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Journal For Immunotherapy of Cancer May 2024Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer...
BACKGROUND
Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.
METHODS
We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.
RESULTS
We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4 and CD8 TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.
CONCLUSIONS
Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation.
TRIAL REGISTRATION NUMBER
NCT00068003, NCT01174121, and NCT03412877.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Antigens, Neoplasm; Receptors, Antigen, T-Cell; Mice; Immunologic Memory; Animals; Female; Phenotype; Neoplasms
PubMed: 38816232
DOI: 10.1136/jitc-2023-008645 -
ESC Heart Failure May 2024This study aimed to investigate the prevalence, risk factors and prognostic implications of cognitive impairment in young and middle-aged patients with acute heart...
AIMS
This study aimed to investigate the prevalence, risk factors and prognostic implications of cognitive impairment in young and middle-aged patients with acute heart failure (HF).
METHODS
In a prospective cohort of patients with acute HF, we assessed cognitive function by the Mini-Cog, predictors of the cognitive impairment and its associations with 30 day and 1 year cardiovascular death or HF rehospitalization among young and middle-aged patients (<65 years old).
RESULTS
Among 1958 young and middle-aged patients, the prevalence of cognitive impairment was 19.6%. Predictors of cognitive impairment included older age, females, lower education levels and prior strokes. Compared with patients having normal cognitive function, cognitive impairment was associated with a higher risk of 30 day cardiovascular death or HF rehospitalization [hazard ratio (HR), 1.52, 95% confidence interval (CI), 1.07-2.17, P = 0.02], but not for 1 year cardiovascular death or HF rehospitalization (HR, 1.06, 95% CI, 0.87-1.30, P = 0.55).
CONCLUSIONS
Cognitive impairment is present in a notable proportion of young and middle-aged patients with acute HF and is associated with an increased risk of short-term adverse outcomes. Strategies for screening and intervention for cognitive impairment at a younger age are necessary, particularly for those at high risk.
PubMed: 38816208
DOI: 10.1002/ehf2.14885 -
BMJ Open May 2024Multiple sclerosis (MS) is an immune-mediated demyelinating disease with a significant burden of neuropsychiatric sequelae. These symptoms, including depression and...
INTRODUCTION
Multiple sclerosis (MS) is an immune-mediated demyelinating disease with a significant burden of neuropsychiatric sequelae. These symptoms, including depression and anxiety, are predictors of morbidity and mortality in people with MS. Despite a high prevalence of obsessive-compulsive disorder in MS, potentially shared pathophysiological mechanisms and overlap in possible treatments, no review has specifically examined the clinical dimensions of people with obsessive-compulsive and related disorders (OCRD) and MS. In this scoping review, we aim to map the available knowledge on the clinical dimensions of people with co-occurring OCRD and MS. Understanding the characteristics of this population in greater detail will inform more patient-centred care and create a framework for future studies.
METHODS AND ANALYSIS
We developed a search strategy to identify all articles that include people with co-occurring OCRD and MS. The search strategy (extending to the grey literature) was applied to MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science and ProQuest Dissertations & Theses. Records will undergo title and abstract screening by two independent reviewers. Articles meeting inclusion criteria based on title and abstract screening will go on to full-text review by the two independent reviewers. After reaching a consensus about articles for inclusion in the final review, data will be extracted using a standardised extraction form. The extracted data will include clinical characteristics of patients such as age, gender, medication use and severity of MS, among others.
ETHICS AND DISSEMINATION
This scoping review does not require research ethics approval. Results will be shared at national and/or international conferences, in a peer-reviewed journal publication, in a plain language summary and in a webinar for the general public.
Topics: Humans; Multiple Sclerosis; Obsessive-Compulsive Disorder; Research Design; Review Literature as Topic; Comorbidity
PubMed: 38816059
DOI: 10.1136/bmjopen-2023-074929 -
BMJ Open May 2024To determine the prevalence, causes and risk factors associated with visual impairment (VI) in the Nirmal district of Telangana, India, using extended Rapid Assessment...
OBJECTIVE
To determine the prevalence, causes and risk factors associated with visual impairment (VI) in the Nirmal district of Telangana, India, using extended Rapid Assessment of Visual Impairment (RAVI) methodology.
DESIGN
Cross-sectional study.
SETTING
Community setting.
PARTICIPANTS
Participants aged ≥16 years were enumerated from 90 randomly selected clusters and 4629/5400 (85.7%) participants were examined. Presenting visual acuity (VA) was assessed using a Snellen chart with E optotypes at a 6 m distance. Near vision was assessed binocularly using an N notation chart with tumbling E optotypes at a 40 cm distance. An anterior segment examination done followed by distance direct ophthalmoscopy at 50 cm. Non-mydriatic fundus images were obtained. VI was defined as presenting VA worse than 6/12 in the better eye. The prevalence of VI in the current study was compared with a RAVI study conducted in 2014 to assess the trends in VI among those aged ≥40 years.
PRIMARY OUTCOME
Prevalence, causes and risk factors for VI.
RESULTS
Among those examined, 55% were women, 53% had at least school-level education, 2.3% self-reported diabetes and 8.7% self-reported hypertension. The prevalence of VI was 8.81% (95% CI 8.01% to 9.67%). Overall, uncorrected refractive errors (49.5%) were the leading cause of VI, followed by cataracts (40.2%) and posterior segment diseases (4.9%). Among those aged ≥40 years, the prevalence of VI declined by 19.3% compared with the 2014 baseline study (from 20.2% to 16.3%; p<0.01).
CONCLUSION
The extended RAVI study conducted in the Nirmal district showed a considerable decline in the prevalence of VI. Targeted interventions are needed to provide adequate eye care for the high-risk groups in this district.
Topics: Humans; Cross-Sectional Studies; India; Female; Male; Middle Aged; Adult; Prevalence; Risk Factors; Aged; Young Adult; Adolescent; Visual Acuity; Vision Disorders; Cataract
PubMed: 38816051
DOI: 10.1136/bmjopen-2023-083199 -
BMJ Open May 2024This study aimed to describe the clinical characteristics of adults with suspected acute community-acquired pneumonia (CAP) on hospitalisation, evaluate their prediction...
Community-acquired pneumonia: use of clinical characteristics of acutely admitted patients for the development of a diagnostic model - a cross-sectional multicentre study.
OBJECTIVES
This study aimed to describe the clinical characteristics of adults with suspected acute community-acquired pneumonia (CAP) on hospitalisation, evaluate their prediction performance for CAP and compare the performance of the model to the initial assessment of the physician.
DESIGN
Cross-sectional, multicentre study.
SETTING
The data originated from the INfectious DisEases in Emergency Departments study and were collected prospectively from patient interviews and medical records. The study included four Danish medical emergency departments (EDs) and was conducted between 1 March 2021 and 28 February 2022.
PARTICIPANTS
A total of 954 patients admitted with suspected infection were included in the study.
PRIMARY AND SECONDARY OUTCOME
The primary outcome was CAP diagnosis assessed by an expert panel.
RESULTS
According to expert evaluation, CAP had a 28% prevalence. 13 diagnostic predictors were identified using least absolute shrinkage and selection operator regression to build the prediction model: dyspnoea, expectoration, cough, common cold, malaise, chest pain, respiratory rate (>20 breaths/min), oxygen saturation (<96%), abnormal chest auscultation, leucocytes (<3.5×10/L or >8.8×10/L) and neutrophils (>7.5×10/L). C reactive protein (<20 mg/L) and having no previous event of CAP contributed negatively to the final model. The predictors yielded good prediction performance for CAP with an area under the receiver-operator characteristic curve (AUC) of 0.85 (CI 0.77 to 0.92). However, the initial diagnosis made by the ED physician performed better, with an AUC of 0.86 (CI 84% to 89%).
CONCLUSION
Typical respiratory symptoms combined with abnormal vital signs and elevated infection biomarkers were predictors for CAP on admission to an ED. The clinical value of the prediction model is questionable in our setting as it does not outperform the clinician's assessment. Further studies that add novel diagnostic tools and use imaging or serological markers are needed to improve a model that would help diagnose CAP in an ED setting more accurately.
TRIAL REGISTRATION NUMBER
NCT04681963.
Topics: Humans; Community-Acquired Infections; Cross-Sectional Studies; Male; Female; Middle Aged; Aged; Pneumonia; Emergency Service, Hospital; Hospitalization; Denmark; Adult; ROC Curve; Prospective Studies; C-Reactive Protein
PubMed: 38816044
DOI: 10.1136/bmjopen-2023-079123 -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2024This study investigates the 10-year trend in the sedative and anticholinergic burden among older adults in Slovenia, with the aim of identifying opportunities to...
This study investigates the 10-year trend in the sedative and anticholinergic burden among older adults in Slovenia, with the aim of identifying opportunities to optimize pharmacotherapy in this population. A retrospective drug utilization analysis was conducted based on a national anonymized database of dispensed prescriptions from 2009 to 2019. The study employed the sedative load model and the anticholinergic cognitive burden scale to assess the sedative and anti cholinergic burden, respectively. The findings indicate that in 2019, 45.6 % and 40.8 % of older adults (≥ 65 years) used sedative and anticholinergic medications, respectively. A high sedative load and a clinically significant anticholinergic burden were observed in a considerable proportion of older adults (13.2 % and 11.2 %, respectively, in 2019). The age-standardized prevalence of sedative load and anti-cholinergic burden significantly decreased over the 10-year study period by 5.6 % and 1.7 %, respectively (absolute difference), while the prevalence of clinically significant anticholinergic burden remained stable. Notably, the age groups 85-89 years and above 90 years had an increase in the proportion of individuals with a clinically significant anticholinergic burden over the years. These results emphasize the need for targeted interventions, particularly in the oldest age groups, to promote safe and effective medication use among older adults.
Topics: Humans; Cholinergic Antagonists; Slovenia; Aged; Aged, 80 and over; Male; Retrospective Studies; Female; Hypnotics and Sedatives; Drug Utilization; Databases, Factual; Age Factors; Prevalence
PubMed: 38815203
DOI: 10.2478/acph-2024-0017 -
PLoS Genetics May 2024Whether single-cell RNA-sequencing (scRNA-seq) captures the same biological information as single-nucleus RNA-sequencing (snRNA-seq) remains uncertain and likely to be...
Whether single-cell RNA-sequencing (scRNA-seq) captures the same biological information as single-nucleus RNA-sequencing (snRNA-seq) remains uncertain and likely to be context-dependent. Herein, a head-to-head comparison was performed in matched normal-adenocarcinoma human lung samples to assess biological insights derived from scRNA-seq versus snRNA-seq and better understand the cellular transition that occurs from normal to tumoral tissue. Here, the transcriptome of 160,621 cells/nuclei was obtained. In non-tumor lung, cell type proportions varied widely between scRNA-seq and snRNA-seq with a predominance of immune cells in the former (81.5%) and epithelial cells (69.9%) in the later. Similar results were observed in adenocarcinomas, in addition to an overall increase in cell type heterogeneity and a greater prevalence of copy number variants in cells of epithelial origin, which suggests malignant assignment. The cell type transition that occurs from normal lung tissue to adenocarcinoma was not always concordant whether cells or nuclei were examined. As expected, large differential expression of the whole-cell and nuclear transcriptome was observed, but cell-type specific changes of paired normal and tumor lung samples revealed a set of common genes in the cells and nuclei involved in cancer-related pathways. In addition, we showed that the ligand-receptor interactome landscape of lung adenocarcinoma was largely different whether cells or nuclei were evaluated. Immune cell depletion in fresh specimens partly mitigated the difference in cell type composition observed between cells and nuclei. However, the extra manipulations affected cell viability and amplified the transcriptional signatures associated with stress responses. In conclusion, research applications focussing on mapping the immune landscape of lung adenocarcinoma benefit from scRNA-seq in fresh samples, whereas snRNA-seq of frozen samples provide a low-cost alternative to profile more epithelial and cancer cells, and yield cell type proportions that more closely match tissue content.
PubMed: 38814983
DOI: 10.1371/journal.pgen.1011301 -
PloS One 2024To assess the attitudes of women towards intimate partner violence (IPV) in Guyana.
BACKGROUND
To assess the attitudes of women towards intimate partner violence (IPV) in Guyana.
METHODS
We used national data from the publicly available Multiple Indicator Cluster Survey (MICS) conducted in Guyana in 2019 for women aged 15 to 49 years. The prevalence of women who agreed that a husband is justified in beating his wife was analyzed. Respondent reasons included if she: "goes out without telling him", "neglects the children", "argues with him", "refuses sex with him", "burns the food", "has another partner", "stays out late/partying", "refuses to cook or clean", "overspends", and/or "he doesn't have access to her cellphone". Descriptive analyses were carried for all the variables. Logistic regression was used to identify factors associated with these 10 respondent reasons, separately and in combination.
RESULTS
The overall prevalence of women's attitudes justifying IPV against women if there was a 'yes' response to any of the 10 reasons was 17.9% (95%CI: 16.6-19.3%), and varied from 2.7% if she "goes out without telling him", "burns the food", or "overspends" to 10.0% if she "has another partner". This prevalence ranged from 10.2% in urban areas to 19.3% in rural areas (p<0.001), and from 16.1% in coastal to 30.1% in interior areas (p<0.001). Similarly, 25.9% of women from the poorest household agreed that a husband has the right in beating his wife for any of the 10 reasons compared to 11.6% of the richest women (11.6%) (p<0.001). Rural place of residence, ethnicity, geographic region, level of education, wealth quintile, ever used of a computer, and frequency of listening to the radio were significant factors associated with women's attitudes justifying IPV against women (p<0.05).
CONCLUSION
Over one-sixth of the respondents agreed that a husband was justified in committing IPV against women in Guyana. Public health programs focusing on geographic locations, ethnicity, and economic status must be implemented to change attitudes justifying IPV and reduce this significant public health challenge.
Topics: Humans; Female; Adult; Cross-Sectional Studies; Intimate Partner Violence; Adolescent; Middle Aged; Young Adult; Guyana; Male; Prevalence; Attitude; Surveys and Questionnaires; Rural Population
PubMed: 38814974
DOI: 10.1371/journal.pone.0303902 -
PloS One 2024Women living with HIV (WLWH) have high risk of developing cervical cancer. High- risk Human papillomavirus (hrHPV) is the single most important cause of cervical cancer....
BACKGROUND
Women living with HIV (WLWH) have high risk of developing cervical cancer. High- risk Human papillomavirus (hrHPV) is the single most important cause of cervical cancer. Vaccination for and early detection of pre-malignant cervical changes, through cervical cancer screening contributes to prevention of cervical cancer. This study sought to determine the prevalence of HPV among WLWH, genotypes present and the risk factors associated with cervical cancer development.
METHODS AND FINDINGS
An analytical cross-sectional study of 250 sexually active women aged 18 years and above, attending HIV clinic at a tertiary health facility in Accra. Demographic data collection and risk factor assessments were done using interviewer-administered questionnaire, and patient records. Cervical swabs were collected and tested for HPV using real-time PCR assays. Genotype analysis was performed on 92 samples. Descriptive statistics and logistic regression analysis were used to establish associations between hrHPV and risk factors among WLWH. Approximately 60% of study participants tested positive for HPV. The prevalence of hr-HPV among WLH was 44.4%. Factors identified to be protective of hrHPV were employment (AOR = 0.19, 95% CI = 0.06, 0.56, p = 0.003) and highly active antiretroviral therapy (HAART) Tenofovir-Lamivudine-Ritonavir-Lopinavir (TLRL) (AOR = 0.30, 95% CI = 0.09, 0.95, p = 0.04). Women with HIV diagnosis within 6 to10 years (AOR = 4.89, 95% CI = 1.05, 22.70, p = 0.043) and diagnosis >10 years (AOR = 8.25, 95% CI = 1.24, 54.84, p = 0.029) had higher odds of hrHPV. Approximately 25% of samples analysed tested positive for hr-HPV group 1 (genotypes 16, 18, 31, 33, 35, 39, 45,51, 52, 56, 58, 69) and 46.8% for multiple HPV genotypes.
CONCLUSION
A high prevalence of genotypes that include high risk genotypes 16 and 18 and multiple HPV infections was found among WLWH. Almost half of the women screened had high-risk HPV and were prone to cervical cancer without their knowledge. Regular HPV screening is recommended for high-risk patient groups.
Topics: Humans; Female; Adult; Papillomavirus Infections; HIV Infections; Risk Factors; Prevalence; Ghana; Cross-Sectional Studies; Middle Aged; Young Adult; Uterine Cervical Neoplasms; Adolescent; Papillomaviridae; Tertiary Care Centers
PubMed: 38814956
DOI: 10.1371/journal.pone.0303535 -
PloS One 2024The prevalence of gastrointestinal tumors continues to be significant. To uncover promising therapeutic targets for these tumors, we rigorously executed a Mendelian...
BACKGROUND
The prevalence of gastrointestinal tumors continues to be significant. To uncover promising therapeutic targets for these tumors, we rigorously executed a Mendelian randomization (MR) study to comprehensively screen the blood metabolomes for potential causal mediators of five frequently encountered gastrointestinal tumors (Liver Cancer, Colorectal Cancer, Esophageal Cancer, Gastric Cancer and Pancreatic Cancer).
METHODS
We selected a comprehensive set of 137 distinct blood metabolites derived from three large-scale genome-wide association studies (GWASs) involving a total of 147827 participants of European ancestry. The gastrointestinal tumors-related data were obtained from a GWAS conducted within the Finnish study. Through meticulous MR analyses, we thoroughly assessed the associations between blood metabolites and gastrointestinal tumors. Additionally, a phenome-wide MR (Phe-MR) analysis was employed to investigate the potential on-target side effects of metabolite interventions.
RESULTS
We have identified 1 blood metabolites, namely isovalerylcarnitine (ORlog10: 1.01; 95%CI, 1.01-1.02; P = 1.81×10-7), as the potential causal mediators for liver cancer. However, no potential pathogenic mediators were detected for the other four tumors.
CONCLUSIONS
The current systematic MR analysis elucidated the potential role of isovalerylcarnitine as a causal mediator in the development of liver cancer. Leveraging the power of Phe-MR study facilitated the identification of potential adverse effects associated with drug targets for liver cancer prevention. Considering the weighing of pros and cons, isovalerylcarnitine emerges as a promising candidate for targeted drug interventions in the realm of liver cancer prevention.
Topics: Humans; Gastrointestinal Neoplasms; Metabolome; Genome-Wide Association Study; Mendelian Randomization Analysis; Male; Female; Finland; Carnitine; Middle Aged; Risk Factors; Liver Neoplasms
PubMed: 38814898
DOI: 10.1371/journal.pone.0304574