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JAMA Surgery Jul 2024Exception From Informed Consent (EFIC) research requires community consultation (CC) and public disclosure (PD). Traditional methods of conducting CC and PD are slow,...
IMPORTANCE
Exception From Informed Consent (EFIC) research requires community consultation (CC) and public disclosure (PD). Traditional methods of conducting CC and PD are slow, expensive, and labor intensive.
OBJECTIVE
To describe the feasibility and reach of a novel interactive, media-based approach to CC and PD and to identify the similarities and differences between trial sites in website views, survey responses, online community forum attendance, and opt-out requests.
DESIGN, SETTING, AND PARTICIPANTS
This survey study analyzed the CC and PD campaigns conducted for the TAP trial (Evaluation of BE1116 in Patients With Traumatic Injury and Acute Major Bleeding to Improve Survival), an EFIC trial of the early administration of prothrombin complex concentrate in patients with trauma. The CC and PD campaigns consisted of social media advertisements, linked websites, community surveys, and online community forums. These activities were coordinated from a central site and approved by a central institutional review board. This study focused on the first 52 of 91 TAP trial sites (level I trauma centers) in the US to have completed their CC and PD campaigns. Community members in the catchment areas of the participating trauma centers were targeted. Data analysis was conducted between October 2023 and February 2024.
EXPOSURE
Social media advertisements, surveys, and online community meetings conducted as part of the CC and PD campaign for the TAP trial.
MAIN OUTCOMES AND MEASURES
Social media campaign reach and engagement, web page views, survey results, online community forum attendance, and opt-out requests.
RESULTS
Fifty-two trial sites were approved for participant enrollment. Social media advertisements were displayed 92 million times, reaching 11.8 million individuals. The median (IQR) number of people reached in each location was 210 317 (172 068-276 968). Site-specific websites were viewed 144 197 times (median [IQR] viewings per site, 2984 [1267-4038]). A total of 17 206 fully or partly completed surveys were received, and survey respondents had a median (IQR) age of 40.1 (15-65) years and included 10 444 females (60.7%). Overall, 60.6% survey respondents said they would want to be entered into the trial even if they could not give consent, 87.7% agreed that emergency care research was necessary, and 88.0% agreed that the TAP trial should be conducted in their community. Online community forums were attended by a median (IQR) number of 38 (20-63) people. Four opt-out requests were received.
CONCLUSIONS AND RELEVANCE
The interactive media-based approach to CC and PD for the ongoing TAP trial showed the feasibility and benefits of executing an efficient, coordinated, centrally run series of locally branded and geographically targeted CC and PD campaigns for a large EFIC study.
PubMed: 38959020
DOI: 10.1001/jamasurg.2024.2147 -
JAMA Oncology Jul 2024Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based...
IMPORTANCE
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven.
OBJECTIVE
To compare the survival of patients with surveillance-detected PDAC with US national data.
DESIGN, SETTING, AND PARTICIPANTS
This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023.
EXPOSURES
Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment.
MAIN OUTCOMES AND MEASURES
Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted.
RESULTS
A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]).
CONCLUSIONS AND RELEVANCE
These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.
PubMed: 38959011
DOI: 10.1001/jamaoncol.2024.1930 -
Journal of the American Chemical Society Jul 2024The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. This...
The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. This challenge is compounded when emphasis is placed on the preparation of new chemotypes that have distinct and practical functions. To expand the structural diversity of boron-containing heterocycles, we report herein the preparation of novel monocyclic hemiboronic acids, diazaborines. These compounds have enabled the study of a pseudoaromatic boranol-containing (B-OH) ring free of influence from an appended aromatic system. Synthetic and spectroscopic studies have provided insight into the aromatic character, Lewis acidic nature, chemical reactivity, and unique ability of the exocyclic B-OH unit to participate in hydroxy exchange, suggesting their use in organocatalysis and as reversible covalent inhibitors. Moreover, density functional theory and nucleus-independent chemical shift calculations reveal that the aromatic character of the boroheterocyclic ring is increased significantly in comparison to known bicyclic benzodiazaborines (naphthoid congeners), consequently leading to attenuated Lewis acidity. Direct structural comparison to a well-established biaryl isostere, 2-phenylphenol, through X-ray crystallographic analysis reveals that -aryl derivatives are strikingly similar in size and conformation, with attenuated log values underscoring the value of the polar BNN unit. Their potential application as low-molecular-weight scaffolds in drug discovery is demonstrated through orthogonal diversification and preliminary antifungal evaluation (), which unveiled analogs with low micromolar inhibitory concentration.
PubMed: 38959009
DOI: 10.1021/jacs.4c06360 -
JAMA Psychiatry Jul 2024Supporting healthy aging is a US public health priority, and gratitude is a potentially modifiable psychological factor that may enhance health and well-being in older...
IMPORTANCE
Supporting healthy aging is a US public health priority, and gratitude is a potentially modifiable psychological factor that may enhance health and well-being in older adults. However, the association between gratitude and mortality has not been studied.
OBJECTIVE
To examine the association of gratitude with all-cause and cause-specific mortality in later life.
DESIGN, SETTING, AND PARTICIPANTS
This population-based prospective cohort study used data from self-reported questionnaires and medical records of 49 275 US older female registered nurses who participated in the Nurses' Health Study (2016 questionnaire wave to December 2019). Cox proportional hazards regression models estimated the hazard ratio (HR) of deaths by self-reported levels of gratitude at baseline. These models adjusted for baseline sociodemographic characteristics, social participation, physical health, lifestyle factors, cognitive function, and mental health. Data analysis was conducted from December 2022 to April 2024.
EXPOSURE
Gratitude was assessed with the 6-item Gratitude Questionnaire, a validated and widely used measure of one's tendency to experience grateful affect.
MAIN OUTCOMES AND MEASURES
Deaths were identified from the National Death Index, state statistics records, reports by next of kin, and the postal system. Causes of death were ascertained by physicians through reviewing death certificates and medical records.
RESULTS
Among the 49 275 participants (all female; mean [SD] age at baseline, 79 [6.16] years), 4608 incident deaths were identified over 151 496 person-years of follow-up. Greater gratitude at baseline was associated with a lower hazard of mortality in a monotonic fashion. For instance, the highest tertile of gratitude, compared with the lowest tertile, was associated with a lower hazard of all-cause deaths (HR, 0.91; 95% CI, 0.84-0.99) after adjusting for baseline sociodemographic characteristics, social participation, religious involvement, physical health, lifestyle factors, cognitive function, and mental health. When considering cause-specific deaths, death from cardiovascular disease was inversely associated with gratitude (HR, 0.85; 95% CI, 0.73-0.995).
CONCLUSIONS AND RELEVANCE
This study provides the first empirical evidence suggesting that experiencing grateful affect is associated with increased longevity among older adults. The findings will need to be replicated in future studies with more representative samples.
PubMed: 38959002
DOI: 10.1001/jamapsychiatry.2024.1687 -
Ultrasound Quarterly Sep 2024The objective of the study was to use a deep learning model to differentiate between benign and malignant sentinel lymph nodes (SLNs) in patients with breast cancer... (Comparative Study)
Comparative Study
Characterizing Sentinel Lymph Node Status in Breast Cancer Patients Using a Deep-Learning Model Compared With Radiologists' Analysis of Grayscale Ultrasound and Lymphosonography.
The objective of the study was to use a deep learning model to differentiate between benign and malignant sentinel lymph nodes (SLNs) in patients with breast cancer compared to radiologists' assessments.Seventy-nine women with breast cancer were enrolled and underwent lymphosonography and contrast-enhanced ultrasound (CEUS) examination after subcutaneous injection of ultrasound contrast agent around their tumor to identify SLNs. Google AutoML was used to develop image classification model. Grayscale and CEUS images acquired during the ultrasound examination were uploaded with a data distribution of 80% for training/20% for testing. The performance metric used was area under precision/recall curve (AuPRC). In addition, 3 radiologists assessed SLNs as normal or abnormal based on a clinical established classification. Two-hundred seventeen SLNs were divided in 2 for model development; model 1 included all SLNs and model 2 had an equal number of benign and malignant SLNs. Validation results model 1 AuPRC 0.84 (grayscale)/0.91 (CEUS) and model 2 AuPRC 0.91 (grayscale)/0.87 (CEUS). The comparison between artificial intelligence (AI) and readers' showed statistical significant differences between all models and ultrasound modes; model 1 grayscale AI versus readers, P = 0.047, and model 1 CEUS AI versus readers, P < 0.001. Model 2 r grayscale AI versus readers, P = 0.032, and model 2 CEUS AI versus readers, P = 0.041.The interreader agreement overall result showed κ values of 0.20 for grayscale and 0.17 for CEUS.In conclusion, AutoML showed improved diagnostic performance in balance volume datasets. Radiologist performance was not influenced by the dataset's distribution.
Topics: Humans; Female; Breast Neoplasms; Deep Learning; Sentinel Lymph Node; Middle Aged; Aged; Adult; Radiologists; Ultrasonography, Mammary; Contrast Media; Lymphatic Metastasis; Ultrasonography; Sentinel Lymph Node Biopsy; Breast; Reproducibility of Results
PubMed: 38958999
DOI: 10.1097/RUQ.0000000000000683 -
FASEB Journal : Official Publication of... Jul 2024This study aimed to explore how mechanical stress affects osteogenic differentiation via the miR-187-3p/CNR2 pathway. To conduct this study, 24 female C57BL/6 mice, aged...
This study aimed to explore how mechanical stress affects osteogenic differentiation via the miR-187-3p/CNR2 pathway. To conduct this study, 24 female C57BL/6 mice, aged 8 weeks, were used and divided into four groups. The Sham and OVX groups did not undergo treadmill exercise, while the Sham + EX and OVX + EX groups received a 8-week treadmill exercise. Post-training, bone marrow and fresh femur samples were collected for further analysis. Molecular biology analysis, histomorphology analysis, and micro-CT analysis were conducted on these samples. Moreover, primary osteoblasts were cultured under osteogenic conditions and divided into GM group and CTS group. The cells in the CTS group underwent a sinusoidal stretching regimen for either 3 or 7 days. The expression of early osteoblast markers (Runx2, OPN, and ALP) was measured to assess differentiation. The study findings revealed that mechanical stress has a regulatory impact on osteoblast differentiation. The expression of miR-187-3p was observed to decrease, facilitating osteogenic differentiation, while the expression of CNR2 increased significantly. These observations suggest that mechanical stress, miR-187-3p, and CNR2 play crucial roles in regulating osteogenic differentiation. Both in vivo and in vitro experiments have confirmed that mechanical stress downregulates miR-187-3p and upregulates CNR2, which leads to the restoration of distal femoral bone mass and enhancement of osteoblast differentiation. Therefore, mechanical stress promotes osteoblasts, resulting in improved osteoporosis through the miR-187-3p/CNR2 signaling pathway. These findings have broad prospect and provide molecular biology guidance for the basic research and clinical application of exercise in the prevention and treatment of PMOP.
Topics: Animals; MicroRNAs; Osteoblasts; Female; Osteoporosis, Postmenopausal; Mice; Cell Differentiation; Mice, Inbred C57BL; Osteogenesis; Stress, Mechanical; Humans; Signal Transduction; Cells, Cultured
PubMed: 38958998
DOI: 10.1096/fj.202400113RR -
JAMA Oncology Jul 2024There is limited evidence with regard to the benefit of adjuvant chemotherapy chemoradiotherapy in resected gallbladder cancers (GBCs).
IMPORTANCE
There is limited evidence with regard to the benefit of adjuvant chemotherapy chemoradiotherapy in resected gallbladder cancers (GBCs).
OBJECTIVE
To establish a baseline survival rate for operated GBCs in patients receiving either gemcitabine plus cisplatin (GC) or capecitabine and capecitabine concurrent with chemoradiation (CCRT).
DESIGN, SETTING, AND PARTICIPANTS
The GECCOR-GB study was a multicenter, open-label, randomized phase 2 noncomparator "pick the winner" design trial of adjuvant GC and CCRT in patients with resected histologically confirmed adenocarcinoma or adenosquamous carcinoma of the gallbladder, (stage II/III) with no local residual tumor (R0) or microscopic residual tumor (R1). The study was carried out in 3 tertiary cancer institutions in India. Patients 18 years or older with adequate end-organ functions, and Eastern Cooperative Oncology Group Performance Status of 1 or lower between May 2019 and February 2022 were enrolled. The cutoff date for data analysis was February 28, 2023.
INTERVENTIONS
Patients were randomized 1:1 to receive either GC every 3 weeks (maximum of 6 cycles) or CCRT comprising capecitabine with concurrent chemoradiation (capecitabine concurrent with radiotherapy) sandwiched between capecitabine chemotherapy.
MAIN OUTCOMES AND MEASURES
The primary outcome was disease-free survival (DFS) at 1 year in randomized patients. This study was conducted as 2 parallel, single-stage phase 2 clinical trials. Within each treatment arm, a 1-year DFS rate of less than 59% was considered as insufficient activity, whereas a 1-year DFS rate of 77% or higher would be considered as sufficient activity.
RESULTS
With a median follow-up of 23 months, 90 patients were randomized, 45 in each arm. Overall, there were 31 women (69%) and 14 men (31%) in the GC arm with a mean (range) age of 56 (33-72) years and 34 women (76%) and 11 men (24%) in the CCRT group with a mean (range) age of 55 (26-69) years. In the GC and CCRT arms, 1-year DFS and estimated 2-year DFS was 88.9% (95% CI, 79.5-98.3) and 74.8% (95% CI, 60.4-89.2), and 77.8% (95% CI, 65.4-90.2) and 74.8% (95% CI, 59.9-86.3), respectively. Completion rates for planned treatment was 82% in the GC arm and 62% in the CCRT arm.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, GC and CCRT crossed the prespecified trial end points of 1-year DFS in patients with resected stage II/III GBCs. The results set a baseline for a larger phase 3 trial evaluating both regimens in operated GBCs.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: CTRI/2019/05/019323I.
PubMed: 38958997
DOI: 10.1001/jamaoncol.2024.1944 -
JAMA Dermatology Jul 2024Seborrheic dermatitis is a prevalent chronic inflammatory skin disease, yet its global prevalence, pathogenesis, and epidemiology remain inadequately defined.
IMPORTANCE
Seborrheic dermatitis is a prevalent chronic inflammatory skin disease, yet its global prevalence, pathogenesis, and epidemiology remain inadequately defined.
OBJECTIVE
To provide a detailed estimation of the global prevalence of seborrheic dermatitis, analyze demographic variations, and explore differences in various settings.
DATA SOURCES
Embase, PubMed, Scopus, and Cochrane Database of Systematic Reviews were searched from inception through October 2023.
STUDY SELECTION
Original investigations on seborrheic dermatitis prevalence were included after duplicate screening of titles, abstracts, and full articles, including only studies with clinician-diagnosed cases.
DATA EXTRACTION AND SYNTHESIS
Following PRISMA guidelines, data were extracted and quality was assessed independently by multiple reviewers. A random-effects model using restricted maximum likelihood was used for meta-analysis and subgroup analyses.
MAIN OUTCOME AND MEASURE
The primary outcome was the pooled estimate of global seborrheic dermatitis prevalence.
RESULTS
From 1574 identified articles, 121 studies were included, encompassing 1 260 163 individuals and revealing a pooled global seborrheic dermatitis prevalence of 4.38% (95% CI, 3.58%-5.17%), with significant heterogeneity (I2 = 99.94%). Subgroup analyses showed variations by age, with a higher prevalence in adults (5.64% [95% CI, 4.01%-7.27%]) compared to children (3.70% [95% CI, 2.69%-4.80%]) and neonates (0.23% [95% CI, 0.04%-0.43%]). Geographic analyses indicated variability, with the highest prevalence in South Africa (8.82% [95% CI, 3.00%-14.64%]) and the lowest in India (2.62% [95% CI, 1.33%-3.92%]).
CONCLUSIONS AND RELEVANCE
This comprehensive meta-analysis provides a detailed estimation of the global prevalence of seborrheic dermatitis, highlighting significant variability across different demographics and settings.
PubMed: 38958996
DOI: 10.1001/jamadermatol.2024.1987 -
JAMA Cardiology Jul 2024Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for...
IMPORTANCE
Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial.
OBJECTIVE
To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti-PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C-lowering treatment.
DESIGN, SETTING, AND PARTICIPANTS
This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD were included.
INTERVENTIONS
Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks.
MAIN OUTCOMES AND MEASURES
The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets.
RESULTS
Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy.
CONCLUSIONS AND RELEVANCE
In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04806893.
PubMed: 38958989
DOI: 10.1001/jamacardio.2024.1659 -
FASEB Journal : Official Publication of... Jul 2024This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms...
This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high-throughput single-cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS-STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti-tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti-tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS-STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies.
Topics: Tripartite Motif-Containing Protein 28; Animals; Mice; Humans; Male; CD8-Positive T-Lymphocytes; Prostatic Neoplasms, Castration-Resistant; Mice, Knockout; Membrane Proteins; Macrophages; Nucleotidyltransferases; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Mice, Inbred C57BL; Signal Transduction
PubMed: 38958986
DOI: 10.1096/fj.202400061RR