Alternative Sequences Research Articles

Genes to therapy: a comprehensive literature review of whole-exome sequencing in neurology and neurosurgery

Whole-exome sequencing (WES), a ground-breaking technology, has emerged as a linchpin in neurology and neurosurgery, offering a comprehensive elucidation of the genetic landscape of various neurological disorders. This transformative methodology concentrates on the exonic portions of DNA, which constitute approximately 1% of the human genome, thus facilitating an expedited and efficient sequencing process. WES has been instrumental in advancing our understanding of neurodegenerative diseases, neuro-oncology, cerebrovascular disorders, and epilepsy by revealing rare variants and novel mutations and providing intricate insights into their genetic complexities. This has been achieved while maintaining a substantial diagnostic yield, thereby offering novel perspectives on the pathophysiology and personalized management of these conditions. The utilization of WES boasts several advantages over alternative genetic sequencing methodologies, including cost-effectiveness, reduced incidental findings, simplified analysis and interpretation process, and reduced computational demands. However, despite its benefits, there are challenges, such as the interpretation of variants of unknown significance, cost considerations, and limited accessibility in resource-constrained settings. Additionally, ethical, legal, and social concerns are raised, particularly in the context of incidental findings and patient consent. As we look to the future, the integration of WES with other omics-based approaches could help revolutionize the field of personalized medicine through its implications in predictive models and the development of targeted therapeutic strategies, marking a significant stride toward more effective and clinically oriented solutions.Graphical

Unified specification tests in partially linear time series models

Based on a residual marked empirical process, Cramér–von Mises and Kolmogorov–Smirnov tests are proposed for the correct specification of the nonparametric components in partially linear time series models. The tests are unified in the sense that the asymptotic distribution of residual marked empirical process is invariant across different nν-consistent estimators in calculating residuals (where ν>1/4) under the null. In addition, the residual marked empirical process has the same power property under the sequence of local alternatives regardless of the estimators used. Achieved through a projection method, these features also enable using a computationally convenient multiplier bootstrap to approximate the unified null distributions of the test statistics. Simulations show satisfactory finite-sample performance of the proposed method. The application to validate the parametric form of conditional variance in the ARCH-X model is also highlighted, along with an empirical analysis of the conditional variance of the FTSE 100 index return series.

Synthesis and immunological study of tetrasaccharide repeating units of capsular polysaccharide of Group B Streptococcus serotype VIII and their protein conjugates

This study reports the efficient synthesis of three tetrasaccharide derivatives of Group B Streptococcus (GBS) serotype VIII capsular polysaccharide with alternative glycan sequences and spacer chains through a convergent chemical glycosylation manner or a one-pot three-enzyme assembly protocol. Using bifunctional glutarate ester as the linker, these synthesized oligosaccharides were efficiently conjugated with recombinant ScpA193 protein, generating the resultant oligosaccharide-ScpA193 conjugates with desirable carbohydrate loading. ELISA analysis of the antisera obtained from mice inoculated with the synthetic glycoconjugates showed the elicitation of strong oligosaccharide-specific immunoglobulin G (IgG) antibodies, suggesting the potential of the synthesized oligosaccharides for use in the development of GBS vaccines.

Phase diagram of the three-dimensional subsystem toric code

Subsystem quantum error-correcting codes typically involve measuring a sequence of noncommuting parity check operators. They can sometimes exhibit greater fault tolerance than conventional codes, which use commuting checks. However, unlike subspace codes, it is unclear if subsystem codes—in particular their advantages—can be understood in terms of ground-state properties of a physical Hamiltonian. In this paper, we address this question for the three-dimensional subsystem toric code (3D STC), as recently constructed by Kubica and Vasmer [], which exhibits single-shot error correction. Motivated by a conjectured relation between single-shot properties and thermal stability, we study the zero- and finite-temperature phases of an associated noncommuting Hamiltonian. By mapping the Hamiltonian model to a pair of 3D Z2 gauge theories coupled by a kinetic constraint, we find various phases at zero temperature, all separated by first-order transitions: There are 3D toric code-like phases with deconfined point-like excitations in the bulk, and there are phases with a confined bulk supporting a 2D toric code on the surface when appropriate boundary conditions are chosen. The latter is similar to the surface topological order present in 3D STC. However, the similarities between the single-shot correction in 3D STC and the confined phases are only partial: they share the same sets of degrees of freedom, but they are governed by different dynamical rules. Instead, we argue that the process of single-shot error correction can more suitably be associated with a path (rather than a point) in the zero-temperature phase diagram, a perspective, which inspires alternative measurement sequences enabling single-shot error correction. Moreover, since none of the above-mentioned phases survives at nonzero temperature, the single-shot error-correction property of the code does not imply thermal stability of the associated Hamiltonian phase. Published by the American Physical Society 2024

16S rRNA phylogeny and clustering is not a reliable proxy for genome-based taxonomy in Streptomyces.

Streptomyces is among the most extensively studied genera of bacteria but its complex taxonomy remains contested and is suspected to contain significant species-level misclassification. Resolving the classification of Streptomyces would benefit many areas of applied microbiology that rely on an accurate ground truth for grouping of related organisms, including comparative genomics-based searches for novel antimicrobials. We survey taxonomic conflicts between 16S rRNA and whole genome-based Streptomyces classifications using 2276 publicly available Streptomyces genome assemblies and 48 981 publicly available full-length 16S rRNA Streptomyces sequences from silva, Greengenes, Ribosomal Database Project (RDP), and NCBI (National Centre for Biotechnology Information) databases. We construct a full-length 16S gene tree for 14 239 distinct Streptomyces sequences that resolves three major lineages of Streptomyces, but whose topology is not consistent with existing taxonomic assignments. We use these sequence data to delineate 16S and whole genome landscapes for Streptomyces, demonstrating that 16S and whole-genome classifications are frequently in disagreement, and that 16S zero-radius Operational Taxonomic Units (zOTUs) are often inconsistent with Average Nucleotide Identity (ANI)-based taxonomy. Our results strongly imply that 16S rRNA sequence data does not map to taxonomy sufficiently well to delineate Streptomyces species routinely. We propose that alternative marker sequences should be adopted by the community for classification and metabarcoding. Insofar as Streptomyces taxonomy has been determined or supported by 16S sequence data and may in parts be in error, we also propose that reclassification of the genus by alternative approaches may benefit the Streptomyces community.

Updating and calibrating the Real-World Progression In Diabetes (RAPIDS) model in a non-Veterans Affairs population.

To present the Real-World Progression In Diabetes (RAPIDS) 2.0 Risk Engine, the only simulation model to study the long-term trajectories of outcomes arising from dynamic sequences of glucose-lowering treatments in type 2 diabetes (T2DM). The RAPIDS model's risk equations were re-estimated using a Least Absolute Shrinkage and Selection Operator (LASSO)-based regularization of features that spanned baseline data from the last two quarters of current time and interactions with age. These equations were supplemented with estimates for the impact of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitor classes of drugs as monotherapies and their combinations with metformin based on newer trial data and comprehensive meta-analyses. The probabilistic RAPIDS 2.0 model was calibrated (N = 25 000) and validated (N = 263 816) using electronic medical records (EMR) data between 2008 and 2021 from a national network of US healthcare organizations. The EMR-based cohort had a mean age of 61 years at baseline, with 50% women, 70% non-Hispanic White individuals and 20% non-Hispanic Black individuals, and was followed for 17.5 quarters (range: 3-50). The final RAPIDS 2.0 risk engine accurately predicted the long-term trajectories of all nine biomarkers and nine outcomes in the hold-out validation sample. Similar accuracies in predictions were observed in each of the 14 subgroups studied. The RAPIDS 2.0 model demonstrated valid long-term predictions of outcomes in individuals with T2DM in the United States as a function of dynamic sequences of treatment use patterns. This highlights its potential to project long-term comparative effectiveness between alternative sequences of glucose-lowering treatment uses in the United States.

Unified specification tests in partially linear quantile regression models

We propose specification tests for parametric quantile regression models versus semiparametric alternatives over a continuum of quantile levels. The test statistics are constructed as continuous functionals of a quantile-marked residual process. We show that using an orthogonal projection on the tangent space of nuisance parameters at each quantile index delivers unified asymptotic properties for tests based on different estimators. Consistency of the tests and asymptotic power under a sequence of local alternatives converging to the null at a parametric rate are also discussed. We propose a simple multiplier bootstrap procedure to carry out the tests, whose nominal levels are well approximated in our simulation study for modest sample sizes.

Mitigation of Performance Degradation of PEM Water Electrolyzers by Power Distribution Control of Fluctuating Renewable Energy

Introduction Hydrogen production by water electrolysis using renewable energy such as wind and solar power generation (i.e., green hydrogen production) has attracted considerable attention as a key technology towards decarbonization. Proton exchange membrane (PEM) water electrolyzers are often used in combination with renewable energy source since they show fast response to input power fluctuation. However, lifetime of PEM electrolyzer needs to be improved for reducing hydrogen production cost. Recently we reported a durability analysis of PEM electrolyzers under wind power voltage fluctuations, where the reversible and irreversible voltage losses were analyzed in terms of gas bubble transport and catalyst degradation [1]. We also developed a novel control strategy called the power distribution control (PDC) that controls the power converters so that the input fluctuating power is decomposed to several fluctuating patterns that less degrade the electrolyzers than the input pattern [2]. The purpose of this study is to validate the effect of the PDC on mitigation of performance degradation of PEM electrolyzers under wind power fluctuations. Experimental method A membrane electrode assembly (MEA) with an active area of 1 cm2 was prepared using Nafion 117 membrane, IrO2 anode catalyst and Pt/KB cathode catalyst. The catalyst loading for anode and cathode was 0.5 mg IrO2/cm2 and 0.3 mg Pt/cm2, respectively. A PEM water electrolysis cell was prepared by assembling the MEA into a cell holder. The cell temperature was kept at 80°C during the durability test.Figure 1a) and 1b) show a schematic system diagram for performing the PDC and the two voltage fluctuation patterns (A and B) used for the durability test, respectively. As in our previous study [1], actual 24-h voltage fluctuation of wind power turbine was used as the primary data. The pattern A was prepared from the primary data by (i) scaling down the maximum voltage by 1/100 and setting the minimum voltage higher than the standard potential of water electrolysis and (ii) accelerating the time scale by 5 times. The pattern B was prepared by applying the PDC, that is, converting the pattern A into an alternative sequence of a high-operating rate pattern and a low-operating rate pattern as described in Ref. [2]. Here we set the average voltage of the high-operating rate pattern (~2.4 V) and the low-operating rate pattern (~1.7 V) as the same value with the voltage of the pattern A (~2.05 V) for each time, ensuring that we model the situation in which the input fluctuating power is distributed between two series of electrolyzers as shown in Fig. 1a). We performed 240-h durability tests and analyzed performance degradation of the PEM cell for the pattern A and B, respectively. Results and Discussion Figure 2 summarizes the performance degradation of the PEM cell during the 240-h durability test. The cell current density at the cell voltage of 2.1 V showed a steep decrease during the initial ~30 h for both pattern A and B. For 30 – 240 h, the current density continuously decreased for the pattern A (−0.68 mAcm-2/h), while no distinguishable decrease was observed for the pattern B (+0.06 mAcm-2/h). Therefore we successfully demonstrated that performance degradation of the PEM electrolyzers can be effectively suppressed by the PDC when using actual wind power voltage fluctuation as the input power.To further investigate the performance degradation behavior, the increase in overpotential components of the PEM cell was analyzed. Figure 2b) shows the comparison of overpotential components before and after the 240-h test. For the pattern A, the diffusion overpotential (E diff) showed a significant increase after the test for the current density higher than 1.0 mAcm-2. In contrast, for the pattern B, increase in E diff was suppressed and confirmed only for > 1.4 Acm-2. Increase in the activation overpotential (E act) was small compared to increase in E diff for both pattern A and B. Furthermore, we confirmed that the performance degradation confirmed in this study was reversible, that is, the current density was almost recovered within 24-h rest time after the test. These results are consistent with our previous study [1] in that the reversible degradation is related to gas bubble transport, that is, the increase in E diff. Therefore it was shown that the PDC suppresses reversible degradation, which is important for mitigating irreversible degradation during long-term operation. Our results demonstrate that PDC is a promising technique for improving lifetime of PEM electrolyzers operating under fluctuating renewable energy.

μ-Opioid receptor transcriptional variants in the murine forebrain and spinal cord

Oprm1, the gene encoding the μ-opioid receptor, has multiple reported transcripts, with a variable 3′ region and many alternative sequences encoding the C-terminus of the protein. The functional implications of this variability remain mostly unexplored, though a recurring notion is that it could be exploited by developing selective ligands with improved clinical profiles. Here, we comprehensively examined Oprm1 transcriptional variants in the murine central nervous system, using long-read RNAseq as well as spatial and single-cell transcriptomics. The results were validated with RNAscope in situ hybridization. We found a mismatch between transcripts annotated in the mouse genome (GRCm38/mm10) and the RNA-seq results. Sequencing data indicated that the primary Oprm1 transcript has a 3′ terminus located on chr10:6,860,027, which is ∼ 9.5 kilobases downstream of the longest annotated exon 4 end. Long-read sequencing confirmed that the final Oprm1 exon included a 10.2 kilobase long 3′ untranslated region, and the presence of the long variant was unambiguously confirmed using RNAscope in situ hybridization in the thalamus, striatum, cortex and spinal cord. Conversely, expression of the Oprm1 reference transcript or alternative transcripts of the Oprm1 gene was absent or close to the detection limit. Thus, the primary transcript of the Oprm1 mouse gene is a variant with a long 3′ untranslated region, which is homologous to the human OPRM1 primary transcript and encodes the same conserved C-terminal amino acid sequence.

Blended Genome Exome (BGE) as a Cost Efficient Alternative to Deep Whole Genomes or Arrays.

Genomic scientists have long been promised cheaper DNA sequencing, but deep whole genomes are still costly, especially when considered for large cohorts in population-level studies. More affordable options include microarrays + imputation, whole exome sequencing (WES), or low-pass whole genome sequencing (WGS) + imputation. WES + array + imputation has recently been shown to yield 99% of association signals detected by WGS. However, a method free from ascertainment biases of arrays or the need for merging different data types that still benefits from deeper exome coverage to enhance novel coding variant detection does not exist. We developed a new, combined, "Blended Genome Exome" (BGE) in which a whole genome library is generated, an aliquot of that genome is amplified by PCR, the exome regions are selected and enriched, and the genome and exome libraries are combined back into a single tube for sequencing (33% exome, 67% genome). This creates a single CRAM with a low-coverage whole genome (2-3x) combined with a higher coverage exome (30-40x). This BGE can be used for imputing common variants throughout the genome as well as for calling rare coding variants. We tested this new method and observed >99% r 2 concordance between imputed BGE data and existing 30x WGS data for exome and genome variants. BGE can serve as a useful and cost-efficient alternative sequencing product for genomic researchers, requiring ten-fold less sequencing compared to 30x WGS without the need for complicated harmonization of array and sequencing data.

Investigating cold tolerance mechanisms in rice seedlings: Alternative splicing, promoter analysis, and their applications for marker development

Cold stress harms rice seedlings, causing yield reduction. Enhancing cold tolerance at the seedling stage is crucial for rice breeding. OsFH10, OsFER1, ONAC045, and OsProT were selected to study gene expression including alternative splicing and promoter sequence analysis in rice seedlings. Under cold stress, the four genes exhibited alternative splicing showing intron retention isoforms, and displayed a consistent pattern of upregulation in a group of cold-tolerant varieties, while no isoforms were presented in a group of sensitive varieties. These intron retention isoforms might play a role in facilitating improved cold adaptation in rice seedlings. Promoter sequence analysis revealed polymorphisms of Single nucleotide polymorphisms (SNPs) or Insertions and Deletions (InDels) in ONAC045 and OsProT that distinguished cold-tolerant from cold-sensitive varieties. ONAC045 SNP and OsProT InDel markers were developed and validated using 159 rice lines. These markers were associated with cold tolerance (P < 0.05) and practical to use with general agarose gel. The ONAC045 marker showed high efficacy in predicting tolerance in rice germplasm seedlings, achieving an accuracy of 43.8%. Furthermore, the OsProT marker exhibited greater sensitivity towards cold-tolerant indica seedlings. Both markers have a wide distribution in all rice subspecies. Our findings elucidate the cold response mechanisms and provide insights into potential application in developing cold-tolerant indica rice varieties.

Optimization of Selection Suppliers for Rice Raw Material Using AHP (Analytical Hierarchy Processes) and TOPSIS (Technique for Order Preference by Similarity to Ideal Solution) Methods in CV Gembira

CV Gembira is engaged in the production of Rice Mill with the trademark Osing Rice, and has 3 variants, namely Osing Super, Osing Premium and Osing Gold. Problems CV Gembira one of them is the delay in the delivery of rice raw materials carried out by supplier and also the quality of goods that do not meet the criteria. The AHP method is the preferred method. There are several reasons, namely, AHP provides a hierarchical representation of a problem that is useful in assisting decision making. The selection of the TOPSIS method as an auxiliary method is based on simple logic and has the farthest distance to the negative ideal solution. After performing calculations using the AHP and TOPSIS methods, alternative sequence results are obtained supplier the best that can be used by CV Gembira with a preference value of 0.6249 is owned by UD Bintang Timur.

Single-cell mitochondrial sequencing reveals low-frequency mitochondrial mutations in naturally aging mice.

Mitochondria play a crucial role in numerous biological processes; however, limited methods and research have focused on revealing mitochondrial heterogeneity at the single-cell level. In this study, we optimized the DNBelab C4 single-cell ATAC (assay for transposase-accessible chromatin) sequencing workflow for single-cell mitochondrial sequencing (C4_mtscATAC-seq). We validated the effectiveness of our C4_mtscATAC-seq protocol by sequencing the HEK-293T cell line with two biological replicates, successfully capturing both mitochondrial content (~68% of total sequencing data) and open chromatin status simultaneously. Subsequently, we applied C4_mtscATAC-seq to investigate two mouse tissues, spleen and bone marrow, obtained from two mice aged 2 months and two mice aged 23 months. Our findings revealed higher mitochondrial DNA (mtDNA) content in young tissues compared to more variable mitochondrial content in aged tissues, consistent with higher activity scores of nuclear genes associated with mitochondrial replication and transcription in young tissues. We detected a total of 22, 15, and 21 mtDNA mutations in the young spleen, aged spleen, and bone marrow, respectively, with most variant allele frequencies (VAF) below 1%. Moreover, we observed a higher number of mtDNA mutations with higher VAF in aged tissues compared to young tissues. Importantly, we identified three mtDNA variations (m.9821A>T, m.15219T>C, and m.15984C>T) with the highest VAF in both aged spleen and aged bone marrow. By comparing cells with and without these mtDNA variations, we analyzed differential open chromatin status to identify potential genes associated with these mtDNA variations, including transcription factors such as KLF15 and NRF1. Our study presents an alternative single-cell mitochondrial sequencing method and provides crude insights into age-related single-cell mitochondrial variations.

Outcomes of advanced/metastatic breast cancer (aMBC) treated with BRIA-IMT, an allogeneic whole cell immunotherapy.

1022 Background: The Bria-IMT regimen is a combination immunotherapy using an allogeneic whole cell cancer vaccine combined with checkpoint inhibitors (CPIs). Intradermally administered irradiated SV-BR-1-GM breast cancer cells secrete GM-CSF and present tumor associated antigens (TAAs) on HLA-I and –II molecules to directly stimulate anti-tumor immunity. Anti-PD1 CPI further stimulates T-cells and synergizes with SV-BR-1-GM. Here we report the results of the phase 1/2 trial (NCT03328026) of Bria-IMT in metastatic/advanced breast cancer evaluating sequencing of SV-BR-1-GM inoculation and CPI. Methods: Analysis of the phase 1 with expansion phase 2 cohort randomized by sequence using SV-BR-1-GM, checkpoint inhibitor (pembrolizumab or retifanlimab), low dose cyclophosphamide (Day –2) and post-dose local pegylated interferon α, with cycles every 3 weeks. In the 1:1 randomized cohort, CPI is either dosed at C1 prior to SV-BR-1-GM (original sequence) or delayed to C2 post-SV-BR-1-GM (alternative sequence). Cancer-associated macrophage-like cells (CAMLs) and circulating tumor cells (CTCs) were monitored as biomarkers. Results: A total of 54 patients were dosed: 11 with pembrolizumab, 44 with retifanlimab (1 patient received pembrolizumab and later retifanlimab). Median age=61 (38-81); Median prior regimen=6 (2-13); 72% ER+/PR+/HER2-; 6% HER2+ and 22% triple negative. Bria-IMT regimen was well tolerated with only 9% drop-out rate due to AE. AEs related to IPs were seen in 74% of patients; the majority (91%) being grade 1-2, and few (1.7%) grade 4 cases including pulmonary embolism, dehydration and increased lipase. Among 30 patients with post-dose CAML/CTC data and evaluable outcome, CAML count &lt;5 associates with disease control (p=0.06, Chi square test). Patients who developed DTH to SV-BR-1-GM had significantly better PFS and higher OS. Patients treated with phase III formulation had an increase in PFS. Quality of life improvement correlates with disease outcome and survival. Among the patients treated with the phase III formulation of SV-BR-1-GM (n=23 with evaluable outcomes), objective response rate (ORR) is 13% and disease control rate (DCR) is 61%, with median PFS and OS are 4.1 and 13.3 months, respectively. In the randomized portion, the original sequence cohort had higher DCR (43% vs 36%) and OS (P=0.08, HR 0.30, 95%CI 0.08-1.17) compared to the alternative sequence cohort. Conclusions: BRIA-IMT has shown a favorable safety profile while providing benefits to heavily treated aMBC patients. Superior outcomes and survival were seen in patients treated with the phase III formulation and regimen now being used in the ongoing Ph3 trial, confirming the improvement in efficacy of the novel regimen. The results from this randomized phase 2 study informed the study design of the ongoing Ph3 trial comparing BRIA-IMT to standard of care physician choice treatments (NCT06072612). Clinical trial information: NCT03328026 .

Phylogenetic analysis of a novel Hepatozoon species (Hepatozoon sp. SK3) and an additional yet unknown Hepatozoon species (Hepatozoon sp. BV2) besides H. erhardovae in small rodents from Central Europe.

Hepatozoon spp. are tick-borne apicomplexan parasites of terrestrial vertebrates that occur worldwide. Tissue samples from small rodents and their parasitizing fleas were sampled for molecular detection and phylogenetic analysis of Hepatozoon-specific 18S rRNA gene region. After alignment and tree inference the Hepatozoon-sequences retrieved from a yellow-necked mouse (Apodemus flavicollis) placed into a strongly supported single clade demonstrating the presence of a novel species, designated Hepatozoon sp. SK3. The mode of transmission of Hepatozoon sp. SK3 is yet unknown. It is important to note that this isolate may be identical with the previously morphologically described Hepatozoon sylvatici infecting Apodemus spp.; however, no sequences are available for comparison. Furthermore, the previously reported variants Hepatozoon sp. BV1/SK1 and BV2/SK2 were detected in bank voles (Clethrionomys glareolus). It has been suggested that these variants should be identified as Hepatozoon erhardovae leading to the assumption that BV1 and BV2 are paralogous 18S rRNA gene loci of this species. Evidence has also been presented that fleas are vectors of H. erhardovae. In this study, we show with high significance that only the Hepatozoon sp. BV1 variant, but not BV2, infects the studied flea species Ctenophthalmus agyrtes, Ctenophthalmus assimilis, and Megabothris turbidus (p < 0.001). This finding suggests that Hepatozoon sp. BV2 represents an additional species besides H. erhardovae (= Hepatozoon sp. BV1), for which alternative arthropod vectors or non-vectorial modes of transmission remain to be identified. Future studies using alternative molecular markers or genome sequencing are required to demonstrate that BV1/SK1 and BV2/SK2 are different Hepatozoon species.

Changes in non-small cell lung cancer (NSCLC) next-generation sequencing (NGS) rates after electronic health record (EHR) integration using large-scale, multi-institutional, real-world data.

e13619 Background: NSCLC treatment guidelines recommend comprehensive NGS testing to detect genomic alterations and gene expression in key biomarkers that are relevant in diagnosis, therapy selection, prognosis, and clinical trials. While 70% of patients with NSCLC will have biomarker alterations related to therapeutic options, a large minority of patients still do not receive biomarker testing. Clinical workflow challenges outside the EHR ecosystem, like paper requisitions and faxed results, have been cited as barriers to adoption. To reduce sequencing barriers, Tempus deploys NGS through direct result EHR connection. To evaluate whether integrating comprehensive NGS ordering and resulting into the EHR would improve testing rates, we retrospectively analyzed NSCLC NGS orders from 29 clinical networks which represent over 1500 medical oncologists, before and after EHR integration. Methods: Clinical networks that partnered with Tempus to perform an NGS EHR integration were identified. Only networks with at least 6 months of pre- and post-integration unique patient NGS orders were included. De-identified patient information from these sites were obtained from the Tempus laboratory information management system. NSCLC diagnosis was determined through ICD9/10 codes. NGS tests ordered were limited to xT/xR (solid tumor DNA and RNA), xE (solid tumor whole exome), or xF (circulating tumor DNA). Aggregate unique patients with orders were summated on a per site basis. Descriptive statistics were used to characterize the findings. Results: From May 2019 to July 2023, 29 clinical cancer networks (48% academic medical center, 45% regional health system) that underwent a Tempus NGS EHR integration were identified. Of the 29 networks considered, 3 were excluded due to insufficient data. Of the evaluable 26 networks, Epic EHR was used in the majority (24 of 26). In aggregate, a total of 1825 NSCLC patients were sequenced pre-integration as compared to 2796 patients sequenced post-integration, representing a 53% increase. Academic medical centers experienced a higher increase versus regional health systems (65% v 48%). When examined on a per network basis, the median and mean increase in NSCLC patients sequenced were 49% and 118%, respectively. Conclusions: In this retrospective analysis, Tempus EHR integrations increased ordering of comprehensive NSCLC NGS by 53%. Despite study limitations such as the incomplete resolution into internal alternate sequencing workflows, this large-scale analysis provides further evidence that EHR-based workflow improvements reduce the barrier to appropriate sequencing.

Mitigation of Performance Degradation of PEM Water Electrolyzers by Power Distribution Control of Fluctuating Renewable Energy

Durability of a PEM electrolysis cell against voltage fluctuation prepared from actual wind power data was analyzed. Two fluctuation patterns were prepared; the pattern A prepared by scaling the wind power data and the pattern B prepared by applying the power distribution control (PDC), that is, converting the pattern A into an alternative sequence of a high-operating rate pattern and a low-operating rate pattern. During 240-h durability tests, the current density continuously decreased for the pattern A, while no distinguishable decrease was observed for the pattern B except the initial 30 h. It was found that the performance degradation is mostly reversible and attributed to increase in the diffusion overpotential consistently with the previous studies. Our results suggest that the PDC suppresses reversible degradation by avoiding gas stagnation at the anode surface, which is important for mitigating irreversible degradation during long-term operation.

Hybridization of woven kenaf and unidirectional glass fibre roving for unsaturated polyester composite

This is a study on the mechanical properties of kenaf/glass-reinforced polyester composites intended for use in structural profiles with a wall thickness by max. 6 mm. Mechanical properties such as tensile, compression, bending and interlaminar shear stress were investigated by comparing the hybrid variants with the pure fibreglass variant. According to the study, woven kenaf/unidirectional glass roving (WK/UG) alternate recorded the highest tensile properties among hybrid samples. It demonstrated a decrement of about 8.2% of the tensile strength (404.54 MPa) and 10.7% of tensile modulus (24.54 GPa) compared to conventional fibreglass samples. Alternating WK/UG samples demonstrated higher compressive strength (417.15 MPa) compared to other hybrid specimens, recording a slight decrease at 6.09% compared to pure fibreglass composites. The highest bending properties were also observed in hybrid alternate WK/UG samples among other hybrid laminates with only a decrement of 4.13% in modulus of rupture (456.33 MPa) and 1.9% in modulus of elasticity (14.49 GPa) when compared to the control specimen. The ILSS of hybrid composites 2WK/3UG/2WK (30.97 MPa) and WK/UG alternate (34.90 MPa) showed good agreement with the pure fibreglass (42.33 MPa) composites. Using SEM images, tensile fractured specimens were examined to comprehend composites’ failure mechanism and interfacial adhesion. Overall, woven kenaf/unidirectional glass roving alternate sequence is chosen as a potential alternative in developing structural profiles for moderate load-bearing structural applications. In contrast, 3WK/UG/3WK with a higher kenaf to glass ratio demonstrate potential in low load-bearing structural profile applications.Graphical abstract

Shipment lead time hedging and coordination in prefabricated construction supply chain

This paper aims to coordinate a shipment lead time hedging (SLTH) problem between a building contractor and a logistics provider in the prefabricated construction supply chain (PCSC). In the PCSC, untimely (early or late) delivery of prefabs can lead to project time and cost overruns. To mitigate this challenge, the building contractor requires the logistics provider to reduce the shipping time variability, which is termed the SLTH strategy. While this benefits the building contractor, it also puts more investment and operational pressures on the logistics provider. To solve this conflict, we introduce a coordination mechanism which involves two terms: an SLTH level related cost term is charged by the logistics provider to the building contractor, and a constant transfer term is adopted to fairly allocate the system surplus. Three decentralized models are investigated: i.e., two Stackelberg game models with alternative decision-making sequences and an equal power model. Further comparative analysis and numerical studies reveal that our proposed coordination mechanism increases the SLTH level and ensures a win–win situation. Moreover, some interesting managerial implications are derived.

Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.

Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95). Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.