Category: Nevin Manimala

Elife. 2023 Apr 20;12:e83118. doi: 10.7554/eLife.83118.

ABSTRACT

BACKGROUND: Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours.

METHODS: We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343).

RESULTS: Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity.

CONCLUSIONS: This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.

FUNDING: Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17-022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).

PMID:37079368 | DOI:10.7554/eLife.83118

JMIR Res Protoc. 2023 Apr 20;12:e46187. doi: 10.2196/46187.

ABSTRACT

BACKGROUND: End-stage kidney disease (ESKD) is treated with dialysis or kidney transplantation, with most patients with ESKD receiving in-center hemodialysis treatment. This life-saving treatment can result in cardiovascular and hemodynamic instability, with the most common form being low blood pressure during the dialysis treatment (intradialytic hypotension [IDH]). IDH is a complication of hemodialysis that can involve symptoms such as fatigue, nausea, cramping, and loss of consciousness. IDH increases risks of cardiovascular disease and ultimately hospitalizations and mortality. Provider-level and patient-level decisions influence the occurrence of IDH; thus, IDH may be preventable in routine hemodialysis care.

OBJECTIVE: This study aims to evaluate the independent and comparative effectiveness of 2 interventions-one directed at hemodialysis providers and another for patients-in reducing the rate of IDH at hemodialysis facilities. In addition, the study will assess the effects of interventions on secondary patient-centered clinical outcomes and examine factors associated with a successful implementation of the interventions.

METHODS: This study is a pragmatic, cluster randomized trial to be conducted in 20 hemodialysis facilities in the United States. Hemodialysis facilities will be randomized using a 2 × 2 factorial design, such that 5 sites will receive a multimodal provider education intervention, 5 sites will receive a patient activation intervention, 5 sites will receive both interventions, and 5 sites will receive none of the 2 interventions. The multimodal provider education intervention involved theory-informed team training and the use of a digital, tablet-based checklist to heighten attention to patient clinical factors associated with increased IDH risk. The patient activation intervention involves tablet-based, theory-informed patient education and peer mentoring. Patient outcomes will be monitored during a 12-week baseline period, followed by a 24-week intervention period and a 12-week postintervention follow-up period. The primary outcome of the study is the proportion of treatments with IDH, which will be aggregated at the facility level. Secondary outcomes include patient symptoms, fluid adherence, hemodialysis adherence, quality of life, hospitalizations, and mortality.

RESULTS: This study is funded by the Patient-Centered Outcomes Research Institute and approved by the University of Michigan Medical School’s institutional review board. The study began enrolling patients in January 2023. Initial feasibility data will be available in May 2023. Data collection will conclude in November 2024.

CONCLUSIONS: The effects of provider and patient education on reducing the proportion of sessions with IDH and improving other patient-centered clinical outcomes will be evaluated, and the findings will be used to inform further improvements in patient care. Improving the stability of hemodialysis sessions is a critical concern for clinicians and patients with ESKD; the interventions targeted to providers and patients are predicted to lead to improvements in patient health and quality of life.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03171545; https://clinicaltrials.gov/ct2/show/NCT03171545.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46187.

PMID:37079365 | DOI:10.2196/46187

J Med Internet Res. 2023 Apr 20;25:e45249. doi: 10.2196/45249.

ABSTRACT

BACKGROUND: The COVID-19 pandemic disrupted the needs and concerns of the cystic fibrosis community. Patients with cystic fibrosis were particularly vulnerable during the pandemic due to overlapping symptoms in addition to the challenges patients with rare diseases face, such as the need for constant medical aid and limited information regarding their disease or treatments. Even before the pandemic, patients vocalized these concerns on social media platforms like Reddit and formed communities and networks to share insight and information. This data can be used as a quick and efficient source of information about the experiences and concerns of patients with cystic fibrosis in contrast to traditional survey- or clinical-based methods.

OBJECTIVE: This study applies topic modeling and time series analysis to identify the disruption caused by the COVID-19 pandemic and its impact on the cystic fibrosis community’s experiences and concerns. This study illustrates the utility of social media data in gaining insight into the experiences and concerns of patients with rare diseases.

METHODS: We collected comments from the subreddit r/CysticFibrosis to represent the experiences and concerns of the cystic fibrosis community. The comments were preprocessed before being used to train the BERTopic model to assign each comment to a topic. The number of comments and active users for each data set was aggregated monthly per topic and then fitted with an autoregressive integrated moving average (ARIMA) model to study the trends in activity. To verify the disruption in trends during the COVID-19 pandemic, we assigned a dummy variable in the model where a value of “1” was assigned to months in 2020 and “0” otherwise and tested for its statistical significance.

RESULTS: A total of 120,738 comments from 5827 users were collected from March 24, 2011, until August 31, 2022. We found 22 topics representing the cystic fibrosis community’s experiences and concerns. Our time series analysis showed that for 9 topics, the COVID-19 pandemic was a statistically significant event that disrupted the trends in user activity. Of the 9 topics, only 1 showed significantly increased activity during this period, while the other 8 showed decreased activity. This mixture of increased and decreased activity for these topics indicates a shift in attention or focus on discussion topics during this period.

CONCLUSIONS: There was a disruption in the experiences and concerns the cystic fibrosis community faced during the COVID-19 pandemic. By studying social media data, we were able to quickly and efficiently study the impact on the lived experiences and daily struggles of patients with cystic fibrosis. This study shows how social media data can be used as an alternative source of information to gain insight into the needs of patients with rare diseases and how external factors disrupt them.

PMID:37079359 | DOI:10.2196/45249

J Med Internet Res. 2023 Apr 20;25:e46254. doi: 10.2196/46254.

ABSTRACT

BACKGROUND: Previous studies have investigated the association between suicide and internet search volumes of terms related to suicide or self-harm. However, the results varied by people’s age, period, and country, and no study has exclusively investigated suicide or self-harm rates among adolescents.

OBJECTIVE: This study aims to determine the association between the internet search volumes of terms related to suicide/self-harm and the number of suicides among South Korean adolescents. We investigated gender differences in this association and the time lag between the internet search volumes of the terms and the connected suicide deaths.

METHODS: We selected 26 search terms related to suicide and self-harm among South Korean adolescents, and the search volumes of these terms for adolescents aged 13-18 years were obtained from the leading internet search engine in South Korea (Naver Datalab). A data set was constructed by combining data from Naver Datalab and the number of suicide deaths of adolescents on a daily basis from January 1, 2016, to December 31, 2020. Spearman rank correlation and multivariate Poisson regression analyses were performed to identify the association between the search volumes of the terms and the suicide deaths during that period. The time lag between suicide death and the increasing trend in the search volumes of the related terms was estimated from the cross-correlation coefficients.

RESULTS: Significant correlations were observed within the search volumes of the 26 terms related to suicide/self-harm. The internet search volumes of several terms were associated with the number of suicide deaths among South Korean adolescents, and this association differed by gender. The search volume for “dropout” showed a statistically significant correlation with the number of suicides in all adolescent population groups. The correlation between the internet search volume for “dropout” and the connected suicide deaths was the strongest for a time lag of 0 days. In females, self-harm and academic score showed significant associations with suicide deaths, but academic score showed a negative correlation, and the time lags with the strongest correlations were 0 and -11 days, respectively. In the total population, self-harm and suicide method were associated with the number of suicides, and the time lags with the strongest correlations were +7 and 0 days, respectively.

CONCLUSIONS: This study identifies a correlation between suicides and internet search volumes related to suicide/self-harm among South Korean adolescents, but the relatively weak correlation (incidence rate ratio 0.990-1.068) should be interpreted with caution.

PMID:37079349 | DOI:10.2196/46254

JAMA Oncol. 2023 Apr 20. doi: 10.1001/jamaoncol.2023.0356. Online ahead of print.

ABSTRACT

IMPORTANCE: Spine metastasis can be treated with high-dose radiation therapy with advanced delivery technology for long-term tumor and pain control.

OBJECTIVE: To assess whether patient-reported pain relief was improved with stereotactic radiosurgery (SRS) as compared with conventional external beam radiotherapy (cEBRT) for patients with 1 to 3 sites of vertebral metastases.

DESIGN, SETTING, AND PARTICIPANTS: In this randomized clinical trial, patients with 1 to 3 vertebral metastases were randomized 2:1 to the SRS or cEBRT groups. This NRG 0631 phase 3 study was performed as multi-institutional enrollment within NRG Oncology. Eligibility criteria included the following: (1) solitary vertebral metastasis, (2) 2 contiguous vertebral levels involved, or (3) maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients enrolled in the trial, and 339 patients were analyzed. This analysis includes data extracted on March 9, 2020.

INTERVENTIONS: Patients randomized to the SRS group were treated with a single dose of 16 or 18 Gy (to convert to rad, multiply by 100) given to the involved vertebral level(s) only, not including any additional spine levels. Patients assigned to cEBRT were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below.

MAIN OUTCOMES AND MEASURES: The primary end point was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale (NRPS) without worsening in pain at the secondary site(s) or the use of pain medication. Secondary end points included treatment-related toxic effects, quality of life, and long-term effects on vertebral bone and spinal cord.

RESULTS: A total of 339 patients (mean [SD] age of SRS group vs cEBRT group, respectively, 61.9 [13.1] years vs 63.7 [11.9] years; 114 [54.5%] male in SRS group vs 70 [53.8%] male in cEBRT group) were analyzed. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the SRS group and 5.88 (2.41) in the cEBRT group. The primary end point of pain response at 3 months favored cEBRT (41.3% for SRS vs 60.5% for cEBRT; difference, -19 percentage points; 95% CI, -32.9 to -5.5; 1-sided P = .99; 2-sided P = .01). Zubrod score (a measure of performance status ranging from 0 to 4, with 0 being fully functional and asymptomatic, and 4 being bedridden) was the significant factor influencing pain response. There were no differences in the proportion of acute or late adverse effects. Vertebral compression fracture at 24 months was 19.5% with SRS and 21.6% with cEBRT (P = .59). There were no spinal cord complications reported at 24 months.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, superiority of SRS for the primary end point of patient-reported pain response at 3 months was not found, and there were no spinal cord complications at 2 years after SRS. This finding may inform further investigation of using spine radiosurgery in the setting of oligometastases, where durability of cancer control is essential.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00922974.

PMID:37079324 | DOI:10.1001/jamaoncol.2023.0356

JAMA Oncol. 2023 Apr 20. doi: 10.1001/jamaoncol.2023.0260. Online ahead of print.

ABSTRACT

IMPORTANCE: Recently, several large, high-quality analyses have shown opposing results regarding the association between 5α-reductase inhibitor (5-ARI) use and prostate cancer (PCa) mortality.

OBJECTIVE: To systematically evaluate the current evidence regarding 5-ARI use and PCa mortality.

DATA SOURCES: A literature search began in and was conducted through August 2022 using PubMed/Medline, Embase, and Web of Science databases.

STUDY SELECTION: Studies were deemed eligible if they included male patients of any age who were 5-ARI users and were compared with those who were nonusers if they analyzed PCa mortality in randomized clinical trials and prospective or retrospective cohort studies.

DATA EXTRACTION AND SYNTHESIS: This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Adjusted hazard ratios (HRs) were extracted from published articles. Data analysis was performed in August 2022.

MAIN OUTCOMES AND MEASURES: The primary outcome was PCa mortality among 5-ARI users vs nonusers. The inverse variance method with adjusted HRs and random-effect models were used to determine the association between 5-ARI use and PCa mortality. Two subgroup analyses were performed to assess the effect of 2 main confounders: prostate-specific antigen level and PCa diagnosis at baseline.

RESULTS: Among 1200 unique records screened, 11 studies met the inclusion criteria. A total of 3 243 575 patients were included: 138 477 users of 5-ARI and 3 105 098 nonusers. There was no statistically significant association between 5-ARI use and PCa mortality (adjusted HR, 1.04; 95% CI, 0.80-1.35; P = .79). No significant association was found when the analysis was restricted to studies that excluded patients with a diagnosis of PCa at baseline (adjusted HR, 1.00; 95% CI, 0.60-1.67; P = .99) or the analysis was restricted to prostate-specific antigen-adjusted studies (adjusted HR, 0.76; 95% CI, 0.57-1.03; P = .08).

CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis, which draws on 2 decades of epidemiologic literature and includes more than 3 million patients, found no statistically significant association between 5-ARI use and PCa mortality but provides important data to inform clinical care.

PMID:37079318 | DOI:10.1001/jamaoncol.2023.0260

Minerva Anestesiol. 2023 Apr 20. doi: 10.23736/S0375-9393.23.17080-5. Online ahead of print.

ABSTRACT

BACKGROUND: Mechanical power (MP) is the amount of energy transferred from the ventilator to the patient within a unit of time. It has been emphasized in ventilation-induced lung injury (VILI) and mortality. However, its measurement and use in clinical practice are challenging. “Electronic recording systems (ERS)” using mechanical ventilation parameters provided by the ventilator can be helpful to measure and record the MP. The MP (J/minutes) formula is 0.098 x tidal volume x respiratory rate x (Ppeak – ½ ∆P), in which ∆P is the driving pressure and Ppeak is the peak pressure. We aimed to define the association between MP values and ICU mortality, mechanical ventilation days, and intensive care unit length of stay (ICU-LOS). The secondary outcome was to determine the most potent or essential component of power in the equation that has a role in mortality.

METHODS: This retrospective study was performed in two centers (VKV American Hospital and Bakırköy Sadi Konuk Hospital ICUs) that used ERS (Metavision IMDsoft) between 2014 and 2018. We uploaded the power formula (MP (J/minutes)=0.098×VT×RR×(Ppeak – ½ ∆P) to ERS (METAvision, iMDsoft, and Consult Orion Health) and calculated the MP value by using MV parameters automatically sent from the ventilator. (∆P; driving pressure, VT; tidal volume, RR; respiratory rate and Ppeak; peak pressure).

RESULTS: A total of 3042 patients were included in the study. The median value of MP was 11.3 J/min. Mortality in MP<11.3 J/min was 35.4%, and 49.1% in MP>11.3J/min.; P<0.001. Mechanical ventilation days and ICU-LOS were also statistically longer in the MVP>11.3 J/min group.

CONCLUSIONS: The first 24 h MP maybe a predictive value for the ICU patients’ prognosis. This implies that MP may be used as a decision-making system to define the clinical approach and as a scoring system to predict patient prognosis.

PMID:37079284 | DOI:10.23736/S0375-9393.23.17080-5

Anat Sci Int. 2023 Apr 20. doi: 10.1007/s12565-023-00727-5. Online ahead of print.

ABSTRACT

This study purposed to develop statistical models to predict palatal (PRL), mesial (MRL), and distal (DRL) root canal length and pulp volume (PV) of the maxillary first permanent molar using stature, gender, mesiodistal (MD), and buccopalatal (BP) crown diameters and some facial morphometries. 57 individuals were included in the study. Cone beam computed tomography was used to measure root canal lengths and PV. The PV calculation was carried out using the software ITK-SNAP 3.4.0. PRL was positively correlated with BP, stature, middle facial height, interalar distance, and bicommissural distance (BCD) (p < 0.05). DRL was positively correlated with BP, MD, and stature (p < 0.05). MRL was positively correlated with BP, MD, stature, lower face height, bizygomatic distance, and BCD (p < 0.05). PV was negatively correlated with age and BCD (p < 0.05). Although all models have significant predictive power for the root lengths and PV, no model could explain variances greater than 30%. The highest and lowest predictive ability was obtained for PRL and DRL, respectively. While the most significant predictor was BP for PRL and DRL, it was the age for PV.

PMID:37079264 | DOI:10.1007/s12565-023-00727-5

Environ Sci Pollut Res Int. 2023 Apr 20. doi: 10.1007/s11356-023-26813-9. Online ahead of print.

ABSTRACT

Exposure to arsenic even at low levels can lead to adverse health outcomes, however, there is a paucity of research from South Africa in relation to human exposure to arsenic. We investigated long-term exposure of residents in Limpopo province, South Africa, in a cross-sectional study by analysing water, soil and blood arsenic concentrations from two arsenic-exposed (high and medium-low exposure) villages and one non-exposed (control) village. There were statistically significant differences in the distribution of arsenic in water, soil and blood amongst the three sites. The median drinking water arsenic concentration in the high-exposure village was 1.75 µg/L (range = 0.02 to 81.30 µg/L), 0.45 µg/L (range = 0.100 to 6.00 µg/L) in the medium- / low-exposure village and 0.15 µg/L (range = < limit of detection (LOD) to 29.30 µg/L) in the control site. The median soil arsenic concentration in the high-exposure village was 23.91 mg/kg (range = < LOD to 92.10 mg/kg) whilst arsenic concentrations were below the limit of detection in all soil samples collected from the medium-/low-exposure and control villages. In the high-exposure village, the median blood arsenic concentration was 1.6 µg/L (range = 0.7 to 4.2 µg/L); 0.90 µg/L (range = < LOD to 2.5 µg/L) in the medium-/low-exposure village and 0.6 µg/L (range = < LOD to 3.3 µg/L) in the control village. Significant percentages of drinking water, soil and blood samples from the exposed sites were above the internationally recommended guidelines (namely, 10 µg/L, 20 mg/kg and 1 µg/L, respectively). Majority of participants (86%) relied on borehole water for drinking and there was a significant positive correlation between arsenic in blood and borehole water (p-value = 0.031). There was also a statistically significant correlation between arsenic concentrations in participants’ blood and soil samples collected from gardens (p-value = 0.051). Univariate quantile regression found that blood arsenic concentrations increased by 0.034 µg/L (95% CI = 0.02-0.05) for each one unit increase in water arsenic concentrations (p < 0.001). After adjusting for age, water source and homegrown vegetable consumption in multivariate quantile regression, participants from the high-exposure site had significantly higher blood concentrations than those in the control site (coefficient: 1.00; 95% CI = 0.25-1.74; p-value = 0.009) demonstrating that blood arsenic is a good biomarker of arsenic exposure. Our findings also provide new evidence for South Africa on the association between drinking water and arsenic exposure, emphasising the need for the provision of potable water for human consumption in areas with high environmental arsenic concentrations.

PMID:37079235 | DOI:10.1007/s11356-023-26813-9

Geroscience. 2023 Apr 20. doi: 10.1007/s11357-023-00785-7. Online ahead of print.

ABSTRACT

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells’ (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo-derived senescence signature (SenSig) using a foreign body response-driven fibrosis model in a p16-CreER^T2;Ai14 reporter mouse. We identified pericytes and “cartilage-like” fibroblasts as senescent and defined cell type-specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34-CSF1R-TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.

PMID:37079217 | DOI:10.1007/s11357-023-00785-7