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1.
Exp Dermatol ; 33(5): e15067, 2024 May.
Article En | MEDLINE | ID: mdl-38757460

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS.


Antibodies, Monoclonal, Humanized , Psoriasis , Psoriasis/drug therapy , Humans , Japan , Male , Female , Middle Aged , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Biological Products/administration & dosage , Biological Products/therapeutic use , Severity of Illness Index , Dermatologic Agents/administration & dosage , Dermatologic Agents/therapeutic use , Ustekinumab/therapeutic use , Ustekinumab/administration & dosage , Dose-Response Relationship, Drug , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Interleukins , Aged
2.
Brain Neurosci Adv ; 8: 23982128241255798, 2024.
Article En | MEDLINE | ID: mdl-38800359

The binding of information from different sensory or neural sources is critical for associative memory. Previous research in animals suggested that the timing of theta oscillations in the hippocampus is critical for long-term potentiation, which underlies associative and episodic memory. Studies with human participants showed correlations between theta oscillations in medial temporal lobe and episodic memory. Clouter et al. directly investigated this link by modulating the intensity of the luminance and the sound of the video clips so that they 'flickered' at certain frequencies and with varying synchronicity between the visual and auditory streams. Across several experiments, better memory was found for stimuli that flickered synchronously at theta frequency compared with no-flicker, asynchronous theta, or synchronous alpha and delta frequencies. This effect - which they called the theta-induced memory effect - is consistent with the importance of theta synchronicity for long-term potentiation. In addition, electroencephalography data showed entrainment of cortical regions to the visual and auditory flicker, and that synchronicity was achieved in neuronal oscillations (with a fixed delay between visual and auditory streams). The theoretical importance, large effect size, and potential application to enhance real-world memory mean that a replication of theta-induced memory effect would be highly valuable. The present study aimed to replicate the key differences among synchronous theta, asynchronous theta, synchronous delta, and no-flicker conditions, but within a single experiment. The results do not show evidence of improved memory for theta synchronicity in any of the comparisons. We suggest a reinterpretation of theta-induced memory effect to accommodate this non-replication.

4.
Cancer Res Commun ; 2024 May 10.
Article En | MEDLINE | ID: mdl-38727208

Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from peripheral TCL patients treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in interferon signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation.

5.
Ann Biomed Eng ; 2024 May 23.
Article En | MEDLINE | ID: mdl-38780890

Military personnel are commonly at risk of lower back pain and thoracolumbar spine injury. Human volunteers and postmortem human subjects have been used to understand the scenarios where injury can occur and the tolerance of the warfighter to these loading regimes. Finite element human body models (HBMs) can accurately simulate the mechanics of the human body and are a useful tool for understanding injury. In this study, a HBM thoracolumbar spine was developed and hierarchically ï»¿validated as part of the Incapacitation Prediction for Readiness in Expeditionary Domains: an Integrated Computational Tool (I-PREDICT) program. Constitutive material models were sourced from literature and the vertebrae and intervertebral discs were hexahedrally meshed from a 50th percentile male CAD dataset. Ligaments were modeled through attaching beam elements at the appropriate anatomical insertion sites. 94 simulations were replicated from experimental PMHS tests at the vertebral body, functional spinal unit (FSU), and regional lumbar spine levels. The BioRank (BRS) biofidelity ranking system was used to assess the response of the I-PREDICT model. At the vertebral body level, the I-PREDICT model showed good agreement with experimental results. The I-PREDICT FSUs showed good agreement in tension and compression and had comparable stiffness values in flexion, extension, and axial rotation. The regional lumbar spine exhibited "good" biofidelity when tested in tension, compression, extension, flexion, posterior shear, and anterior shear (BRS regional average = 1.05). The validated thoracolumbar spine of the I-PREDICT model can be used to better understand and mitigate injury risk to the warfighter.

6.
Res Sq ; 2024 May 17.
Article En | MEDLINE | ID: mdl-38798474

Previous studies have identified G protein-coupled receptor (GPCR) kinase 5 (GRK5) as a genetic factor contributing to obesity pathogenesis, but the underlying mechanism remains unclear. We demonstrate here that Grk5 mRNA is more abundant in stromal vascular fractions of mouse white adipose tissue, the fraction that contains adipose progenitor cells, or committed pre-adipocytes, than in adipocyte fractions. Thus, we generated a GRK5 knockout (KO) 3T3-L1 pre-adipocyte to further investigate the mechanistic role of GRK5 in regulating adipocyte differentiation. During adipogenic stimulation, GRK5 KO pre-adipocytes were unable to achieve mature adipocyte morphology and lipid accumulation compared to wildtype cells coupled with suppressed adipogenic and lipogenic gene expression. Beside GPCR signaling, RNA sequencing and pathway analysis identified insulin-like growth factor 1 (IGF-1) signaling to be one of the top 5 significantly dysregulated pathways in GRK5 KO cells. GRK5 KO cells also displayed decreased insulin-stimulated ERK phosphorylation, a downstream target of insulin-stimulated IGF-1 receptor activation, suggesting that GRK5 acts through this critical pathway to impact 3T3-L1 adipocyte differentiation. To find a more translational approach, we identified a new small molecule GRK5 inhibitor that was able to reduce 3T3-L1 adipogenesis. These data suggest that GRK5 is required for adipocyte differentiation through IGF-1 receptor/ERK activation and may be a promising translational target for obesity.

7.
Fortune J Health Sci ; 7(1): 128-137, 2024 Mar.
Article En | MEDLINE | ID: mdl-38651007

Purpose: The objective of this study is to describe patterns in barriers to breast cancer screening uptake with the end goal of improving screening adherence and decreasing the burden of mortality due to breast cancer. This study looks at social determinants of health and their association to screening and mortality. It also investigates the extent that models trained on county data are generalizable to individuals. Methods: County level screening uptake and age adjusted mortality due to breast cancer are combined with the Centers for Disease Controls Social Vulnerability Index (SVI) to train a model predicting screening uptake rates. Patterns learned are then applied to de-identified electronic medical records from individual patients to make predictions on mammogram screening follow through. Results: Accurate predictions can be made about a county's breast cancer screening uptake with the SVI. However, the association between increased screening, and decreased age adjusted mortality, doesn't hold in areas with a high proportion of minority residents. It is also shown that patterns learned from county SVI data have little discriminative power at the patient level. Conclusion: This study demonstrates that social determinants in the SVI can explain much of the variance in county breast cancer screening rates. However, these same patterns fail to discriminate which patients will have timely follow through of a mammogram screening test. This study also concludes that the core association between increased screening and decreased age adjusted mortality does not hold in high proportion minority areas. Objective: The objective of this study is to describe patterns in social determinants of health and their association with female breast cancer screening uptake, age adjusted breast cancer mortality rate and the extent that models trained on county data are generalizable to individuals.

8.
Article En | MEDLINE | ID: mdl-38655024

A pharmacist-driven protocol for methicillin-resistant Staphylococcus aureus nares screening and empiric vancomycin discontinuation was instituted in a community healthcare system utilizing a tele-antimicrobial stewardship program to reduce inappropriate use of vancomycin. The protocol and associated intervention resulted in a significant decrease in both vancomycin utilization and the rate of acute kidney injury.

9.
JAAD Int ; 15: 185-191, 2024 Jun.
Article En | MEDLINE | ID: mdl-38651039

Background: Artificial intelligence (AI) enabled tools have been proposed as 1 solution to improve health care delivery. However, research on downstream effects of AI integration into the clinical workflow is lacking. Objective: We aim to analyze how integration of an automated basal cell carcinoma detection and tumor mapping algorithm in a Mohs micrographic surgery unit impacts the work efficiency of clinical and laboratory staff. Methods: Slide, staff, and histotechnician waiting times were analyzed over a 20-day period in a Mohs micrographic surgery unit. A simulated AI workflow was created and the time differences between the real and simulated workflows were compared. Results: Simulated nonautonomous algorithm integration led to savings of 35.6% of slide waiting time, 18.4% of staff waiting time, and 18.6% of histotechnician waiting time per day. Algorithm integration on days with increased reconstruction complexity resulted in the greatest time savings. Limitations: One Mohs micrographic surgery unit was analyzed and simulated AI integration was performed retrospectively. Conclusions: AI integration results in reduced staff waiting times, enabling increased productivity and a streamlined clinical workflow. Schedules containing surgical cases with either increased repair complexity or numerous tumor removal stages stand to benefit most. However, significant logistical challenges must be addressed before broad adoption into clinical practice is realistic.

10.
Pediatrics ; 153(5)2024 May 01.
Article En | MEDLINE | ID: mdl-38660734

OBJECTIVES: Respiratory syncytial virus (RSV) is a common pediatric infection, with young infants being at the highest risk of hospitalization and long-term sequela. New preventive agents have been recommended to prevent severe RSV illness in infants, including a vaccine administered during pregnancy. The current rates of recommended vaccination in pregnancy are suboptimal. Our objective was to characterize interest in RSV vaccination during pregnancy among people across the United States who were pregnant or planning to become pregnant. METHODS: In March 2023, we conducted a national cross-sectional online survey of individuals 18 to 45 years old who were currently pregnant or trying to become pregnant on their perceptions of RSV-related illness and intentions to get vaccinated against RSV. We performed logistic regression analyses to determine the odds and predicted proportions of the likelihood of RSV vaccination during pregnancy, controlling for sociodemographic factors. RESULTS: Of 1619 completed surveys, 1528 were analyzed. 54% of respondents indicated that they were "very likely" to get vaccinated against RSV during pregnancy. The perception of RSV as a serious illness was the strongest predictor of vaccination likelihood. In the full regression model, predicted proportions of "very likely" to vaccinate against RSV followed a similar pattern (63% if RSV infection was perceived as serious and likely, 55% if serious and unlikely, 35% if not serious; P < .001). CONCLUSIONS: Raising awareness of RSV infection as likely and potentially serious for infants may be an influential component of targeted communications that promote RSV vaccine uptake during pregnancy.


Intention , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus Vaccines , Humans , Female , Pregnancy , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/epidemiology , Cross-Sectional Studies , Adult , Respiratory Syncytial Virus Vaccines/administration & dosage , Adolescent , Young Adult , United States , Vaccination/statistics & numerical data , Vaccination/psychology , Pregnancy Complications, Infectious/prevention & control , Middle Aged , Male
11.
Fam Syst Health ; 42(1): 34-49, 2024 Mar.
Article En | MEDLINE | ID: mdl-38647492

BACKGROUND: Up to 20% of youth have impairing mental health problems as early as age 3. Early identification and intervention of mental health risks in pediatric primary care could mitigate this crisis via prevention prior to disease onset. The purpose of this study was to establish the feasibility and acceptability of implementing a brief transdiagnostic screening instrument in pediatric primary care for irritability and corollary impairment. METHOD: Five pediatric clinicians in a Midwest clinic implemented the Multidimensional Assessment Profiles-Early Assessment Screener of Irritability (MAPS-EASI) for toddlers (24-30 months) and their families. MAPS-EASI (psychometrically derived from the well-validated MAPS-Scales) includes six items (scored 0-5) about symptoms (e.g., tantrums, grumpy mood), context, and frequency and two items (scored 0-3) assessed impairment. Positive screens (MAPS-EASI ≥ 5 plus impairment ≥ 2) were referred to an evidence-based parenting intervention. We assessed reach and outcomes of MAPS-EASI screening. Follow-up interviews with clinicians assessed perspectives on irritability screening and MAPS-EASI implementation. RESULTS: Of 201 eligible families, 100 (49.8%) completed the screener for a 24- or 30-month well-child visit. Mean MAPS-EASI scores were 5.8 (SD = 3.2), mean impairment scores were 0.9 (SD = 0.9), and 24 (24.0%) screened positive. Clinicians indicated that irritability screening for toddlers was aligned with their prevention-oriented, developmentally based practice. MAPS-EASI had face validity and increased clinician decision-making confidence. Finally, clinicians identified barriers and facilitators to large-scale implementation. CONCLUSIONS: MAPS-EASI proved to be feasible and acceptable in pediatric primary care. Further tailoring will be needed as the MAPS-EASI processes are scaled out to new contexts and populations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Irritable Mood , Mass Screening , Primary Health Care , Humans , Female , Child, Preschool , Male , Primary Health Care/methods , Primary Health Care/statistics & numerical data , Primary Health Care/standards , Mass Screening/methods , Mass Screening/instrumentation , Mass Screening/standards , Psychometrics/instrumentation , Psychometrics/methods , Pediatricians/statistics & numerical data , Pediatricians/psychology , Pediatricians/standards , Surveys and Questionnaires
12.
Fam Syst Health ; 42(1): 68-75, 2024 Mar.
Article En | MEDLINE | ID: mdl-38647493

BACKGROUND: Strength of evidence is key to advancing children's mental health care but may be inadequate for driving practice change. The Designing for Accelerated Translation (DART) framework proposes a multifaceted approach: pace of implementation as a function of evidence of effectiveness, demand for the intervention, sum of risks, and costs. To inform empirical applications of DART, we solicited caregiver preferences on key elements. METHOD: In March-April 2022, we fielded a population-representative online survey in Illinois households (caregivers N = 1,326) with ≥1 child <8 years old. Six hypothetical scenarios based on the DART framework were used to elucidate caregivers' preferences on a 0-10 scale (0 = never; 10 = as soon as possible) for pace of implementation of a family-based program to address mental health concerns. RESULTS: Caregivers' pace preference scores varied significantly for each scenario. The highest mean score (7.28, 95% confidence interval [95% CI: 7.06, 7.50]) was for a scenario in which the child's provider thinks the program would be helpful (effectiveness) and the caregiver believes the program is needed (demand). In contrast, the lowest mean score (5.13, 95% CI [4.91, 5.36]) was for a scenario in which online information implies the program would be helpful (effectiveness) and the parent is concerned about the program's financial costs (cost). Caregivers' pace preference scores did not vary consistently by sociodemographic factors. CONCLUSION: In this empirical exploration of the DART framework, factors such as demand, cost, and risk, in combination with evidence of effectiveness, may influence caregivers' preferred pace of implementation for children's mental health interventions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Evidence-Based Practice , Parents , Humans , Female , Child , Male , Evidence-Based Practice/methods , Parents/psychology , Surveys and Questionnaires , Illinois , Child, Preschool , Mental Health Services/statistics & numerical data , Mental Health Services/standards , Mental Health Services/trends , Adult , Caregivers/psychology , Caregivers/statistics & numerical data
13.
Fam Syst Health ; 42(1): 6-17, 2024 Mar.
Article En | MEDLINE | ID: mdl-38647490

INTRODUCTION: Primary care is at the forefront of addressing the pediatric mental health (MH) crisis due to its broad reach to young children and prevention and health promotion orientation. However, the promise of the delivery system for population impact remains unrealized due to several barriers, including pragmatic screening, decisional uncertainty, and limited access to evidence-based services. METHOD: This article lays the conceptual foundations for the articles in this Special Section on Mental Health, Earlier in Pediatric Primary Care, which all apply a translational mindset to proposed strategies and solutions to overcome the barriers that have limited the potential of pediatric primary care for improving the MH and wellbeing of all children. RESULTS: Valid, pragmatic, transdiagnostic, developmentally-based screening measures to identify children at heightened risk are needed. Risk screening for MH problems should assess and empirically weight socioecological risk and protective factors, as well as the child's own assets for resilience to determine probabilistic risk. Pediatric clinicians require clear clinical cutoffs and guidelines for action when risk for MH problems is identified. DISCUSSION: These strategies-a developmentally-based screener with associated risk calculator that offers clear guidance to pediatric clinicians-address decisional uncertainty regarding when to worry and when to act. The communication of probabilistic risk requires additional client-centered communication skills to overcome different types of biases (e.g., implicit, benevolent, and cognitive) that contribute to MH inequities and decisional uncertainty in acting on identified risk. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Pediatrics , Primary Health Care , Resilience, Psychological , Humans , Primary Health Care/methods , Primary Health Care/standards , Pediatrics/methods , Pediatrics/standards , Child , Mental Health , Child, Preschool
14.
Article En | MEDLINE | ID: mdl-38642467

BACKGROUND: The development of disability related to activities of daily living (ADL) is of great concern in the aging population, particularly for Hispanic and Non-Hispanic (NH) Black older adults, where disability prevalence is greater compared to NH Whites. ADL-disability is typically measured across many functional tasks without differentiating upper- versus lower-limb limitations, hindering our understanding of disability burden. Despite the importance of the upper limbs for completing ADL and known age-related declines in function, racial/ethnic differences in upper limb function remain largely unknown. METHODS: We identified 4,292 NH White, NH Black, and Mexican American older adults (≥65) from the 2011-2018 waves of the National Health and Nutrition Examination Survey (NHANES). We classified participants as having a limitation based on their ability to complete five upper limb tasks (preparing meals, eating, dressing, reaching overhead, grasping small objects) and compared limitation rates across racial/ethnic groups. RESULTS: Compared to NH Whites, NH Black older adults had significantly greater odds of reporting difficulties preparing meals (OR: 1.36, 95% CI: 1.01, 1.86) and dressing (OR: 1.55, 95% CI: 1.19, 2.02), while Mexican Americans had greater difficulty preparing meals (OR: 1.70, 95% CI: 1.12, 2.58), dressing (OR: 1.63, 95% CI: 1.12, 2.36), and grasping small objects (OR: 1.48, 95% CI: 1.06, 2.07). CONCLUSIONS: Our results demonstrate differences in self-reported upper limb ADL-disability across racial/ethnic groups, particularly for Mexican American older adults. Such findings underscore the need for routine monitoring of upper limb function throughout adulthood to identify limitations and target therapeutic interventions before independence is compromised.

15.
Phys Rev Lett ; 132(10): 103402, 2024 Mar 08.
Article En | MEDLINE | ID: mdl-38518323

We consider the far-from-equilibrium quantum transport dynamics in a 1D Josephson junction chain of multimode Bose-Einstein condensates. We develop a theoretical model to examine the experiment of Labouvie et al. [Phys. Rev. Lett. 115, 050601 (2015)PRLTAO0031-900710.1103/PhysRevLett.115.050601], wherein the phenomenon of negative differential conductivity (NDC) was reported in the refilling dynamics of an initially depleted site within the chain. We demonstrate that a unitary c-field description can quantitatively reproduce the experimental results over the full range of tunnel couplings, and requires no fitted parameters. With a view toward atomtronic implementations, we further demonstrate that the filling is strongly dependent on spatial phase variations stemming from quantum fluctuations. Our findings suggest that the interpretation of the device in terms of NDC is invalid outside of the weak coupling regime. Within this restricted regime, the device exhibits a hybrid behavior of NDC and the ac Josephson effect. A simplified circuit model of the device will require an approach tailored to atomtronics that incorporates quantum fluctuations.

17.
Urol Oncol ; 42(6): 175.e19-175.e25, 2024 Jun.
Article En | MEDLINE | ID: mdl-38522975

OBJECTIVE: The European POUT III randomized controlled trial provided level-one evidence that adjuvant platinum-based chemotherapy is the standard of care following nephroureterectomy (RNU) for locally invasive or node-positive upper tract urothelial carcinoma. We aim to assess this European randomized controlled trial's generalizability (external validity) to a North American cohort, using a nationwide database. MATERIALS AND METHODS: To compare trial patients with those seen in real-world practice, we simulated the trial inclusion criteria using data from the National Cancer Database (NCDB). We identified patients with histologically confirmed transitional cell carcinoma who underwent RNU. The available demographic characteristics of the NCDB cohort were compared with the POUT III trial cohort using Chi-squared test. RESULTS: The NCDB cohort (n = 3,380) had a significantly higher proportion of older patients (age ≥ 80: 23.5% vs. 5%), and more males (68% vs. 56.2%) than the POUT cohort (Table 1, both p < 0.001). Additionally, the rate of advanced nodal disease was higher in the NCDB (N1 9.6%, N2 9.3%) than in the POUT (N1 6%, N2 3%) cohort (p < 0.001). A more extensive lymph node dissection was performed in NCDB vs. POUT patients (node≥10 10.9% vs. 3%, p < 0.001). Sensitivity analysis removing all subjects with a Charlson Comorbidity Index > 0 did not change the significance of any results. CONCLUSIONS: While the primary disease stage was similar, the rate of advanced nodal disease was significantly higher in NCDB, which might be explained partially by the more extensive lymph node dissection performed in the latter. These differences warrant caution when applying the POUT III findings to North American patients.


Carcinoma, Transitional Cell , Humans , Male , Female , Aged , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/surgery , Carcinoma, Transitional Cell/pathology , Chemotherapy, Adjuvant , Aged, 80 and over , Cohort Studies , North America , Nephroureterectomy/methods , Middle Aged , Urologic Neoplasms/drug therapy , Urologic Neoplasms/surgery , Cisplatin/therapeutic use , Ureteral Neoplasms/drug therapy , Ureteral Neoplasms/surgery
18.
Nat Med ; 30(4): 1013-1022, 2024 Apr.
Article En | MEDLINE | ID: mdl-38538867

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .


Cancer Vaccines , Neoplasms , Vaccines , Humans , Antigens, Neoplasm , Cancer Vaccines/adverse effects , HLA Antigens , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Vaccines/therapeutic use
19.
Transpl Infect Dis ; 26(2): e14249, 2024 Apr.
Article En | MEDLINE | ID: mdl-38319665

BACKGROUND: Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear. METHODS: We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality. RESULTS: Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes. CONCLUSION: Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.


Dibenzothiepins , Influenza, Human , Morpholines , Pyridones , Thiepins , Triazines , Adult , Humans , Oseltamivir/therapeutic use , Influenza, Human/drug therapy , Retrospective Studies , Oxazines/therapeutic use , Pyridines/therapeutic use , Thiepins/adverse effects , Antiviral Agents/therapeutic use , Immunocompromised Host , Hypoxia
20.
Urol Pract ; 11(2): 312-323, 2024 03.
Article En | MEDLINE | ID: mdl-38377155

INTRODUCTION: Medical misinformation regarding COVID-19 immunization remains rampant and a public concern, and as such, there is a need for national studies evaluating the immunization's safety profile. We sought to quantify and analyze urologic adverse events and symptoms after COVID-19 immunization, compare these events reported between COVID-19 vaccine types, and compare these events reported following COVID-19 immunization relative to those reported following other immunizations. METHODS: We conducted a retrospective case-control disproportionality analysis by querying the Food and Drug Administration Vaccine Adverse Event Reporting System for all reported symptoms following COVID-19 immunization through December 23, 2022, as well as for all non-COVID immunizations. RESULTS: Using a total of 704,231 event reports containing 2,982,187 symptoms related to COVID vaccination and a total of 770,975 event reports containing 2,198,993 symptoms related to all vaccinations other than COVID-19 for disproportionality analysis, no urologic symptom produced a positive signal when grouping all vaccinations. When stratifying by manufacturer, some symptoms related to Janssen vaccination were positive, but this may be in part due to overreporting secondary to media attention rather than a strong association between Janssen vaccination and urologic adverse events. CONCLUSIONS: Although there have been anecdotal reports of adverse events associated with the COVID-19 vaccine, our review of the Vaccine Adverse Event Reporting System database did not produce positive signals across all 4 measures for any potential adverse event. Our findings do not suggest increased scrutiny is required regarding these adverse events potentially related to the COVID-19 immunization. Further evaluation and analysis of the COVID-19 immunization is ongoing.


COVID-19 Vaccines , COVID-19 , Humans , Adverse Drug Reaction Reporting Systems , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , Retrospective Studies , Vaccination/adverse effects , Urologic Diseases/epidemiology
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