Category: Nevin Manimala

Nat Genet. 2023 Jan 19. doi: 10.1038/s41588-022-01284-9. Online ahead of print.

ABSTRACT

Atrial fibrillation (AF) is a common cardiac arrhythmia resulting in increased risk of stroke. Despite highly heritable etiology, our understanding of the genetic architecture of AF remains incomplete. Here we performed a genome-wide association study in the Japanese population comprising 9,826 cases among 150,272 individuals and identified East Asian-specific rare variants associated with AF. A cross-ancestry meta-analysis of >1 million individuals, including 77,690 cases, identified 35 new susceptibility loci. Transcriptome-wide association analysis identified IL6R as a putative causal gene, suggesting the involvement of immune responses. Integrative analysis with ChIP-seq data and functional assessment using human induced pluripotent stem cell-derived cardiomyocytes demonstrated ERRg as having a key role in the transcriptional regulation of AF-associated genes. A polygenic risk score derived from the cross-ancestry meta-analysis predicted increased risks of cardiovascular and stroke mortalities and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide new biological and clinical insights into AF genetics and suggest their potential for clinical applications.

PMID:36653681 | DOI:10.1038/s41588-022-01284-9

Ann Surg Oncol. 2023 Jan 18. doi: 10.1245/s10434-022-12972-5. Online ahead of print.

ABSTRACT

BACKGROUND: The ACOSOG Z1031 trial addressed the ability of three neoadjuvant aromatase inhibitors (NAIs) to reduce residual disease (cohort A) and to assess whether switching to neoadjuvant chemotherapy (NCT) after 4 weeks of receiving NAI with Ki67 greater than 10% increases pathologic complete response (pCR) in postmenopausal women with estrogen receptor-enriched (Allred score 6-8) breast cancer (BC).

METHODS: The study enrolled 622 women with clinical stage 2 or 3 estrogen receptor-positive (ER+) BC. Cohort A comprised 377 patients, and cohort B had 245 patients. The analysis cohort consisted of 509 patients after exclusion of patients who did not meet the trial eligibility criteria, switched to NCT or surgery due to 4-week Ki67 greater than 10%, or withdrew before surgery. Distribution of time to local-regional recurrence (LRR) was estimated using the competing-risk approach, in which distant recurrence and second primaries were considered to be competing-risk events. Patients who died without LRR, distant recurrence, or a second primary were censored at the last evaluation.

RESULTS: Of the 509 patients, 342 (67.2%) had breast-conserving surgery (BCS). Of 221 patients thought to require mastectomy at presentation, 50% were able to have BCS. Five (1%) patients had no residual disease in the breast or nodes at surgery. Among 382 women alive at this writing, 90% have been followed longer than 5 years. The 5-year cumulative incidence rate for LRR is estimated to be 1.53% (95% confidence interval 0.7-3.0%).

CONCLUSIONS: Rarely does NAI result in pCR for patients with stage 2 or 3 ER+ BC. However, a significant proportion will have downstaged to allow for BCS. Local-regional recurrence after surgery is uncommon (1.5% at 5 years), supporting the use of BCS after NAI.

PMID:36653664 | DOI:10.1245/s10434-022-12972-5

Methods Mol Biol. 2023;2625:313-321. doi: 10.1007/978-1-0716-2966-6_26.

ABSTRACT

Advances in computational and data processing technology have enabled the development of many novel tools for analyzing metabolomic and lipidomic data. These advances involved the catalyst for the creation of publicly accessible complex web-based databases such as the Metabolomics Workbench. Open Source internet-based software packages such as MetaboAnalyst 5.0 enable researchers to perform a wide range of analyte identification and statistical analyses of their own and other researchers’ data in order to identify biomarkers and classify compounds. In this paper, we set forth a protocol for obtaining experimental data of interest from a public data repository (Metabolomics Workbench), converting the data into a format suitable for submission to MetaboAnalyst 5.0, and then uploading the data to the MetaboAnalyst server for identification and statistical analysis.

PMID:36653653 | DOI:10.1007/978-1-0716-2966-6_26

Eur Spine J. 2023 Jan 19. doi: 10.1007/s00586-022-07512-4. Online ahead of print.

ABSTRACT

PURPOSE: Patient blood management has been recently emphasized to avoid perioperative blood transfusion in AIS surgery. Hydroxyapatite charged collagen sponge (HCS) is a bone substitute material made of collagen and ceramized hydroxyapatite, with associated haemostatic properties. The goal of this study was to assess the impact of HCS in the perioperative blood loss in AIS surgery.

METHODS: After IRB approval, all AIS patients undergoing primary correction were prospectively included over a 15-month period. Patients receiving HCS at the end of the procedure were compared to a control group (matched for age, gender, and fusion levels) without any haemostatic agent or bone substitute. The same perioperative blood saving strategies were used in both groups. Two subfascial drains were used for 48 h in all patients. Perioperative blood loss and transfusion rates were analysed.

RESULTS: A total of 34 patients were included in each group. No difference in drainage volume was observed at day 1, but the reduction was statistically different at day 3 (1135 mL [800-1640] versus 930 [480-1510], p = 0.028, 0.63 ml/Kg/h [0.4-0.92] versus 0.46 [0.29-0.7], p = 0.042). Multivariate analysis found that the use of HCS was associated with a decrease in the postoperative blood loss (OR = 1.17 [1.10-1.25]). The transfusion rate was lower in the HCS group [0 (0% vs. 3(8.8%), p = 0.076)]. No infection occurred, and no complication was reported.

CONCLUSION: With 27% reduction in drain volume, hydroxyapatite charged collagen sponge can be considered as a blood salving strategy in AIS surgery. The role of the biomaterial in fusion rate still needs to be further assessed.

PMID:36653577 | DOI:10.1007/s00586-022-07512-4

Nature. 2023 Jan;613(7944):449-459. doi: 10.1038/s41586-022-05500-8. Epub 2023 Jan 18.

ABSTRACT

River networks represent the largest biogeochemical nexus between the continents, ocean and atmosphere. Our current understanding of the role of rivers in the global carbon cycle remains limited, which makes it difficult to predict how global change may alter the timing and spatial distribution of riverine carbon sequestration and greenhouse gas emissions. Here we review the state of river ecosystem metabolism research and synthesize the current best available estimates of river ecosystem metabolism. We quantify the organic and inorganic carbon flux from land to global rivers and show that their net ecosystem production and carbon dioxide emissions shift the organic to inorganic carbon balance en route from land to the coastal ocean. Furthermore, we discuss how global change may affect river ecosystem metabolism and related carbon fluxes and identify research directions that can help to develop better predictions of the effects of global change on riverine ecosystem processes. We argue that a global river observing system will play a key role in understanding river networks and their future evolution in the context of the global carbon budget.

PMID:36653564 | DOI:10.1038/s41586-022-05500-8

J Speech Lang Hear Res. 2023 Jan 18:1-28. doi: 10.1044/2022_JSLHR-22-00387. Online ahead of print.

ABSTRACT

PURPOSE: This study conducted a transcription-based and spectral moments’ analysis of alveolar and alveopalatal fricatives in monolingual and bilingual French-speaking children, aged 2;6-6;10 (years;months). We measured the percent accuracy of fricatives and investigated whether young children could distinguish alveolar and alveopalatal fricatives on the basis of spectral moments. In addition, we examined which child- (i.e., age, gender, bilingualism, and alveopalatal fricative inventory size) and word/sound-related (i.e., place-of-articulation [PoA], voicing, vowel quality, and word position) factors influenced spectral moments and fricative duration.

METHOD: Children (N = 89) participated in a picture-naming task in which they produced words containing alveolar /s, z/ and alveopalatal /ʃ, ʒ/ fricatives in word-initial, -medial, and -final positions. The words were transcribed and analyzed acoustically, and the first and third spectral moments (i.e., centroid and skewness) and the duration of fricatives were calculated. The data were subject to mixed-effects linear regression.

RESULTS: Percent accuracy results indicated effects of age on alveopalatal fricatives and effects of word position on voiced fricatives. Statistical models indicated that age, gender, and alveopalatal fricative inventory size influenced spectral moments. Age and inventory size interacted significantly with PoA. Children as young as age 2;6 distinguished alveopalatal and alveolar fricatives on the basis of centroid but not skewness values. The distinction between the two sets of fricatives increased with age. Bilingual children who spoke languages with greater numbers of alveopalatal fricatives distinguished alveopalatal and alveolar fricatives less well than monolinguals and bilinguals who spoke languages with fewer numbers of alveopalatal fricatives. Girls had higher centroid and lower skewness values than boys. Models also revealed a significant influence of word/sound-related factors (voicing, vowel quality, and word position) on spectral moments and fricative duration.

CONCLUSIONS: Findings indicated that multiple factors influence the spectral moments and duration measures of children’s alveolar and alveopalatal fricatives. In particular, we found that spectral moments were sensitive to gender and bilingualism effects.

PMID:36652703 | DOI:10.1044/2022_JSLHR-22-00387

J Clin Psychiatry. 2023 Jan 16;84(1):22m14430. doi: 10.4088/JCP.22m14430.

ABSTRACT

Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure.

Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors.

Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16).

Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.

PMID:36652686 | DOI:10.4088/JCP.22m14430

JCO Precis Oncol. 2023 Jan;7:e2200113. doi: 10.1200/PO.22.00113.

ABSTRACT

PURPOSE: Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma.

METHODS: cfDNA was isolated from diagnostic plasma samples from 57 patients enrolled in the EpSSG RMS2005 study. To study the diagnostic potential, shallow whole genome sequencing (shWGS) and cell-free reduced representation bisulphite sequencing (cfRRBS) were performed in a subset of samples and all samples were tested using droplet digital polymerase chain reaction to detect methylated RASSF1A (RASSF1A-M). Correlation with outcome was studied by combining cfDNA RASSF1A-M detection with analysis of our rhabdomyosarcoma-specific RNA panel in paired cellular blood and bone marrow fractions and survival analysis in 56 patients.

RESULTS: At diagnosis, ctDNA was detected in 16 of 30 and 24 of 26 patients using shallow whole genome sequencing and cfRRBS, respectively. Furthermore, 21 of 25 samples were correctly classified as embryonal by cfRRBS. RASSF1A-M was detected in 21 of 57 patients. The presence of RASSF1A-M was significantly correlated with poor outcome (the 5-year event-free survival [EFS] rate was 46.2% for 21 RASSF1A-M‒positive patients, compared with 84.9% for 36 RASSF1A-M‒negative patients [P < .001]). RASSF1A-M positivity had the highest prognostic effect among patients with metastatic disease. Patients both negative for RASSF1A-M and the rhabdomyosarcoma-specific RNA panel (28 of 56 patients) had excellent outcome (5-year EFS 92.9%), while double-positive patients (11/56) had poor outcome (5-year EFS 13.6%, P < .001).

CONCLUSION: Analyzing ctDNA at diagnosis using various techniques is feasible in pediatric rhabdomyosarcoma and has potential for clinical use. Measuring RASSF1A-M in plasma at initial diagnosis correlated significantly with outcome, particularly when combined with paired analysis of blood and bone marrow using a rhabdomyosarcoma-specific RNA panel.

PMID:36652664 | DOI:10.1200/PO.22.00113

J Patient Saf. 2023 Jan 19. doi: 10.1097/PTS.0000000000001104. Online ahead of print.

ABSTRACT

OBJECTIVES: Improving patient safety by investigating sentinel events (SEs) is hampered by the focus on isolated events within hospitals and a narrow scope of traditional root cause analysis methods. We aimed to examine if performing cross-hospital aggregate analysis of SEs applying a novel generic analysis method (GAM) bearing a human factor perspective can enhance learning from SEs.

METHODS: A retrospective cross-sectional review of SE reports from 28 Dutch general hospitals using the GAM to reanalyze events was performed. A qualitative approach was used to identify contributing factors and system issues. Findings were discussed with a patient safety expert panel. Descriptive statistics and measures of associations between domains were calculated.

RESULTS: Sixty-nine SE reports were reviewed. Applying the GAM provided a more holistic SE analysis than a traditional method. Of the 405 identified contributing factors in all SEs, the majority was related to the persons involved (patients and professionals, n = 146 [36.2%]) and the organization (n = 121 [30%]). The most frequently recurring pattern was the combination of factors related to the persons involved, the technology used, the tasks of professionals, and organizational factors influencing the event. Cross-hospital aggregate GAM analysis of SEs helped to identify system issues and propose more system-oriented overarching recommendations.

CONCLUSIONS: This study found that applying the GAM to analyze SEs across hospitals can help to improve learning from SEs and may result in proposing stronger recommendations. The method can support hospitals, working together in a network of hospitals, to jointly learn from SEs.

PMID:36652656 | DOI:10.1097/PTS.0000000000001104

ACS Appl Mater Interfaces. 2023 Jan 18. doi: 10.1021/acsami.2c17198. Online ahead of print.

ABSTRACT

Water management in the catalyst layers (CLs) of proton-exchange membrane fuel cells is crucial for its commercialization and popularization. However, the high experimental or computational cost in obtaining water distribution and diffusion remains a bottleneck in the existing experimental methods and simulation algorithms, and further mechanistic exploration at the nanoscale is necessary. Herein, we integrate, for the first time, molecular dynamics simulation with our customized analysis framework based on a multiattribute point cloud dataset and an advanced deep learning network. This was achieved through our workflow that generates simulated transport data of water molecules in the CLs as the training and test dataset. Deep learning framework models the multibody solid-liquid system of CLs on a molecular scale and completes the mapping from the Pt/C substrate structure and Nafion aggregates to the density distribution and diffusion coefficient of water molecules. The prediction results are comprehensively analyzed and error evaluated, which reveals the highly anisotropic interaction landscape between 50,000 pairs of interacting nanoparticles and explains the structure and water transport property relationship in the hydrated Nafion film on the molecular scale. Compared to the conventional methods, the proposed deep learning framework shows computational cost efficiency, accuracy, and good visual display. Further, it has a generality potential to model macro- and microscopic mass transport in different components of fuel cells. Our framework is expected to make real-time predictions of the distribution and diffusion of water molecules in CLs as well as establish statistical significance in the structural optimization and design of CLs and other components of fuel cells.

PMID:36652634 | DOI:10.1021/acsami.2c17198