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Natural photosystems couple light harvesting to charge separation using a 'special pair' of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C2-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry. Spectroscopy revealed that the chlorophylls are excitonically coupled, and fluorescence lifetime imaging demonstrated energy transfer. The cryo-electron microscopy structure of a designed 24-chlorophyll octahedral nanocage with a special pair on each edge closely matched the design model. The results suggest that the de novo design of artificial photosynthetic systems is within reach of current computational methods.

A wooden house frame consists of many different lumber pieces, but because of the regularity of these building blocks, the structure can be designed using straightforward geometrical principles. The design of multicomponent protein assemblies, in comparison, has been much more complex, largely owing to the irregular shapes of protein structures1. Here we describe extendable linear, curved and angled protein building blocks, as well as inter-block interactions, that conform to specified geometric standards; assemblies designed using these blocks inherit their extendability and regular interaction surfaces, enabling them to be expanded or contracted by varying the number of modules, and reinforced with secondary struts. Using X-ray crystallography and electron microscopy, we validate nanomaterial designs ranging from simple polygonal and circular oligomers that can be concentrically nested, up to large polyhedral nanocages and unbounded straight 'train track' assemblies with reconfigurable sizes and geometries that can be readily blueprinted. Because of the complexity of protein structures and sequence-structure relationships, it has not previously been possible to build up large protein assemblies by deliberate placement of protein backbones onto a blank three-dimensional canvas; the simplicity and geometric regularity of our design platform now enables construction of protein nanomaterials according to 'back of an envelope' architectural blueprints.

Magnetic resonance imaging (MRI) is known for its accurate soft tissue delineation of tumors and normal tissues. This development has significantly impacted the imaging and treatment of cancers. Radiomics is the process of extracting high-dimensional features from medical images. Several studies have shown that these extracted features may be used to build machine-learning models for the prediction of treatment outcomes of cancer patients. Various feature selection techniques and machine models interrogate the relevant radiomics features for predicting cancer treatment outcomes. This study aims to provide an overview of MRI radiomics features used in predicting clinical treatment outcomes with machine learning techniques. The review includes examples from different disease sites. It will also discuss the impact of magnetic field strength, sample size, and other characteristics on outcome prediction performance.

Abstract Background Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success. Methods We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after $$2\,\text{Gy} \times 35$$ 2 Gy × 35 whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling. Results In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control. Conclusion This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation.

Emanuele Soricelli, Giovanni Casella, Giorgio Di Rocco, Adriano Redler, Nicola BassoDepartment of Surgical Sciences, Policlinico Umberto I, Sapienza, University of Rome, ItalyAbstract: Since the early 2000s, laparoscopic sleeve gastrectomy has increasingly gained consensus in bariatric surgery, thanks to good to excellent results in terms of weight loss and comorbidity resolution, and to simpler technical aspects than in Roux-en-Y gastric bypass and biliopancreatic diversion. In yearly consensus summits, surgical indications, technical details, and management of complications, together with continuous update of data concerning clinical outcome, have been debated on the basis of increasing collective experience. In experimental studies and clinical trials, the pathophysiological mechanisms of weight loss and remission of cardiometabolic comorbidities subsequent to sleeve gastrectomy have been extensively discussed. The aim of this paper is to offer a review of state of the art laparoscopic sleeve gastrectomy and to focus attention on the currently most debated topics and future prospects of this procedure.Keywords: sleeve gastrectomy, type 2 diabetes mellitus, gastroesophageal reflux disease, revisional, quality of life

Monitoring the reputation of Higher Education Institutions is a key challenge. Despite decades of research and theory in Higher Education marketing addressing this issue, a definitive method for capturing and monitoring reputation of such institutions has yet to emerge. This paper argues that research into a theoretically sound method for capturing and monitoring the reputation of Higher Education Institutions has stalled due to three significant obstacles: (a) the complexity of defining the construct of reputation itself, (b) ongoing disputes regarding the appropriate methods of measurement for the constructs of reputation, (c) insufficient tailoring of the construct of reputation to the distinctive nature of Higher Education Institutions.

Abstract Background Definitive local therapy with stereotactic ablative radiation therapy (SABR) for ultracentral lung lesions is associated with a high risk of toxicity, including treatment related death. Stereotactic MR-guided adaptive radiation therapy (SMART) can overcome many of the challenges associated with SABR treatment of ultracentral lesions. Methods We retrospectively identified 14 consecutive patients who received SMART to ultracentral lung lesions from 10/2019 to 01/2021. Patients had a median distance from the proximal bronchial tree (PBT) of 0.38 cm. Tumors were most often lung primary (64.3%) and HILUS group A (85.7%). A structure-specific rigid registration approach was used for cumulative dose analysis. Kaplan-Meier log-rank analysis was used for clinical outcome data and the Wilcoxon Signed Rank test was used for dosimetric data. Results Here we show that SMART dosimetric improvements in favor of delivered plans over predicted non-adapted plans for PBT, with improvements in proximal bronchial tree DMax of 5.7 Gy (p = 0.002) and gross tumor 100% prescription coverage of 7.3% (p = 0.002). The mean estimated follow-up is 17.2 months and 2-year local control and local failure free survival rates are 92.9% and 85.7%, respectively. There are no grade ≥ 3 toxicities. Conclusions SMART has dosimetric advantages and excellent clinical outcomes for ultracentral lung tumors. Daily plan adaptation reliably improves target coverage while simultaneously reducing doses to the proximal airways. These results further characterize the therapeutic window improvements for SMART. Structure-specific rigid dose accumulation dosimetric analysis provides insights that elucidate the dosimetric advantages of SMART more so than per fractional analysis alone.

Abstract Background Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. Methods Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. Discussion This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. Trial registration NCT05301283. Trial status The trial started recruitment on March 17, 2022.

The confrontation of complex Earth system model (ESM) codes with novel supercomputing architectures poses challenges to efficient modeling and job submission strategies. The modular setup of these models naturally fits a modular supercomputing architecture (MSA), which tightly integrates heterogeneous hardware resources into a larger and more flexible high-performance computing (HPC) system. While parts of the ESM codes can easily take advantage of the increased parallelism and communication capabilities of modern GPUs, others lag behind due to the long development cycles or are better suited to run on classical CPUs due to their communication and memory usage patterns. To better cope with these imbalances between the development of the model components, we performed benchmark campaigns on the Jülich Wizard for European Leadership Science (JUWELS) modular HPC system. We enabled the weather and climate model Icosahedral Nonhydrostatic (ICON) to run in a coupled atmosphere–ocean setup, where the ocean and the model I/O is running on the CPU Cluster, while the atmosphere is simulated simultaneously on the GPUs of JUWELS Booster (ICON-MSA). Both atmosphere and ocean are running globally with a resolution of 5 km. In our test case, an optimal configuration in terms of model performance (core hours per simulation day) was found for the combination of 84 GPU nodes on the JUWELS Booster module to simulate the atmosphere and 80 CPU nodes on the JUWELS Cluster module, of which 63 nodes were used for the ocean simulation and the remaining 17 nodes were reserved for I/O. With this configuration the waiting times of the coupler were minimized. Compared to a simulation performed on CPUs only, the MSA approach reduces energy consumption by 45 % with comparable runtimes. ICON-MSA is able to scale up to a significant portion of the JUWELS system, making best use of the available computing resources. A maximum throughput of 170 simulation days per day (SDPD) was achieved when running ICON on 335 JUWELS Booster nodes and 268 Cluster nodes.

Obtaining a proper position for total hip arthroplasty components is a crucial aspect of implant performance and consequently of patient outcomes. Restoring the original hip center and maintaining the limb length are key factors in reaching the optimal implant positioning. The aim of this study was to assess the accuracy and safety of a computed dynamic analysis system that, through patient-specific guides, tries to improve implant positioning and functional orientation according to patients’ spinopelvic mobility and anatomy. A total of 100 consecutive patients were prospectively enrolled. All patients received an Optimized Positioning System dynamic hip preoperative planning schedule. A CT scan protocol follow-up analysis was performed 6 months after surgery. The mean deviations from the planned acetabular inclination and anteversion were 4.3° and 3.8°, respectively. In total, 98% of cases were within ± 10° of the Lewinnek safe zone, both for inclination and anteversion. The height of osteotomy deviated, on average, 1.6 mm. In total, 100% of cases were included within 4 mm of osteotomy. Patient-specific and laser-guided instrumentation was found to be safe and accurately reproduced dynamic planning in terms of the component orientation, osteotomy level, leg length and offset.

Abstract In anterior resection of rectum, the section level of inferior mesenteric artery is still subject of controversy between the advocates of high and low tie. The low tie is the division and ligation to the branching of the left colic artery and the high tie is the division and ligation at its origin at the aorta. We intend to assess current scientific evidence in literature and to establish the differences comparing technique, anatomy and physiology. The aim of this protocol is to achieve a meta-analysis that tests safety and feasibility of the two procedures with several types of outcome measures.

Abstract Background We conducted a systematic review to evaluate the role of Ultrasonic dissector (UAS) versus conventional clamp and tie in thyroidectomy. Materials and methods We searched for all published RCT in into electronic databases. To be included in the analysis, the studies had to compare thyroidectomy with UAS versus conventional vessel ligation and tight (conventional technique = CT). The following outcomes were used to compare the total thyroidectomy group with UAS versus CT group: operative duration, operative blood loss, overall drainage volume during the first 24 hours, transiet laryngeal nerve palsy, permanent laryngeal nerve palsy, transiet hypocalcaemia and permanent hypocalcaemia. Results There are currently 7 RCT on this issue to compare thyroidectomy with UAS versus CT. From the analysis of these studies it was possible to confront 608 cases: 303 undergoing to thyroidectomy with UAS versus 305 that were treated with CT. Actually, it was shown a relevant advantage of cost-effectiveness in patients treated with UAS; there is a statistically significant reduction of the operative duration (weighted mean difference [WMD], -18.74 minutes; 95% confidence interval [CI], (-26.97 to -10.52 minutes) (P = 0.00001), intraoperative blood loss (WMD, -60.10 mL; 95% CI, -117.04 to 3.16 mL) (P = 0.04) and overall drainage volume (WMD, -35.30 mL; 95% CI, -49.24 to 21.36 mL) (P = 0.00001) in the patients underwent thyroidectomy with UAS. Although the analysis showed that the patients who were treated with USA presented more favourable results in incidence of post-operative complications (transient laryngeal nerve palsy: P = 0.11; permanent laryngeal nerve palsy: not estimable; transient hypocalcaemia: P = 0.24; permanent hypocalcaemia: P = 0.45), these data didn't present statistical relevance. Conclusion This meta-analysis shown a relevant advantage only in terms of cost-effectiveness in patients treated with UAS; it is subsequent to statistically significant reduction of operation duration, intraoperative blood loss and of overall drainage volume during the first 24 hours. Although the analysis showed that the patients who were treated with UAS presented more favourable results in incidence of post-operative complications (transiet laryngeal nerve palsy; transiet hypocalcaemia and permanent hypocalcaemia), these data didn't present statistical relevance.

Background and purpose: Diffusion weighted imaging (DWI) allows for the interrogation of tissue cellularity, which is a surrogate for cellular proliferation. Previous attempts to incorporate DWI into the workflow of a 0.35 T MR-linac (MRL) have lacked quantitative accuracy. In this study, accuracy, repeatability, and geometric precision of apparent diffusion coefficient (ADC) maps produced using an echo planar imaging (EPI)-based DWI protocol on the MRL system is illustrated, and in vivo potential for longitudinal patient imaging is demonstrated. Materials and methods: Accuracy and repeatability were assessed by measuring ADC values in a diffusion phantom at three timepoints and comparing to reference ADC values. System-dependent geometric distortion was quantified by measuring the distance between 93 pairs of phantom features on ADC maps acquired on a 0.35 T MRL and a 3.0 T diagnostic scanner and comparing to spatially precise CT images. Additionally, for five sarcoma patients receiving radiotherapy on the MRL, same-day in vivo ADC maps were acquired on both systems, one of which at multiple timepoints. Results: Phantom ADC quantification was accurate on the 0.35 T MRL with significant discrepancies only seen at high ADC. Average geometric distortions were 0.35 (±0.02) mm and 0.85 (±0.02) mm in the central slice and 0.66 (±0.04) mm and 2.14 (±0.07) mm at 5.4 cm off-center for the MRL and diagnostic system, respectively. In the sarcoma patients, a mean pretreatment ADC of 910x10-6 (±100x10-6) mm2/s was measured on the MRL. Conclusions: The acquisition of accurate, repeatable, and geometrically precise ADC maps is possible at 0.35 T with an EPI approach.

State-of-the-art Earth system models typically employ grid spacings of O(100 km), which is too coarse to explicitly resolve main drivers of the flow of energy and matter across the Earth system. In this paper, we present the new ICON-Sapphire model configuration, which targets a representation of the components of the Earth system and their interactions with a grid spacing of 10 km and finer. Through the use of selected simulation examples, we demonstrate that ICON-Sapphire can (i) be run coupled globally on seasonal timescales with a grid spacing of 5 km, on monthly timescales with a grid spacing of 2.5 km, and on daily timescales with a grid spacing of 1.25 km; (ii) resolve large eddies in the atmosphere using hectometer grid spacings on limited-area domains in atmosphere-only simulations; (iii) resolve submesoscale ocean eddies by using a global uniform grid of 1.25 km or a telescoping grid with the finest grid spacing at 530 m, the latter coupled to a uniform atmosphere; and (iv) simulate biogeochemistry in an ocean-only simulation integrated for 4 years at 10 km. Comparison of basic features of the climate system to observations reveals no obvious pitfalls, even though some observed aspects remain difficult to capture. The throughput of the coupled 5 km global simulation is 126 simulated days per day employing 21 % of the latest machine of the German Climate Computing Center. Extrapolating from these results, multi-decadal global simulations including interactive carbon are now possible, and short global simulations resolving large eddies in the atmosphere and submesoscale eddies in the ocean are within reach.