Safety and immunogenicity of a next-generation live-attenuated yellow fever vaccine produced in a Vero cell line in the USA: a phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial.

BACKGROUND: Recent outbreaks between 2015-17 and production delays have led to a yellow fever vaccine shortage. Therefore, there is an urgent need for new yellow fever vaccines with improved production scalability. A next-generation live-attenuated yellow fever vaccine candidate (vYF), produced in a Vero cell line has shown similar immunogenicity to licensed yellow fever vaccines in preclinical studies. In this study, we aimed to report the safety and immunogenicity of vYF in human clinical trial participants. METHODS: In this first in-human, phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial conducted at a single centre in the USA (Walter Reed Army Institute of Research, Silver Spring, MD, USA), 72 healthy adults (aged 18-60 years), without a known history of flavivirus infection or vaccination were randomly assigned (1:1:1:1) using interactive response technology to receive one dose of either vYF at 4, 5 or 6 Log CCID50 or the licensed YF-VAX (18 individuals per group). The primary outcomes were safety, neutralising antibody (NAb) titres through D180 post-vaccination in the per-protocol analysis set (comprised of yellow fever-naive participants who received their intended vaccine and provided a valid post-vaccination blood sample), and occurrence, and level of yellow fever viraemia in each vaccine group through D14 post-vaccination. FINDINGS: All vYF doses had a safety and tolerability profile similar to YF-VAX. The most frequently reported solicited injection site reactions (vYF groups vs YF-VAX group) were pain (22% [12 of 54 participants, 95% CI 12-36] vs 28% [five of 18 participants, 10-54]), and erythema (13% [seven of 54 participants, 5-25] vs 39% [seven of 18 participants, 17-64]), with headache (32% [17 of 54 participants, 20-46] vs 44% [eight of 18 participants, 22-69]) and malaise (26% [14 of 54 participants, 15-40] vs 33% [six of 18 participants, 13-59]) as the most frequently reported solicited systemic reactions. One grade 3 solicited reaction (erythema) reported in the YF-VAX group resolved spontaneously. No serious unsolicited adverse events or deaths were reported. Viraemia was transiently detected in 50 participants between D4 and D10 in all groups and was observed in more participants or for a longer time in the vYF 6 Log CCID50 and YF-VAX groups. All yellow fever-naive vaccine recipients across the study groups seroconverted yielding four-fold increase from baseline in yellow fever NAb titres measured by yellow fever microneutralisation assay by D28 and were seroprotected with yellow fever NAb titres of at least 10 [1/dil]). Overall, 100% (18 of 18 participants, 95% CI 82-100), 89% (16 participants, 65-99), 100% (18 participants, 82-100), and 94% (17 participants, 73-100) of participants in the vYF 4 Log, vYF 5 Log, vYF 6 Log CCID50 groups, and YF-VAX group, respectively, remained seroprotected through D180. INTERPRETATION: vYF has a similar safety and immunogenicity profile to YF-VAX. In general, the vYF 5 Log CCID50 dose appeared to show optimal viraemia, safety, and immunogenicity, and was chosen for subsequent development. FUNDING: Sanofi.

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Vertebrate and invertebrate animal infection models of Candida auris pathogenicity.

Candida auris is an emerging fungal pathogen with several concerning qualities. First recognized in 2009, it has arisen in multiple geographically distinct genomic clades nearly simultaneously. C. auris strains are typically multidrug resistant and colonize the skin much better than most other pathogenic fungi; it also persists on abiotic surfaces, enabling outbreaks due to transmission in health care facilities. All these suggest a biology substantially different from the 'model' fungal pathogen, Candida albicans and support intensive investigation of C. auris biology directly. To uncover novel virulence mechanisms in this species requires the development of appropriate animal infection models. Various studies using mice, the definitive model, are inconsistent due to differences in mouse and fungal strains, immunosuppressive regimes, doses, and outcome metrics. At the same time, developing models of skin colonization present a route to new insights into an aspect of fungal pathogenesis that has not been well studied in other species. We also discuss the growing use of nonmammalian model systems, including both vertebrates and invertebrates, such as zebrafish, C. elegans, Drosophila, and Galleria mellonella, that have been productively employed in virulence studies with other fungal species. This review will discuss progress in developing appropriate animal models, outline current challenges, and highlight opportunities in demystifying this curious species.

The 2023 top 10 list of endoscopy topics in medical publishing: an annual review by the American Society for Gastrointestinal Endoscopy Editorial Board.

Using a systematic literature search of original articles published during 2023 in Gastrointestinal Endoscopy (GIE) and other high-impact medical and gastroenterology journals, the GIE Editorial Board of the American Society for Gastrointestinal Endoscopy compiled a list of the top 10 most significant topic areas in general and advanced GI endoscopy during the year. Each GIE Editorial Board member was directed to consider 3 criteria in generating candidate topics-significance, novelty, and impact on global clinical practice-and subject matter consensus was facilitated by the Chair through electronic voting and a meeting of the entire GIE Editorial Board. The 10 identified areas collectively represent advances in the following endoscopic spheres: GI bleeding, endohepatology, endoscopic palliation, artificial intelligence and polyp detection, artificial intelligence beyond the colon, better polypectomy and EMR, how to make endoscopy units greener, high-quality upper endoscopy, endoscopic tissue apposition and closure devices, and endoscopic submucosal dissection. Each board member was assigned a topic area around which to summarize relevant important articles, thereby generating this overview of the "top 10" endoscopic advances of 2023.

Cochlear dysfunction as an early biomarker of cognitive decline in normal hearing and mild hearing loss.

INTRODUCTION: Age-related hearing loss is an important risk factor for cognitive decline. However, audiogram thresholds are not good estimators of dementia risk in subjects with normal hearing or mild hearing loss. Here we propose to use distortion product otoacoustic emissions (DPOAEs) as an objective and sensitive tool to estimate the risk of cognitive decline in older adults with normal hearing or mild hearing loss. METHODS: We assessed neuropsychological, brain magnetic resonance imaging, and auditory analyses on 94 subjects > 64 years of age. RESULTS: We found that cochlear dysfunction, measured by DPOAEs-and not by conventional audiometry-was associated with Clinical Dementia Rating Sum of Boxes (CDR-SoB) classification and brain atrophy in the group with mild hearing loss (25 to 40 dB) and normal hearing (<25 dB). DISCUSSION: Our findings suggest that DPOAEs may be a non-invasive tool for detecting neurodegeneration and cognitive decline in the older adults, potentially allowing for early intervention.

Timing of withdrawal of life-sustaining therapy in traumatic brain injury: exploring indicators of poor prognosis in adult and geriatric populations.

OBJECTIVE: The lack of objective prognostication tools for severe traumatic brain injury (TBI) causes variability in the application of withdrawal of life-saving treatment (WLST). We aimed to determine whether WLST in persons with severe TBI is associated with known indicators of poor prognosis. METHODS: This retrospective descriptive study focused on adult (18-64 years) and geriatric (≥65 years) patients with severe TBI who were admitted between August 1, 2018 and July 31, 2021 at a Level I trauma center and subsequently underwent WLST. The data collected from the Trauma Registry and electronic health records included information regarding demographic characteristics, injury severity, clinical variables, and length of hospital stay and were used to examine the indicators of poor prognosis and WLST. RESULTS: Among the 164 participants with TBI who met the inclusion criteria, 61.0% were geriatric, and 122 (74.4%) patients had 0 or only 1 of the poor prognostic indicators prior to WLST. The non-geriatric group had more indicators of poor prognosis than the geriatric group. Participants with fewer indicators of poor prognosis had a longer length-of-stay. CONCLUSION: In severe TBI cases, standardized prognostication tools can help guide informed WLST decisions, particularly in geriatric patients, improving care consistency.

Stable isotopic composition of Bothrops atrox (common lancehead) in four distinct land covers in eastern Amazonia

Since consumers reflect the isotopic composition of an assimilated diet, stable isotopes can be a useful tool to address the feeding ecology of tropical snakes. This is the first study reporting carbon and nitrogen stable isotopic composition of Bothrops atrox (Linnaeus, 1758) living in different landscapes located in the lower Amazon river, encompassing four main natural landscapes of the Amazon: old-growth forests, várzeas (flooded forests), savannas, and pastures. Our null hypothesis is that the δ13C of forest specimens of B.atrox is more negative because forests are dominated by C3 plants, while C4 plants are common in the other landscapes. On the other hand, δ15N of forest specimens should be more positive, since the δ15N of old-growth forests are higher than plants of savanna, várzea, and pastures. Confirming our hypothesis, the δ13C of B. atrox scales of the Tapajós National Forest was approximate −25‰ to −24‰, increased to approximately −23.5‰ to −23.0‰ in the savanna and pasture, and to −21‰ in the várzea, showing an increased contribution of C4-derived carbon. Some specimens of B. atrox had δ15N as high as 18‰, which is much higher than the average δ15N of the snake's prey (7‰), confirming the apex position of B. atrox in the Amazon region. The δ15N values of the forest specimens were 5‰ higher than the savanna specimens, and this difference decreased to 3‰ between the forest and the pasture, and the várzea specimens. Finally, there were not large differences between δ15N values of livers and scales in any of the landscapes, suggesting a constant diet through time, and reinforcing the possibility of the use of snake's scale as a less invasive and non-lethal tissue to analyze.

Community-Driven Conversations: Partnership Building through CHEC-Ins.

BACKGROUND: Chicago's systemically underserved communities have disproportionately high cancer rates. The Chicago Cancer Health Equity Collaborative (ChicagoCHEC) brings together academic and community partners to address these health inequities. The community conversations known as "CHEC-Ins" provide a space for community members to voice their experiences and needs and for ChicagoCHEC to fulfill its commitment to advancing health equity through collaboration and action. OBJECTIVE: This paper presents a community-generated approach to social networking about cancer health issues known as CHEC-Ins. Through this innovative approach, community members and organizations share cancer related information and experiences, as well as needs and concerns, which are then channeled to ChicagoCHEC academic and administrative members who incorporate them into outreach and research activities. In this way, community members set the agenda and the process and collect the information they deem relevant and important. This paper describes the process of organizing and conducting two pilot CHEC-Ins and the model of this approach, which we intend to employ moving forward to advance partnership building and collaborative research practice between academic institutions and community partners and organizations. This paper contributes a unique model of community-generated and led outreach as a cornerstone of the ChicagoCHEC approach to community engagement. METHODS: The leaders of the ChicagoCHEC Community Steering Committee spearheaded the design and implementation of CHEC-Ins, including developing the question guide and hosting events within their organizations. LESSONS LEARNED: CHEC-Ins proved to be a valuable strategy for defining the role of community partners and establishing the basis for a bi-directional flow of information, resources, and productive action. The two pilot CHEC-Ins revealed important insights related to sources of cancer information, meanings and associated attitudes, barriers to access and use of health services, and social support systems in the communities where ChicagoCHEC works. We will implement this approach and continue to refine it as we conduct CHECIns moving forward.

CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma.

Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.

Effectiveness and Clinical Usefulness of Electronic Agenda-setting in Psychiatric Practices: A South Texas Psychiatric PBRN Study.

There is a general consensus that the doctor-patient interview should be as productive and efficient as possible. This is becoming increasingly difficult in a health care insurance system that demands shorter appointment times. Clinicians must therefore find ways to condense the clinical encounter without sacrificing quality. The purposes of this study were: (1) to facilitate shared decision-making between psychiatrist and patient via pre-visit patient agenda-setting, (2) to evaluate the effectiveness and ease of use of the agenda-setting tool, and (3) to determine patient and clinician satisfaction with the clinical encounter. Patients completed questionnaires to assist in agenda-setting via an electronic tablet while in the waiting area before seeing the psychiatrist. Both patients and psychiatrists then completed post-visit questionnaires to assess their satisfaction with the encounter. We measured patient satisfaction and the extent to which the psychiatrist addressed concerns before and after the visit, as well as ease of use for the patient, psychiatrist satisfaction, and clinical helpfulness to the treating psychiatrist. Additional analyses also indicated that there was a significant increase in patient satisfaction scores, compared with an average of all previous visits, and a significant increase in the number of concerns addressed during the current visit when compared with the average number of previous concerns addressed. Patients reported little difficulty using the tablet. Similarly, psychiatrists reported that the device was helpful in the clinical setting and they expressed high levels of satisfaction with the visit. We hope our work will encourage others to use this agenda-setting tool in their practices to facilitate better patient care.

The novel HLA-A*30:172 allele identified in a donor from the Colombian bone marrow donor registry.

HLA-A*30:172 differs from HLA-A*30:01:01:01 by a single nucleotide in codon 153 in exon 3.

Using different multivariate approaches to assess water quality of qanats in arid zones of Southern Central Mexico.

Qanats in the aquifer of the Tehuacán Valley (Mexico) represent an ancient way of using groundwater that is still practiced today. They are used mainly for agricultural irrigation. However, anthropogenic activities have jeopardized the use of these aquifers. We analyzed 24 qanats in the Tehuacán Valley to assess water quality. Based on 24 physicochemical variables, a water quality index (WQI) was constructed on a zero-to-100 scale, divided into five water quality classes. A decision-tree analysis was applied to identify the parameters with the highest influence on the WQI, considering the water quality classes as categorical responses and the values of physicochemical variables as drivers of these categories. We produced interpolation maps to identify trends. The relationship between the WQI and the normalized difference indices of vegetation and salinity (NDVI and NDSI, respectively) was analyzed using a ternary diagram. WQI scores showed that 12.5% of the qanats have very good quality; 25%, good quality; and the remaining (62.5%) range from moderate to unacceptable quality. The CHAID classification-tree method correctly explained 83.3% of the categories, with sulfates, alkalinity, conductivity, and nitrates as the main parameters that explain water quality. WQI was inversely related to NDVI and NDSI, showing seasonal differences. Interpolation maps suggest a better water quality in the northern zone of the aquifer.

Characterization of the novel HLA-DRB1*04:315 allele by next-generation sequencing.

HLA-DRB1*04:315 differs from HLA-DRB1*04:07:01:02 by a single nucleotide substitution in codon 147 of exon 3.

Identification of a novel HLA-DRB1 null allele, HLA-DRB1*13:298N, in two siblings from Colombia.

Identification of a novel null allele, HLA-DRB1*13:298N, resulting from a deletion of two nucleotides.

MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have demonstrated efficacy in patients with EGFR-mutant non-small-cell lung cancer; however, almost all patients will eventually relapse. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. In the ongoing CHRYSALIS study (NCT02609776), amivantamab in combination with lazertinib, a potent, brain-penetrant third-generation EGFR TKI, demonstrated antitumor activity in the treatment-naive and osimertinib-relapsed setting. Here the authors present the methodology for the MARIPOSA study (NCT04487080), a phase 3, multicenter, randomized study designed to compare the efficacy and safety of amivantamab and lazertinib combination therapy versus single-agent osimertinib as first-line treatment for EGFR-mutant non-small-cell lung cancer.

Plain language summary Osimertinib is the standard-of-care treatment for patients with non-small-cell lung cancer caused by mutations in the EGFR. However, patients will eventually see their disease return because their tumors will develop new mutations that are resistant to osimertinib treatment. Amivantamab is a new antibody treatment that blocks the EGFR and another receptor called the MET receptor, to stop the growth of lung tumor cells. In an ongoing clinical trial, called the CHRYSALIS study, when amivantamab was given with lazertinib (another drug that blocks the EGFR), lung tumors shrank in patients whose lung cancer had not been previously treated. A new clinical trial called the MARIPOSA study (NCT04487080) aims to compare the antitumor activity and safety of the amivantamab + lazertinib combination versus osimertinib alone in patients with EGFR-mutant non-small-cell lung cancer who have not received treatment for their lung cancer. Trial registration number: NCT04487080 (ClinicalTrials.gov).

Identification of five novel HLA-B alleles in donors from the Colombian Bone Marrow Donor Registry.

Identification of five novel HLA-B alleles in five samples from Colombian bone marrow donors.

Description of HLA-DRB1*14:02:09, a novel HLA allele identified in a Colombian donor.

HLA-DRB1*14:02:09 differs from HLA-DRB1*14:02:01:02 by a single nucleotide substitution in codon 169 of exon 3.

Urinary glyphosate concentration in pregnant women in relation to length of gestation.

Human exposure to glyphosate-based herbicides (GBH) is increasing rapidly worldwide. Most existing studies on health effects of glyphosate have focused on occupational settings and cancer outcomes and few have examined this common exposure in relation to the health of pregnant women and newborns in the general population. We investigated associations between prenatal glyphosate exposure and length of gestation in The Infant Development and the Environment Study (TIDES), a multi-center US pregnancy cohort. Glyphosate and its primary degradation product [aminomethylphosphonic acid (AMPA)] were measured in urine samples collected during the second trimester from 163 pregnant women: 69 preterm births (<37 weeks) and 94 term births, the latter randomly selected as a subset of TIDES term births. We examined the relationship between exposure and length of gestation using multivariable logistic regression models (dichotomous outcome; term versus preterm) and with weighted time-to-event Cox proportional hazards models (gestational age in days). We conducted these analyses in the overall sample and secondarily, restricted to women with spontaneous deliveries (n = 90). Glyphosate and AMPA were detected in most urine samples (>94 %). A shortened gestational length was associated with maternal glyphosate (hazard ratio (HR): 1.31, 95 % confidence interval (CI) 1.00-1.71) and AMPA (HR: 1.32, 95%CI: 1.00-1.73) only among spontaneous deliveries using adjusted Cox proportional hazards models. In binary analysis, glyphosate and AMPA were not associated with preterm birth risk (<37 weeks). Our results indicate widespread exposure to glyphosate in the general population which may impact reproductive health by shortening length of gestation. Given the increasing exposure to GBHs and the public health burden of preterm delivery, larger confirmatory studies are needed, especially in vulnerable populations such as pregnant women and newborns.

Association between oral care challenges and sensory over-responsivity in children with Down syndrome.

BACKGROUND: Sensory over-responsivity has been linked to oral care challenges in children with special healthcare needs. Parents of children with Down syndrome (cDS) have reported sensory over-responsivity in their children, but the link between this and oral care difficulties has not been explored. AIM: To investigate the relationship between sensory over-responsivity and oral care challenges in cDS. DESIGN: An online survey examined parent-reported responses describing the oral care of their cDS (5-14 years; n = 367). Children were categorized as either sensory over-responders (SORs) or sensory not over-responders (SNORs). Chi-square analyses tested associations between groups (SORs vs. SNORs) and dichotomous oral care variables. RESULTS: More parents of SOR children than of SNOR reported that child behavior (SOR:86%, SNOR:77%; p < .05) and sensory sensitivities (SOR:34%, SNOR:18%; p < .001) make dental care challenging, their child complains about ≥3 types of sensory stimuli encountered during care (SOR:39%, SNOR:28%; p = .04), their dentist is specialized in treating children with special healthcare needs (SOR:45%, SNOR:33%; p = .03), and their child requires full assistance to brush teeth (SOR:41%, SNOR:28%; p = .008). No intergroup differences were found in items examining parent-reported child oral health or care access. CONCLUSIONS: Parents of SOR children reported greater challenges than parents of SNOR children at the dentist's office and in the home, including challenging behaviors and sensory sensitivities.

The novel HLA-A*24 allele, HLA-A*24:487, identified in three unrelated bone marrow donors in Colombia.

Identification of the novel HLA-A*24:487 allele, which differs from HLA-A*24:02:01:01 at one position.