Association between the Static and Dynamic Lung Function and CT-Derived Thoracic Skeletal Muscle Measurements-A Retrospective Analysis of a 12-Month Observational Follow-Up Pilot Study.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) with low skeletal muscle mass and severe airway obstruction have higher mortality risks. However, the relationship between dynamic/static lung function (LF) and thoracic skeletal muscle measurements (SMM) remains unclear. This study explored patient characteristics (weight, BMI, exacerbations, dynamic/static LF, sex differences in LF and SMM, and the link between LF and SMM changes. METHODS: A retrospective analysis of a 12-month prospective follow-up study patients with stable COPD undergoing standardized treatment, covering mild to severe stages, was conducted. The baseline and follow-up assessments included computed tomography and body plethysmography. RESULTS: This study included 35 patients (17 females and 18 males). This study revealed that females had more stable LF but tended to have greater declines in SMM areas and indices than males (-5.4% vs. -1.9%, respectively), despite the fact that females were younger and had higher LF and less exacerbation than males. A multivariate linear regression showed a negative association between the inspiratory capacity/total lung capacity ratio (IC/TLC) and muscle fat area. CONCLUSIONS: The findings suggest distinct LF and BC progression patterns between male and female patients with COPD. A low IC/TLC ratio may predict increased muscle fat. Further studies are necessary to understand these relationships better.

Unveiling the formation mechanism of PbxPdy intermetallic phases in solvothermal synthesis using in situ X-ray total scattering.

Pd possesses attractive catalytic properties and nano-structuring is an obvious way to enhance catalytic activity. Alloying Pd with Pb has been shown to enhance the catalytic effect of alcohol oxidation. Further optimization of the catalytic effect can be accomplished by controlling the particle size and key to this is understanding the formation mechanism. By monitoring solvothermal syntheses using in situ X-ray total scattering, this study unveils the formation mechanism of PbxPdy intermetallic nanoparticles. The formation occurs through a multi-step mechanism. Initially, Pd nanoparticles are formed, followed by incorporation of Pb into the Pd-structure, thus forming PbxPdy intermetallic nanoparticles. By varying the reaction time and temperature, the incorporation of Pb can be controlled, thereby tailoring the phase outcome. Based on the in situ solvothermal syntheses, ex situ autoclave syntheses were performed, resulting in the synthesis of Pb3Pd5 and Pb9Pd13 with a purity above 93%. The catalytic effect of these intermetallic phases towards the hydrogen evolution reaction (HER) is assessed. It is found that Pd, Pb3Pd5, and Pb9Pd13 have comparable stabilities, however, the overpotential increases with increasing amounts of Pb.

Pair Distribution Function from Liquid Jet Nanoparticle Suspension using Femtosecond X-ray Pulses.

X-ray scattering data measured on femtosecond timescales at the SACLA X-ray Free Electron Laser (XFEL) facility on a suspension of HfO2 nanoparticles in a liquid jet were used for pair distribution function (PDF) analysis. Despite a non-optimal experimental setup resulting in a modest Qmax of ~8 Å-1 , a promising PDF was obtained. The main features were reproduced when comparing the XFEL PDF to a PDF obtained from data measured at the PETRA III synchrotron light source. Refining structural parameters such as unit cell dimension and particle size from the XFEL PDF provided reliable values. Although the reachable Qmax limited the obtainable information, the present results indicate that good quality PDFs can be obtained on femtosecond timescales if the experimental conditions are further optimized. The study therefore encourages a new direction in ultrafast structural science where structural features of amorphous and disordered systems can be studied.

Medium-Range Order Structure Controls Thermal Stability of Pores in Zeolitic Imidazolate Frameworks.

Metal-organic framework (MOF) glasses have multiple potential applications, as they combine advantages of traditional glasses with those of MOFs. The melt-quenching process used to form MOF glasses typically leads to a significant decrease in porosity, but the structural origin of this thermally induced pore collapse remains largely unknown. Here, we study the melting process of three zeolitic imidazolate frameworks (ZIFs), namely ZIF-4, ZIF-62, and ZIF-76, using ab initio molecular dynamics (MD) simulations. By analyzing the MD data using topological data analysis, we show that while the three ZIF systems exhibit similar short-range order structural changes upon heating, they exhibit significant differences in their medium-range order structure. Specifically, ZIF-76 retains more of its medium-range order structures in the liquid state compared to the other glass-forming ZIF systems, which allows it to remain more porous than ZIF-4 and ZIF-62. As such, our results may aid in understanding the structural features that govern the ability to maintain porosity in the melt-quenched glassy state.

A reactor for time-resolved X-ray studies of nucleation and growth during solvothermal synthesis.

Understanding the nucleation and growth mechanisms of nanocrystals under hydro- and solvothermal conditions is key to tailoring functional nanomaterials. High-energy and high-flux synchrotron radiation is ideal for characterization by powder X-ray diffraction and X-ray total scattering in real time. Different versions of batch-type cell reactors have been employed in this work, exploiting the robustness of polyimide-coated fused quartz tubes with an inner diameter of 0.7 mm, as they can withstand pressures up to 250 bar and temperatures up to 723 K for several hours. Reported here are recent developments of the in situ setups available for general users on the P21.1 beamline at PETRA III and the DanMAX beamline at MAX IV to study nucleation and growth phenomena in solvothermal synthesis. It is shown that data suitable for both reciprocal-space Rietveld refinement and direct-space pair distribution function refinement can be obtained on a timescale of 4 ms.

Meltable, Glass-Forming, Iron Zeolitic Imidazolate Frameworks.

We describe the first meltable iron-based zeolitic imidazolate framework (ZIF), denoted MUV-24. This material, elusive from direct synthesis, is obtained from the thermal treatment of [Fe3(im)6(Him)2], which yields Fe(im)2 upon loss of the neutral imidazole molecules. Different crystalline phase transformations are observed upon further heating, until the material melts at 482 °C. Vitrification upon cooling of the liquid phase gives rise to the first Fe-metal-organic framework glass. X-ray total scattering experiments show that the tetrahedral environment of the crystalline solids is maintained in the glass, whereas nanoindentation measurements reveal an increase in Young's modulus, in agreement with stiffening upon vitrification.

Evaluation of automated radiostereometric image registration in total knee arthroplasty utilizing a synthetic-based and a CT-based volumetric model.

Radiostereometic analysis (RSA) is an accurate method for rigid body pose (position and orientation) in three-dimensional space. Traditionally, RSA is based on insertion of periprosthetic tantalum markers and manual implant contour selection which limit clinically application. We propose an automated image registration technique utilizing digitally reconstructed radiographs (DRR) of computed tomography (CT) volumetric bone models (autorsa-bone) as a substitute for tantalum markers. Furthermore, an automated synthetic volumetric representation of total knee arthroplasty implant models (autorsa-volume) to improve previous silhouette-projection methods (autorsa-surface). As reference, we investigated the accuracy of implanted tantalum markers (marker) or a conventional manually contour-based method (mbrsa) for the femur and tibia. The data are presented as mean (standard deviation). The autorsa-bone method displayed similar accuracy of -0.013 (0.075) mm compared to the gold standard method (marker) of -0.013 (0.085). The autorsa-volume with 0.034 (0.106) mm did not markedly improve the autorsa-surface with 0.002 (0.129) mm, and none of these reached the mbrsa method of -0.009 (0.094) mm. In conclusion, marker-free RSA is feasible with similar accuracy as gold standard utilizing DRR and CT obtained volumetric bone models. Furthermore, utilizing synthetic generated volumetric implant models could not improve the silhouette-based method. However, with a slight loss of accuracy the autorsa methods provide a feasible automated alternative to the semi-automated method.

Zr4+ solution structures from pair distribution function analysis.

The structures of metal ions in solution constitute essential information for obtaining chemical insight spanning from catalytic reaction mechanisms to formation of functional nanomaterials. Here, we explore Zr4+ solution structures using X-ray pair distribution function (PDF) analysis across pH (0-14), concentrations (0.1-1.5 M), solvents (water, methanol, ethanol, acetonitrile) and metal sources (ZrCl4, ZrOCl2·8H2O, ZrO(NO3)2·xH2O). In water, [Zr4(OH)8(OH2)16]8+-tetramers are predominant, while non-aqueous solvents contain monomeric complexes. The PDF analysis also reveals second sphere coordination of chloride counter ions to the aqueous tetramers. The results are reproducible across data measured at three different beamlines at the PETRA-III and MAX IV synchrotron light sources.

Delineation uncertainties of tumour volumes on MRI of head and neck cancer patients.

Background: During the last decade, radiotherapy using MR Linac has gone from research to clinical implementation for different cancer locations. For head and neck cancer (HNC), target delineation based only on MR images is not yet standard, and the utilisation of MRI instead of PET/CT in radiotherapy planning is not well established. We aimed to analyse the inter-observer variation (IOV) in delineating GTV (gross tumour volume) on MR images only for patients with HNC. Material/methods: 32 HNC patients from two independent departments were included. Four clinical oncologists from Denmark and four radiation oncologists from Australia had independently contoured primary tumour GTVs (GTV-T) and nodal GTVs (GTV-N) on T2-weighted MR images obtained at the time of treatment planning. Observers were provided with sets of images, delineation guidelines and patient synopsis. Simultaneous truth and performance level estimation (STAPLE) reference volumes were generated for each structure using all observer contours. The IOV was assessed using the DICE Similarity Coefficient (DSC) and mean absolute surface distance (MASD). Results: 32 GTV-Ts and 68 GTV-Ns were contoured per observer. The median MASD for GTV-Ts and GTV-Ns across all patients was 0.17 cm (range 0.08-0.39 cm) and 0.07 cm (range 0.04-0.33 cm), respectively. Median DSC relative to a STAPLE volume for GTV-Ts and GTV-Ns across all patients were 0.73 and 0.76, respectively. A significant correlation was seen between median DSCs and median volumes of GTV-Ts (Spearman correlation coefficient 0.76, p < 0.001) and of GTV-Ns (Spearman correlation coefficient 0.55, p < 0.001). Conclusion: Contouring GTVs in patients with HNC on MRI showed that the median IOV for GTV-T and GTV-N was below 2 mm, based on observes from two separate radiation departments. However, there are still specific regions in tumours that are difficult to resolve as either malignant tissue or oedema that potentially could be improved by further training in MR-only delineation.

Characterisation of intravenous pharmacokinetics in Göttingen minipig and clearance prediction using established in vitro to in vivo extrapolation methodologies.

The use of the Göttingen minipig as an animal model for drug safety testing and prediction of human pharmacokinetics (PK) continues to gain momentum in pharmaceutical research and development. The aim of this study was to evaluate in vitro to in vivo extrapolation (IVIVE) methodologies for prediction of hepatic, metabolic clearance (CLhep,met) in Göttingen minipig, using a comprehensive set of compounds.In vivo clearance was determined in Göttingen minipig by intravenous cassette dosing and hepatocyte intrinsic clearance, plasma protein binding and non-specific incubation binding were determined in vitro. Prediction of CLhep,met was performed by IVIVE using conventional and adapted formats of the well-stirred liver model.The best prediction of in vivo CLhep,met from scaled in vitro kinetic data was achieved using an empirical correction factor based on a 'regression offset' of the IVIV relationship.In summary, these results expand the in vitro and in vivo PK knowledge in Göttingen minipig. We show regression corrected IVIVE provides superior prediction of in vivo CLhep,met in minipig offering a practical, unified scaling approach to address systematic under-predictions. Finally, we propose a reference set for researchers to establish their own 'lab-specific' regression correction for IVIVE in minipig.

Rocuronium 0.3 or 0.9 mg/kg comparing onset time, duration of action, and intubating conditions in patients 80 years and older: A randomized study.

BACKGROUND: Limited data exist about the optimal dose of rocuronium for intubation in elderly patients. We hypothesized that rocuronium 0.9 mg/kg would lead to a shorter onset time than 0.3 mg/kg in patients above 80 years. METHODS: Thirty-four patients were randomized to either rocuronium 0.3 or 0.9 mg/kg. The primary outcome was onset time defined as time to train-of-four (TOF) count of 0. Other outcomes included duration of action (time to TOF ratio >0.9), proportion of excellent intubating conditions using the Fuchs-Buder scale and tracheal intubating conditions using the Intubating Difficulty Scale (IDS). RESULTS: Rocuronium 0.9 mg/kg resulted in shorter onset time compared to rocuronium 0.3 mg/kg; 108 s (SD 40) vs. 228 s (SD 140) (difference: 119 s [95% CI: 41-196], p = .005), respectively. However, in 66% of the patients receiving rocuronium 0.3 mg/kg a TOF count of 0 was not obtained. Duration of action was longer after rocuronium 0.9 mg/kg: 118 min (SD 43) vs. 46 min (SD 13) (difference: 72 min [95% CI: 49-95] p < .0001), and a greater proportion of excellent intubating conditions (Fuchs-Buder) was obtained; 11/16 (69%) vs 4/18 (22%) (p = .006). No difference was found regarding IDS score. CONCLUSION: Rocuronium 0.9 mg/kg resulted in a shorter onset time compared to rocuronium 0.3 mg/kg in patients above 80 years of age. In 66% of the patients receiving rocuronium 0.3 mg/kg a TOF count of 0 was not obtained.

A high fraction of inspired oxygen may increase mortality in intubated trauma patients - A retrospective cohort study.

BACKGROUND: Mechanical ventilation of trauma patients is common, and many will require a higher than normal fraction of inspired oxygen (FiO2) to avoid hypoxaemia. The primary objective of this study was to assess the association between FiO2 and all-cause, one-year mortality in intubated trauma patients. METHODS: Adult trauma patients intubated in the initial phase post-trauma between 2015 and 2017 were retrospectively identified. Information on FiO2 during the first 24 hours of hospitalisation and mortality was registered. For each patient the number of hours of the first 24 hours exposed to an FiO2 ≥ 80%, ≥ 60%, and ≥ 40%, respectively, were determined and categorised into exposure durations. The associations of these FiO2 exposures with mortality were evaluated using Cox regression adjusting for age, sex, body mass index (BMI), Injury Severity Score (ISS), prehospital Glasgow Coma Scale (GCS) score, and presence of thoracic injuries. RESULTS: We included 218 intubated trauma patients. The median prehospital GCS score was 6 and the median ISS was 25. One-year mortality was significantly increased when patients had received an FiO2 above 80% for 3-4 hours compared to <2 hours (hazard ratio (95% CI) 2.7 (1.3-6.0), p= 0.011). When an FiO2 above 80% had been administered for more than 4 hours, there was a trend towards a higher mortality as well, but this was not statistically significant. There was a significant, time-dependent increase in mortality for patients who had received an FiO2 ≥ 60%. There was no significant relationship observed between mortality and the duration of FiO2 ≥ 40%. CONCLUSION: A fraction of inspired oxygen above 60% for more than 2 hours during the first 24 hours of admission was associated with increased mortality in intubated trauma patients in a duration-dependent manner. However, given the limitations of this retrospective study, the findings need to be confirmed in a larger, randomized set-up.

Supplemental oxygen for traumatic brain injury: A systematic review.

BACKGROUND: Oxygen supplementation is recommended after traumatic brain injury (TBI) but excessive oxygen may be harmful. The aim of this study was to investigate the effect of supplemental oxygen or high/low inspiratory oxygen fraction (FiO2 ) for TBI patients on in-hospital mortality. METHODS: We searched Medline (Pubmed), EMBASE and the Cochrane Library for interventional and observational studies fulfilling the following criteria: TBI patients >17 years (population); initial use of supplemental oxygen/high (≥0.6) FiO2 (intervention) vs no supplemental oxygen/low (<0.6) FiO2 (control) for spontaneously breathing or mechanically ventilated TBI patients, respectively with in-hospital mortality as primary outcome. Secondary outcomes were 30-day and 1-year mortality, length of stay in hospital or intensive care unit, days on mechanical ventilation, complications, and neurological impairment. RESULTS: We screened 4846 citations. Two interventional studies comparing high vs low FiO2 for mechanically ventilated TBI patients were included. No difference in in-hospital mortality was found. The first study found a statistically significant shorter length of stay in the intensive care unit for the high FiO2 -group (6.5 [4.6-11.4] vs. 11.4 [5.8-17.2] days, p = 0.02). The second study found a lower disability at 6 months in the high FiO2 -group with low disability in 25 (73.5%) vs. 15 (44.1%), moderate disability in 9 (26.5%) vs. 16 (47.1%), and severe disability in 0 (0.0%) vs. 3 (8.8%), p = 0.02. CONCLUSION: Evidence on the effect of initial use of high/low FiO2 for TBI patients on in-hospital mortality was extremely limited. Evidence on the use of supplemental oxygen for spontaneously breathing TBI patients is lacking.

Ketamine versus propofol for rapid sequence induction in trauma patients: a retrospective study.

BACKGROUND: Rapid Sequence Induction (RSI) is used for emergency tracheal intubation to minimise the risk of pulmonary aspiration of stomach contents. Ketamine and propofol are two commonly used induction agents for RSI in trauma patients. Yet, no consensus exists on the optimal induction agent for RSI in the trauma population. The aim of this study was to compare 30-day mortality in trauma patients after emergency intubation prehospitally or within 30 min after arrival in the trauma centre using either ketamine or propofol for RSI. METHODS: In this investigator-initiated, retrospective study we included adult trauma patients emergently intubated with ketamine or propofol registered in the local trauma registry at Rigshospitalet, a tertiary university hospital that hosts a level-1 trauma centre. The primary outcome was 30-day mortality. Secondary outcomes included hospital and Intensive Care Unit length of stay as well as duration of mechanical ventilation. We analysed outcomes using multivariable logistic regression models adjusting for age, sex, injury severity score, shock (systolic blood pressure < 90 mmHg) and Glasgow Coma Scale score before intubation and present results as odds ratios (ORs) with 95% confidence intervals. RESULTS: From January 1st, 2015 through December 31st, 2019 we identified a total of 548 eligible patients. A total of 228 and 320 patients received ketamine and propofol, respectively. The 30-day mortality for patients receiving ketamine and propofol was 20.2% and 22.8% (P = 0.46), respectively. Adjusted OR for 30-day mortality was 0.98 [0.58-1.66], P = 0.93. We found no significant association between type of induction agent and hospital length of stay, Intensive Care Unit length of stay or duration of mechanical ventilation. CONCLUSIONS: In this study, trauma patients intubated with ketamine did not have a lower 30-day mortality as compared with propofol.

Unravelling the complex formation mechanism of HfO2 nanocrystals using in situ pair distribution function analysis.

Hafnia, HfO2, which is a wide band gap semiconducting oxide, is much less studied than the chemically similar zirconia (ZrO2). Here, we study the formation of hafnia nanocrystals from hafnium tetrachloride in methanol under solvothermal conditions (248 bar, 225-450 °C) using complementary in situ powder X-ray diffraction (PXRD) and Pair Distribution Function (PDF) analysis. The main structural motif of the precursor solution (HfCl4 dissolved in methanol) is a Hf oxide trimer with very similar local structure to that of m-HfO2. Different measurements on precursor solutions show large intensity variation for the Hf-Cl correlations signifying different extents of HCl elimation. A few seconds of heating lead to a correlation appearing at 3.9 Å corresponding to corner-sharing Hf-polyhedra in a disordered solid matrix. During the next minutes (depending on temperature) the disordered structure rearranges and the nearest neighbour Hf-Hf distance contracts while the Hf-O coordination number increases. After approximately 90 seconds (at T = 250 °C) the structural rearrangement terminates and 1-2 nm nanocrystals of m-HfO2 nucleate. Initially the m-HfO2 nanocrystals have significant disorder as reflected in large Hf atomic displacement parameter (ADP) values, but as the nanocrystals grow to 5-6 nm in size during extended heating, the Hf ADPs decrease toward the values obtained for ordered bulk structures. The nanocrystal growth is not well modelled by the Johnson-Mehl-Avrami expression reflecting that multiple complex chemical processes occur during this highly nonclassical nanocrystal formation under solvothermal conditions.

A blinded randomized study comparing intubating conditions after either rocuronium 0.6 mg·kg-1 or remifentanil 2 µg·kg-1 in elderly patients.

BACKGROUND: To facilitate tracheal intubation, either a neuromuscular blocking agent or a bolus dose of remifentanil can be administered. We hypothesized that rocuronium 0.6 mg·kg-1 provided a larger proportion of excellent intubating conditions compared to remifentanil 2 µg·kg-1 in patients above 80 years. METHODS: A total of 78 patients were randomized to either rocuronium 0.6 mg·kg-1 or remifentanil 2 µg·kg-1 . General anaesthesia was initiated with fentanyl and propofol. Two minutes after the administration of either rocuronium or remifentanil, tracheal intubating conditions were evaluated using the Fuchs-Buder scale by a blinded investigator, and our primary outcome was the proportion of patients presenting intubating conditions deemed as excellent. Further outcomes included the Intubating Difficulty Scale (IDS), hoarseness or sore throat 24 h postoperatively, and intervention against hypotension. RESULTS: No difference in the occurrence of excellent intubating conditions was found comparing the rocuronium group with the remifentanil group; 10 (28%) versus 15 (39%) (p = .29), respectively, relative risk = 0.72. Interventions against hypotension were used in 24 (67%) versus 28 (74%) (p = .51), respectively. Hoarseness and sore throat 24 h postoperatively were found in 37% versus 35% p = .86, and 14% versus 5% p = .20, respectively. The IDS score was 2 versus 2 p = .48. CONCLUSION: No difference in intubating conditions was found 2 min after the administration of either rocuronium 0.6 mg·kg-1 or remifentanil 2 µg·kg-1 in patients aged above 80 years. Intubation conditions were less than optimal in a large proportion of this patient population. CLINICAL TRIALS REGISTRATION: NCT04287426.

Preoperative CHA2DS2-VASc Score is Associated With Postoperative Survival Following Surgical Ablation Concomitantly With Other Cardiac Surgery.

BACKGROUND: The CHA2DS2-VASc scoring system has been shown to predict long-term outcomes in patients undergoing catheter ablation but has not yet been investigated for patients undergoing surgical ablation. Therefore, the objective was to evaluate the ability of CHA2DS2-VASc to predict long-term outcomes after surgical ablation. METHOD: In a retrospective study, patients were included if they underwent surgical ablation concomitantly with other cardiac surgery. Patients were divided into low-risk (score 0-1), medium-risk (score 2-4) and high-risk (score ≥5) groups based on their CHA2DS2-VASc score. Data on survival, atrial fibrillation (AF) recurrence, and stroke were collected retrospectively at the end of the follow-up period. RESULTS: A total of 587 patients underwent surgical ablation concomitantly with other cardiac surgery. Survival analysis revealed a difference between the three stratified CHA2DS2-VASc risk groups, (p<0.001). Similarly, there was a difference in AF recurrence rates between stratified CHA2DS2-VASc groups among patients with persistent/long-standing persistent AF (p=0.018). There were no statistically significant differences between stratified CHA2DS2-VASc risk groups in terms of recurrence rates of paroxysmal AF or stroke. Finally, the CHA2DS2-VASc scoring system was an independent predictor of 5-year mortality after adjusting for potential confounders (hazard ratio 1.25; p=0.002). CONCLUSIONS: Preoperative CHA2DS2-VASc scores were associated with postoperative survival in patients undergoing surgical ablation for AF. Post-hoc analyses showed that CHA2DS2-VASc was also a predictor of AF recurrence in patients with persistent/long-standing persistent AF. However, this needs to be confirmed in a prospective study.

Search and Rescue Helicopters for Emergency Medical Service Assistance: A Retrospective Study.

OBJECTIVE: The time until treatment is a crucial factor for the outcome after medical emergencies. One way of reducing transportation time is the use of helicopter-based emergency medical services, but poor weather conditions, commitment to another mission, or technical problems may limit the availability. In these cases, military search and rescue (SAR) helicopters can be used. The aim of this study was to investigate the role of SAR helicopters in the civilian emergency medical system. METHODS: We conducted a retrospective study of SAR mission reports and SAR medical records collected from the archives of the Royal Danish Air Force for the years 2016 and 2017. RESULTS: A total of 1,262 mission reports were included with a total of 628 medical records available in the study period. There were 490 of 1,246 (39.3%) missions involving patients. Interhospital transfers accounted for 306 of 604 (50.7%) of cases, whereas island evacuation constituted 110 of 604 (18.2%) cases. The most prevalent suspected diagnosis was acute coronary syndrome (14.4%). The 30-day survival rate was 87.6%. CONCLUSION: The military SAR helicopters were most commonly activated for civilian emergency medical service mission assistance due to poor weather conditions. The most frequent medical condition was acute coronary syndrome.

Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined.

BACKGROUND: Weight regain after weight loss is a major problem in the treatment of persons with obesity. METHODS: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed. RESULTS: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group. CONCLUSIONS: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).

Bond Switching in Densified Oxide Glass Enables Record-High Fracture Toughness.

Humans primarily interact with information technology through glass touch screens, and the world would indeed be unrecognizable without glass. However, the low toughness of oxide glasses continues to be their Achilles heel, limiting both future applications and the possibility to make thinner, more environmentally friendly glasses. Here, we show that with proper control of plasticity mechanisms, record-high values of fracture toughness for transparent bulk oxide glasses can be achieved. Through proper combination of gas-mediated permanent densification and rational composition design, we increase the glasses' propensity for plastic deformation. Specifically, we demonstrate a fracture toughness of an aluminoborate glass (1.4 MPa m0.5) that is twice as high as that of commercial glasses for mobile devices. Atomistic simulations reveal that the densification of the adaptive aluminoborate network increases coordination number changes and bond swapping, ultimately enhancing plasticity and toughness upon fracture. Our findings thus provide general insights into the intrinsic toughening mechanisms of oxide glasses.