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O-GlcNAc transferase (OGT) is an essential mammalian enzyme that binds thousands of different proteins, including substrates that it glycosylates and nonsubstrate interactors that regulate its biology. OGT also has one proteolytic substrate, the transcriptional coregulator host cell factor 1 (HCF-1), which it cleaves in a process initiated by glutamate side chain glycosylation at a series of central repeats. Although HCF-1 is OGT’s most prominent binding partner, its affinity for the enzyme has not been quantified. Here, we report a time-resolved Förster resonance energy transfer assay to measure ligand binding to OGT and show that an HCF-1-derived polypeptide (HCF3R) binds with picomolar affinity to the enzyme (KD≤ 85 pM). This high affinity is driven in large part by conserved asparagines in OGT’s tetratricopeptide repeat domain, which form bidentate contacts to the HCF-1 peptide backbone; replacing any one of these asparagines with alanine reduces binding by more than 5 orders of magnitude. Because the HCF-1 polypeptide binds so tightly to OGT, we tested its ability to inhibit enzymatic function. We found that HCF3R potently inhibits OGT both in vitro and in cells and used this finding to develop a genetically encoded, inducible OGT inhibitor that can be degraded with a small molecule, allowing for reversible and tunable inhibition of OGT.

The COVID-19 pandemic exacerbated social isolation among people with traumatic brain injury (TBI). Yet, little is known about how changes in personal factors, environmental factors, or the characteristics of activities affected social participation. We examined experiences with social isolation and barriers to social participation using the person–environment–occupation–performance model as a framework. Twelve adults with TBI participated in a series of three focus groups. Data were analyzed using thematic analysis. We identified two primary themes with sub-themes: (1) social isolation experiences: (1a) emotional impact and (1b) managing personal risk; and (2) greater barriers but a lack of strategies to address them: (2a) access and opportunities and (2b) social and societal factors. New environmental barriers and task demands affected occupational performance, and participants identified few successful strategies to overcome these barriers. Occupational therapy can develop new strategies to re-balance the person–environment fit and enhance social participation.

A social housing estate in Denmark was designated for demolition due to exceedance of guidance values for polychlorinated biphenyls (PCBs) in indoor air. Here, we deployed precleaned silicone wristbands (n= 46) among demolition workers of these contaminated buildings during single workdays while conducting various work tasks. We established a method to analyze all 209 PCBs in wristbands to identify prominent congeners of exposure and evaluate differences between tasks. Wristbands were extracted using microwave-assisted extraction and then concentrated for gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis. Twenty-nine chromatographic peaks representing 37 congeners were detected in every wristband, and tetra-CBs were the dominant homologue group. PCB-66, -44, and -70 were the most abundant congeners measured in worker wristbands, none of which are included within the typical seven indicator or WHO 12 PCBs. Workers who cut PCB-containing sealants had wristbands with the highest PCB concentrations (geometric mean ∑209PCBs = 1963 ng/g wristband), which were followed by those handling concrete elements on the building roof. Additionally, wristbands captured a broader range of PCBs than has been previously measured in air and serum samples. Taken together, our results highlight the importance of total congener analysis in assessing current PCB exposure in demolition work and the utility of wristbands for assessing these exposures.

IMPORTANCE: The interindividual differences in severity of acute radiation dermatitis are not well understood. To date, the pathomechanism and interplay of microbiome and radiodermatitis before and during treatment remain largely unknown. OBJECTIVE: To assess the association of skin microbiome baseline composition and dynamics with severity of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal prospective pilot observational study was conducted between January 2017 and January 2019. Sequencing results were received in March 2021, and the data were analyzed from August 2021 to March 2023. This study was performed at an urban academic university cancer center. A total of 21 female patients with breast cancer after surgery were consecutively approached, of which 1 patient withdrew consent before the study started. EXPOSURE: Adjuvant radiotherapy for breast cancer for 7 weeks. MAIN OUTCOMES AND MEASURES: The main outcome was the association of baseline skin microbiome composition and its dynamics with the severity of radiodermatitis. A total of 360 skin microbiome samples from patients were analyzed, taken before, during, and after radiotherapy, from both the treated and contralateral healthy sides. The skin microbiome samples were analyzed using 16S (V1-V3) amplicon sequencing and quantitative polymerase chain reaction bacterial enumeration. RESULTS: Twenty female patients with breast cancer after surgery who underwent radiotherapy enrolled in the study had a median (range) age of 61 (37-81) years. The median (range) body mass index of the patients was 24.2 (17.6-38.4). The 16S sequencing revealed that low (<5%) relative abundance of commensal skin bacteria (Staphylococcus epidermidis, Staphylococcus hominis, Cutibacterium acnes) at baseline composition was associated with the development of severe radiodermatitis with an accuracy of 100% (sensitivity and specificity of 100%, P < .001). Furthermore, in patients with severe radiodermatitis, quantitative polymerase chain reaction bacterial enumeration revealed a general non–species-specific overgrowth of skin bacterial load before the onset of severe symptoms. Subsequently, the abundance of commensal bacteria increased in severe radiodermatitis, coinciding with a decline in total bacterial load. CONCLUSIONS AND RELEVANCE: The findings of this observational study indicated a potential mechanism associated with the skin microbiome for the pathogenesis of severe radiodermatitis, which may be a useful biomarker for personalized prevention of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer.

ABSTRACTTriple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset. The unresponsiveness to hormone therapies and immunotherapy and the toxicity of chemotherapeutics account for the limited treatment options for TNBC. Ion channels have emerged as possible therapeutic candidates for cancer therapy, but little is known about how ligand gated ion channels, specifically, GABA type A ligand-gated ion channel receptors (GABAAR), affect cancer pathogenesis. Our results show that the GABAAβ3 subunit is expressed at higher levels in TNBC cell lines than non-tumorigenic cells, therefore contributing to the idea that limiting the GABAAR via knockdown of the GABAAβ3 subunit is a potential strategy for decreasing the proliferation and migration of TNBC cells. We employed pharmacological and genetic approaches to investigate the role of the GABAAβ3 subunit in TNBC proliferation, migration, and cell cycle progression. The results suggest that pharmacological antagonism or genetic knockdown of GABAAβ3 subunit decreases TNBC proliferation and migration. In addition, GABAAβ3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. Our findings suggest that membrane bound GABAAreceptors containing the β3 subunit can be further developed as a potential novel target for the treatment of TNBC.

Abstract: Purpose: Little data exist regarding infliximab use in surgical decision making and postoperative complications in ulcerative colitis. Our goals were to determine the rate of postoperative complications in infliximab-treated ulcerative colitis patients undergoing restorative proctocolectomy and to determine whether three-stage procedures are more often necessary. Methods: We studied a group of infliximab-treated patients and matched control subjects who underwent two-stage restorative proctocolectomy between 2000 and 2006. Postoperative complications were compared. In addition, the rate of three-stage procedures was compared between all infliximab- and noninfliximab-treated patients. Results: A total of 523 restorative proctocolectomies were performed. In the infliximab group, there were 46 two-stage and 39 three-stage procedures. Covariate-adjusted odds of early complication for the inflixmab group was 3.54 times that of controls (P = 0.004; 95 percent confidence interval (CI), 1.51–8.31). The odds of sepsis were 13.8 times greater (P = 0.011; 95 percent CI, 1.82–105) and the odds of late complication were 2.19 times greater (P = 0.08; 95 percent CI, 0.91–5.28) for infliximab. The odds of requirement for three-stage procedures was 2.07 times greater in the infliximab group (P = 0.011; 95 percent CI, 1.18–3.63). Conclusions: Infliximab increases the risk of postoperative complications after restorative proctocolectomy and has altered the surgical approach to ulcerative colitis. Potential benefits of infliximab should be balanced against these risks.

Abstract: Purpose: Adjuvant radiotherapy is currently recommended for all node-positive rectal cancers to reduce local recurrence. This study evaluated if an adequate mesorectal excision can obviate the need for radiotherapy in early node-positive cancer. Methods: Stage IIIA rectal cancer patients were identified in a prospectively maintained database. Patients who received postoperative radiotherapy (radiotherapy) and those who did not (no radiotherapy) were compared for recurrence, survival, bowel function, and quality of life. Quality of life was assessed using the Short Form-36 Medical Outcomes Survey. Results: Eighty-six patients underwent proctectomy for T1-T2,N1 rectal cancers from 1978 to 2004. Patients receiving radiotherapy (n = 34) were younger and had a higher percentage of T1 tumors than patients who did not receive radiotherapy (n = 52). Other tumor characteristics, type of surgery, and number of involved lymph nodes were comparable. Estimated 5-year local recurrence was radiotherapy 3.4 percent and no radiotherapy 4.7 percent; distant recurrence was radiotherapy 13.5 percent and no radiotherapy 16.5 percent; and disease-specific mortality rates were similar 13.5 vs. 11.3 percent, for radiotherapy and no radiotherapy (all P > .05). Patients receiving radiotherapy had higher frequency of daytime bowel movements, urgency, and usage of pads and antidiarrheal medications. Age adjusted quality of life parameters were comparable between treatments. Conclusion: Postoperative radiotherapy did not reduce recurrence or mortality. Function but not quality of life was adversely affected. Routine postoperative radiotherapy for Stage IIIA rectal cancer should be reconsidered.

Pancreatic ductal adenocarcinoma is associated with a poor prognosis and there are few treatment options. The development of immunotherapy in pancreatic ductal adenocarcinoma has been difficult, and immune checkpoint inhibitors are only effective in a very small subset of patients. Most obstacles for treatment have been related to intertumoural and intratumoural heterogeneity, the composition of tumour stroma, and crosstalk with cancer cells. Improved molecular characterisation of pancreatic ductal adenocarcinoma and a better understanding of its microenvironment have paved the way for novel immunotherapy strategies, including the identification of predictive biomarkers, the development of rational combinations to optimise effectiveness, and the targeting of new mechanisms. Future immunotherapy strategies should consider individual characteristics to move beyond the traditional immune targets and circumvent the resistance to therapies that have been developed so far.

The Miocene amber from Zhangpu (Fujian Province, southeastern China) has recently displayed a significant palaeobiodiversity with numerous inclusions of insects, fungi, angiosperms as well as a few gastropods and feathers. In this paper, we investigate for the first time flower inclusions from the Zhangpu amber, using synchrotron-radiation-based X-ray micro-computed tomography (SRμCT). Our results show that both flowers are morphologically bisexual but functionally male, whorled, and trimerous. The perianth is differentiated into a synsepalous calyx and a polypetalous corolla. The obdiplostemonous androecium comprises six connate stamens forming a staminal tube around a fleshy nectary disk and an aborted syncarpous gynoecium with a superior ovary. Both flowers also share a subtending bract, a pair of bracteoles and secretory ducts. We recognize two new fossil species of Canarium, C. wangboin. sp. and C. leenhoutsiin. sp., distinguished from one another by the shape, length and extent of fusion of the calyx, the shape and length of the corolla, the fusion and length of the staminal tube and the shape of the nectary disk. The genus, which belongs to the Burseraceae family, is nowadays distributed pantropically in the warm regions of Africa, Asia and Northeast Oceania. This study represents the first fossil record of Canariumflowers and gives new insights into the diversity of the Zhangpu amber forest. Moreover, it supports the palaeoenvironmental interpretation of the sedimentary plant fossils deriving from the amber bearing layer, indicating a warm and humid climate in Zhangpu during the Mid-Miocene Climatic Optimum.

A large proportion of today's building projects are realized in existing buildings. This almost always requires the sensitive deconstruction of existing building fabric. Deconstruction technologies have to fulfill high requirements particularly in inner-city residential areas and during ongoing building use, both for construction projects in the existing building stock and for new construction activities. Currently used demolition technologies rarely meet the growing requirements in building practice. Common demolition and separation methods are characterized by high emissions, such as vibrations and noise, large quantities of blasting material, slow performance progress or high physical effort. An alternative technology is the electrodynamic Electric-Impulse-Technology (EIT). The process technology, initially developed for applications in mining and special civil engineering, is based on the destruction of solid materials by high-voltage pulses. On the basis of large-scale tests in mining dimensions, it was possible to demonstrate high dissolving capacities with low energy input. The research project aimed to investigate the basics for transferring the EIT to low-emission and selective material removal in civil and structural engineering. Extensive laboratory tests were conducted on sand-lime and concrete specimens to verify the adaptation of the EIT. It was found out that the technology is suitable for use in the construction industry. Further research is to be conducted to investigate the identified areas of application in greater depth and to further develop EIT for practical use.

The microstructural architecture of remodeled bone in the peri-implant region of screw implants plays a vital role in the distribution of strain energy and implant stability. We present a study in which screw implants made from titanium, polyetheretherketone and biodegradable magnesium-gadolinium alloys were implanted into rat tibia and subjected to a push-out test four, eight and twelve weeks after implantation. Screws were 4 mm in length and with an M2 thread. The loading experiment was accompanied by simultaneous three-dimensional imaging using synchrotron-radiation microcomputed tomography at 5 μm resolution. Bone deformation and strains were tracked by applying optical flow-based digital volume correlation to the recorded image sequences. Implant stabilities measured for screws of biodegradable alloys were comparable to pins whereas non-degradable biomaterials experienced additional mechanical stabilization. Peri-implant bone morphology and strain transfer from the loaded implant site depended heavily on the biomaterial utilized. Titanium implants stimulated rapid callus formation displaying a consistent monomodal strain profile whereas the bone volume fraction in the vicinity of magnesium-gadolinium alloys exhibited a minimum close to the interface of the implant and less ordered strain transfer. Correlations in our data suggest that implant stability benefits from disparate bone morphological properties depending on the biomaterial utilized. This leaves the choice of biomaterial as situational depending on local tissue properties.

The application of an artificial intelligence (AI)-based screening tool for retinal disease in India and Thailand highlighted the myths and reality of introducing medical AI, which may form a framework for subsequent tools

The recent clinical and commercial success of lipid nanoparticles (LNPs) for nucleic acid delivery has incentivized the development of new technologies to manufacture LNPs. As new technologies emerge, researchers must determine which technologies to assess and how to perform comparative evaluations. In this article, we use a quality-by-design approach to systematically investigate how the mixer technology used to form LNPs influences LNPstructure. Specifically, a coaxial turbulent jet mixer and a staggered herringbone microfluidic mixer were systematically compared via matched formulation and process conditions. A full-factorial design-of-experiments study with three factors and three levels was executed for each mixer to compare process robustness in the production of antisense oligonucleotide (ASO) LNPs. ASO-LNPs generated with the coaxial turbulent jet mixer were consistently smaller, had a narrower particle size distribution, and had a higher ASO encapsulation as compared to the microfluidic mixer, but had a greater variation in internal structure with less ordered cores. A subset of the study was replicated for mRNA-LNPs with comparable trends in particle size and encapsulation, but more frequent bleb features for LNPs produced by the coaxial turbulent jet mixer. The study design used here provides a road map for how researchers may compare different mixer technologies (or process changes more broadly) and how such studies can inform process robustness and manufacturing control strategies.

With three FDA-approved products, lipid nanoparticles (LNPs) are under intensive development for delivering wide-ranging nucleic acid therapeutics. A significant challenge for LNP development is insufficient understanding of structure–activity relationship (SAR). Small changes in chemical composition and process parameters can affect LNP structure, significantly impacting performance in vitroand in vivo. The choice of polyethylene glycol lipid (PEG-lipid), one of the essential lipids for LNP, has been proven to govern particle size. Here we find that PEG-lipids can further modify the core organization of antisense oligonucleotide (ASO)-loaded LNPs to govern its gene silencing activity. Furthermore, we also have found that the extent of compartmentalization, measured by the ratio of disordered vs ordered inverted hexagonal phases within an ASO-lipid core, is predictive of in vitrogene silencing. In this work, we propose that a lower ratio of disordered/ordered core phases correlates with stronger gene knockdown efficacy. To establish these findings, we developed a seamless high-throughput screening approach that integrated an automated LNP formulation system with structural analysis by small-angle X-ray scattering (SAXS) and in vitro TMEM106bmRNA knockdown assessment. We applied this approach to screen 54 ASO-LNP formulations while varying the type and concentration of PEG-lipids. Representative formulations with diverse SAXS profiles were further visualized using cryogenic electron microscopy (cryo-EM) to help structural elucidation. The proposed SAR was built by combining this structural analysis with in vitrodata. Our integrated methods, analysis, and resulting findings on PEG-lipid can be applied to rapidly optimize other LNP formulations in a complex design space.

Photographs of the external eye were recently shown to reveal signs of diabetic retinal disease and elevated glycated haemoglobin. This study aimed to test the hypothesis that external eye photographs contain information about additional systemic medical conditions.

Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation.

AbstractCasePerilunate dislocation is an uncommon injury in children. We report the case of an 11-year-old boy who presented a trans-scapho-perilunate fracture-dislocation of the carpus after falling from his bike. Treatment consisted of a closed reduction under general anesthesia followed by cast immobilization for 12 weeks. The injury healed with good wrist function on follow-up.ConclusionClosed reduction should be attempted because it can be successful and allows for closed treatment with the cast. It provides good radiological healing and satisfying functional results.

Citizen science (CS) can foster transformative impact for science, citizen empowerment and socio-political processes. To unleash this impact, a clearer understanding of its current status and challenges for its development is needed. Using quantitative indicators developed in a collaborative stakeholder process, our study provides a comprehensive overview of the current status of CS in Germany, Austria and Switzerland. Our online survey with 340 responses focused on CS impact through (1) scientific practices, (2) participant learning and empowerment, and (3) socio-political processes. With regard to scientific impact, we found that data quality control is an established component of CS practice, while publication of CS data and results has not yet been achieved by all project coordinators (55%). Key benefits for citizen scientists were the experience of collective impact (“making a difference together with others”) as well as gaining new knowledge. For the citizen scientists’ learning outcomes, different forms of social learning, such as systematic feedback or personal mentoring, were essential. While the majority of respondents attributed an important value to CS for decision-making, only few were confident that CS data were indeed utilized as evidence by decision-makers. Based on these results, we recommend (1) that project coordinators and researchers strengthen scientific impact by fostering data management and publications, (2) that project coordinators and citizen scientists enhance participant impact by promoting social learning opportunities and (3) that project initiators and CS networks foster socio-political impact through early engagement with decision-makers and alignment with ongoing policy processes. In this way, CS can evolve its transformative impact.

Main-belt comets are small Solar System bodies located in the asteroid belt that repeatedly exhibit comet-like activity (that is, dust comae or tails) during their perihelion passages, strongly indicating ice sublimation1,2. Although the existence of main-belt comets implies the presence of extant water ice in the asteroid belt, no gas has been detected around these objects despite intense scrutiny with the world’s largest telescopes3. Here we present James Webb Space Telescope observations that clearly show that main-belt comet 238P/Read has a coma of water vapour, but lacks a significant CO2gas coma. Our findings demonstrate that the activity of comet Read is driven by water–ice sublimation, and implies that main-belt comets are fundamentally different from the general cometary population. Whether or not comet Read experienced different formation circumstances or evolutionary history, it is unlikely to be a recent asteroid belt interloper from the outer Solar System. On the basis of these results, main-belt comets appear to represent a sample of volatile material that is currently unrepresented in observations of classical comets and the meteoritic record, making them important for understanding the early Solar System’s volatile inventory and its subsequent evolution.

Rhamnogalacturonan I (RGI) is a structurally complex pectic polysaccharide with a backbone of alternating rhamnose and galacturonic acid residues substituted with arabinan and galactan side chains. Galactan synthase 1 (GalS1) transfers galactose and arabinose to either extend or cap the β-1,4-galactan side chains of RGI, respectively. Here we report the structure of GalS1 from Populus trichocarpa, showing a modular protein consisting of an N-terminal domain that represents the founding member of a new family of carbohydrate-binding module, CBM95, and a C-terminal glycosyltransferase family 92 (GT92) catalytic domain that adopts a GT-A fold. GalS1 exists as a dimer in vitro, with stem domains interacting across the chains in a ‘handshake’ orientation that is essential for maintaining stability and activity. In addition to understanding the enzymatic mechanism of GalS1, we gained insight into the donor and acceptor substrate binding sites using deep evolutionary analysis, molecular simulations and biochemical studies. Combining all the results, a mechanism for GalS1 catalysis and a new model for pectic galactan side-chain addition are proposed.

Jupiter's Great Red Spot (GRS) was mapped by the James Webb Space Telescope (JWST)/Mid‐Infrared Instrument (4.9–27.9 μ${\upmu }$m) in July and August 2022. These observations took place alongside a suite of visual and infrared observations from; Hubble, JWST/NIRCam, Very Large Telescope/VISIR and amateur observers which provided both spatial and temporal context across the jovian disc. The stratospheric temperature structure retrieved using the NEMESIS software revealed a series of hot‐spots above the GRS. These could be the consequence of GRS‐induced wave activity. In the troposphere, the temperature structure was used to derive the thermal wind structure of the GRS vortex. These winds were only consistent with the independently determined wind field by JWST/NIRCam at 240 mbar if the altitude of the Hubble‐derived winds were located around 1,200 mbar, considerably deeper than previously assumed. No enhancement in ammonia was found within the GRS but a link between elevated aerosol and phosphine abundances was observed within this region. North‐south asymmetries were observed in the retrieved temperature, ammonia, phosphine and aerosol structure, consistent with the GRS tilting in the north‐south direction. Finally, a small storm was captured north‐west of the GRS that displayed a considerable excess in retrieved phosphine abundance, suggestive of vigorous convection. Despite this, no ammonia ice was detected in this region. The novelty of JWST required us to develop custom‐made software to resolve challenges in calibration of the data. This involved the derivation of the “FLT‐5” wavelength calibration solution that has subsequently been integrated into the standard calibration pipeline. Regularly observed for over 150 years, Jupiter's Great Red Spot (GRS) is one of the best documented storms in the Solar System. Despite the frequency of observations, crucial questions remain unanswered regarding the internal composition, dynamics and driving mechanism for the storm. Mid‐infrared observations acquired by the James Webb Space Telescope allowed us to peer past the colorful clouds to assess the composition and dynamics of the jovian weather layer. Data from the mid‐infrared instrument was modeled in the 7.30–10.75 μ${\upmu }$m range to “retrieve” the temperature distribution. Further modeling of these temperatures allowed us to derive the wind speeds throughout the vortex, enabling us to assess the dynamics of the GRS and how the vortex interacts with its surroundings. In addition, a series of hot‐spots were observed above the GRS that could be the result of atmospheric wave activity. The distribution of ammonia was also mapped in this spectral range. Comparison of the distribution of ammonia to the cloud distribution implied that this molecule may condense into the thick layers of cloud above the GRS. Finally phosphine, indicative of upwelling air was mapped and allowed us to identify a small convective storm north‐west of the GRS. Jupiter's Great Red Spot (GRS) was observed by James Webb Space Telescope/Mid‐Infrared Instrument in 2022 to study the 3D structure of temperature, aerosols and gaseous speciesA series of stratospheric hot‐spots were discovered to be co‐moving with the GRS in the longitude directionElevated phosphine and a complex distribution of ammonia gas were observed inside the GRS Jupiter's Great Red Spot (GRS) was observed by James Webb Space Telescope/Mid‐Infrared Instrument in 2022 to study the 3D structure of temperature, aerosols and gaseous species A series of stratospheric hot‐spots were discovered to be co‐moving with the GRS in the longitude direction Elevated phosphine and a complex distribution of ammonia gas were observed inside the GRS

IMPORTANCE: Early results at 3 years from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial showed survival benefits with adjuvant treatment with modified FOLFIRINOX vs gemcitabine in patients with resected pancreatic ductal adenocarcinoma; mature data are now available. OBJECTIVE: To report 5-year outcomes and explore prognostic factors for overall survival. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3 randomized clinical trial was conducted at 77 hospitals in France and Canada and included patients aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who had undergone complete macroscopic (R0/R1) resection within 3 to 12 weeks before randomization. Patients were included from April 16, 2012, through October 3, 2016. The cutoff date for this analysis was June 28, 2021. INTERVENTIONS: A total of 493 patients were randomized (1:1) to receive treatment with modified FOLFIRINOX (oxaliplatin, 85 mg/m2 of body surface area; irinotecan, 150-180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 2400 mg/m2, every 2 weeks) or gemcitabine (1000 mg/m2, days 1, 8, and 15, every 4 weeks) as adjuvant therapy for 24 weeks. MAIN OUTCOMES AND MEASURES: Primary end point was disease-free survival. Secondary end points included overall survival, metastasis-free survival, and cancer-specific survival. Prognostic factors for overall survival were determined. RESULTS: Of the 493 patients, 216 (43.8%) were women, and the mean (SD) age was 62.0 (8.9) years. At a median of 69.7 months’ follow-up, 367 disease-free survival events were observed. In patients receiving chemotherapy with modified FOLFIRINOX vs gemcitabine, median disease-free survival was 21.4 months (95% CI, 17.5-26.7) vs 12.8 months (95% CI, 11.6-15.2) (hazard ratio [HR], 0.66; 95% CI, 0.54-0.82; P < .001) and 5-year disease-free survival was 26.1% vs 19.0%; median overall survival was 53.5 months (95% CI, 43.5-58.4) vs 35.5 months (95% CI, 30.1-40.3) (HR, 0.68; 95% CI, 0.54-0.85; P = .001), and 5-year overall survival was 43.2% vs 31.4%; median metastasis-free survival was 29.4 months (95% CI, 21.4-40.1) vs 17.7 months (95% CI, 14.0-21.2) (HR, 0.64; 95% CI, 0.52-0.80; P < .001); and median cancer-specific survival was 54.7 months (95% CI, 45.8-68.4) vs 36.3 months (95% CI, 30.5–43.9) (HR, 0.65; 95% CI, 0.51-0.82; P < .001). Multivariable analysis identified modified FOLFIRINOX, age, tumor grade, tumor staging, and larger-volume center as significant favorable prognostic factors for overall survival. Shorter relapse delay was an adverse prognostic factor. CONCLUSIONS AND RELEVANCE: The final 5-year results from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial indicate that adjuvant treatment with modified FOLFIRINOX yields significantly longer survival than gemcitabine in patients with resected pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: EudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135

The atmospheric boundary layer experiences multiple changes in coastal regions, especially with wind directions from land towards the sea, where the wind speed usually increases due to the smaller roughness of the ocean surface. These effects are of particular relevance for offshore wind energy utilization; they are summarized under the term coastal effects. This paper provides an overview of coastal effects and their potential impact on the operating conditions of offshore wind farms with a focus on the German Bight. Common numerical and experimental tools to study coastal effects and developing internal boundary layers (IBL) are introduced, and a review on the current state of research is given. The German Bight is an interesting example to illustrate impacts of coastal effects on offshore wind energy, because of the large number of wind turbines with a coastal distance of 100 km or less. Phenomena related to the stability of the boundary layer, like low level jets, are discussed. Spatial variations of vertical heat fluxes in the coastal zone related to variable water depths or Wadden Sea areas are analysed. The study illustrates that due to the increasing size of offshore wind farms, horizontal wind speed gradients caused by coastal effects can lead to significant wind variations within a single farm. Research topics which still need further attention are discussed in the framework of the rapidly developing wind energy sector with increasing wind turbine hub heights and rotor diameters as well as growing wind farm sizes. One example is the interaction of coastal effects with offshore wind farm wakes. The necessity to consider a large spectrum of spatial and temporal scales to understand and describe coastal effects is highlighted. We summarize modelling and observation tools, which are suitable for the investigation and prediction of the boundary layer dynamics in coastal areas. Existing applications and results are described based on several examples with collocated observation and model results obtained in the X‑Wakes project. The study puts particular focus on the large potential provided by the combination of different measurements and modelling techniques and gives recommendations for future developments of integrated approaches including the formulation of priorities.

The RAS–RAF pathway is one of the most commonly dysregulated in human cancers1–3. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation4of the kinase RAF remains limited. Recent structures of inactive RAF monomer5and active RAF dimer5–8bound to 14-3-39,10have revealed the mechanisms by which 14-3-3 stabilizes both RAF conformations via specific phosphoserine residues. Prior to RAF dimerization, the protein phosphatase 1 catalytic subunit (PP1C) must dephosphorylate the N-terminal phosphoserine (NTpS) of RAF11to relieve inhibition by 14-3-3, although PP1C in isolation lacks intrinsic substrate selectivity. SHOC2 is as an essential scaffolding protein that engages both PP1C and RAS to dephosphorylate RAF NTpS11–13, but the structure of SHOC2 and the architecture of the presumptive SHOC2–PP1C–RAS complex remain unknown. Here we present a cryo-electron microscopy structure of the SHOC2–PP1C–MRAS complex to an overall resolution of 3 Å, revealing a tripartite molecular architecture in which a crescent-shaped SHOC2 acts as a cradle and brings together PP1C and MRAS. Our work demonstrates the GTP dependence of multiple RAS isoforms for complex formation, delineates the RAS-isoform preference for complex assembly, and uncovers how the SHOC2 scaffold and RAS collectively drive specificity of PP1C for RAF NTpS. Our data indicate that disease-relevant mutations affect complex assembly, reveal the simultaneous requirement of two RAS molecules for RAF activation, and establish rational avenues for discovery of new classes of inhibitors to target this pathway.

To validate the generalizability of a deep learning system (DLS) that detects diabetic macular edema (DME) from 2-dimensional color fundus photographs (CFP), for which the reference standard for retinal thickness and fluid presence is derived from 3-dimensional OCT.

Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, [...]

In a burning plasma state1–7, alpha particles from deuterium–tritium fusion reactions redeposit their energy and are the dominant source of heating. This state has recently been achieved at the US National Ignition Facility8using indirect-drive inertial-confinement fusion. Our experiments use a laser-generated radiation-filled cavity (a hohlraum) to spherically implode capsules containing deuterium and tritium fuel in a central hot spot where the fusion reactions occur. We have developed more efficient hohlraums to implode larger fusion targets compared with previous experiments9,10. This delivered more energy to the hot spot, whereas other parameters were optimized to maintain the high pressures required for inertial-confinement fusion. We also report improvements in implosion symmetry control by moving energy between the laser beams11–16and designing advanced hohlraum geometry17that allows for these larger implosions to be driven at the present laser energy and power capability of the National Ignition Facility. These design changes resulted in fusion powers of 1.5 petawatts, greater than the input power of the laser, and 170 kJ of fusion energy18,19. Radiation hydrodynamics simulations20,21show energy deposition by alpha particles as the dominant term in the hot-spot energy balance, indicative of a burning plasma state.

Engineering magnetic anisotropy in a ferro- or ferrimagnetic (FM) thin film is crucial in a spintronic device. One way to modify the magnetic anisotropy is through the surface of the FM thin film. Here, we report the emergence of a perpendicular magnetic anisotropy (PMA) induced by interfacial interactions in a heterostructure comprised of a garnet ferrimagnet, Y3Fe5O12(YIG), and a low-symmetry, high spin-orbit coupling (SOC) transition metal dichalcogenide, WTe2. At the same time, we also observed an enhancement in Gilbert damping in the WTe2-covered YIG area. Both the magnitude of interface-induced PMA and the Gilbert damping enhancement have no observable WTe2thickness dependence down to a single quadruple layer, indicating that the interfacial interaction plays a critical role. The ability of WTe2to enhance the PMA in FM thin film, combined with its previously reported capability to generate out-of-plane damping like spin torque, makes it desirable for magnetic memory applications.

Obtaining a burning plasma is a critical step towards self-sustaining fusion energy1. A burning plasma is one in which the fusion reactions themselves are the primary source of heating in the plasma, which is necessary to sustain and propagate the burn, enabling high energy gain. After decades of fusion research, here we achieve a burning-plasma state in the laboratory. These experiments were conducted at the US National Ignition Facility, a laser facility delivering up to 1.9 megajoules of energy in pulses with peak powers up to 500 terawatts. We use the lasers to generate X-rays in a radiation cavity to indirectly drive a fuel-containing capsule via the X-ray ablation pressure, which results in the implosion process compressing and heating the fuel via mechanical work. The burning-plasma state was created using a strategy to increase the spatial scale of the capsule2,3through two different implosion concepts4–7. These experiments show fusion self-heating in excess of the mechanical work injected into the implosions, satisfying several burning-plasma metrics3,8. Additionally, we describe a subset of experiments that appear to have crossed the static self-heating boundary, where fusion heating surpasses the energy losses from radiation and conduction. These results provide an opportunity to study α-particle-dominated plasmas and burning-plasma physics in the laboratory.

This report is informed by the themes of the session Trisomy 13/18, Exploring the Changing Landscape of Interventions at NeoHeart 2020—The Fifth International Conference of the Neonatal Heart Society. The faculty reviewed the present evidence in the management of patients and the support of families in the setting of trisomy 13 and trisomy 18 with congenital heart disease. Until recently medical professionals were taught that T13 and 18 were “lethal conditions” that were “incompatible with life” for which measures to prolong life are therefore ethically questionable and likely futile. While the medical literature painted one picture, family support groups shared stories of the long-term survival of children who displayed happiness and brought joy along with challenges to families. Data generated from such care shows that surgery can, in some cases, prolong survival and increase the likelihood of time at home. The authors caution against a change from never performing heart surgery to always—we suggest that the pendulum of intervention find a balanced position where all therapies including comfort care and surgery can be reviewed. Families and clinicians should typically be supported and empowered to define the best care for their children and patients. Key concepts in communication and case vignettes are reviewed including the importance of supportive relationships and the fact that palliative care may serve as an additional layer of support for decision-making and quality of life interventions. While cardiac surgery may be beneficial in some cases, surgery should not be the primary focus of initial family education and support.

Two-dimensional (2D) Talbot array illuminators (TAIs) were designed, fabricated, and evaluated for high-resolution high-contrast x-ray phase imaging of soft tissue at 10–20 keV. The TAIs create intensity modulations with a high compression ratio on the micrometer scale at short propagation distances. Their performance was compared with various other wavefront markers in terms of period, visibility, flux efficiency, and flexibility to be adapted for limited beam coherence and detector resolution. Differential x-ray phase contrast and dark-field imaging were demonstrated with a one-dimensional, linear phase stepping approach yielding 2D phase sensitivity using unified modulated pattern analysis (UMPA) for phase retrieval. The method was employed for x-ray phase computed tomography reaching a resolution of 3 µm on an unstained murine artery. It opens new possibilities for three-dimensional, non-destructive, and quantitative imaging of soft matter such as virtual histology. The phase modulators can also be used for various other x-ray applications such as dynamic phase imaging, super-resolution structured illumination microscopy, or wavefront sensing.

IMPORTANCE: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and is driven by a complex pathophysiology underlying highly heterogeneous phenotypes. Current advances in precision medicine emphasize the need for stratification. OBJECTIVE: To perform deep phenotyping and identification of severity-associated factors in adolescent and adult patients with AD. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional data from the baseline visit of a prospective longitudinal study investigating the phenotype among inpatients and outpatients with AD from the Department of Dermatology and Allergy of the University Hospital Bonn enrolled between November 2016 and February 2020. MAIN OUTCOMES AND MEASURES: Patients were stratified by severity groups using the Eczema Area and Severity Index (EASI). The associations of 130 factors with AD severity were analyzed applying a machine learning–gradient boosting approach with cross-validation–based tuning as well as multinomial logistic regression. RESULTS: A total of 367 patients (157 male [42.8%]; mean [SD] age, 39 [17] years; 94% adults) were analyzed. Among the participants, 177 (48.2%) had mild disease (EASI ≤7), 120 (32.7%) had moderate disease (EASI >7 and ≤ 21), and 70 (19.1%) had severe disease (EASI >21). Atopic stigmata (cheilitis: odds ratio [OR], 8.10; 95% CI, 3.35-10.59; white dermographism: OR, 4.42; 95% CI, 1.68-11.64; Hertoghe sign: OR, 2.75; 95% CI, 1.27-5.93; nipple eczema: OR, 4.97; 95% CI, 1.56-15.78) was associated with increased probability of severe AD, while female sex was associated with reduced probability (OR, 0.30; 95% CI, 0.13-0.66). The probability of severe AD was associated with total serum immunoglobulin E levels greater than 1708 IU/mL and eosinophil values greater than 6.8%. Patients aged 12 to 21 years or older than 52 years had an elevated probability of severe AD; patients aged 22 to 51 years had an elevated probability of mild AD. Age at AD onset older than 12 years was associated with increased probability of severe AD up to a peak at 30 years; age at onset older than 33 years was associated with moderate to severe AD; and childhood onset was associated with mild AD (peak, 7 years). Lifestyle factors associated with severe AD were physical activity less than once per week and (former) smoking. Alopecia areata was associated with moderate (OR, 5.23; 95% CI, 1.53-17.88) and severe (OR, 4.67; 95% CI, 1.01-21.56) AD. Predictive performance of machine learning–gradient boosting vs multinomial logistic regression differed only slightly (mean multiclass area under the curve value: 0.71 [95% CI, 0.69-0.72] vs 0.68 [0.66-0.70], respectively). CONCLUSIONS AND RELEVANCE: The associations found in this cross-sectional study among patients with AD might contribute to a deeper disease understanding, closer monitoring of predisposed patients, and personalized prevention and therapy.

The genus Clusia(Clusiaceae) is notorious for its difficult taxonomy; most species are dioecious, with distantly related species having similar morphology, and closely related species having cryptic morphological differences. Because of this, Clusiaspp. are often misidentified or, as in the case of C. suborbicularisand C. flava, considered to be the same species. Chemometric analyses of the HPLC metabolic profiles from bark extracts of C. suborbicularisand C. flava, combined with molecular evidence from ITS molecular markers were used to establish the metabolomic similarities and phylogenetic relationship between C. suborbicularisand C. flava, previously identified on the basis of their morphological characteristics. The principal component analyses of the HPLC metabolic profiles of bark extracts from individuals of C. suborbicularisand C. flavashowed significant differences, suggesting they should be recognized as distinct species. This assumption was confirmed by phylogenetic reconstructions based on the molecular marker ITS. Furthermore, a theoretical geographical distribution analysis suggests C. suborbiculariscould be considered a native species to the Yucatán Peninsula. The results from this investigation support C. suborbicularisas a distinct species, and not a synonym of C. flava. The identification of these two species represents a relevant contribution for the cataloguing, conservation and bioprospecting of Clusiaspp. occurring in the Yucatán Peninsula.

The replication transcription complex (RTC) from the virus SARS-CoV-2 is responsible for recognizing and processing RNA for two principal purposes. The RTC copies viral RNA for propagation into new virus and for ribosomal transcription of viral proteins. To accomplish these activities, the RTC mechanism must also conform to a large number of imperatives, including RNA over DNA base recognition, basepairing, distinguishing viral and host RNA, production of mRNA that conforms to host ribosome conventions, interfacing with error checking machinery, and evading host immune responses. In addition, the RTC will discontinuously transcribe specific sections of viral RNA to amplify certain proteins over others. Central to SARS-CoV-2 viability, the RTC is therefore dynamic and sophisticated. We have conducted a systematic structural investigation of three components that make up the RTC: Nsp7, Nsp8, and Nsp12 (also known as RNA-dependent RNA polymerase). We have solved high-resolution crystal structures of the Nsp7/8 complex, providing insight into the interaction between the proteins. We have used small-angle x-ray and neutron solution scattering (SAXS and SANS) on each component individually as pairs and higher-order complexes and with and without RNA. Using size exclusion chromatography and multiangle light scattering-coupled SAXS, we defined which combination of components forms transient or stable complexes. We used contrast-matching to mask specific complex-forming components to test whether components change conformation upon complexation. Altogether, we find that individual Nsp7, Nsp8, and Nsp12 structures vary based on whether other proteins in their complex are present. Combining our crystal structure, atomic coordinates reported elsewhere, SAXS, SANS, and other biophysical techniques, we provide greater insight into the RTC assembly, mechanism, and potential avenues for disruption of the complex and its functions.

Mandible morphology has an essential role in biting performance, but the mandible cuticle can have regional differences in its mechanical properties. The effects of such a heterogeneous distribution of cuticle material properties in the mandible responses to biting loading are still poorly explored in chewing insects. Here, we tested the mechanical properties of mandibles of the ant species Formica cuniculariaby nanoindentation and investigated the effects of the cuticular variation in Young's modulus (E) under bite loading with finite-element analysis (FEA). The masticatory margin of the mandible, which interacts with the food, was the hardest and stiffest region. To unravel the origins of the mechanical property gradients, we characterized the elemental composition by energy-dispersive X-ray spectroscopy. The masticatory margin possessed high proportions of Cu and Zn. When incorporated into the FEA, variation in E effectively changed mandible stress patterns, leading to a relatively higher concentration of stresses in the stiffer mandibular regions and leaving the softer mandible blade with relatively lower stress. Our results demonstrated the relevance of cuticle E heterogeneity in mandibles under bite loading, suggesting that the accumulation of transition metals such as Cu and Zn has a relevant correlation with the mechanical characteristics in F. cuniculariamandibles.

The article focuses on fostering a culture of belonging in music classes and ensembles for students with differences and disabilities. Topics include implementing adaptations based on a universal design for learning framework, including strategies related to modality, size, color, and pacing, to promote access and inclusivity.

Glycosylation of nuclear and cytoplasmic proteins is an essential post-translational modification in mammals. O-GlcNAc transferase (OGT), the sole enzyme responsible for this modification, glycosylates more than 1000 unique nuclear and cytoplasmic substrates. How OGT selects its substrates is a fundamental question that must be answered to understand OGT’s unusual biology. OGT contains a long tetratricopeptide repeat (TPR) domain that has been implicated in substrate selection, but there is almost no information about how changes to this domain affect glycosylation of individual substrates. By profiling O-GlcNAc in cell extracts and probing glycosylation of purified substrates, we show here that ladders of asparagines and aspartates that extend the full length of OGT’s TPR lumen control substrate glycosylation. Different substrates are sensitive to changes in different regions of OGT’s TPR lumen. We also found that substrates with glycosylation sites close to the C-terminus bypass lumenal binding. Our findings demonstrate that substrates can engage OGT in a variety of different ways for glycosylation.

Interruption of the ascending aorta is an extremely rare anomaly defined by a point of interruption between the intrapericardial and extrapericardial aorta and can be explained by developmental errors proximal to the embryologic right aortic sac. Herein, we present a case of interruption of the ascending aorta and describe a successful biventricular surgical repair of this unique anomaly.

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage‐specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer‐specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy. This article presents consensus expert opinion transplant recommendations for patients with a prior breast, colorectal, anal, urological, gynecological, or non‐small cell lung cancer. See the companion review on page 475and an editorial from Hart and Engels on page 447.

Patients undergoing evaluation for solid organ transplantation (SOT) frequently have a history of malignancy. Only patients with treated cancer are considered for SOT but the benefits of transplantation need to be balanced against the risk of tumor recurrence, taking into consideration the potential effects of immunosuppression. Prior guidelines on timing to transplant in patients with a prior treated malignancy do not account for current staging, disease biology, or advances in cancer treatments. To update these recommendations, the American Society of Transplantation (AST) facilitated a consensus workshop to comprehensively review contemporary literature regarding cancer therapies, cancer stage specific prognosis, the kinetics of cancer recurrence, as well as the limited data on the effects of immunosuppression on cancer‐specific outcomes. This document contains prognosis, treatment, and transplant recommendations for melanoma and hematological malignancies. Given the limited data regarding the risk of cancer recurrence in transplant recipients, the goal of the AST‐sponsored conference and the consensus documents produced are to provide expert opinion recommendations that help in the evaluation of patients with a history of a pretransplant malignancy for transplant candidacy. This article presents consensus expert opinion recommendations regarding the timing of transplantation for patients with a history of melanoma or hematological malignancies. The companion review is on page 460and an editorial from Hart and Engels is on page 447.

Diabetic retinopathy screening is instrumental to preventing blindness, but scaling up screening is challenging because of the increasing number of patients with all forms of diabetes. We aimed to create a deep-learning system to predict the risk of patients with diabetes developing diabetic retinopathy within 2 years.

Hintergrund: Digitale Gesundheitsanwendungen (DiGA) halten in vielen Bereichen der Medizin Einzug und haben das Potenzial, die Patientenversorgung zu revolutionieren. In der Rheumatologie wäre der Einsatz bei der axialen Spondyloarthritis (axSpA) in Form einer Trainings- und Bewegungs-App denkbar. In einer repräsentativen Umfrage unter Patienten mit axSpA sollte daher ermittelt werden, ob eine solche App aktuell benötigt wird. Methodik: Durchführung einer anonymen Onlinebefragung bei axSpA-Patienten der Deutschen Vereinigung Morbus Bechterew e. V. mittels eines Fragebogens; Datenauswertung mittels Excel und GraphPad Prism. Ergebnisse: Es nahmen 435 axSpA-Patienten an der Befragung teil. Von den Befragten sehen 84 % die Entwicklung einer speziell auf axSpA abgestimmten Bewegungs-App als notwendig an und genauso viele wollen diese auch nutzen. Patienten unter 60 Jahre, Patienten unter 60-Jahre mit Biologika- oder Januskinase-Inhibitor-Therapie und Patienten mit häufigen Rückenschmerzen geben im Vergleich zur jeweiligen Kontrollsubgruppe einen höheren Bedarf an (jeweils p< 0,001). Schlussfolgerung: Die Entwicklung einer Bewegungs-App für die axSpA wird von einem Großteil der Betroffenen als notwendig angesehen, wobei jüngere und intensiver medikamentös therapierte Patienten einen höheren Bedarf zu haben scheinen.

Qualitätsstandards (QS) sind messbare Konstrukte, die helfen sollen, Versorgungslücken quantitativ zu erfassen, um langfristig die Versorgungsqualität zu verbessern. Die Assessment of SpondyloArthritis International Society (ASAS) hat kürzlich erstmals internationale QS für das Management von Patient*innen mit axialer Spondyloarthritis (axSpA) konsentiert und veröffentlicht. Die Deutsche Gesellschaft für Rheumatologie (DGRh) hat daraufhin beschlossen, diese Standards durch eine Gruppe von Expert*innen aus unterschiedlichen Versorgungsbereichen zu übersetzen, zu prüfen und ggf. zu übernehmen. Vor diesem Hintergrund wurden erstmals nationale QS für das Management von Patient*innen mit axSpA für Deutschland entwickelt. Hierbei wurde v. a. auf Machbarkeit und Praxisrelevanz geachtet. Letztlich wurden 9 QS definiert, mit denen die Qualität der Versorgung in Deutschland gemessen und verbessert werden kann bzw. soll.