates were similar across patients, but individuals with infections lasting longer than 56 days accumulated spike mutations, which were distinct from those seen globally. Populations at high risk should be targeted for repeated testing and treatment and monitored for the emergence of antiviral resistance. FUNDING: US Centers for Disease Control and Prevention.

Cardiac Amyloid Detection by PET/CT Imaging of Iodine (124I) Evuzamitide (124I-p5+14): A Phase 1/2 Study.

BACKGROUND: The noninvasive detection of cardiac amyloid, as well as deposits in other vital organs, is critical for early diagnosis and quantitative disease monitoring. Positron emission tomography is an intrinsically quantitative imaging modality suitable for high-resolution amyloid detection. OBJECTIVES: This study sought to evaluate the safety and efficacy of a novel amyloid-reactive peptide, designated p5+14, labeled with iodine-124 (124I), in patients with diverse types of systemic amyloidosis. METHODS: In a single-site, open label phase 1/2 study (NCT03678259), the safety, biodistribution, and sensitivity of a single intravenous infusion of 124I-evuzamitide was assessed in patients with systemic amyloidosis (n = 50), asymptomatic transthyretin sequence variant carriers (n = 2), and healthy volunteers (n = 5). Subjects were administered 1.4 ± 0.2 mg of 124I-evuzamitide (71.5 ± 12.4 MBq) and positron emission tomography/x-ray computed tomography images acquired at 5.2 hours (Q25-Q75: 4.9-5.4 hours) postinfusion. Images were assessed visually and semi-quantitatively for positive uptake of radiotracer in the heart and other major organs. RESULTS: Uptake of 124I-evuzamitide in the heart and other abdominothoracic organs was consistent with the patient's clinical presentation and the type of amyloidosis. The patient- and cardiac-associated sensitivity for imaging and clinical observations was 93.6% (95% CI: 82.8%-97.8%) and 96.2% (95% CI: 81.8%-99.8%), respectively. Semi-quantitative uptake of the radiotracer correlated significantly with serum N-terminal pro-B-type natriuretic peptide measurements in patients with light chain-associated amyloidosis. Cardiac uptake was not observed in any healthy volunteers. The agent was well tolerated, with 1 drug-related adverse event and no deaths. CONCLUSIONS: 124I-evuzamitide is an amyloid-binding radiotracer capable of detecting cardiac amyloid in patients with high sensitivity.

Development and characterization of a prototypic pan-amyloid clearing agent - a novel murine peptide-immunoglobulin fusion.

Introduction: Systemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues. Amyloid accumulation causes organ dysfunction and is not generally cleared by the immune system. Current treatment focuses on reducing amyloid precursor protein synthesis and slowing amyloid deposition. However, curative interventions will likely also require removal of preexisting amyloid deposits to restore organ function. Here we describe a prototypic pan-amyloid binding peptide-antibody fusion molecule (mIgp5) that enhances macrophage uptake of amyloid. Methods: The murine IgG1-IgG2a hybrid immunoglobulin with a pan amyloid-reactive peptide, p5, fused genetically to the N-terminal of the immunoglobulin light chain was synthesized in HEK293T/17 cells. The binding of the p5 peptide moiety was assayed using synthetic amyloid-like fibrils, human amyloid extracts and amyloid-laden tissues as substrates. Binding of radioiodinated mIgp5 with amyloid deposits in vivo was evaluated in a murine model of AA amyloidosis using small animal imaging and microautoradiography. The bioactivity of mIgp5 was assessed in complement fixation and in vitro phagocytosis assays in the presence of patient-derived amyloid extracts and synthetic amyloid fibrils as substrates and in the presence or absence of human serum. Results: Murine Igp5 exhibited highly potent binding to AL and ATTR amyloid extracts and diverse types of amyloid in formalin-fixed tissue sections. In the murine model of systemic AA amyloidosis, 125I-mIgp5 bound rapidly and specifically to amyloid deposits in all organs, including the heart, with no evidence of non-specific uptake in healthy tissues. The bioactivity of the immunoglobulin Fc domain was uncompromised in the context of mIgp5 and served as an effective opsonin. Macrophage-mediated uptake of amyloid extract and purified amyloid fibrils was enhanced by the addition of mIgp5. This effect was exaggerated in the presence of human serum coincident with deposition of complement C5b9. Conclusion: Immunostimulatory, amyloid-clearing therapeutics can be developed by incorporating pan-amyloid-reactive peptides, such as p5, as a targeting moiety. The immunologic functionality of the IgG remains intact in the context of the fusion protein. These data highlight the potential use of peptide-antibody fusions as therapeutics for all types of systemic amyloidosis.

Stereotactic body radiation therapy versus conventional external beam radiotherapy for spinal metastases: A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: This study aimed to compare SBRT and cEBRT for treating spinal metastases through a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: PubMed, EMBASE and Cochrane Library were searched up to 6 May 2023 for RCTs comparing SBRT and cEBRT for spinal metastases. Overall and complete pain response, local progression, overall survival, quality of life and adverse events were extracted. Data were pooled using random-effects models. Results were reported as risk ratios (RRs) for dichotomous outcomes, and hazard ratios (HRs) for time-to-event outcomes, along with their 95% confidence intervals (CIs). Heterogeneity was evaluated using the I2 statistic. RESULTS: Three RCTs were identified involving 642 patients. No differences were seen in overall pain response comparing SBRT and cEBRT (RR at 3 months: 1.12, 95% CI, 0.74-1.70, p = 0.59; RR at 6 months: 1.29, 95% CI, 0.97-1.72, p = 0.08). Only two of three studies presented complete pain response data. SBRT demonstrated a statistically significant improvement in complete pain response compared to cEBRT (RR at 3 months: 2.52; 95% CI, 1.58-4.01; P < 0.0001; RR at 6 months: 2.48; 95% CI, 1.23-4.99; P = 0.01). There were no significant differences in local progression and overall survival. Adverse events were similar, except for any grade radiation dermatitis, which was significantly lower in SBRT arm (RR 0.17, 95% CI 0.03-0.96, P = 0.04). CONCLUSION: SBRT is a safe treatment option for spine metastases. It may provide better complete pain response compared to cEBRT. Additional trials are needed to determine the potential benefits of SBRT in specific patient subsets.

SARS-CoV-2 shedding and evolution in immunocompromised hosts during the Omicron period: a multicenter prospective analysis.

Background: Prolonged SARS-CoV-2 infections in immunocompromised hosts may predict or source the emergence of highly mutated variants. The types of immunosuppression placing patients at highest risk for prolonged infection and associated intrahost viral evolution remain unclear. Methods: Adults aged ≥18 years were enrolled at 5 hospitals and followed from 4/11/2022 - 2/1/2023. Eligible patients were SARS-CoV-2-positive in the previous 14 days and had a moderate or severely immunocompromising condition or treatment. Nasal specimens were tested by rRT-PCR every 2-4 weeks until negative in consecutive specimens. Positive specimens underwent viral culture and whole genome sequencing. A Cox proportional hazards model was used to assess factors associated with duration of infection. Results: We enrolled 150 patients with: B cell malignancy or anti-B cell therapy (n=18), solid organ or hematopoietic stem cell transplant (SOT/HSCT) (n=59), AIDS (n=5), non-B cell malignancy (n=23), and autoimmune/autoinflammatory conditions (n=45). Thirty-eight (25%) were rRT-PCR-positive and 12 (8%) were culture-positive ≥21 days after initial SARS-CoV-2 detection or illness onset. Patients with B cell dysfunction had longer duration of rRT-PCR-positivity compared to those with autoimmune/autoinflammatory conditions (aHR 0.32, 95% CI 0.15-0.64). Consensus (>50% frequency) spike mutations were identified in 5 individuals who were rRT-PCR-positive >56 days; 61% were in the receptor-binding domain (RBD). Mutations shared by multiple individuals were rare (<5%) in global circulation. Conclusions: In this cohort, prolonged replication-competent Omicron SARS-CoV-2 infections were uncommon. Within-host evolutionary rates were similar across patients, but individuals with infections lasting >56 days accumulated spike mutations, which were distinct from those seen globally.

Hacking the Immune Response to Solid Tumors: Harnessing the Anti-Cancer Capacities of Oncolytic Bacteria.

Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley's Toxin), Proteus, Salmonella, and Clostridium. Advancements in techniques and methodology, including genetic engineering, create opportunities to "hijack" typical host-pathogen interactions and subsequently harness oncolytic capacities. Engineering, sometimes termed "domestication", of oncolytic bacterial species is especially beneficial when solid tumors are inaccessible or metastasize early in development. This review examines reported oncolytic bacteria-host immune interactions and details the known mechanisms of these interactions to the protein level. A synopsis of the presented membrane surface molecules that elicit particularly promising oncolytic capacities is paired with the stimulated localized and systemic immunogenic effects. In addition, oncolytic bacterial progression toward clinical translation through engineering efforts are discussed, with thorough attention given to strains that have accomplished Phase III clinical trial initiation. In addition to therapeutic mitigation after the tumor has formed, some bacterial species, referred to as "prophylactic", may even be able to prevent or "derail" tumor formation through anti-inflammatory capabilities. These promising species and their particularly favorable characteristics are summarized as well. A complete understanding of the bacteria-host interaction will likely be necessary to assess anti-cancer capacities and unlock the full cancer therapeutic potential of oncolytic bacteria.

Clinical Confirmation of Pan-Amyloid Reactivity of Radioiodinated Peptide 124I-p5+14 (AT-01) in Patients with Diverse Types of Systemic Amyloidosis Demonstrated by PET/CT Imaging.

There are at least 20 distinct types of systemic amyloidosis, all of which result in the organ-compromising accumulation of extracellular amyloid deposits. Amyloidosis is challenging to diagnose due to the heterogeneity of the clinical presentation, yet early detection is critical for favorable patient outcomes. The ability to non-invasively and quantitatively detect amyloid throughout the body, even in at-risk populations, before clinical manifestation would be invaluable. To this end, a pan-amyloid-reactive peptide, p5+14, has been developed that is capable of binding all types of amyloid. Herein, we demonstrate the ex vivo pan-amyloid reactivity of p5+14 by using peptide histochemistry on animal and human tissue sections containing various types of amyloid. Furthermore, we present clinical evidence of pan-amyloid binding using iodine-124-labeled p5+14 in a cohort of patients with eight (n = 8) different types of systemic amyloidosis. These patients underwent PET/CT imaging as part of the first-in-human Phase 1/2 clinical trial evaluating this radiotracer (NCT03678259). The uptake of 124I-p5+14 was observed in abdominothoracic organs in patients with all types of amyloidosis evaluated and was consistent with the disease distribution described in the medical record and literature reports. On the other hand, the distribution in healthy subjects was consistent with radiotracer catabolism and clearance. The early and accurate diagnosis of amyloidosis remains challenging. These data support the utility of 124I-p5+14 for the diagnosis of varied types of systemic amyloidosis by PET/CT imaging.

Comparing the Etiology of Viral Acute Respiratory Illnesses Between Children Who Do and Do Not Attend Childcare.

BACKGROUND AND OBJECTIVE: Childcare attendance is a common risk factor for acute respiratory illness (ARI) in young children. Our goal was to better understand the specific respiratory viruses that predominate in childcare, which may support the development of tailored illness prevention and intervention strategies in childcare settings. METHODS: Using data from a prospective household cohort of ARI surveillance, we assessed specimen from 1418 ARIs reported by 359 childcare-aged children over 6 study seasons (2012/2013 through 2017/2018). Respiratory swabs were tested by polymerase chain reaction for 9 respiratory viruses. A mixed-effect logistic regression model was used to compare odds of various viral detection outcomes. The Shannon's Diversity index was used to compare the richness (ie, number of species) and diversity (ie, relative species abundance) associated with respiratory viruses detected in both groups. RESULTS: At least 1 virus was detected in 75.5% of childcare-associated ARIs and in 80.1% of homecare ARIs. Compared with illnesses among homecare children, childcare illnesses were associated with significantly higher odds of detected adenovirus (odds ratio = 1.86, 95% confidence interval = 1.05-3.28) and human metapneumovirus (odds ratio = 1.76, 95% confidence interval = 1.03-3.0). The pool of viruses associated with childcare ARI was found to be significantly richer and more diverse than that of viruses associated with homecare ARI ( P < 0.0001). CONCLUSIONS: Children attending childcare experience a higher risk of adenovirus and human metapneumovirus infection and are regularly exposed to a rich and diverse pool of respiratory viruses in childcare environments. Our results underscore the necessity of thorough and multifaceted viral prevention strategies in childcare settings.

Absolute and Relative Vaccine Effectiveness of Primary and Booster Series of COVID-19 Vaccines (mRNA and Adenovirus Vector) Against COVID-19 Hospitalizations in the United States, December 2021-April 2022.

Background: Coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) studies are increasingly reporting relative VE (rVE) comparing a primary series plus booster doses with a primary series only. Interpretation of rVE differs from traditional studies measuring absolute VE (aVE) of a vaccine regimen against an unvaccinated referent group. We estimated aVE and rVE against COVID-19 hospitalization in primary-series plus first-booster recipients of COVID-19 vaccines. Methods: Booster-eligible immunocompetent adults hospitalized at 21 medical centers in the United States during December 25, 2021-April 4, 2022 were included. In a test-negative design, logistic regression with case status as the outcome and completion of primary vaccine series or primary series plus 1 booster dose as the predictors, adjusted for potential confounders, were used to estimate aVE and rVE. Results: A total of 2060 patients were analyzed, including 1104 COVID-19 cases and 956 controls. Relative VE against COVID-19 hospitalization in boosted mRNA vaccine recipients versus primary series only was 66% (95% confidence interval [CI], 55%-74%); aVE was 81% (95% CI, 75%-86%) for boosted versus 46% (95% CI, 30%-58%) for primary. For boosted Janssen vaccine recipients versus primary series, rVE was 49% (95% CI, -9% to 76%); aVE was 62% (95% CI, 33%-79%) for boosted versus 36% (95% CI, -4% to 60%) for primary. Conclusions: Vaccine booster doses increased protection against COVID-19 hospitalization compared with a primary series. Comparing rVE measures across studies can lead to flawed interpretations of the added value of a new vaccination regimen, whereas difference in aVE, when available, may be a more useful metric.

Psychosocial Interventions for Pain Management in Breast Cancer Survivors: A RE-AIM Evaluation.

Psychosocial interventions for breast-cancer-related pain are effective, yet over 45% of survivors continue to struggle with this often-chronic side effect. This study evaluated multilevel indicators that can influence successful translation of interventions into clinical practice. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was applied to evaluate reporting of individual and setting/staff-level intervention indicators. A systematic search and multi-step screening process identified 31 randomized controlled trials for psychosocial interventions for breast cancer-related pain. Average reporting of indicators for individual-level dimensions (Reach and Effectiveness) were 65.2% and 62.3%, respectively. Comparatively, indicators for setting/staff-level dimensions were reported at a lower average frequency (Implementation, 46.8%; Adoption, 15.2%; Maintenance, 7.7%). Low reporting of setting/staff-level dimensions suggests gaps in the sustained implementation of psychosocial interventions. Implementation science methods and frameworks could improve trial design and accelerate the translation of psychosocial interventions for breast cancer-related pain into clinical practice.

Collagen inhibits phagocytosis of amyloid in vitro and in vivo and may act as a 'don't eat me' signal.

BACKGROUND: Systemic amyloidosis refers to a group of protein misfolding disorders characterized by the extracellular deposition of amyloid fibrils in organs and tissues. For reasons heretofore unknown, amyloid deposits are not recognized by the immune system, and progressive deposition leads to organ dysfunction. METHODS: In vitro and in vivo phagocytosis assays were performed to elucidate the impact of collagen and other amyloid associated proteins (eg serum amyloid p component and apolipoprotein E) had on amyloid phagocytosis. Immunohistochemical and histopathological staining regimens were employed to analyze collagen-amyloid interactions and immune responses. RESULTS: Histological analysis of amyloid-laden tissue indicated that collagen is intimately associated with amyloid deposits. We report that collagen inhibits phagocytosis of amyloid fibrils by macrophages. Treatment of 15 patient-derived amyloid extracts with collagenase significantly enhanced amyloid phagocytosis. Preclinical mouse studies indicated that collagenase treatment of amyloid extracts significantly enhanced clearance as compared to controls, coincident with increased immune cell infiltration of the subcutaneous amyloid lesion. CONCLUSIONS: These data suggest that amyloid-associated collagen serves as a 'don't eat me' signal, thereby hindering clearance of amyloid. Targeted degradation of amyloid-associated collagen could result in innate immune cell recognition and clearance of pathologic amyloid deposits.

A novel method for generating glutamatergic SH-SY5Y neuron-like cells utilizing B-27 supplement.

The human SH-SY5Y neuroblastoma cell line is widely used in neuroscience research as a neuronal cell model. Following differentiation to a neuron-like state, SH-SY5Y cells become more morphologically similar to neurons and form functional synapses. Previous studies have managed to differentiate SH-SY5Y cells towards cholinergic, dopaminergic and adrenergic fates. However, their application in disease modeling remains limited as other neuronal subtypes (e.g., glutamatergic, GABAergic) are also implicated in neurological disorders, and no current protocols exist to generate these subtypes of differentiated SH-SY5Y cells. Our study aimed to evaluate the use of a xeno-free version of B-27, a supplement commonly used in neuronal culture, for SH-SY5Y maintenance and differentiation. To evaluate the proliferative capacity of SH-SY5Y cells cultured in B-27, we performed growth curve analyses, immunocytochemical staining for Ki-67 and qRT-PCR to track changes in cell cycle progression. SH-SY5Y cells cultured in FBS or under serum-starved conditions were used as controls. We observed that SH-SY5Y cells show reduced growth and proliferation rates accompanied by decreased CDK6 and CDK1 expression following 4-day exposure to B-27, suggesting B-27 induces a quiescent state in SH-SY5Y cells. Importantly, this reduced growth rate was not due to increased apoptosis. As cell cycle exit is associated with differentiation, we next sought to determine the fate of SH-SY5Y cells cultured in B-27. B-27-cultured SH-SY5Y cells show changes in cell morphology, adopting pyramidal shapes and extending neurites, and upregulation of neuronal differentiation markers (GAP43, TUBB3, and SYP). B-27-cultured SH-SY5Y cells also show increased expression of glutamatergic markers (GLUL and GLS). These findings suggest that B-27 may be a non-toxic inducer of glutamatergic SH-SY5Y differentiation. Our study demonstrates a novel way of using B-27 to obtain populations of glutamatergic SH-SY5Y cells. As dysregulated glutamatergic signaling is associated with a variety of neuropsychiatric and neurodegenerative disorders, the capability to generate glutamatergic neuron-like SH-SY5Y cells creates endless disease modeling opportunities. The ease of SH-SY5Y culture allows researchers to generate large-scale cultures for high-throughput pharmacological or toxicity studies. Also compatible with the growing popularity of animal-component-free studies, this xeno-free B-27/SH-SY5Y culture system will be a valuable tool to boost the translational potential of preliminary studies requiring glutamatergic neuronal cells of human origin.

Guided imagery for treatment (GIFT): protocol of a pilot trial of guided imagery versus treatment as usual to address radiotherapy-related distress in head and neck cancer.

BACKGROUND: Cancers of the head and neck region are associated with high symptom burden and elevated levels of psychological distress. Radiotherapy (RT) is a common treatment for patients with head and neck cancer (HNC) that is associated with psychological distress related to the immobilizing nature of the treatment, frequency of treatment delivery, and side effects. Guided imagery is a relaxation technique that is beneficial in reducing psychological distress in patients with other cancer diagnoses but has not been studied in this patient population. The purpose of this study is to evaluate the feasibility and acceptability of a brief guided imagery intervention (guided imagery for treatment, GIFT) to reduce RT-related anxiety and depression in patients with HNC relative to treatment as usual (TAU). METHODS: Patients with HNC planning to receive RT will be recruited to participate in a randomized controlled trial evaluating a brief, two-session guided imagery intervention (GIFT) relative to TAU alone. Primary aims include acceptability and feasibility evaluated through quantitative and qualitative methods. Measures of anxiety and depression, symptom burden, health-related quality of life, and anxiolytic medication use will be collected at baseline, during treatment, and at 1-month follow-up. DISCUSSION: There are no published interventions of guided imagery for anxiety and depression in patients with HNC despite its efficacy in other populations of patients with cancer. This proposed project evaluates the feasibility and acceptability of an intervention that has the potential to reduce psychological distress in a vulnerable population. Additionally, we will preliminarily examine the impact of behavioral intervention on psychological distress and the use of anxiolytic medication, a novel area of study. TRIAL REGISTRATION: Clinicaltrials.gov NCT03662698 ; registered on 9/6/2018.

Effectiveness of the Ad26.COV2.S (Johnson & Johnson) Coronavirus Disease 2019 (COVID-19) Vaccine for Preventing COVID-19 Hospitalizations and Progression to High Disease Severity in the United States.

Background . Adults in the United States (US) began receiving the adenovirus vector coronavirus disease 2019 (COVID-19) vaccine, Ad26.COV2.S (Johnson & Johnson [Janssen]), in February 2021. We evaluated Ad26.COV2.S vaccine effectiveness (VE) against COVID-19 hospitalization and high disease severity during the first 10 months of its use. Methods . In a multicenter case-control analysis of US adults (≥18 years) hospitalized 11 March to 15 December 2021, we estimated VE against susceptibility to COVID-19 hospitalization (VEs), comparing odds of prior vaccination with a single dose Ad26.COV2.S vaccine between hospitalized cases with COVID-19 and controls without COVID-19. Among hospitalized patients with COVID-19, we estimated VE against disease progression (VEp) to death or invasive mechanical ventilation (IMV), comparing odds of prior vaccination between patients with and without progression. Results . After excluding patients receiving mRNA vaccines, among 3979 COVID-19 case-patients (5% vaccinated with Ad26.COV2.S) and 2229 controls (13% vaccinated with Ad26.COV2.S), VEs of Ad26.COV2.S against COVID-19 hospitalization was 70% (95% confidence interval [CI]: 63-75%) overall, including 55% (29-72%) among immunocompromised patients, and 72% (64-77%) among immunocompetent patients, for whom VEs was similar at 14-90 days (73% [59-82%]), 91-180 days (71% [60-80%]), and 181-274 days (70% [54-81%]) postvaccination. Among hospitalized COVID-19 case-patients, VEp was 46% (18-65%) among immunocompetent patients. Conclusions . The Ad26.COV2.S COVID-19 vaccine reduced the risk of COVID-19 hospitalization by 72% among immunocompetent adults without waning through 6 months postvaccination. After hospitalization for COVID-19, vaccinated immunocompetent patients were less likely to require IMV or die compared to unvaccinated immunocompetent patients.