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BackgroundRoot cause analyses of surgical complications are of high importance to ensure surgical quality, but specific details on technical causes often remain unclear. Identifying subclinical intraoperative incidents attributable to technical errors is essential for developing rescue mechanisms to prevent adverse outcomes.ObjectiveDescriptive study to characterise intraoperative technical error-event patterns in successful laparoscopic procedures.MethodsEvents (injuries) identified during prior blinded analyses of 54 unedited recordings of bariatric laparoscopic procedures were subjected to a secondary review to determine the presumed underlying error mechanism. The recordings were obtained from one university-based bariatric collaborative programme, and represented consultant, fellow and shared trainee cases.ResultsSixty-six events were identified in 38 recordings, while 16 videos showed no events. In 25 (66%) of the videos that showed events, additional measures such as haemostasis or suture repair were required. Common identified events were minor bleeding (n=39, 59%), thermal injury to non-target tissue (n=7, 11%), serosal tears (n=6, 9%). Common error mechanisms were ‘inadequate use of force/distance (too much)’ (n=20, 30%) and ‘inadequate visualisation’ during grasping/dissecting (n=6, 9%), ‘inadequate use of force/distance (too much)’ using an energy device (n=6, 9%), or during suturing (n=6, 9%). All events were recognised intraoperatively.ConclusionsAnalysis of successful operations allowed the identification of numerous error-event sequences. Reviewing injury mechanisms can enhance surgeons’ understanding of relevant errors. This error awareness may aid surgeons in preparing for cases, help avoid errors and mitigate their consequences. Thus, this approach may impact future surgical education and quality initiatives aimed at reducing surgical risks.

To the Editor: Chan et al. (April 18 issue) 1 found discrepancies between survey-derived procedure times used by the Relative Value Scale Update Committee (RUC) of the American Medical Association and benchmark times in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) data set. A major confounder, however, was not explored: secondary procedures. Whereas the RUC’s estimates of procedure times are based on single procedures, NSQIP times often reflect multiple procedures performed during an operation. 2,3 Fair comparisons must consider these differences. We received permission from the NSQIP to analyze the effect of secondary procedures on procedure times, using . . .

Thermoresponsive polymers, such as poly(N-isopropyl acrylamide) (PNIPAM), have been identified and used as cell culture substrates, taking advantage of the polymer's lower critical solution temperature (LCST) to mechanically harvest cells. This technology bypasses the use of biochemical enzymes that cleave important cell-cell and cell-matrix interactions. In this study, the process of electrospinning is used to fabricate and characterize aligned PNIPAM nanofiber scaffolds that are biocompatible and thermoresponsive. Nanofiber scaffolds produced by electrospinning possess a 3D architecture that mimics native extracellular matrix, providing physical and chemical cues to drive cell function and phenotype. We present a factorial design of experiments (DOE) approach to systematically determine the effects of different electrospinning process parameters on PNIPAM nanofiber diameter and alignment. Results show that high molecular weight PNIPAM can be successfully electrospun into both random and uniaxially aligned nanofiber mats with similar fiber diameters by simply altering the speed of the rotating mandrel collector from 10,000 to 33,000 RPM. PNIPAM nanofibers were crosslinked with OpePOSS, which was verified using FTIR. The mechanical properties of the scaffolds were characterized using dynamic mechanical analysis, revealing an order of magnitude difference in storage modulus (MPa) between cured and uncured samples. In summary, cross-linked PNIPAM nanofiber scaffolds were determined to be stable in aqueous culture, biocompatible, and thermoresponsive, enabling their use in diverse cell culture applications.

The acidification of water in mining areas is a global environmental issue primarily catalyzed by sulfur-oxidizing bacteria (SOB). Little is known about microbial sulfur cycling in circumneutral pH mine tailing impoundment waters. Here we investigate biological sulfur oxidation over four years in a mine tailings impoundment water cap, integrating aqueous sulfur geochemistry, genome-resolved metagenomics and metatranscriptomics. The microbial community is consistently dominated by neutrophilic, chemolithoautotrophic SOB (relative abundances of ~76% in 2015, ~55% in 2016/2017 and ~60% in 2018). Results reveal two SOB strategies alternately dominate across the four years, influencing acid generation and sulfur speciation. Under oxic conditions, novel Halothiobacillus drive lower pH conditions (as low as 4.3) and lower [S 2 O 3 2− ] via the complete Sox pathway coupled to O 2 . Under anoxic conditions, Thiobacillus spp. dominate in activity, via the incomplete Sox and rDSR pathways coupled to NO 3 − , resulting in higher [S 2 O 3 2− ] and no net significant acidity generation. This study provides genomic evidence explaining acidity generation and thiosulfate accumulation patterns in a circumneutral mine tailing impoundment and has significant environmental applications in preventing the discharge of sulfur compounds that can impact downstream environments. These insights illuminate opportunities for in situ biotreatment of reduced sulfur compounds and prediction of acidification events using gene-based monitoring and in situ RNA detection. Microbial genomics is a widely under-utilized tool in mining in understanding water quality drivers. Here the authors show early acid generation and thiosulfate concentrations are driven by O2 dependent microbial sulfur oxidizing bacterial niches in a mine tailings impoundment

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

The stability and resilience of the Earth system and human well-being are inseparably linked 1 – 3 , yet their interdependencies are generally under-recognized; consequently, they are often treated independently 4 , 5 . Here, we use modelling and literature assessment to quantify safe and just Earth system boundaries (ESBs) for climate, the biosphere, water and nutrient cycles, and aerosols at global and subglobal scales. We propose ESBs for maintaining the resilience and stability of the Earth system (safe ESBs) and minimizing exposure to significant harm to humans from Earth system change (a necessary but not sufficient condition for justice) 4 . The stricter of the safe or just boundaries sets the integrated safe and just ESB. Our findings show that justice considerations constrain the integrated ESBs more than safety considerations for climate and atmospheric aerosol loading. Seven of eight globally quantified safe and just ESBs and at least two regional safe and just ESBs in over half of global land area are already exceeded. We propose that our assessment provides a quantitative foundation for safeguarding the global commons for all people now and into the future. We find that justice considerations constrain the integrated Earth system boundaries more than safety considerations for climate and atmospheric aerosol loading, and our assessment provides a foundation for safeguarding the global commons for all people.

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1 -amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum. Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.

Background Establishing a comprehensive characterization of the regulatory landscapes of cattle tissues facilitates a better understanding of the biological mechanisms responsible for condition-dependent phenotypes that drive tissue-specific gene regulation, developmental processes, and responses to environmental or physiological cues. This can be achieved through the characterization of gene expression, transcript usage and open chromatin accessibility. While much of this work has been done in human and biomedical model species, there is a lack of research in cattle that jointly characterizes chromatin accessibility and transcript usage alongside gene expression to define tissue-specific regulatory landscapes in cattle. Samples of prefrontal cortex (PFC), liver (L), and gracilis skeletal muscle (SM) were collected from four 3-month-old Angus steers and subjected to ATAC-seq and RNA-seq analyses. Differential gene expression (DGE) and transcript usage (DTU) were quantified across the tissues and evaluated in PFC-L, PFC-SM, and L-SM pairwise comparisons. Results In total, 4,840, 4,151, and 3,663 genes were identified as differentially expressed, while 209, 236, and 154 genes exhibited differential transcript usage in PFC-L, PFC-SM, and L-SM comparisons, respectively. The genes CLTA , SLC25A3 and P2RX5 were highlighted for DTU between tissues, and further comparison of predicted protein sequences identified structural differences between CLTA and P2RX5 isoforms suggesting tissue-specific roles. Differential chromatin accessibility analysis revealed 2,576, 1,820, and 2,960 differential peaks in promoter regions across the same pairwise tissue comparisons. Functional enrichment revealed that PFC regulatory genes were associated with synaptic formation, myelination, and neurodevelopment, L genes with homeostatic regulation and lipid metabolism, and SM genes with muscle differentiation, myonuclear addition, and hypertrophy. These patterns aligned with ATF, HNF, and MEF2 motif enrichment in PFC, L, and SM promoter peaks, respectively. Furthermore, the integration of ATAC-seq and RNA-seq results revealed 62 genes in PFC, 93 genes in L, and 59 genes in SM as potential tissue-specific regulatory genes. Conclusions These findings provide insight into the complex regulatory mechanisms governing biological processes in the PFC, L, and SM of young Angus steers. This work integrates chromatin accessibility, transcript usage, and gene expression across multiple physiologically important cattle tissues, providing a comprehensive view of tissue-specific regulatory landscapes and generating a resource to support future studies in cattle genomics.

Y chromosomes across diverse species convergently evolve a gene-poor, heterochromatic organization enriched for duplicated genes, LTR retrotransposons, and satellite DNA. Sexual antagonism and a loss of recombination play major roles in the degeneration of young Y chromosomes. However, the processes shaping the evolution of mature, already degenerated Y chromosomes are less well-understood. Because Y chromosomes evolve rapidly, comparisons between closely related species are particularly useful. We generated de novo long-read assemblies complemented with cytological validation to reveal Y chromosome organization in three closely related species of the Drosophila simulans complex, which diverged only 250,000 years ago and share >98% sequence identity. We find these Y chromosomes are divergent in their organization and repetitive DNA composition and discover new Y-linked gene families whose evolution is driven by both positive selection and gene conversion. These Y chromosomes are also enriched for large deletions, suggesting that the repair of double-strand breaks on Y chromosomes may be biased toward microhomology-mediated end joining over canonical non-homologous end-joining. We propose that this repair mechanism contributes to the convergent evolution of Y chromosome organization across organisms.

Humans have more than doubled the amount of reactive nitrogen (Nr) added to the biosphere, yet most of what is known about its accumulation and ecological effects is derived from studies of heavily populated regions. Nitrogen (N) stable isotope ratios (¹⁵N:¹⁴ N) in dated sediments from 25 remote Northern Hemisphere lakes show a coherent signal of an isotopically distinct source of N to ecosystems beginning in 1895 ± 10 years (±1 standard deviation). Initial shifts in N isotope composition recorded in lake sediments coincide with anthropogenic CO₂ emissions but accelerate with widespread industrial Nr production during the past half century. Although current atmospheric Nr deposition rates in remote regions are relatively low, anthropogenic N has probably influenced watershed N budgets across the Northern Hemisphere for over a century.