Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants.

BACKGROUND: Metabolic-bariatric surgery delivers substantial weight loss and can induce remission or improvement of obesity-related risks and complications. However, more robust estimates of its effect on long-term mortality and life expectancy-especially stratified by pre-existing diabetes status-are needed to guide policy and facilitate patient counselling. We compared long-term survival outcomes of severely obese patients who received metabolic-bariatric surgery versus usual care. METHODS: We did a prespecified one-stage meta-analysis using patient-level survival data reconstructed from prospective controlled trials and high-quality matched cohort studies. We searched PubMed, Scopus, and MEDLINE (via Ovid) for randomised trials, prospective controlled studies, and matched cohort studies comparing all-cause mortality after metabolic-bariatric surgery versus non-surgical management of obesity published between inception and Feb 3, 2021. We also searched grey literature by reviewing bibliographies of included studies as well as review articles. Shared-frailty (ie, random-effects) and stratified Cox models were fitted to compare all-cause mortality of adults with obesity who underwent metabolic-bariatric surgery compared with matched controls who received usual care, taking into account clustering of participants at the study level. We also computed numbers needed to treat, and extrapolated life expectancy using Gompertz proportional-hazards modelling. The study protocol is prospectively registered on PROSPERO, number CRD42020218472. FINDINGS: Among 1470 articles identified, 16 matched cohort studies and one prospective controlled trial were included in the analysis. 7712 deaths occurred during 1·2 million patient-years. In the overall population consisting 174 772 participants, metabolic-bariatric surgery was associated with a reduction in hazard rate of death of 49·2% (95% CI 46·3-51·9, p<0·0001) and median life expectancy was 6·1 years (95% CI 5·2-6·9) longer than usual care. In subgroup analyses, both individuals with (hazard ratio 0·409, 95% CI 0·370-0·453, p<0·0001) or without (0·704, 0·588-0·843, p<0·0001) baseline diabetes who underwent metabolic-bariatric surgery had lower rates of all-cause mortality, but the treatment effect was considerably greater for those with diabetes (between-subgroup I2 95·7%, p<0·0001). Median life expectancy was 9·3 years (95% CI 7·1-11·8) longer for patients with diabetes in the surgery group than the non-surgical group, whereas the life expectancy gain was 5·1 years (2·0-9·3) for patients without diabetes. The numbers needed to treat to prevent one additional death over a 10-year time frame were 8·4 (95% CI 7·8-9·1) for adults with diabetes and 29·8 (21·2-56·8) for those without diabetes. Treatment effects did not appear to differ between gastric bypass, banding, and sleeve gastrectomy (I2 3·4%, p=0·36). By leveraging the results of this meta-analysis and other published data, we estimated that every 1·0% increase in metabolic-bariatric surgery utilisation rates among the global pool of metabolic-bariatric candidates with and without diabetes could yield 5·1 million and 6·6 million potential life-years, respectively. INTERPRETATION: Among adults with obesity, metabolic-bariatric surgery is associated with substantially lower all-cause mortality rates and longer life expectancy than usual obesity management. Survival benefits are much more pronounced for people with pre-existing diabetes than those without. FUNDING: None.

Correction: Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

[This corrects the article DOI: 10.1371/journal.pgen.1005591.].

Structure and Properties of Cs7(H4PO4)(H2PO4)8: A New Superprotonic Solid Acid Featuring the Unusual Polycation (H4PO4).

We report the discovery of a new superprotonic compound, Cs7(H4PO4)(H2PO4)8, or CPP, which forms at elevated temperatures from the reaction of CsH2PO4 and CsH5(PO4)2. The structure, solved using high-temperature single-crystal X-ray diffraction and confirmed by high-temperature 31P NMR spectroscopy, crystallizes in space group Pm3̅n and has a lattice constant of 20.1994(9) Å at 130 °C. The unit cell resembles a 4 × 4 × 4 superstructure of superprotonic CsH2PO4, but features an extraordinary chemical moiety, rotationally disordered H4PO4+ cations, which periodically occupy one of every eight cation sites. The influence of this remarkable cation on the structure, thermodynamics, and proton transport properties of the CPP phase is discussed. Notably, CPP forms at a temperature of 90 °C, much lower than the superprotonic transition temperature of 228 °C of CsH2PO4, and the compound does not appear to have an ordered, low-temperature form. Under nominally dry conditions, the material is stable against dehydration to ∼151 °C, and this results in a particularly wide region of stability of a superprotonic material in the absence of active humidification. The conductivity of Cs7(H4PO4)(H2PO4)8 is moderate, 5.8 × 10-4 S cm-1 at 140 °C, but appears nevertheless facilitated by polyanion (H2PO4-) group reorientation.

Survival Advantage of Laparoscopic Versus Open Resection For Colorectal Liver Metastases: A Meta-analysis of Individual Patient Data From Randomized Trials and Propensity-score Matched Studies.

OBJECTIVE: To perform an individual participant data meta-analysis using randomized trials and propensity-score matched (PSM) studies which compared laparoscopic versus open hepatectomy for patients with colorectal liver metastases (CLM). BACKGROUND: Randomized trials and PSM studies constitute the highest level of evidence in addressing the long-term oncologic efficacy of laparoscopic versus open resection for CLM. However, individual studies are limited by the reporting of overall survival in ways not amenable to traditional methods of meta-analysis, and violation of the proportional hazards assumption. METHODS: Survival information of individual patients was reconstructed from the published Kaplan-Meier curves with the aid of a computer vision program. Frequentist and Bayesian survival models (taking into account random-effects and nonproportional hazards) were fitted to compare overall survival of patients who underwent laparoscopic versus open surgery. To handle long plateaus in the tails of survival curves, we also exploited "cure models" to estimate the fraction of patients effectively "cured" of disease. RESULTS: Individual patient data from 2 randomized trials and 13 PSM studies involving 3148 participants were reconstructed. Laparoscopic resection was associated with a lower hazard rate of death (stratified hazard ratio = 0.853, 95% confidence interval: 0.754-0.965, P = 0.0114), and there was evidence of time-varying effects (P = 0.0324) in which the magnitude of hazard ratios increased over time. The fractions of long-term cancer survivors were estimated to be 47.4% and 18.0% in the laparoscopy and open surgery groups, respectively. At 10-year follow-up, the restricted mean survival time was 8.6 months (or 12.1%) longer in the laparoscopy arm (P < 0.0001). In a subgroup analysis, elderly patients (≥65 years old) treated with laparoscopy experienced longer 3-year average life expectancy (+6.2%, P = 0.018), and those who live past the 5-year milestone (46.1%) seem to be cured of disease. CONCLUSIONS: This patient-level meta-analysis of high-quality studies demonstrated an unexpected survival benefit in favor of laparoscopic over open resection for CLM in the long-term. From a conservative viewpoint, these results can be interpreted to indicate that laparoscopy is at least not inferior to the standard open approach.

Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.

Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.

High-Frequency Echocardiography　- Transformative Clinical and Research Applications in Humans, Mice, and Zebrafish.

Echocardiography is an invaluable tool for characterizing cardiac structure and function in vivo. Technological advances in high-frequency ultrasound over the past 3 decades have increased spatial and temporal resolution, and facilitated many important clinical and basic science discoveries. Successful reverse translation of established echocardiographic techniques, including M-mode, B-mode, color Doppler, pulsed-wave Doppler, tissue Doppler and, most recently, myocardial deformation imaging, from clinical cardiology into the basic science laboratory has enabled researchers to achieve a deeper understanding of myocardial phenotypes in health and disease. With high-frequency echocardiography, detailed evaluation of ventricular systolic function in a range of small animal models is now possible. Furthermore, improvements in frame rate and the advent of diastolic strain rate imaging, when coupled with the use of select pulsed-wave Doppler parameters, such as isovolumic relaxation time and E wave deceleration, have enabled nuanced interpretation of ventricular diastolic function. Comparing pulsed-wave Doppler indices of atrioventricular inflow during early and late diastole with parameters that describe the simultaneous myocardial deformation (e.g., tissue Doppler é and á, global longitudinal strain rate and global longitudinal velocity) may yield additional insights related to myocardial compliance. This review will provide a historical perspective of the development of high-frequency echocardiography and consider how ongoing innovation will help future-proof this important imaging modality for 21st century translational research.

Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration.

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling.

The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.

Impact of New-generation Hybrid Imaging Technology on Radiation Dose during Percutaneous Coronary Interventions and Trans-femoral Aortic Valve Implantations: A comparison with conventional flat-plate angiography.

BACKGROUND: Technological advancements in newer-generation catheterisation laboratories may reduce patient and occupational radiation exposure. METHODS: We compared fluoroscopy time and dose-area product (DAP) between a Philips Allura X-PER FD20 and Siemens Artis Zeego Hybrid systems for 47 single-vessel percutaneous coronary interventions (PCI) and 35 transcatheter aortic valve implantations (21 Corevalve, 14 Edwards Sapien TAVI) using the FD20, versus 30 PCI and 28 TAVI (15 Corevalve, 13 Sapien) with the Zeego over a 24-month period. RESULTS: Multivariate analysis revealed that, adjusting for patient weight and fluoroscopy time, DAP (median, interquartile range) was 26% lower for PCI with the Zeego than the FD20 [55.6 (27.0-91.5) vs 77.6 (51.2-129.1) Gy.cm(2), P=0.03)] and using tomographic imaging with the Zeego did not increase DAP for TAVI procedures [98.1 (65.9-136.6) vs 112.4 (64.9-156.2) Gy.cm(2) (P=NS). Although fluoroscopy times were longer for TAVI procedures than PCI with both systems (23.5-24.4 vs 7.3-9.2mins, p<0.0001), there was a significant difference in DAP between PCI and combined TAVI with the Zeego (55.6 vs 112.4Gy.cm(2), P<0.006) but not with the FD20 (77.6 vs 98.1Gy.cm(2), P=NS). CONCLUSION: Specific dose-reducing features of the new-generation system reduced DAP more for PCI than TAVI, as valve replacement procedures use additional cine-acquisition not necessary for PCI.

Quantitative identification of metastable magnesium carbonate minerals by solid-state 13C NMR spectroscopy.

In the conversion of CO2 to mineral carbonates for the permanent geosequestration of CO2, there are multiple magnesium carbonate phases that are potential reaction products. Solid-state (13)C NMR is demonstrated as an effective tool for distinguishing magnesium carbonate phases and quantitatively characterizing magnesium carbonate mixtures. Several of these mineral phases include magnesite, hydromagnesite, dypingite, and nesquehonite, which differ in composition by the number of waters of hydration or the number of crystallographic hydroxyl groups. These carbonates often form in mixtures with nearly overlapping (13)C NMR resonances which makes their identification and analysis difficult. In this study, these phases have been investigated with solid-state (13)C NMR spectroscopy, including both static and magic-angle spinning (MAS) experiments. Static spectra yield chemical shift anisotropy (CSA) lineshapes that are indicative of the site-symmetry variations of the carbon environments. MAS spectra yield isotropic chemical shifts for each crystallographically inequivalent carbon and spin-lattice relaxation times, T1, yield characteristic information that assist in species discrimination. These detailed parameters, and the combination of static and MAS analyses, can aid investigations of mixed carbonates by (13)C NMR.

Radiation dose during percutaneous treatment of structural heart disease.

BACKGROUND: With the increased application of structural heart intervention techniques, there is concern over increasing radiation dose, especially during lengthy procedures. METHODS: We compared data from 91 consecutive single-vessel percutaneous coronary interventions, 69 patent foramen ovale closures, 25 atrial septal defect closures, 49 percutaneous transluminal mitral valvuloplasties, 57 balloon aortic valvuloplasties, 53 trans-catheter aortic valve implantations (TAVI), 21 left atrial appendage occlusions and 7 MitraClip procedures. RESULTS: The following fluoroscopy times and dose-area product (median, interquartile range) were recorded: patent foramen ovale closure (7.8, 5.3-10.9 minutes; 16.9, 7.5-30.6 Gycm(2)), atrial septal defect closure (10.1, 7.3-13 minutes; 15.5, 11.6-30.5 Gycm(2)), percutaneous transluminal mitral valvuloplasty (14.3, 11.4-24.2 minutes; 37.4, 19.8-87.0 Gycm(2)), balloon aortic valvuloplasty (8.4, 5.2-13.2 minutes; 19.8, 10.2-30.0 Gycm(2)), Edwards Sapien TAVI (24.0, 19.3-34.4 minutes; 86.4, 64.0-111.4 Gycm(2)), Medtronic CoreValve TAVI (19.4, 15.0-26.0 minutes; 101.9, 52.6-143.2 Gycm(2)), left atrial appendage occlusion (18.5, 15.7-29.1 minutes; 84.1, 36.4-140.0 Gycm(2)), Mitraclip procedures (37.2, 14.2-59.9 minutes; 89.1, 26.2-118.7 Gycm(2)), coronary angiography and single vessel percutaneous coronary intervention (6.6, 5.1-11.0 minutes; 62.5, 37.0-95.8 Gycm(2)). CONCLUSION: For structural heart interventions, dose-area product was not significantly greater than for coronary angiography with single-vessel percutaneous coronary artery intervention. This should be reassuring to patients and staff attending prolonged structural heart interventions.

Correction: Superprotonic conductivity in RbH2-3y(PO4)1-y: a phosphate deficient analog to cubic CsH2PO4 in the (1 - x)RbH2PO4 - xRb2HPO4 system.

Correction for 'Superprotonic conductivity in RbH2-3y(PO4)1-y: a phosphate deficient analog to cubic CsH2PO4 in the (1 - x)RbH2PO4 - xRb2HPO4 system' by Grace Xiong et al., Mater. Horiz., 2023, 10, 5555-5563, https://doi.org/10.1039/D3MH00852E.

Every Problem, Every Step, All in Focus: Learning to Solve Vision-Language Problems With Integrated Attention.

Integrating information from vision and language modalities has sparked interesting applications in the fields of computer vision and natural language processing. Existing methods, though promising in tasks like image captioning and visual question answering, face challenges in understanding real-life issues and offering step-by-step solutions. In particular, they typically limit their scope to solutions with a sequential structure, thus ignoring complex inter-step dependencies. To bridge this gap, we propose a graph-based approach to vision-language problem solving. It leverages a novel integrated attention mechanism that jointly considers the importance of features within each step as well as across multiple steps. Together with a graph neural network method, this attention mechanism can be progressively learned to predict sequential and non-sequential solution graphs depending on the characterization of the problem-solving process. To tightly couple attention with the problem-solving procedure, we further design new learning objectives with attention metrics that quantify this integrated attention, which better aligns visual and language information within steps, and more accurately captures information flow between steps. Experimental results on VisualHow, a comprehensive dataset of varying solution structures, show significant improvements in predicting steps and dependencies, demonstrating the effectiveness of our approach in tackling various vision-language problems.

NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo.

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.

Superprotonic conductivity in RbH2-3y(PO4)1-y: a phosphate deficient analog to cubic CsH2PO4 in the (1 - x)RbH2PO4 - xRb2HPO4 system.

In contrast to CsH2PO4 (cesium dihydrogen phosphate, CDP), a material with a well-established superprotonic transition to a high conductivity state at 228 °C, RbH2PO4 (rubidium dihydrogen phosphate, RDP) decomposes upon heating under ambient pressure conditions. Here we find, from study of the (1 - x)RbH2PO4 - xRb2HPO4 system, the remarkable occurrence of cubic, off-stoichiometric RbH2-3y(PO4)1-y, or α-RDP, with a variable Rb : PO4 ratio. Materials were characterized by simultaneous thermal analysis and in situ X-ray powder diffraction performed under high steam partial pressure, from which the phase diagram between RbH2PO4 (x = 0) and Rb5H7(PO4)4 (x = 1/4) was established. The system displays eutectoid behavior, with a eutectoid transition temperature of 242.0 ± 0.5 °C and eutectoid composition of x = 0.190 ± 0.004. Even the end-member Rb5H7(PO4)4 appears to transform to α-RDP, implying y in the chemical formula of 0.2 and a phosphate site vacancy concentration as high as 20%. Charge balance is attained by a decrease in the average number of protons on the remaining phosphate groups. The cubic lattice parameter at x = 0.180, near the eutectoid composition, and at a temperature of 249 °C is 4.7138(2) Å. This value is substantially smaller than the estimated ambient-pressure lattice parameter of stoichiometric RbH2PO4 of 4.837(12) Å, consistent with the proposal of phosphate site vacancies in the former. The superprotonic conductivity of the x = 0.180 material is 6 × 10-3 S cm-1 at 244 °C, a factor of three lower than that of CDP at the same temperature. While the engineering properties of α-RDP do not suggest immediate technological relevance, the discovery of a superprotonic solid acid with a high concentration of phosphate site vacancies opens new avenues for developing proton conducting electrolytes, and in particular, for controlling their transition behavior.

Trial watch: immunotherapeutic strategies on the horizon for hepatocellular carcinoma.

The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation - which is a potentially curative strategy unique to HCC management - as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.

Splinters in the fingernails, heart and brain: thromboembolic complications of non-bacterial thrombotic endocarditis despite treatment with a direct-acting oral anticoagulant.

Non-bacterial thrombotic endocarditis (NBTE) is a rare condition characterized by non-infectious vegetations affecting the cardiac valves. Although systemic thromboembolism is a commonly associated condition, antiphospholipid syndrome is less common. Nevertheless, treatment generally involves long-term anticoagulation. We report a case of a patient with previously undiagnosed NBTE who suffered systemic thromboembolic events despite pre-existing treatment with a direct-acting oral anticoagulant.