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We applied reaction microscopy to elucidate fast non-adiabatic dissociation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV with synchrotron radiation. For the very rare D+ + O+ + D breakup channel, the particle momenta, angular, and energy distributions of electrons and ions, measured in coincidence, reveal distinct electronic dication states and their dissociation pathways via spin-orbit coupling and charge transfer at crossings and seams on the potential energy surfaces. Notably, we could distinguish between direct and fast sequential dissociation scenarios. For the latter case, our measurements reveal the geometry and orientation of the deuterated water molecule with respect to the polarization vector that leads to this rare 3-body molecular breakup channel. Aided by multi-reference configuration-interaction calculations, the dissociation dynamics could be traced on the relevant potential energy surfaces and particularly their crossings and seams. This approach also unraveled the ultrafast time scales governing these processes.

IntroductionEmerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.MethodsWe used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).ResultsEighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups.DiscussionThese findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD.HighlightsMicrobial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Schistosomiasis is a disease affecting >200 million people worldwide, but its treatment relies on a single agent, praziquantel. To investigate new avenues for schistosomiasis control, we have conducted the first systematic analysis of bromodomain-containing proteins (BCPs) in a causative species, Schistosoma mansoni. Having identified 29 putative bromodomains (BRDs) in 22 S. mansoni proteins, we selected SmBRD3, a tandem BRD-containing BCP that shows high similarity to the human bromodomain and extra terminal domain (BET) family, for further studies. Screening 697 small molecules identified the human BET BRD inhibitor I-BET726 as a ligand for SmBRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of SmBRD3 [SmBRD3(2)] enabled rational design of a quinoline-based ligand (15) with an ITC Kd = 364 ± 26.3 nM for SmBRD3(2). The ethyl ester pro-drug of compound 15 (compound 22) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in ex vivo assays.

We have captured an 8.7 A conformational change that takes place in the cleavage site of the hammerhead ribozyme during self-cleavage, using X-ray crystallography combined with physical and chemical trapping techniques. This rearrangement brings the hammerhead ribozyme from the ground state into a conformation that is poised to form the transition state geometry required for hammerhead RNA self-cleavage. Use of a 5’-C-methylated ribose adjacent to the cleavage site permits this ordinarily transient conformational change to be kinetically trapped and observed crystallographically after initiating the hammerhead ribozyme reaction in the crystal. Cleavage of the corresponding unmodified hammerhead ribozyme in the crystal under otherwise identical conditions is faster than in solution, indicating that we have indeed trapped a catalytically relevant intermediate form of this RNA enzyme

BackgroundSchwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.MethodsWe performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.ResultsWe identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.ConclusionsWe thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

Human-driven environmental changes shape ecological communities from local to global scales. Within cities, landscape-scale patterns and processes and species characteristics generally drive local-scale wildlife diversity. However, cities differ in their structure, species pools, geographies and histories, calling into question the extent to which these drivers of wildlife diversity are predictive at continental scales. In partnership with the Urban Wildlife Information Network, we used occurrence data from 725 sites located across 20 North American cities and a multi-city, multi-species occupancy modelling approach to evaluate the effects of ecoregional characteristics and mammal species traits on the urbanization-diversity relationship. Among 37 native terrestrial mammal species, regional environmental characteristics and species traits influenced within-city effects of urbanization on species occupancy and community composition. Species occupancy and diversity were most negatively related to urbanization in the warmer, less vegetated cities. Additionally, larger-bodied species were most negatively impacted by urbanization across North America. Our results suggest that shifting climate conditions could worsen the effects of urbanization on native wildlife communities, such that conservation strategies should seek to mitigate the combined effects of a warming and urbanizing world.

Xiao-Dong Huang,1,* Jia-Bao Chen,2,* Xiao-Yun Dong,1 Wei-Long Wang,1 Jin Zhou,1 Zhen-Feng Zhou1 1Department of Anesthesiology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital, Hangzhou First People’s Hospital Qianjiang New City Campus, Zhejiang Chinese Medical University), Hangzhou, People’s Republic of China; 2Department of Anesthesiology, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medicine College), Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhen-Feng Zhou, Department of Anesthesiology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital, Hangzhou First People’s Hospital Qianjiang New City Campus, Zhejiang Chinese Medical University), Hangzhou, 310008, People’s Republic of China, Tel +86-571-56005077, Email zhenfeng9853@163.comPurpose: This study aimed to investigate the influence of fentanyl on the effective dose of remimazolam-induced sedation in elderly female patients undergoing general anesthesia.Patients and Methods: Sixty female patients aged 65– 80 years undergoing selective general anesthesia were randomized into two groups: Group R+F received an initial dose of remimazolam (7.5 mg) with fentanyl (1 μg/kg), while Group R received remimazolam alone. Dosing adjustments (± 2.5 mg) were made based on the response of the preceding patient using the up-and-down allocation technique. The ED50 and ED95 were calculated using a sequential formula and probit regression. Probit regression was also used to assess the relative potency of remimazolam between groups. Sedation levels were evaluated using the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale.Results: The ED50 for remimazolam was significantly lower in Group R+F compared to Group R (p= 0.007). Probit regression estimated the ED50 and ED95 values for Group R+F at 4.878 mg (95% CI, 3.845– 5.859) and 8.184 mg (95% CI, 6.636– 13.546), respectively. In contrast, Group R demonstrated ED50 and ED95 values of 6.733 mg (95% CI, 5.533– 8.068) and 11.298 mg (95% CI, 9.101– 19.617), respectively.Conclusion: This study provides compelling evidence that the administration of 1 μg/kg of fentanyl significantly reduces the required sedative dose of remimazolam by approximately 30% during induction in elderly patients. Importantly, the concomitant use of 1 μg/kg of fentanyl does not increase the risk of adverse effects such as hypotension, respiratory depression.Keywords: remimazolam, fentanyl, effective dose, elderly

Dan-Dan Li,1,&ast; Xue Yang,1,&ast; Yang Yang,2,&ast; Li-Hua Zhao,1 Tian-Tian Zhang,3 Yi-Nan Wang,1 Jian-Bin Su,1 Li-Hua Wang,4 Hai-Yan Shi3 1Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 2Department of General Practice, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 3Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 4Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Hua Wang, Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email wlh512512@163.com Hai-Yan Shi, Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email 1198827119@qq.comBackground: Physical activity (PA) exerts an important influence on glycemic control in type 2 diabetes (T2D) patients. Alterations in body composition in patients with T2D may be involved in the overall pathophysiologic process, but PAs and alterations in body composition have been poorly studied.Methods: A total of 615 patients with T2D were selected by convenient sampling. The patients were investigated with the International Physical Activity Questionnaire (IPAQ-S). Moreover, biochemical indices were collected, and the progression of the body composition of the subjects was determined via dual-energy X-ray absorptiometry (DXA). The variables included lumbar bone mineral density (LSBMD), femoral neck bone mineral density (FNBMD), hip bone mineral density (HBMD), whole-body bone mineral density (TBMD), limb skeletal muscle mass index (ASMI), whole-body fat percentage (B-FAT) and trunk fat percentage (T-FAT). Moreover, the levels of physical activity (high level of physical activity [H-PA], medium level of physical activity [M-PA] and low level of physical activity [L-PA]) were divided into three groups to analyze the changes in patient body composition with changes in physical activity level.Results: One-way analysis of variance showed that β-CTX, TP1NP, HbA1c, B-FAT and T-FAT increased significantly (p< 0.05), while 25(OH)D, LSBMD, FNBMD, HBMD, TBMD and ASMI decreased significantly (p< 0.001) with the decrease of physical activity. However, there was no significant difference in serum lipids between lnHOMA-ir and lnHOMA-β (p> 0.05). Multiple linear regression model was established to gradually adjust for clinical confounding factors. It was found that physical activity level was independently positively correlated with LSBMD, FNBMD, HBMD, TBMD, and ASMI, and was independently negatively correlated with B-FAT and T-FAT in patients with type 2 diabetes.Conclusion: A lack of physical activity is an independent risk factor for decreased bone mineral density, decreased skeletal muscle content and increased fat content in patients with T2D.Keywords: type 2 diabetes, physical activity, body composition, correlation

Summary Background: Malaria remains one of the most common threats to child survival in Nigeria. Chloroquine (CQ) is the first line drug of choice against uncomplicated malaria. In view of reports indicating an increasing resistance of P. falciparum to CQ, a regular surveillance of malaria therapy requires constant evaluation of its efficacy and that of suitable alternatives. Objective: To compare the current efficacy of CQ with that of sulphadoxine/pyrimethamine (SP) in the treatment of P falciparum infection in Plateau State. Patients and Methods: Using a 14-day protocol, an open randomized study of the efficacy of CQ and SP in the treatinent of uncomplicated P. falciparum infection was conducted in 109 febrile children under five years of age in the Barkin Ladi Local Government Area of Plateau State. Adequate clinical response (ACR), adequate clinical and parasitological response (ACPR) and clinical efficacy (CE) were assessed in the two treatment groups. Results: Out of the 708 children screened for P. falciparum parasitaemia, 378 (53.4 percent) tested positive. One hundred and nine of the 115 children who qualified for enrollment, completed the study. Fifty-four and 55 children received CQ and SP, respectively. The mean (SD) duration of illness before presentation at the hospital was 1.5 (0.71) days. The means of age, temperature, packed cell volume and parasite counts on admission to the study were similar in the two treatment groups. Thirty-nine (75 percent) of the 52 children who received CQ, and in respect of whom the data was complete, attained clinical cure compared to 52 (94.5 percent) of 55 children on SP (p=0.013). Twenty-seven (51.9 percent) of 52 children treated with CQ versus 48 (87.3 percent) of 55 children on SP achieved adequate clinical and parasitological cure (p=0.00010). Thirty (57.7 percent) of 52 children on CQ versus 48 (87.3 percent) of 55 children who received SP were clinically cured (p = 0.0012). Failure to achieve fever clearance by day 14 was noted in eight (16.7 percent) of 48 children on CQ against four (7.3 percent) of 55 children on SP. Conclusion: Although both drugs fell short of a hundred percent cure rate, CQ performed less creditably than SP in the treatment of uncomplicated malaria. There appears to be an urgent need to seek other effective alternative first-line anti-malarial drugs in the country.

We present an investigation of the relaxation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV. We focus on the very rare D+ + O+ + D reaction channel in which the sequential fragmentation mechanisms were found to dominate the dynamics. Aided by theory, the state-selective formation and breakup of the transient OD+(a1Δ, b1Σ+) is traced, and the most likely dissociation path-OD+: a1Δ or b1Σ+ → A 3Π → X 3Σ- → B 3Σ--involving a combination of spin-orbit and non-adiabatic charge transfer transitions is determined. The multi-step transition probability of this complex transition sequence in the intermediate fragment ion is directly evaluated as a function of the energy of the transient OD+ above its lowest dissociation limit from the measured ratio of the D+ + O+ + D and competing D+ + D+ + O sequential fragmentation channels, which are measured simultaneously. Our coupled-channel time-dependent dynamics calculations reproduce the general trends of these multi-state relative transition rates toward the three-body fragmentation channels.

The radiation pattern within high energy quark- and gluon-initiated jets (jet substructure) is used extensively as a precision probe of the strong force as well as an environment for optimizing event generators with numerous applications in high energy particle and nuclear physics. Looking at electron-proton collisions is of particular interest as many of the complications present at hadron colliders are absent. A detailed study of modern jet substructure observables, jet angularities, in electron-proton collisions is presented using data recorded using the H1 detector at HERA. The measurement is unbinned and multi-dimensional, using machine learning to correct for detector effects. All of the available reconstructed object information of the respective jets is interpreted by a graph neural network, achieving superior precision on a selected set of jet angularities. Training these networks was enabled by the use of a large number of GPUs in the Perlmutter supercomputer at Berkeley Lab. The particle jets are reconstructed in the laboratory frame, using the kT jet clustering algorithm. Results are reported at high transverse momentum transfer Q2>150GeV2, and inelasticity 0.2

We present the relaxation dynamics of deuterated water molecules via autoionization, initiated by the absorption of a 61 eV photon, producing the very rare D+ + O+ + D breakup channel. We employ the COLd target recoil ion momentum spectroscopy method to measure the 3D momenta of the ionic fragments and emitted electrons from the dissociating molecule in coincidence. We interpret the results using the potential energy surfaces extracted from multi-reference configuration interaction calculations. The measured particle energy distributions can be related to a super-excited monocationic state located above the double ionization threshold of D2O. The autoionized electron energy shows a sharp distribution centered around 0.5 eV, which is a signature of the atomic oxygen autoionization occurring in the direct and sequential dissociation processes of D2O+* at a large internuclear distance. In this way, an O+ radical fragment and a low-energy electron are created, both of which can trigger secondary reactions in their environment.

Using the Planck Low Frequency Instrument (LFI) and WMAP data within the global Bayesian BEYONDPLANCK framework, we constrained the polarized foreground emission between 30 and 70 GHz. We combined, for the first time, full-resolution Planck LFI time-ordered data with low-resolution WMAP sky maps at 33, 40, and 61 GHz. The spectral parameters were fit with a likelihood defined at the native resolution of each frequency channel. This analysis represents the first implementation of true multi-resolution component separation applied to CMB observations for both amplitude and spectral energy distribution (SED) parameters. For the synchrotron emission, we approximated the SED as a power-law in frequency and we find that the low signal-to-noise ratio of the current data strongly limits the number of free parameters that can be robustly constrained. We partitioned the sky into four large disjoint regions (High Latitude; Galactic Spur; Galactic Plane; and Galactic Center), each associated with its own power-law index. We find that the High Latitude region is prior-dominated, while the Galactic Center region is contaminated by residual instrumental systematics. The two remaining regions appear to be signal-dominated, and for these we derive spectral indices of βsSpur=3.17±0.06 and βsPlane=3.03±0.07, which is in good agreement with previous results. For the thermal dust emission, we assumed a modified blackbody model and we fit a single power-law index across the full sky. We find βda =â 1.64±0.03, which is slightly steeper than the value reported in Planck HFI data, but still statistically consistent at the 2Ï confidence level.

We describe the computational infrastructure for end-to-end Bayesian cosmic microwave background (CMB) analysis implemented by the BeyondPlanck Collaboration. The code is called Commander3. It provides a statistically consistent framework for global analysis of CMB and microwave observations and may be useful for a wide range of legacy, current, and future experiments. The paper has three main goals. Firstly, we provide a high-level overview of the existing code base, aiming to guide readers who wish to extend and adapt the code according to their own needs or re-implement it from scratch in a different programming language. Secondly, we discuss some critical computational challenges that arise within any global CMB analysis framework, for instance in-memory compression of time-ordered data, fast Fourier transform optimization, and parallelization and load-balancing. Thirdly, we quantify the CPU and RAM requirements for the current BEYONDPLANCK analysis, finding that a total of 1.5 TB of RAM is required for efficient analysis and that the total cost of a full Gibbs sample for LFI is 170 CPU-hrs, including both low-level processing and high-level component separation, which is well within the capabilities of current low-cost computing facilities. The existing code base is made publicly available under a GNU General Public Library (GPL) license.

We constrained the level of polarized anomalous microwave emission (AME) on large angular scales using Planck Low-Frequency Instrument (LFI) and WMAP polarization data within a Bayesian cosmic microwave background (CMB) analysis framework. We modeled synchrotron emission with a power-law spectral energy distribution, as well as the sum of AME and thermal dust emission through linear regression with the Planck High-Frequency Instrument (HFI) 353 GHz data. This template-based dust emission model allowed us to constrain the level of polarized AME while making minimal assumptions on its frequency dependence. We neglected CMB fluctuations, but show through simulations that these fluctuations have a minor impact on the results. We find that the resulting AME polarization fraction confidence limit is sensitive to the polarized synchrotron spectral index prior. In addition, for prior means βsâ

We present a Bayesian calibration algorithm for cosmic microwave background (CMB) observations as implemented within the global end-to-end BEYONDPLANCK framework and applied to the Planck Low Frequency Instrument (LFI) data. Following the most recent Planck analysis, we decomposed the full time-dependent gain into a sum of three nearly orthogonal components: one absolute calibration term, common to all detectors, one time-independent term that can vary between detectors, and one time-dependent component that was allowed to vary between one-hour pointing periods. Each term was then sampled conditionally on all other parameters in the global signal model through Gibbs sampling. The absolute calibration is sampled using only the orbital dipole as a reference source, while the two relative gain components were sampled using the full sky signal, including the orbital and Solar CMB dipoles, CMB fluctuations, and foreground contributions. We discuss various aspects of the data that influence gain estimation, including the dipole-polarization quadrupole degeneracy and processing masks. Comparing our solution to previous pipelines, we find good agreement in general, with relative deviations of 0.67% (0.84%) for 30 GHz, 0.12% (0.04%) for 44 GHz and 0.03% (0.64%) for 70 GHz, compared to Planck PR4 and Planck 2018, respectively. We note that the BEYONDPLANCK calibration was performed globally, which results in better inter-frequency consistency than previous estimates. Additionally, WMAP observations were used actively in the BEYONDPLANCK analysis, which both breaks internal degeneracies in the Planck data set and results in an overall better agreement with WMAP. Finally, we used a Wiener filtering approach to smoothing the gain estimates. We show that this method avoids artifacts in the correlated noise maps as a result of oversmoothing the gain solution, which is difficult to avoid with methods like boxcar smoothing, as Wiener filtering by construction maintains a balance between data fidelity and prior knowledge. Although our presentation and algorithm are currently oriented toward LFI processing, the general procedure is fully generalizable to other experiments, as long as the Solar dipole signal is available to be used for calibration.

We present a Gibbs sampling solution to the mapmaking problem for cosmic microwave background (CMB) measurements that builds on existing destriping methodology. Gibbs sampling breaks the computationally heavy destriping problem into two separate steps: noise filtering and map binning. Considered as two separate steps, both are computationally much cheaper than solving the combined problem. This provides a huge performance benefit as compared to traditional methods and it allows us, for the first time, to bring the destriping baseline length to a single sample. Here, we applied the Gibbs procedure to simulated Planck 30 GHz data. We find that gaps in the time-ordered data are handled efficiently by filling them in with simulated noise as part of the Gibbs process. The Gibbs procedure yields a chain of map samples, from which we are able to compute the posterior mean as a best-estimate map. The variation in the chain provides information on the correlated residual noise, without the need to construct a full noise covariance matrix. However, if only a single maximum-likelihood frequency map estimate is required, we find that traditional conjugate gradient solvers converge much faster than a Gibbs sampler in terms of the total number of iterations. The conceptual advantages of the Gibbs sampling approach lies in statistically well-defined error propagation and systematic error correction. This methodology thus forms the conceptual basis for the mapmaking algorithm employed in the BEYONDPLANCK framework, which implements the first end-to-end Bayesian analysis pipeline for CMB observations.

We present Planck Low Frequency Instrument (LFI) frequency sky maps derived within the BEYONDPLANCK framework. This framework draws samples from a global posterior distribution that includes instrumental, astrophysical, and cosmological parameters, and the main product is an entire ensemble of frequency sky map samples, each of which corresponds to one possible realization of the various modeled instrumental systematic corrections, including correlated noise, time-variable gain, as well as far sidelobe and bandpass corrections. This ensemble allows for computationally convenient end-to-end propagation of low-level instrumental uncertainties into higher-level science products, including astrophysical component maps, angular power spectra, and cosmological parameters. We show that the two dominant sources of LFI instrumental systematic uncertainties are correlated noise and gain fluctuations, and the products presented here support -for the first time -full Bayesian error propagation for these effects at full angular resolution. We compared our posterior mean maps with traditional frequency maps delivered by the Planck Collaboration, and find generally good agreement. The most important quality improvement is due to significantly lower calibration uncertainties in the new processing, as we find a fractional absolute calibration uncertainty at 70 GHz of δg0/g0â =â 5Ã - 105, which is nominally 40 times smaller than that reported by Planck 2018. However, we also note that the original Planck 2018 estimate has a nontrivial statistical interpretation, and this further illustrates the advantage of the new framework in terms of producing self-consistent and well-defined error estimates of all involved quantities without the need of ad hoc uncertainty contributions. We describe how low-resolution data products, including dense pixel-pixel covariance matrices, may be produced from the posterior samples directly, without the need for computationally expensive analytic calculations or simulations. We conclude that posterior-based frequency map sampling provides unique capabilities in terms of low-level systematics modeling and error propagation, and may play an important role for future Cosmic Microwave Background (CMB) B-mode experiments aiming at nanokelvin precision.

We describe the BEYONDPLANCK project in terms of our motivation, methodology, and main products, and provide a guide to a set of companion papers that describe each result in more detail. Building directly on experience from ESA's Planck mission, we implemented a complete end-to-end Bayesian analysis framework for the Planck Low Frequency Instrument (LFI) observations. The primary product is a full joint posterior distribution P(Ï â £d), where Ï represents the set of all free instrumental (gain, correlated noise, bandpass, etc.), astrophysical (synchrotron, free-free, thermal dust emission, etc.), and cosmological (cosmic microwave background -CMB -map, power spectrum, etc.) parameters. Some notable advantages of this approach compared to a traditional pipeline procedure are seamless end-to-end propagation of uncertainties; accurate modeling of both astrophysical and instrumental effects in the most natural basis for each uncertain quantity; optimized computational costs with little or no need for intermediate human interaction between various analysis steps; and a complete overview of the entire analysis process within one single framework. As a practical demonstration of this framework, we focus in particular on low-â CMB polarization reconstruction with Planck LFI. In this process, we identify several important new effects that have not been accounted for in previous pipelines, including gain over-smoothing and time-variable and non-1/f correlated noise in the 30 and 44 GHz channels. Modeling and mitigating both previously known and newly discovered systematic effects, we find that all results are consistent with the Î CDM model, and we constrained the reionization optical depth to Ï â =â 0.066±0.013, with a low-resolution CMB-based Ï 2 probability to exceed of 32%. This uncertainty is about 30% larger than the official pipelines, arising from taking a more complete instrumental model into account. The marginal CMB solar dipole amplitude is 3362.7±1.4â μK, where the error bar was derived directly from the posterior distribution without the need of any ad hoc instrumental corrections. We are currently not aware of any significant unmodeled systematic effects remaining in the Planck LFI data, and, for the first time, the 44 GHz channel is fully exploited in the current analysis. We argue that this framework can play a central role in the analysis of many current and future high-sensitivity CMB experiments, including LiteBIRD, and it will serve as the computational foundation of the emerging community-wide COSMOGLOBE effort, which aims to combine state-of-the-art radio, microwave, and submillimeter data sets into one global astrophysical model.

We present the first application of the COSMOGLOBE analysis framework by analyzing nine-year WMAP time-ordered observations that uses similar machinery to that of BEYONDPLANCK for the Planck Low Frequency Instrument (LFI). We analyzed only the Q-band (41 GHz) data and report on the low-level analysis process based on uncalibrated time-ordered data to calibrated maps. Most of the existing BEYONDPLANCK pipeline may be reused for WMAP analysis with minimal changes to the existing codebase. The main modification is the implementation of the same preconditioned biconjugate gradient mapmaker used by the WMAP team. Producing a single WMAP Q1-band sample requires 22 CPU-hrs, which is slightly more than the cost of a Planck 44 GHz sample of 17 CPU-hrs; this demonstrates that a full end-to-end Bayesian processing of the WMAP data is computationally feasible. In general, our recovered maps are very similar to the maps released by the WMAP team, although with two notable differences. In terms of temperature, we find a ∼2â μK quadrupole difference that most likely is caused by different gain modeling, while in polarization we find a distinct 2.5â μK signal that has been previously referred to as poorly measured modes by the WMAP team. In the COSMOGLOBE processing, this pattern arises from temperature-to-polarization leakage from the coupling between the CMB Solar dipole, transmission imbalance, and sidelobes. No traces of this pattern are found in either the frequency map or TOD residual map, suggesting that the current processing has succeeded in modeling these poorly measured modes within the assumed parametric model by using Planck information to break the sky-synchronous degeneracies inherent in the WMAP scanning strategy.

We present posterior sample-based cosmic microwave background (CMB) constraints from Planck LFI and WMAP observations as derived through global end-to-end Bayesian processing within the BeyondPlanck framework. We first used these samples to study correlations between CMB, foreground, and instrumental parameters. We identified a particularly strong degeneracy between CMB temperature fluctuations and free-free emission on intermediate angular scales (400 ≤ ∫ ≤ 600), mitigated through model reduction, masking, and resampling. We compared our posterior-based CMB results with previous Planck products and found a generally good agreement, however, with notably higher noise due to our exclusion of Planck HFI data.We found a best-fit CMB dipole amplitude of 3362:7 ± 1:4 μK, which is in excellent agreement with previous Planck results. The quoted dipole uncertainty is derived directly from the sampled posterior distribution and does not involve any ad hoc contributions for Planck instrumental systematic effects. Similarly, we find a temperature quadrupole amplitude of φTT 2 = 229 ± 97 μK2, which is in good agreement with previous results in terms of the amplitude, but the uncertainty is one order of magnitude greater than the naive diagonal Fisher uncertainty. Concurrently, we find less evidence of a possible alignment between the quadrupole and octopole than previously reported, due to a much larger scatter in the individual quadrupole coeffcients that is caused both by marginalizing over a more complete set of systematic effects – as well as by requiring a more conservative analysis mask to mitigate the free-free degeneracy. For higher multipoles, we find that the angular temperature power spectrum is generally in good agreement with both Planck and WMAP. At the same time, we note that this is the first time that the sample-based, asymptotically exact Blackwell-Rao estimator has been successfully established for multipoles up to ∫ ≤ 600. It now accounts for the majority of the cosmologically important information. Overall, this analysis demonstrates the unique capabilities of the Bayesian approach with respect to end-to-end systematic uncertainty propagation and we believe it can and should play an important role in the analysis of future CMB experiments. Cosmological parameter constraints are presented in a companion paper.

End-to-end simulations play a key role in the analysis of any high-sensitivity cosmic microwave background (CMB) experiment, providing high-fidelity systematic error propagation capabilities that are unmatched by any other means. In this paper, we address an important issue regarding such simulations, namely, how to define the inputs in terms of sky model and instrument parameters. These may either be taken as a constrained realization derived from the data or as a random realization independent from the data. We refer to these as posterior and prior simulations, respectively. We show that the two options lead to significantly different correlation structures, as prior simulations (contrary to posterior simulations) effectively include cosmic variance, but they exclude realization-specific correlations from non-linear degeneracies. Consequently, they quantify fundamentally different types of uncertainties. We argue that as a result, they also have different and complementary scientific uses, even if this dichotomy is not absolute. In particular, posterior simulations are in general more convenient for parameter estimation studies, while prior simulations are generally more convenient for model testing. Before BEYONDPLANCK, most pipelines used a mix of constrained and random inputs and applied the same hybrid simulations for all applications, even though the statistical justification for this is not always evident. BEYONDPLANCK represents the first end-to-end CMB simulation framework that is able to generate both types of simulations and these new capabilities have brought this topic to the forefront. The BEYONDPLANCK posterior simulations and their uses are described extensively in a suite of companion papers. In this work, we consider one important applications of the corresponding prior simulations, namely, code validation. Specifically, we generated a set of one-year LFI 30 GHz prior simulations with known inputs and we used these to validate the core low-level BEYONDPLANCK algorithms dealing with gain estimation, correlated noise estimation, and mapmaking.

We present cosmological parameter constraints estimated using the Bayesian BeyondPlanck analysis framework. This method supports seamless end-to-end error propagation from raw time-ordered data onto final cosmological parameters. As a first demonstration of the method, we analyzed time-ordered Planck LFI observations, combined with selected external data (WMAP 33–61 GHz, Planck HFI DR4 353 and 857 GHz, and Haslam 408 MHz) in the form of pixelized maps that are used to break critical astrophysical degeneracies. Overall, all the results are generally in good agreement with previously reported values from Planck 2018 and WMAP, with the largest relative difference for any parameter amounting about 1φ when considering only temperature multipoles between 30 ≤ ∫ ≤ 600. In cases where there are differences, we note that the BeyondPlanck results are generally slightly closer to the high- ∫ HFI-dominated Planck 2018 results than previous analyses, suggesting slightly less tension between low and high multipoles. Using low- ∫ polarization information from LFI and WMAP, we find a best-fit value of φ = 0:066±0:013, which is higher than the low value of φ = 0:052 ± 0:008 derived from Planck 2018 and slightly lower than the value of 0:069 ± 0:011 derived from the joint analysis of offcial LFI and WMAP products. Most importantly, however, we find that the uncertainty derived in the BeyondPlanck processing is about 30% greater than when analyzing the offcial products, after taking into account the different sky coverage. We argue that this uncertainty is due to a marginalization over a more complete model of instrumental and astrophysical parameters, which results in more reliable and more rigorously defined uncertainties. We find that about 2000 Monte Carlo samples are required to achieve a robust convergence for a low-resolution cosmic microwave background (CMB) covariance matrix with 225 independent modes, and producing these samples takes about eight weeks on a modest computing cluster with 256 cores.

We present a Bayesian method for estimating instrumental noise parameters and propagating noise uncertainties within the global BEYONDPLANCK Gibbs sampling framework, which we applied to Planck Low Frequency Instrument (LFI) time-ordered data. Following previous works in the literature, we initially adopted a 1/f model for the noise power spectral density (PSD), but we found the need for an additional lognormal component in the noise model in the 30 and 44 GHz bands. We implemented an optimal Wiener-filter (or constrained realization) gap-filling procedure to account for masked data. We then used this procedure to both estimate the gapless correlated noise in the time-domain, ncorr, and to sample the noise PSD parameters, ξnâ =â {Ï0,â fknee,â α,â Ap}. In contrast to previous Planck analyses, we assumed piecewise stationary noise only within each pointing period (PID), and not throughout the full mission, but we adopted the LFI Data Processing Center results as priors on α and fknee. We generally found best-fit correlated noise parameters that are mostly consistent with previous results, with a few notable exceptions. However, a detailed inspection of the time-dependent results has revealed many important findings. First and foremost, we find strong evidence for statistically significant temporal variations in all noise PSD parameters, many of which are directly correlated with satellite housekeeping data. Second, while the simple 1/f model appears to be an excellent fit for the LFI 70 GHz channel, there is evidence for additional correlated noise that is not described by a 1/f model in the 30 and 44 GHz channels, including within the primary science frequency range of 0.1-1 Hz. In general, most 30 and 44 GHz channels exhibit deviations from 1/f at the 2-3Ï level in each one-hour pointing period, motivating the addition of the lognormal noise component for these bands. For certain periods of time, we also find evidence of strong common mode noise fluctuations across the entire focal plane. Overall, we conclude that a simple 1/f profile is not adequate for obtaining a full characterization of the Planck LFI noise, even when fitted hour-by-hour, and a more general model is required. These findings have important implications for large-scale CMB polarization reconstruction with the Planck LFI data and the current work is a first attempt at understanding and mitigating these issues.

Background and Aim: Osteoporosis significantly compromises the quality of life of postmenopausal women. There are DALY (Disability-Adjusted Life Years) losses for postmenopausal women who suffer from osteoporosis. Therefore, this study was taken up with the objective to determine prevalence of osteopenia and osteoporosis among postmenopausal women and to study the association of their anthropometric parameters and lifestyle factors with their bone mineral density (BMD). To study the determinants of BMD among postmenopausal women with special reference to anthropometric and lifestyle factors in an urban slum. Materials and Methods: A community-based, cross-sectional study was conducted in an urban slum of Mumbai. The study was conducted among 148 postmenopausal women. BMD of the study group was measured using portable, noninvasive Calcaneum Ultrasound Bone Densitometer, and T-score reading was noted. Lifestyle factors and dietary habits were assessed through a prestructured, validated questionnaire. Body mass index (BMI) was calculated with a standard procedure. No trial was conducted in the study. Statistical Package for Social Sciences (version 20) was used for statistical analysis. Results: The prevalence of osteopenia among study participants was found to be 43.9% and that of osteoporosis was 12.8%. Their BMI was in the range of 16.44–39.18 kg/m2. Walking, stretching exercises, and yoga were the form of exercise being practiced by 29.1% of postmenopausal women. Conclusions: BMD was significantly associated with age, socioeconomic status, BMI, exercise, walking, and consumption of fruits. Negative correlation was found between duration since menopause and BMD T-score reading, which implied that duration since menopause had an inverse relationship with BMD.

Melanie Gauthier,1,2 Julien Pierson,3 David Moulin,1 Manon Mouginot,1 Valerie Bourguignon,1 Wassim Rhalloussi,1 Jean-Baptiste Vincourt,1 Dominique Dumas,1 Danièle Bensoussan,1,2 Pascal Chastagner,1,4 Cédric Boura,3 Veronique Decot1,2 1CNRS UMR 7365 IMoPA, Université de Lorraine, Nancy, France; 2Cell Therapy and Tissue Bank Unit, Nancy University Hospital, Vandoeuvre-Les-Nancy, France; 3CNRS UMR7039 CRAN, Université de Lorraine, Nancy, France; 4Pediatric Oncology Department, Nancy University Hospital, Vandoeuvre-Les-Nancy, FranceCorrespondence: Veronique Decot, CNRS UMR 7365, IMoPA, Campus Brabois Santé, 9 av de la foret de Haye, Vandoeuvre-Les-Nancy, 54000, France, Tel +0033 – 649574720, Email veronique.decot@univ-lorraine.frPurpose: Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of these patients remains poor owing to the sequelae and relapse risk. An alternative, or, in addition to the current standard treatment, could be considered immunotherapy, such as Natural Killer cells (NK). NK cells are cytotoxic innate lymphoid cells that play a major role in cancer immunosurveillance. To date, the mechanism of cytotoxicity of NK cells, especially regarding the steps of adhesion, conjugation, cytotoxic granule polarisation in the cell contact area, perforin and granzyme release in two and three dimensions, and therapeutic efficacy in vivo have not been precisely described.Materials and Methods: Each step of NK cytotoxicity against the three MB cell lines was explored using confocal microscopy for conjugation, Elispot for degranulation, flow cytometry, and luminescence assays for target cell necrosis and lysis and mediators released by cytokine array, and then confirmed in a 3D spheroid model. Medulloblastoma-xenografted mice were treated with NK cells. Their persistence was evaluated by flow cytometry, and their efficacy in tumour growth and survival was determined. In addition, their effects on the tumour transcriptome were evaluated.Results: NK cells showed variable affinities for conjugation with MB target cells depending on their subgroup and cytokine activation. Chemokines secreted during NK and MB cell co-culture are mainly associated with angiogenesis and immune cell recruitment. NK cell cytotoxicity induces MB cell death in both 2D and 3D co-culture models. NK cells initiated an inflammatory response in a human MB murine model by modulating the MB cell transcriptome.Conclusion: Our study confirmed that NK cells possess both in vitro and in vivo cytotoxic activity against MB cells and are of interest for the development of immunotherapy.Keywords: cancer, medulloblastoma, immune cells, adoptive transfer

Sai-Hong Ignatius Ou,1 Xiuning Le,2 Misako Nagasaka,1 Thanyanan Reungwetwattana,3 Myung-Ju Ahn,4 Darren WT Lim,5 Edgardo S Santos,6 Elaine Shum,7 Sally CM Lau,7 Jii Bum Lee,8 Antonio Calles,9 Fengying Wu,10 Gilberto Lopes,11 Virote Sriuranpong,12 Junko Tanizaki,13 Hidehito Horinouchi,14 Marina C Garassino,15 Sanjay Popat,16 Benjamin Besse,17 Rafael Rosell,18 Ross A Soo19 1University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA; 2University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 4Department of Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 5Duke-NUS School of medicine, National Cancer Center Singapore, Republic of Singapore; 6Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA; 7NYU Langone Perlmutter Cancer Center, NY, NY, USA; 8Yonsei Cancer Center Yonsei University, Seoul, Republic of Korea; 9Department of Medicine, Division of Medical Oncology, Early Drug Development and Phase I Unit, Hospital General Universitario Gregorio Marañón, Madrid, 28007, Spain; 10Shanghai Chest hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 11Department of Medicine, Division of Medical Oncology, Sylvester Comprehensive Cancer Center at the University of Miami and the Miller School of Medicine, Miami, FL, 33136, USA; 12Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 13Department of Medicine, Kindai University School of Medicine, Osaka, Japan; 14Department of Thoracic Oncology, National Cancer Center Hospital Tokyo, Tokyo, Japan; 15Department of Medicine, Division of Medical Oncology-Hematology, University of Chicago Medicine, Chicago, IL, USA; 16Royal Marsden Hospital, London, Imperial College, London, UK; 17Gustave Roussy Cancer Campus, Villejuif, France; Paris-Saclay University, Orsay, France; 18Department of Hematology-Oncology, National University Cancer Institute, National University Hospital Singapore, Republic of Singapore; 19IOR, Quirón-Dexeus University Institute; ICO, Catalan Institute of Oncology; IGTP, Germans Trias i Pujol Research Institute, Barcelona, SpainCorrespondence: Sai-Hong Ignatius Ou, University of California School of Medicine, Department of Medicine, Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, 200 South Manchester Avenue, Suite 400, Orange, CA, 92868, USA, Tel +1 714-456-5153, Fax +1 714-456-2242, Email Siou@hs.uci.eduAbstract: The year 2024 is the 20th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential “cure” in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described “discoveries” of activating EGFR mutations (del19, L858R, exon 20 insertions, and “uncommon” mutations) were published. To commemorate this 20th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered “honorable mention” and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as “syllabus” for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).Keywords: EGFR mutations, expert panel, top 20 papers, 20th anniversary, NSCLC

Sang-Soo Kim,1,2 Manish Moghe,1 Antonina Rait,1 Kathryn Donaldson,1 Joe B Harford,2 Esther H Chang1 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA; 2SynerGene Therapeutics, Inc, Potomac, MD, USACorrespondence: Esther H Chang, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road N.W., Research Building E420, Washington, DC, 20057, USA, Email change@georgetown.eduPurpose: Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach.Methods: We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT.Results: Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice.Conclusion: Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies. Keywords: lipid nanoparticle, nanodelivery, SMARCB1, gene therapy, atypical teratoid rhabdoid tumor

Emmanuel Munyaneza,1 Belson Rugwizangoga,1,2 Emmanuel Rusingiza,1,2 Jean Berchmans Niyibizi,2 Simon Rutayisire Kanyandekwe,1 Jean Claude Byiringiro,1,2 Florence Masaisa1,2 1Clinical Education and Research Division, University Teaching Hospital of Kigali, Kigali, Rwanda; 2School of Medicine and Health Sciences, University of Rwanda, Kigali, RwandaCorrespondence: Emmanuel Munyaneza, Clinical Education and Research Division, University Teaching Hospital of Kigali (CHUK), KN 4 Avenue (Avenue de la Paix), P. O. Box 655, Kigali, Rwanda, Email emmanuel.munyaneza@chuk.rw; emamunyaneza@gmail.comBackground: Continuous professional development (CPD) is an important pillar in healthcare service delivery. Health professionals at all levels and disciplines must continuously update their knowledge and skills to cope with increasing professional demands in the context of a continuously changing spectrum of diseases. This study aimed to assess the CPD programs available in healthcare facilities (HFs) in Rwanda.Methodology: Semi-structured interviews were conducted using purposive sampling. Accordingly, the respondents belonged to different categories of health professionals, namely nurses, midwives, laboratory technicians, pharmacists, general practitioners, and specialist doctors. Thirty-five participants from district, provincial, and national referral hospitals were interviewed between September and October 2020. A thematic analysis was conducted using Atlas ti.7.5.18, and the main findings for each theme were reported as a narrative summary.Results: The CPD program was reported to be available, but not for all HPs and HFs, because of either limited access to online CPD programs or limited HF leaders. Where available, CPD programs have sometimes been reported to be irrelevant to health professionals and patients’ needs. Furthermore, the planning and implementation of current CPD programs seldom involves beneficiaries. Some HFs do not integrate CPD programs into their daily activities, and current CPD programs do not accommodate mentorship programs. The ideal CPD program should be designed around HPs and service needs and delivered through a user-friendly platform. The motivators for HPs to engage in CPD activities include learning new things that help them improve their healthcare services and license renewal.Conclusion: This study provides an overview of the status and perceptions of the CPD program in HFs in Rwanda and provides HPs’ insights on the improvements in designing a standardized and harmonized CPD program in Rwanda.Keywords: continuous professional development, healthcare professionals, program, Rwanda

Oluwasolape Olawore,1 Lindsey E Turner,2,3 Michael D Evans,3 Steven G Johnson,4 Jared D Huling,2 Carolyn T Bramante,5 John B Buse,6 Til Stürmer1 On behalf of the N3C Consortium1Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Division of Biostatistics and Health Data Science, University of Minnesota School of Public Health, Minneapolis, MN, USA; 3Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN, USA; 4Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA; 5Division of General Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA; 6Division of Endocrinology, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USACorrespondence: Oluwasolape Olawore, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, 135 Dauer Drive, Chapel Hill, NC, 27599, USA, Email oolawore@unc.eduBackground: Observed activity of metformin in reducing the risk of severe COVID-19 suggests a potential use of the anti-hyperglycemic in the prevention of post-acute sequelae of SARS-CoV-2 infection (PASC). We assessed the 3-month and 6-month risk of PASC among patients with type 2 diabetes mellitus (T2DM) comparing metformin users to sulfonylureas (SU) or dipeptidyl peptidase-4 inhibitors (DPP4i) users.Methods: We used de-identified patient level electronic health record data from the National Covid Cohort Collaborative (N3C) between October 2021 and April 2023. Participants were adults ≥ 18 years with T2DM who had at least one outpatient healthcare encounter in health institutions in the United States prior to COVID-19 diagnosis. The outcome of PASC was defined based on the presence of a diagnosis code for the illness or using a predicted probability based on a machine learning algorithm. We estimated the 3-month and 6-month risk of PASC and calculated crude and weighted risk ratios (RR), risk differences (RD), and differences in mean predicted probability.Results: We identified 5596 (mean age: 61.1 years; SD: 12.6) and 1451 (mean age: 64.9 years; SD 12.5) eligible prevalent users of metformin and SU/DPP4i respectively. We did not find a significant difference in risk of PASC at 3 months (RR = 0.86 [0.56; 1.32], RD = − 3.06 per 1000 [− 12.14; 6.01]), or at 6 months (RR = 0.81 [0.55; 1.20], RD = − 4.91 per 1000 [− 14.75, 4.93]) comparing prevalent users of metformin to prevalent users of SU/ DPP4i. Similar observations were made for the outcome definition using the ML algorithm.Conclusion: The observed estimates in our study are consistent with a reduced risk of PASC among prevalent users of metformin, however the uncertainty of our confidence intervals warrants cautious interpretations of the results. A standardized clinical definition of PASC is warranted for thorough evaluation of the effectiveness of therapies under assessment for the prevention of PASC.Plain Language Summary: Previous research suggests that metformin, due to its anti-viral, anti-inflammatory, and anti-thrombotic properties may reduce the risk of severe COVID-19. Given the shared etiology of COVID-19 and the post-acute sequelae of SARS-CoV-2 (PASC), and the proposed inflammatory processes of PASC, metformin may also be a beneficial preventive option. We investigated the benefit of metformin for PASC prevention in a population of type 2 diabetes mellitus patients with a COVID-19 diagnosis who were on metformin or two other anti-hyperglycemic medications prior to infection with SARS-CoV-2. Our results were consistent with a reduction in the risk of PASC with the use of metformin, however, the imprecise confidence intervals obtained warrants further investigation of this association of the potential beneficial effect of metformin for preventing PASC in patients with medication-managed diabetes.Keywords: COVID-19, Long COVID, Type 2 diabetes Mellitus, Metformin

Mateo Sanchis-Borja,1 Florian Guisier,2 Aurélie Swalduz,3 Hubert Curcio,4 Victor Basse,5 Christophe Maritaz,6 Christos Chouaid,1 Jean-Bernard Auliac1 1Pulmonology Department, Créteil Intercommunal Hospital, Créteil, France; 2Normandie Univ, UNIROUEN, LITIS Laboratory QuantIF team EA4108, CHU Rouen, Department of Pneumology and Inserm CIC-CRB 1404, Rouen, France; 3Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France; 4Department of Medical Oncology, Centre François Baclesse, Caen, France; 5Department of Oncology CHU Morvan, Brest, France; 6Medical Affairs Department, Oncology, Boehringer Ingelheim France, Paris, FranceCorrespondence: Jean-Bernard Auliac, Pulmonology Department, Créteil Intercommunal Hospital, Créteil, France, Email Jean-Bernard.Auliac@chicreteil.frPurpose: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is an effective first-line therapy for patients with common EGFR mutation-positive non-small cell lung cancer (NSCLC). However, almost all patients become resistant to treatment. In some patients, emergence of tertiary EGFR mutations is implicated as a resistance mechanism. This study describes patients with NSCLC who acquired the rare EGFR mutations, L718Q or G724S, following EGFR TKI treatment.Patients and Methods: This was a retrospective, observational study undertaken in France from Feb–Nov 2021, in patients with EGFR mutation-positive NSCLC with an acquired L718Q or G724S mutation. Primary objectives were description of tumor characteristics, progression, and progression under treatment.Results: Nine eligible patients were identified. Acquired resistance to initial EGFR TKI treatment was associated with T790M emergence in six patients, who then received osimertinib monotherapy. Overall, eight patients received osimertinib monotherapy treatment at some point (average treatment duration: 18.3 months). Following the emergence of L718Q or G724S, patients received chemotherapy (n = 4; two of whom subsequently received afatinib), nivolumab (n = 2), afatinib (n = 2), or immunochemotherapy (n = 1). In the four patients who received afatinib after identification of L718Q or G724S, 2 achieved a partial response, one had stable disease and one had progressive disease. Treatment duration was 1.6– 31.7 months. In patients with controlled disease (n = 3), progression-free survival was 6.1– 31.7 months. Two of these patients had previously received osimertinib.Conclusion: Currently, there is no consensus regarding the treatment of EGFR mutation-positive NSCLC following emergence of the osimertinib resistance mutations, L718Q or G724S. Afatinib appears to be a promising treatment option in this setting.Keywords: osimertinib, afatinib, real-world evidence, tertiary EGFR mutations

Maryam Ibrahim Tukur,1 Ibrahim Babangida Abubakar,2 Isah Musa Fakai,1 Jamilu Bala Danjuma,1 Ibrahim Malami,3 Aliyu Muhammad4 1Department of Biochemistry, Faculty of Life Sciences, Kebbi State University of Science and Technology, Aliero, Kebbi State, Nigeria; 2Department of Biochemistry, Faculty of Biomedical Sciences, Kampala International University, Kampala, Uganda; 3Department of Pharmacognosy and Ethnopharmacy, Faculty of Pharmaceutical Sciences, Usmanu Danfodio University, Sokoto, Nigeria; 4Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University Zaria, Zaria, 810271, NigeriaCorrespondence: Ibrahim Babangida Abubakar, Email Ibrahim.iba@kiu.ac.ugBackground: Faidherbia albida, popularly known as gawo in Hausa, is traditionally used to treat jaundice in Zuru emirate of Kebbi State. Herein, the ameliorative effect of F. albida against 2.4-dinitrophenylhydrazine-induced hyperbilirubinemia in Wistar albino rats was investigated.Methods: Thirty healthy rats were administered 75 mg of 2.4-dinitrophenylhydrazine to induce hyperbilirubinemia. Thereafter, groups 1– 3 received 500, 750, and 1000 mg/kg body weight of the methanol stem-bark extract, and 15 mg/kg of phenobarbitone (standard drug) was administered to group 4. Groups 5 and 6 served as the untreated and normal controls, respectively. The phytochemical composition was evaluated using standard methods, and acute oral toxicity was evaluated using standard OECD 2008 guidelines.Results: Phytochemical analysis revealed the presence of alkaloids, phenols, and a substantial amount of tannins. A significant (P< 0.05) reduction of direct bilirubin, total bilirubin, and total protein levels for all the doses of the extract and standard drug compared to untreated groups was observed. Similarly, there were significant reductions in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels of the group treated with the standard drug and all extract-treated groups compared to elevated levels observed in untreated controls. However, a significant (P< 0.05) increase in serum albumin (ALB) levels, red blood cells, hemoglobin, and pack cell volume was observed in all extract-treated compared to the untreated control in contrast to a significant decrease in MCH levels in treated groups compared to the untreated group.Conclusion: F. albida ameliorated the hyperbilirubinemia induced by 2.4-dinitrophenylhydrazine in Wistar albino rats, thus providing some support for its use in traditional medicine to treat jaundice.Keywords: Faidherbia albida, jaundice, liver enzymes, hyperbilirubinemia, 2, 4-dinitrophenylhydrazine, red blood cells

Jii Bum Lee,1 Sai-Hong Ignatius Ou2,3 1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA; 3Chao Family Comprehensive Cancer Center, Orange, CA, USACorrespondence: Sai-Hong Ignatius Ou, Chao Family Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Medicine, University of California Irvine School of Medicine, 200 South Manchester Ave, Suite 400, Orange, CA, 92868, USA, Tel +1714-456-5153, Fax +1 714-456-2242, Email ignatiusou@gmail.comAbstract: Treatment strategies for post-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in EGFR-mutant non-small cell lung cancer (NSCLC) is an ongoing challenge. Previously, the IMPRESS trial comparing platinum doublet chemotherapy with or without EGFR-TKI did not demonstrate any progression-free survival (PFS) benefit. The retrospective subgroup analysis of IMpower150 indicated that the quad regimen (carboplatin, paclitaxel, bevacizumab, atezolizumab) improved PFS and overall survival (OS) in patients with EGFR-mutant NSCLC who progressed on first-generation EGFR-TKIs. Given the retrospective nature of the analysis, the IMpower150 regimen is not approved in the US for post-EGFR-TKI treatment. Currently, osimertinib or other third-generation (3G) EGFR-TKIs is the first-line standard of care for advanced EGFR-mutant NSCLC. MARIPOSA-2 provided the first randomized trial post-osimertinib in EGFR-mutant NSCLC patients with another quad regimen (platinum, pemetrexed, lazertinib, amivantamab). The IMpower150 and MARIPOSA-2 quad regimens differ in the principle of whether to continue or even “double-down” on EGFR inhibition. Recently, three prospective randomized trials conducted in Asia offered promising results, showing that a quad regimen of doublet platinum chemotherapy plus anti-angiogenesis agent and ICI may be as efficacious as MARIPOSA-2 with a lower rate of toxicities and accounting for the PFS difference if 1L chemotherapy plus osimertinib instead of osimertinib monotherapy. In particular, the median PFS achieved by the quad regimens of ATTLAS and IMpower151 is 8.5 months. However, only 8.2% and 17.9% of the EGFR-mutant NSCLC patients who received the quad regimens progressed on 3G EGFR-TKI, respectively. Here, we discuss how the results of IMpower151 and ATTLAS may rejuvenate interest in a non-EGFR containing quad regimen as a potential post-osimertinib monotherapy treatment. Randomized trials comparing the results of these studies, including the quad regimen of MARIPOSA-2 versus the quad regimen of IMpower151/Impower150/ATTLAS in post-osimertinib (or other 3G EGFR-TKI) progression, are urgently needed.Keywords: atezolizumab, bevacizumab, chemotherapy, EGFR-mutant, NSCLC, FLAURA-2

Ying Chen,1,2,&ast; Wen-Xia Li,1,2,&ast; Jia-Hua Wu,1,2 Geng-Hang Chen,2 Chun-Min Yang,1,2 Hai Lu,1,2 Xi Wang,3 Shu-Sen Wang,4 Heng Huang,5 Li Cai,6 Li Zhao,7 Rou-Jun Peng,8 Ying Lin,9 Jun Tang,3 Jian Zeng,10 Le-Hong Zhang,11 Yong-Li Ke,12 Xian-Ming Wang,13 Xin-Mei Liu,14 An-Qin Zhang,15 Fei Xu,4 Xi-Wen Bi,4 Jia-Jia Huang,4 Ji-Bin Li,16 Dan-Mei Pang,17 Cong Xue,4 Yan-Xia Shi,4 Zhen-Yu He,18 Huan-Xin Lin,18 Xin An,4 Wen Xia,4 Ye Cao,16 Ying Guo,16 Ruo-Xi Hong,4 Kui-Kui Jiang,4 Yong-Yi Zhong,4 Ge Zhang,19 Piyawan Tienchaiananda,20 Masahiro Oikawa,21 Zhong-Yu Yuan,4 Qian-Jun Chen22,23 1Department of Breast Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Breast Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4Department of Medical Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 5Department of Breast Oncology, Lianjiang People’s Hospital, Lianjiang, People’s Republic of China; 6Department of Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, People’s Republic of China; 7Department of Breast Oncology, Guangzhou First People Hospital, Guangzhou, People’s Republic of China; 8Department of Integrated Therapy in Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 9Department of Breast Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 10Department of Breast Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 11Department of Breast Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 12Department of Breast Oncology, General Hospital of PLA Guangzhou Military Area, Guangzhou, People’s Republic of China; 13Department of Breast Oncology, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China; 14Department of Breast Oncology, Haikou People’s Hospital, Haikou, People’s Republic of China; 15Department of Breast Oncology, Maternal and Child Health Care Hospital of Guangdong Province, Guangzhou, People’s Republic of China; 16Department of Good Clinical Practice, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 17Department of Medical Oncology, Foshan First People’s Hospital, Foshan, People’s Republic of China; 18Department of Radiotherapy, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 19Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong; 20Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Rangsit University, Rajavithi Hospital, Bangkok, Thailand; 21The Department of Breast Surgery, New-wa-kai Oikawa Hospital, Fukuoka, Japan; 22State Key Laboratory of Traditional Chinese Medicine Syndrome/Departments of Gynecologic Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 23State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian-Jun Chen, 55N, Neihuanxi Road, Guangzhou, Guangdong, 510006, People’s Republic of China, Tel +86 1868883505, Email cqj55@163.com Zhong-Yu Yuan, 651 Dongfeng Road, Guangzhou, Guangdong, 510060, People’s Republic of China, Tel +86 13798027658, Email yuanzhy@sysucc.org.cnPurpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not.Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into “consistent” (standard acceptable dose) and “inconsistent” (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes.Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the “inconsistent” dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the “inconsistent” dose of anthracycline and taxane did not affect DFS compared with the “consistent” dose. Moreover, in the capecitabine group, the “inconsistent” anthracycline dose did not affect DFS compared with the “consistent” dose. However, patients with “consistent” taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06).Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.Keywords: adjuvant chemotherapy, capecitabine, SYSUCC-001, triple-negative breast cancer, TNBC

Long-Fei Xia,1 Jing-Bo Li,2 Guo-Sheng Tian,2 Wei-Ran Jiang,3 Yao-Shuang Li,1 Chen-Ying Lin,1 Hui-Na Qiu,2 Fan Wu,4 Jun-Jia Wang,5 Chun-Jun Li,2 Jing-Na Lin2 1Tianjin Union Medical Center, Tianjin Medical University, Tianjin, 300070, People’s Republic of China; 2Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, 300121, People’s Republic of China; 3Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, NY, USA; 4School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 5Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of ChinaCorrespondence: Jing-Na Lin; Chun-Jun Li, Email 13207628978@163.com; li_chunjun@126.comObjective: To investigate the impact of sarcopenia on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with type 2 diabetes mellitus (T2DM).Methods: This study included the clinical, laboratory, and body composition data of 1491 patients with T2DM who were admitted to the Department of Endocrinology and Metabolism at Tianjin Union Medical Center from July 2018 to July 2023. The China-PAR model was utilized to evaluate cardiovascular disease risk. Associations between ASCVD risk and various clinical parameters were analyzed, and the relationship between body composition parameters and ASCVD risk was assessed using logistic regression.Results: The analysis revealed that T2DM patients with sarcopenia had a higher 10-year ASCVD risk compared to those without sarcopenia, with reduced muscle mass independently predicting an increased risk of cardiovascular disease. This association was significant among female T2DM patients, while male T2DM patients with sarcopenia showed a marginally higher median ASCVD risk compared to their non-sarcopenic counterparts. ASCVD risk inversely correlated with body muscle parameters and positively correlated with fat content parameters. Specifically, height- and weight-adjusted fat mass (FM, FM%, FMI) were identified as risk factors for ASCVD. Conversely, muscle parameters adjusted for weight and fat (ASM%, SMM%, FFM%, ASM/FM, SMM/FM, FMM/FM) were protective against ASCVD risk. These findings highlight the critical role of sarcopenia in influencing cardiovascular disease risk among Chinese patients with T2DM, as predicted by the China-PAR model.Conclusion: This study highlights the importance of sarcopenia in T2DM patients, not only as an indicator of ASCVD risk, but possibly as an independent risk factor in this demographics.Keywords: atherosclerotic cardiovascular disease, ASCVD, type 2 diabetes, T2DM, sarcopenia, fat content, muscle mass