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Cochlear implants are crucial for addressing severe-to-profound hearing loss, with the success of the procedure requiring careful electrode placement. This scoping review synthesizes the findings from 125 studies examining the factors influencing insertion forces (IFs) and intracochlear pressure (IP), which are crucial for optimizing implantation techniques and enhancing patient outcomes. The review highlights the impact of variables, including insertion depth, speed, and the use of robotic assistance on IFs and IP. Results indicate that higher insertion speeds generally increase IFs and IP in artificial models, a pattern not consistently observed in cadaveric studies due to variations in methodology and sample size. The study also explores the observed minimal impact of robotic assistance on reducing IFs compared to manual methods. Importantly, this review underscores the need for a standardized approach in cochlear implant research to address inconsistencies and improve clinical practices aimed at preserving hearing during implantation.

New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed a sequence-resolved benchmark set for identification of both false-negative and false-positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12,745 isolated, sequence-resolved insertion (7,281) and deletion (5,464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5,262 insertions and 4,095 deletions supported by ≥1 diploid assembly. We demonstrate that the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked- and long-read sequencing and optical mapping. Detection of structural variants in the human genome is facilitated by a benchmark set of large deletions and insertions.

In-vacuum insertion devices have their magnets positioned just a few millimeters from the electron beam orbit. Due to this proximity, the emitted radiation spectrum is highly sensitive to misalignments of the device’s magnetic center. Such misalignments can lead to photon flux losses, spectral shifts toward lower energies, and harmonic bandwidth broadening. This work presents the application of a spectrum-based alignment method to one of the new SIRIUS insertion devices, aiming to optimize its spectral performance at the beamline.

Background Klebsiella pneumoniae is a leading cause of intractable hospital-acquired multidrug-resistant infections and carbapenemase-producing K. pneumoniae (CP Kp ) are particularly feared. Most of the clinical isolates produce capsule as a major virulence factor. Recombination events at the capsule locus are frequent and responsible for capsule diversity within Klebsiella spp . Capsule diversity may also occur within clonal bacterial populations generating differences in colony aspect. However, little is known about this phenomenon of phenotypic variation in CP Kp and its consequences. Results Here, we explored the genetic causes of in vitro switching from capsulated, mucoid to non-mucoid, non-capsulated phenotype in eight clinical CP Kp isolates. We compared capsulated, mucoid colony variants with one of their non-capsulated, non-mucoid isogenic variant. The two colony variants were distinguished by their appearance on solid medium. Whole genome comparison was used to infer mutations causing phenotypic differences. The frequency of phenotypic switch was strain-dependent and increased along with colony development on plate. We observed, for 72 non-capsulated variants that the loss of the mucoid phenotype correlates with capsule deficiency and diverse genetic events, including transposition of insertion sequences or point mutations, affecting genes belonging to the capsule operon. Reduced or loss of capsular production was associated with various in vitro phenotypic changes, affecting susceptibility to carbapenem but not to colistin, in vitro biofilm formation and autoaggregation. Conclusions The different impact of the phenotypic variation among the eight isolates in terms of capsule content, biofilm production and carbapenem susceptibility suggested heterogeneous selective advantage for capsular loss according to the strain and the mutation. Based on our results, we believe that attention should be paid in the phenotypic characterization of CP Kp clinical isolates, particularly of traits related to virulence and carbapenem resistance.

S1 Table.DOC figshare Download List of Primers and cycling conditions of Alu loci studied (DOC) S1 Table. List of Primers and cycling conditions of Alu loci studied https://doi.org/10.1371/journal.pone.0162055.s001 (DOC) 1.

Large-scale high-energy batteries with electrode materials made from the Earth-abundant elements are needed to achieve sustainable energy development. On the basis of material abundance, rechargeable sodium batteries with iron- and manganese-based positive electrode materials are the ideal candidates for large-scale batteries. In this review, iron- and manganese-based electrode materials, oxides, phosphates, fluorides, etc, as positive electrodes for rechargeable sodium batteries are reviewed. Iron and manganese compounds with sodium ions provide high structural flexibility. Two layered polymorphs, O3- and P2-type layered structures, show different electrode performance in Na cells related to the different phase transition and sodium migration processes on sodium extraction/insertion. Similar to layered oxides, iron/manganese phosphates and pyrophosphates also provide the different framework structures, which are used as sodium insertion host materials. Electrode performance and reaction mechanisms of the iron- and manganese-based electrode materials in Na cells are described and the similarities and differences with lithium counterparts are also discussed. Together with these results, the possibility of the high-energy battery system with electrode materials made from only Earth-abundant elements is reviewed.

HighlightsFactors affecting microneedle insertion into skin are reviewed.The use of artificial and computational skin models for the simulation of needle insertion is summarized.Skin structures and models, as well as mechanical analyses, used to determine transdermal microneedle ability to insert into skin are highlighted in the review.Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human stratum corneum (~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.

A thorough understanding of needle–tissue interaction mechanics is necessary to optimize needle design, achieve robotically needle steering, and establish surgical simulation system. It is obvious that the interaction is influenced by numerous variable parameters, which are divided into three categories: needle geometries, insertion methods, and tissue characteristics. A series of experiments are performed to explore the effect of influence factors (material samples n=5 for each factor) on the insertion force. Data were collected from different biological tissues and a special tissue-equivalent phantom with similar mechanical properties, using a 1-DOF mechanical testing system instrumented with a 6-DOF force/torque (F/T) sensor. The experimental results indicate that three basic phases (deformation, insertion, and extraction phase) are existent during needle penetration. Needle diameter (0.7–3.2mm), needle tip (blunt, diamond, conical, and beveled) and bevel angle (10–85°) are turned out to have a great influence on insertion force, so do the insertion velocity (0.5–10mm/s), drive mode (robot-assisted and hand-held), and the insertion process (interrupted and continuous). Different tissues such as skin, muscle, fat, liver capsule and vessel are proved to generate various force cures, which can contribute to the judgement of the needle position and provide efficient insertion strategy.

Background Chimeric Antigen Receptor (CAR) T cells are now standard of care (SOC) for some patients with B cell and plasma cell malignancies and could disrupt the therapeutic landscape of solid tumors. However, access to CAR-T cells is not adequate to meet clinical needs, in part due to high cost and long lead times for manufacturing clinical grade virus. Non-viral site directed CAR integration can be accomplished using CRISPR/Cas9 and double-stranded DNA (dsDNA) or single-stranded DNA (ssDNA) via homology-directed repair (HDR), however yields with this approach have been limiting for clinical application (dsDNA) or access to large yields sufficient to meet the manufacturing demands outside early phase clinical trials is limited (ssDNA). Methods We applied homology-independent targeted insertion (HITI) or HDR using CRISPR/Cas9 and nanoplasmid DNA to insert an anti-GD2 CAR into the T cell receptor alpha constant (TRAC) locus and compared both targeted insertion strategies in our system. Next, we optimized post-HITI CRISPR EnrichMENT (CEMENT) to seamlessly integrate it into a 14-day process and compared our knock-in with viral transduced anti-GD2 CAR-T cells. Finally, we explored the off-target genomic toxicity of our genomic engineering approach. Results Here, we show that site directed CAR integration utilizing nanoplasmid DNA delivered via HITI provides high cell yields and highly functional cells. CEMENT enriched CAR T cells to approximately 80% purity, resulting in therapeutically relevant dose ranges of 5.5 × 10 8 –3.6 × 10 9 CAR + T cells. CRISPR knock-in CAR-T cells were functionally comparable with viral transduced anti-GD2 CAR-T cells and did not show any evidence of off-target genomic toxicity. Conclusions Our work provides a novel platform to perform guided CAR insertion into primary human T-cells using nanoplasmid DNA and holds the potential to increase access to CAR-T cell therapies.

PurposeDespite proven biomechanical superiority and resultant superior clinical outcomes, pedicle instrumentation in cervical spine is not widely practiced due to technical difficulties, steep learning curve, and possible potential catastrophic complications due to screw misplacement. This study was undertaken with the purpose to evaluate the feasibility, accuracy, and complications of cervical pedicle screw instrumentation solely using O-arm-based 3D navigation technology.MethodsProspectively maintained data from a single-surgeon case series were retrospectively analyzed. All the patients had undergone cervical pedicle instrumentation under O-arm 3D navigation. Screw placement accuracy was analyzed and compared among different vertebral levels and also between different patient groups.ResultsA total of 241 cervical pedicle screws were inserted in 44 patients. Out of the 241 screws, 197 (81.74%) were inserted at the level of C3–C6 vertebrae with nearly equal distribution among the 4 vertebrae, followed by 32 (13.28%) and 12 (4.98%) screws at C2 and C7 vertebrae, respectively. After the analysis of screw placement as per Gertzbein classification, the overall breach rates were found to be 7.05% (17 screws) with 52.94% (10 screws) Grade I, 47.06% (7 screws) Grade II, and nil Grade III screw breaches.ConclusionThe use of O-arm-based intra-operative 3D scans for navigation can make cervical pedicle screw placement reliable. High accuracy and better intra-operative control can increase surgeon’s confidence in using cervical pedicle instrumentation on more regular basis.Graphical abstractThese slides can be retrieved under Electronic Supplementary Material.