[Artificial Intelligence in Head and Neck Surgery: Potentials, Challenges, and Ethical Considerations]. / Künstliche Intelligenz in der Kopf-Hals-Chirurgie: Potenziale und ethische Überlegungen.

BACKGROUND: The growing prominence of Artificial Intelligence (AI) in medicine introduces both transformative possibilities and potential challenges. Our study focuses on the current status and perceptions of AI in Head and Neck Surgery (HNS), examining its utilization, benefits, ethical concerns, and protective measures. OBJECTIVES: The study aims to illuminate the existing landscape of AI in HNS in Germany. MATERIALS AND METHODS: Conducted through a questionnaire, key aspects include its current usage, potential applications (e.g., diagnosis, surgical planning), anticipated benefits (e.g., improved patient care ), and significant ethical concerns (e.g., miscalculations by AI, data privacy). RESULTS: The survey reveals limited AI adoption in HNS, with substantial potential for improvement. Ethical considerations, especially miscalculations by AI and data privacy, emerge as central issues. The survey emphasizes the crucial role of physician control and the need for legal oversight to address concerns related to AI integration. While AI's presence in HNS is modest, the study identifies opportunities for enhancement. Ethical guidelines and practitioner-centric control are vital for discussions surrounding AI integration. CONCLUSIONS: This research underscores the significance of ethical considerations and practitioner control in the context of AI in surgical practices. It highlights the demand for targeted training to empower practitioners in navigating the complexities of AI technologies in healthcare, ensuring responsible and patient-centric implementation.

Perfusion in Pedicled Skin Flaps: Initial Insights from Smartphone-Based Thermal Imaging Protocol.

OBJECTIVE: Successful outcomes in head and neck surgery rely on maintaining perfusion in pedicled skin flaps. Thermal imaging offers a noninvasive means to assess tissue perfusion, potentially aiding in predicting flap viability. This pilot study explores the utility of SBTI (smartphone-based thermal imaging) for predicting flap vitality and monitoring during surgery. METHODS: Thermal imaging was employed using the FLIR One System. An imaging protocol was established, defining points of interest (T1-T4) on pedicled skin flaps. Conducted over four months, the study integrated SBTI into reconstructive surgery for the face, head and neck defects post-tumor resections. SBTI's effectiveness was assessed with n = 11 pedicled flaps, capturing images at key stages and correlating them with clinical flap assessment. Thermal images were retrospectively graded by two surgeons, evaluating flap perfusion on a scale from 1 to 5, based on temperature differences (1 = ΔT < 2 °C, 2 = ΔT ≥ 2 °C, 3 = ΔT ≥ 4 °C, 4 = ΔT ≥ 6 °C, and 5 = ΔT ≥ 8 °C), with assessments averaged for consensus and compared with the clinical assessment control group. RESULTS: The study encountered challenges during implementation, leading to the exclusion of six patients. Patient data included 11 cases with n = 44 SBTI images. Intraoperative assessments consistently showed good perfusion. One postoperative dehiscence was noted, which retrospectively coincided with intraoperative SBTI grading, but not with clinical assessment. Statistical analysis indicated consistent outcomes following clinical and SBTI assessments. Thermal imaging accurately predicted flap viability, although it had limitations with small flaps. CONCLUSION: SBTI proved effective, inexpensive, and noninvasive for assessing tissue perfusion, showing promise for predicting flap viability and intraoperative monitoring in head and neck surgery.

Endoplasmic reticulum-plasma membrane contact gradients direct cell migration.

Directed cell migration is driven by the front-back polarization of intracellular signalling1-3. Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front2,4-6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7-9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum-plasma membrane (ER-PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER-PM contacts at the back provides the ER-resident PTP1B phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER-PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER-PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front-back ER-PM contact gradient. Together, our study suggests that the structural polarity mediated by ER-PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.

An intermediate Rb-E2F activity state safeguards proliferation commitment.

Tissue repair, immune defence and cancer progression rely on a vital cellular decision between quiescence and proliferation1,2. Mammalian cells proliferate by triggering a positive feedback mechanism3,4. The transcription factor E2F activates cyclin-dependent kinase 2 (CDK2), which in turn phosphorylates and inactivates the E2F inhibitor protein retinoblastoma (Rb). This action further increases E2F activity to express genes needed for proliferation. Given that positive feedback can inadvertently amplify small signals, understanding how cells keep this positive feedback in check remains a puzzle. Here we measured E2F and CDK2 signal changes in single cells and found that the positive feedback mechanism engages only late in G1 phase. Cells spend variable and often extended times in a reversible state of intermediate E2F activity before committing to proliferate. This intermediate E2F activity is proportional to the amount of phosphorylation of a conserved T373 residue in Rb that is mediated by CDK2 or CDK4/CDK6. Such T373-phosphorylated Rb remains bound on chromatin but dissociates from it once Rb is hyperphosphorylated at many sites, which fully activates E2F. The preferential initial phosphorylation of T373 can be explained by its relatively slower rate of dephosphorylation. Together, our study identifies a primed state of intermediate E2F activation whereby cells sense external and internal signals and decide whether to reverse and exit to quiescence or trigger the positive feedback mechanism that initiates cell proliferation.

A fast-acting lipid checkpoint in G1 prevents mitotic defects.

Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.

Composition and electronic structure of [Formula: see text]/[Formula: see text]/Al passivating carrier selective contacts on n-type silicon solar cells.

Carrier-selective and passivating SiO[Formula: see text]/TiO[Formula: see text] heterocontacts are an attractive alternative to conventional contacts due to their high efficiency potentials combined with relatively simple processing schemes. It is widely accepted that post deposition annealing is necessary to obtain high photovoltaic efficiencies, especially for full area aluminum metallized contacts. Despite some previous high-level electron microscopy studies, the picture of atomic-scale processes underlying this improvement seems to be incomplete. In this work, we apply nanoscale electron microscopy techniques to macroscopically well-characterized solar cells with SiO[Formula: see text]/TiO[Formula: see text]/Al rear contacts on n-type silicon. Macroscopically, annealed solar cells show a tremendous decrease of series resistance and improved interface passivation. Analyzing the microscopic composition and electronic structure of the contacts, we find that partial intermixing of the SiO[Formula: see text] and TiO[Formula: see text] layers occurs due to annealing, leading to an apparent thickness reduction of the passivating SiO[Formula: see text]. However, the electronic structure of the layers remains clearly distinct. Hence, we conclude that the key to obtain highly efficient SiO[Formula: see text]/TiO[Formula: see text]/Al contacts is to tailor the processing such that the excellent chemical interface passivation of a SiO[Formula: see text] layer is achieved for a layer thin enough to allow efficient tunneling through the layer. Furthermore, we discuss the impact of aluminum metallization on the above mentioned processes.

CDT1 inhibits CMG helicase in early S phase to separate origin licensing from DNA synthesis.

Human cells license tens of thousands of origins of replication in G1 and then must stop all licensing before DNA synthesis in S phase to prevent re-replication and genome instability that ensue when an origin is licensed on replicated DNA. However, the E3 ubiquitin ligase CRL4Cdt2 only starts to degrade the licensing factor CDT1 after origin firing, raising the question of how cells prevent re-replication before CDT1 is fully degraded. Here, using quantitative microscopy and in-vitro-reconstituted human DNA replication, we show that CDT1 inhibits DNA synthesis during an overlap period when CDT1 is still present after origin firing. CDT1 inhibits DNA synthesis by suppressing CMG helicase at replication forks, and DNA synthesis commences once CDT1 is degraded. Thus, in contrast to the prevailing model that human cells prevent re-replication by strictly separating licensing from firing, licensing and firing overlap, and cells instead separate licensing from DNA synthesis.

Ablation threshold of GaN films for ultrashort laser pulses and the role of threading dislocations as damage precursors.

The laser-induced ablation threshold of c-plane GaN films upon exposure to ultrashort laser pulses was investigated for different wavelengths from the IR to the UV range and pulse widths between 0.34 and 10 ps. The one-pulse ablation threshold ranges between 0.15 and 3 J/cm2 and shows an increase with the wavelength and the pulse width, except for deep UV pulses. Based on a rate equation model, we attribute this behavior to the efficiency of seed carrier generation by interband absorption. In addition, the multi-pulse ablation threshold was analyzed. Accumulation effects are more prominent in case of IR than with UV pulses and are closely linked to damage precursors. By a thorough structural investigation, we demonstrate that threading dislocations, especially those with a screw component, significantly contribute to laser damage, since they provide a variety of dispersed states within the band gap.

Structural mechanism for bidirectional actin cross-linking by T-plastin.

To orchestrate cell mechanics, trafficking, and motility, cytoskeletal filaments must assemble into higher-order networks whose local subcellular architecture and composition specify their functions. Cross-linking proteins bridge filaments at the nanoscale to control a network's µm-scale geometry, thereby conferring its mechanical properties and functional dynamics. While these interfilament linkages are key determinants of cytoskeletal function, their structural mechanisms remain poorly understood. Plastins/fimbrins are an evolutionarily ancient family of tandem calponin-homology domain (CHD) proteins required to construct multiple classes of actin networks, which feature diverse geometries specialized to power cytokinesis, microvilli and stereocilia biogenesis, and persistent cell migration. Here, we focus on the structural basis of actin network assembly by human T-plastin, a ubiquitously expressed isoform necessary for the maintenance of stable cellular protrusions generated by actin polymerization forces. By implementing a machine-learning-enabled cryo-electron microscopy pipeline for visualizing cross-linkers bridging multiple filaments, we uncover a sequential bundling mechanism enabling T-plastin to bridge pairs of actin filaments in both parallel and antiparallel orientations. T-plastin populates distinct structural landscapes in these two bridging orientations that are selectively compatible with actin networks featuring divergent architectures and functions. Our structural, biochemical, and cell biological data highlight inter-CHD linkers as key structural elements underlying flexible but stable cross-linking that are likely to be disrupted by T-plastin mutations that cause hereditary bone diseases.

Atomistic Insights into Activation and Degradation of La0.6Sr0.4CoO3-δ Electrocatalysts under Oxygen Evolution Conditions.

The stability of perovskite oxide catalysts for the oxygen evolution reaction (OER) plays a critical role in their applicability in water splitting concepts. Decomposition of perovskite oxides under applied potential is typically linked to cation leaching and amorphization of the material. However, structural changes and phase transformations at the catalyst surface were also shown to govern the activity of several perovskite electrocatalysts under applied potential. Hence, it is crucial for the rational design of durable perovskite catalysts to understand the interplay between the formation of active surface phases and stability limitations under OER conditions. In the present study, we reveal a surface-dominated activation and deactivation mechanism of the prominent electrocatalyst La0.6Sr0.4CoO3-δ under steady-state OER conditions. Using a multiscale microscopy and spectroscopy approach, we identify the evolving Co-oxyhydroxide as catalytically active surface species and La-hydroxide as inactive species involved in the transient degradation behavior of the catalyst. While the leaching of Sr results in the formation of mixed surface phases, which can be considered as a part of the active surface, the gradual depletion of Co from a self-assembled active CoO(OH) phase and the relative enrichment of passivating La(OH)3 at the electrode surface result in the failure of the perovskite catalyst under applied potential.

CDC7-independent G1/S transition revealed by targeted protein degradation.

The entry of mammalian cells into the DNA synthesis phase (S phase) represents a key event in cell division1. According to current models of the cell cycle, the kinase CDC7 constitutes an essential and rate-limiting trigger of DNA replication, acting together with the cyclin-dependent kinase CDK2. Here we show that CDC7 is dispensable for cell division of many different cell types, as determined using chemical genetic systems that enable acute shutdown of CDC7 in cultured cells and in live mice. We demonstrate that another cell cycle kinase, CDK1, is also active during G1/S transition both in cycling cells and in cells exiting quiescence. We show that CDC7 and CDK1 perform functionally redundant roles during G1/S transition, and at least one of these kinases must be present to allow S-phase entry. These observations revise our understanding of cell cycle progression by demonstrating that CDK1 physiologically regulates two distinct transitions during cell division cycle, whereas CDC7 has a redundant function in DNA replication.

Phase Transitions in a Perovskite Thin Film Studied by Environmental In Situ Heating Nano-Beam Electron Diffraction.

The rich phase diagram of bulk Pr1-x Cax MnO3 resulting in a high tunability of physical properties gives rise to various studies related to fundamental research as well as prospective applications of the material. Importantly, as a consequence of strong correlation effects, electronic and lattice degrees of freedom are vigorously coupled. Hence, it is debatable whether such bulk phase diagrams can be transferred to inherently strained epitaxial thin films. In this paper, the structural orthorhombic to pseudo-cubic transition for x = 0.1 is studied in ion-beam sputtered thin films and differences to the respective bulk system are pointed out by employing in situ heating nano-beam electron diffraction to follow the temperature dependence of lattice constants. In addition, it is demonstrated that controlling the environment during heating, that is, preventing oxygen loss, is crucial in order to avoid irreversible structural changes, which is expected to be a general problem of compounds containing volatile elements under non-equilibrium conditions.

Molecular control of cell density-mediated exit to quiescence.

Contact inhibition of cell proliferation regulates tissue size and prevents uncontrolled cell expansion. When cell density increases, contact inhibition can force proliferating cells into quiescence. Here we show that the variable memory of local cell density experienced by a mother cell controls the levels of the cyclin-dependent kinase (CDK) activator cyclin D1 and inhibitor p27 in newborn daughters, which direct cells to proliferation or quiescence. Much of this regulation can be explained by rapid suppression of ERK activity by high cell density in mothers, which leads to lower cyclin D1 and higher p27 levels in daughters. Strikingly, cell density and mitogen signals compete by shifting the ratio of cyclin D1/p27 levels below or above a single sharp threshold that controls the proliferation decision. Thus, the history of competing cell density and mitogen signals experienced by mothers is funneled into a precise activator-inhibitor balance that decides the fate of daughter cells.

Swiss Frailty Network and Repository: protocol of a Swiss Personalized Health Network's driver project observational study.

INTRODUCTION: Early identification of frailty by clinical instruments or accumulation of deficit indexes can contribute to improve healthcare for older adults, including the prevention of negative outcomes in acute care. However, conflicting evidence exists on how to best capture frailty in this setting. Simultaneously, the increasing utilisation of electronic health records (EHRs) opens up new possibilities for research and patient care, including frailty. METHODS AND ANALYSIS: The Swiss Frailty Network and Repository (SFNR) primarily aims to develop an electronic Frailty Index (eFI) from routinely available EHR data in order to investigate its predictive value against length of stay and in-hospital mortality as two important clinical outcomes in a study sample of 1000-1500 hospital patients aged 65 years and older. In addition, we will examine the correlation between the eFI and a test-based clinical Frailty Instrument to compare both concepts in Swiss older adults in acute care settings. As a Swiss Personalized Health Network (SPHN) driver project, our study will report on the characteristics and usability of the first nationwide eFI in Switzerland connecting all five Swiss University Hospitals' Geriatric Departments with a representative sample of patients aged 65 years and older admitted to acute care. ETHICS AND DISSEMINATION: The study protocol was approved by the competent ethics committee of the Canton of Zurich (BASEC-ID 2019-00445). All acquired data will be handled according to SPHN's ethical framework for responsible data processing in personalised health research. Analyses will be performed within the secure BioMedIT environment, a national infrastructure to enable secure biomedical data processing, an integral part of SPHN. TRIAL REGISTRATION NUMBER: NCT04516642.

Supercontinuum generation in a carbon disulfide core microstructured optical fiber.

We demonstrate supercontinuum generation in a liquid-core microstructured optical fiber using carbon disulfide as the core material. The fiber provides a specific dispersion landscape with a zero-dispersion wavelength approaching the telecommunication domain where the corresponding capillary-type counterpart shows unsuitable dispersion properties for soliton fission. The experiments were conducted using two pump lasers with different pulse duration (30 fs and 90 fs) giving rise to different non-instantaneous contributions of carbon disulfide in each case. The presented results demonstrate an extraordinary high conversion efficiency from pump to soliton and to dispersive wave, overall defining a platform that enables studying the impact of non-instantaneous responses on ultrafast soliton dynamics and coherence using straightforward pump lasers and diagnostics.

Site-specific plan-view TEM lamella preparation of pristine surfaces with a large field of view.

Transmission electron microscopy has become a major characterization tool with an ever increasing variety of methods being applied in a wide range of scientific fields. However, the probably most famous pitfall in related workflows is the preparation of high-quality electron-transparent lamellae enabling for extraction of valuable information. Particularly in the field of solid state physics and materials science, it often required to study the surface of a macroscopic specimen with plan-view orientation. Nevertheless, despite tremendous advances in instrumentation, i.e. focused ion beam, the yield of existing plan-view lamellae preparation techniques is relatively low compared to cross-sectional extraction methods. Furthermore, techniques relying on mechanical treatments, i.e. conventional preparation, compromise site-specifity. In this paper, we demonstrate that by combining a mechanical grinding step prior to backside lift-out in the focused ion beam plan-view lamellae preparation becomes increasingly easy. The suggested strategy combines site-specifity with micrometer precision as well as possible investigation of pristine surfaces with a field of view of several hundred square micrometers.

Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2.

Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors-palbociclib, ribociclib, or abemaciclib-immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.

Computational tissue staining of non-linear multimodal imaging using supervised and unsupervised deep learning.

Hematoxylin and Eosin (H&E) staining is the 'gold-standard' method in histopathology. However, standard H&E staining of high-quality tissue sections requires long sample preparation times including sample embedding, which restricts its application for 'real-time' disease diagnosis. Due to this reason, a label-free alternative technique like non-linear multimodal (NLM) imaging, which is the combination of three non-linear optical modalities including coherent anti-Stokes Raman scattering, two-photon excitation fluorescence and second-harmonic generation, is proposed in this work. To correlate the information of the NLM images with H&E images, this work proposes computational staining of NLM images using deep learning models in a supervised and an unsupervised approach. In the supervised and the unsupervised approach, conditional generative adversarial networks (CGANs) and cycle conditional generative adversarial networks (cycle CGANs) are used, respectively. Both CGAN and cycle CGAN models generate pseudo H&E images, which are quantitatively analyzed based on mean squared error, structure similarity index and color shading similarity index. The mean of the three metrics calculated for the computationally generated H&E images indicate significant performance. Thus, utilizing CGAN and cycle CGAN models for computational staining is beneficial for diagnostic applications without performing a laboratory-based staining procedure. To the author's best knowledge, it is the first time that NLM images are computationally stained to H&E images using GANs in an unsupervised manner.

LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components.

After two converging DNA replication forks meet, active replisomes are disassembled and unloaded from chromatin. A key process in replisome disassembly is the unloading of CMG helicases (CDC45-MCM-GINS), which is initiated in Caenorhabditis elegans and Xenopus laevis by the E3 ubiquitin ligase CRL2LRR1. Here, we show that human cells lacking LRR1 fail to unload CMG helicases and accumulate increasing amounts of chromatin-bound replisome components as cells progress through S phase. Markedly, we demonstrate that the failure to disassemble replisomes reduces the rate of DNA replication increasingly throughout S phase by sequestering rate-limiting replisome components on chromatin and blocking their recycling. Continued binding of CMG helicases to chromatin during G2 phase blocks mitosis by activating an ATR-mediated G2/M checkpoint. Finally, we provide evidence that LRR1 is an essential gene for human cell division, suggesting that CRL2LRR1 enzyme activity is required for the proliferation of cancer cells and is thus a potential target for cancer therapy.