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JAMA Oncology Aug 2023Little is known about regional nodal irradiation (RNI) practice patterns or rates of locoregional recurrence (LRR) with and without RNI in patients with limited nodal... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Little is known about regional nodal irradiation (RNI) practice patterns or rates of locoregional recurrence (LRR) with and without RNI in patients with limited nodal disease and favorable biology treated with modern surgical and systemic therapy, including approaches that de-escalate those latter treatments.
OBJECTIVE
To investigate how often patients with low-recurrence score breast cancer with 1 to 3 nodes involved receive RNI, incidence and predictors of LRR, and associations between locoregional therapy and disease-free survival.
DESIGN, SETTING, AND PARTICIPANTS
In this secondary analysis of the SWOG S1007 trial, patients with hormone receptor-positive, ERBB2-negative breast cancer, and a Oncotype DX 21-gene Breast Recurrence Score assay result of no more than 25, were randomized to endocrine therapy alone vs chemotherapy then endocrine therapy. Prospectively collected radiotherapy information was collected from 4871 patients treated in diverse settings. Data were analyzed June 2022 to April 2023.
EXPOSURE
Receipt of RNI (targeting at least the supraclavicular region).
MAIN OUTCOME(S) AND MEASURE(S)
Cumulative incidence of LRR was calculated by locoregional treatment received. Analyses were assessed for associations between invasive disease-free survival (IDFS) and locoregional therapy, adjusted for menopausal status, treatment group, recurrence score, tumor size, nodes involved, and axillary surgery. Radiotherapy information was recorded in the first year after randomization, so survival analyses were landmarked as starting at 1 year among those still at risk.
RESULTS
Of 4871 female patients (median [range] age, 57 [18-87] years) with radiotherapy forms, 3947 (81.0%) reported radiotherapy receipt. Of 3852 patients who received radiotherapy and had complete information on targets, 2274 (59.0%) received RNI. With a median follow-up of 6.1 years, the cumulative incidence of LRR by 5 years was 0.85% among patients who received breast-conserving surgery and radiotherapy with RNI; 0.55% after breast-conserving surgery with radiotherapy without RNI; 0.11% after mastectomy with postmastectomy radiotherapy; and 1.7% after mastectomy without radiotherapy. Similarly low LRR was observed within the group assigned to endocrine therapy without chemotherapy. The rate of IDFS did not differ by RNI receipt (premenopausal: hazard ratio [HR], 1.03; 95% CI, 0.74-1.43; P = .87; postmenopausal: HR, 0.85; 95% CI, 0.68-1.07; P = .16).
CONCLUSIONS AND RELEVANCE
In this secondary analysis of a clinical trial, RNI use was divided in the setting of biologically favorable N1 disease, and rates of LRR were low even in patients who did not receive RNI. Disease-free survival was not associated with RNI receipt; omission of chemotherapy among patients similar to those enrolled in the S1007 trial is not an independent indication for use of RNI.
Topics: Humans; Female; Middle Aged; Breast Neoplasms; Mastectomy; Incidence; Neoplasm Recurrence, Local; Mastectomy, Segmental; Radiotherapy, Adjuvant
PubMed: 37410451
DOI: 10.1001/jamaoncol.2023.1984 -
JAMA Pediatrics Oct 2023Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear.
IMPORTANCE
Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear.
OBJECTIVE
To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children.
DESIGN, SETTING, AND PARTICIPANTS
Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded.
EXPOSURES
SARS-CoV-2 hospitalization during the stipulated time frame.
MAIN OUTCOMES AND MEASURES
The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy.
RESULTS
Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children.
CONCLUSIONS AND RELEVANCE
This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.
Topics: Adolescent; Humans; Child; Male; Infant; Child, Preschool; Female; COVID-19; SARS-CoV-2; Pandemics; Oxygen
PubMed: 37603343
DOI: 10.1001/jamapediatrics.2023.3117 -
Methods in Molecular Biology (Clifton,... 2024Structural studies of bio-complexes using single particle cryo-Electron Microscopy (cryo-EM) is nowadays a well-established technique in structural biology and has... (Review)
Review
Structural studies of bio-complexes using single particle cryo-Electron Microscopy (cryo-EM) is nowadays a well-established technique in structural biology and has become competitive with X-ray crystallography. Development of digital registration systems for electron microscopy images and algorithms for the fast and efficient processing of the recorded images and their following analysis has facilitated the determination of structures at near-atomic resolution. The latest advances in EM have enabled the determination of protein complex structures at 1.4-3 Å resolution for an extremely broad range of sizes (from ~100 kDa up to hundreds of MDa (Bartesaghi et al., Science 348(6239):1147-1151, 2015; Herzik et al., Nat Commun 10:1032, 2019; Wu et al., J Struct Biol X 4:100020, 2020; Zhang et al., Nat Commun 10:5511, 2019; Zhang et al., Cell Res 30(12):1136-1139, 2020; Yip et al., Nature 587(7832):157-161, 2020; https://www.ebi.ac.uk/emdb/statistics/emdb_resolution_year )). In 2022, nearly 1200 structures deposited to the EMDB database were at a resolution of better than 3 Å ( https://www.ebi.ac.uk/emdb/statistics/emdb_resolution_year ).To date, the highest resolutions have been achieved for apoferritin, which comprises a homo-oligomer of high point group symmetry (O432) and has rigid organization together with high stability (Zhang et al., Cell Res 30(12):1136-1139, 2020; Yip et al., Nature 587(7832):157-161, 2020). It has been used as a test object for the assessments of modern cryo-microscopes and processing methods during the last 5 years. In contrast to apoferritin bacterial secretion systems are typical examples of multi protein complexes exhibiting high flexibility owing to their functions relating to the transportation of small molecules, proteins, and DNA into the extracellular space or target cells. This makes their structural characterization extremely challenging (Barlow, Methods Mol Biol 532:397-411, 2009; Costa et al., Nat Rev Microbiol 13:343-359, 2015). The most feasible approach to reveal their spatial organization and functional modification is cryo-electron microscopy (EM). During the last decade, structural cryo-EM has become broadly used for the analysis of the bio-complexes that comprise multiple components and are not amenable to crystallization (Lyumkis, J Biol Chem 294:5181-5197, 2019; Orlova and Saibil, Methods Enzymol 482:321-341, 2010; Orlova and Saibil, Chem Rev 111(12):7710-7748, 2011).In this review, we will describe the basics of sample preparation for cryo-EM, the principles of digital data collection, and the logistics of image analysis focusing on the common steps required for reconstructions of both small and large biological complexes together with refinement of their structures to nearly atomic resolution. The workflow of processing will be illustrated by examples of EM analysis of Type IV Secretion System.
Topics: Cryoelectron Microscopy; Apoferritins; Algorithms; Bacterial Secretion Systems; Crystallization
PubMed: 37930544
DOI: 10.1007/978-1-0716-3445-5_27 -
JAMA Otolaryngology-- Head & Neck... Nov 2023There is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated...
IMPORTANCE
There is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue-modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials.
OBJECTIVE
To establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy.
MAIN OUTCOMES AND MEASURES
Per-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing.
RESULTS
Of 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days.
CONCLUSIONS AND RELEVANCE
This cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay's performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.
Topics: Humans; Male; Middle Aged; Female; Human Papillomavirus Viruses; Cohort Studies; Retrospective Studies; Papillomavirus Infections; Carcinoma, Squamous Cell; Oropharyngeal Neoplasms; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Liquid Biopsy
PubMed: 37422913
DOI: 10.1001/jamaoto.2023.1937 -
Annals of Neurology Sep 2023Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products...
Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560.
Topics: Humans; Amyotrophic Lateral Sclerosis; Bayes Theorem; Disease Progression; Time Factors; Clinical Trials as Topic
PubMed: 37245090
DOI: 10.1002/ana.26714 -
Brain Communications 2024Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are... (Review)
Review
Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilitate a future consensus-based statement (e.g. via a modified Delphi) and series of recommendations. The panel convened weekly online meetings from October 2021 to December 2022. Research considerations addressed the nosographic status of disorders of consciousness, case ascertainment and verification, selection of dependent variables, choice of covariates and measurement and analysis of outcomes and covariates, aiming to promote more homogeneous designs and practices in future observational studies. The goal of this review is to inform a broad community of professionals with different backgrounds and clinical interests to address the methodological challenges imposed by the transition of care from acute to chronic stages and to streamline data gathering for patients with disorders of consciousness. A coordinated effort will be a key to allow reliable observational data synthesis and epidemiological estimates and ultimately inform condition-modifying clinical trials.
PubMed: 38344653
DOI: 10.1093/braincomms/fcae022 -
Journal of Endodontics Feb 2024The aim of this study was to leverage label-efficient self-supervised learning (SSL) to train a model that can detect ECR and differentiate it from caries.
INTRODUCTION
The aim of this study was to leverage label-efficient self-supervised learning (SSL) to train a model that can detect ECR and differentiate it from caries.
METHODS
Periapical (PA) radiographs of teeth with ECR defects were collected. Two board-certified endodontists reviewed PA radiographs and cone beam computed tomographic (CBCT) images independently to determine presence of ECR (ground truth). Radiographic data were divided into 3 regions of interest (ROIs): healthy teeth, teeth with ECR, and teeth with caries. Nine contrastive SSL models (SimCLR v2, MoCo v2, BYOL, DINO, NNCLR, SwAV, MSN, Barlow Twins, and SimSiam) were implemented in the assessment alongside 7 baseline deep learning models (ResNet-18, ResNet-50, VGG16, DenseNet, MobileNetV2, ResNeXt-50, and InceptionV3). A 10-fold cross-validation strategy and a hold-out test set were employed for model evaluation. Model performance was assessed via various metrics including classification accuracy, precision, recall, and F1-score.
RESULTS
Included were 190 PA radiographs, composed of 470 ROIs. Results from 10-fold cross-validation demonstrated that most SSL models outperformed the transfer learning baseline models, with DINO achieving the highest mean accuracy (85.64 ± 4.56), significantly outperforming 13 other models (P < .05). DINO reached the highest test set (ie, 3 ROIs) accuracy (84.09%) while MoCo v2 exhibited the highest recall and F1-score (77.37% and 82.93%, respectively).
CONCLUSIONS
This study showed that AI can assist clinicians in detecting ECR and differentiating it from caries. Additionally, it introduced the application of SSL in detecting ECR, emphasizing that SSL-based models can outperform transfer learning baselines and reduce reliance on large, labeled datasets.
Topics: Humans; Cone-Beam Computed Tomography; Artificial Intelligence; Tooth; Tomography, X-Ray Computed; Dental Caries; Supervised Machine Learning
PubMed: 37977219
DOI: 10.1016/j.joen.2023.11.004 -
BMJ Open Oct 2023The objective of this review is to (1) identify barriers and facilitators with respect to women's health services at a primary care level based on a systematic review...
OBJECTIVES
The objective of this review is to (1) identify barriers and facilitators with respect to women's health services at a primary care level based on a systematic review and narrative synthesis and (2) to conclude with recommendations for better services and uptake.
DESIGN
Systematic review and narrative synthesis.
DATA SOURCES
PubMed, BMC Medicine, Medline, CINAHL and the Cochrane Library. Grey literature was also searched.
ELIGIBILITY CRITERIA
Qualitative, quantitative and mixed studies were included in the review.
DATA EXTRACTION AND SYNTHESIS
The search took place at the beginning of June 2021 and was completed at the end of August 2021. Studies were included in the review based on the Sample, Phenomenon of Interest, Design, Evaluation, Research type criteria. The quality of the included studies was assessed using the Mixed Methods Appraisal Tool. Data were synthesised using a narrative synthesis approach.
RESULTS
A total of 33 studies were included in the review. We identified six barriers to the delivery of effective primary healthcare for women's health which have been organised under two core themes of 'service barriers' and 'family/cultural barriers'. Ten barriers to the uptake of primary healthcare for women have been identified, under three core themes of 'perceptions about healthcare service', 'cultural factors' and 'practical issues'. Three facilitators of primary healthcare delivery for women were identified: 'motivating community health workers (CHWs) with continued training, salary, and supervision' and 'selection of CHWs on the basis of certain characteristics'. Five facilitators of the uptake of primary healthcare services for women were identified, under two core themes of 'development of trust and acceptance' and 'use of technology'.
CONCLUSIONS
Change is needed not only to address the limitations of the primary healthcare services themselves, but also the cultural practices and limited awareness and literacy that prevent the uptake of healthcare services by women, in addition to the wider infrastructure in terms of the provision of financial support, public transport and child care centres.
PROSPERO REGISTRATION NUMBER
CRD42020203472.
Topics: Female; Humans; Pakistan; Health Services; Primary Health Care
PubMed: 37899162
DOI: 10.1136/bmjopen-2023-076883 -
The Journal of Pharmacy Technology :... Aug 2023Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and...
The Effectiveness and Adverse Events of Cannabidiol and Tetrahydrocannabinol Used in the Treatment of Anxiety Disorders in a PTSD Subpopulation: An Interim Analysis of an Observational Study.
Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been proposed as potential treatments for anxiety disorders, specifically posttraumatic stress disorder (PTSD). To evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine the effectiveness and associated AEs. An interim analysis of data collected between September 2018 and June 2021 from the CA Clinics Observational Study. Patient-Reported Outcomes Measurement Information System-29 survey scores of 198 participants with an anxiety disorder were compared at baseline and after treatment with medicinal cannabis. The data of 568 anxiety participants were also analyzed to examine the AEs they experienced by the Medical Dictionary for Regulatory Activities organ system class. The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies.
PubMed: 37529155
DOI: 10.1177/87551225231180796