Phase transitions in random circuit sampling.

Undesired coupling to the surrounding environment destroys long-range correlations in quantum processors and hinders coherent evolution in the nominally available computational space. This noise is an outstanding challenge when leveraging the computation power of near-term quantum processors1. It has been shown that benchmarking random circuit sampling with cross-entropy benchmarking can provide an estimate of the effective size of the Hilbert space coherently available2-8. Nevertheless, quantum algorithms' outputs can be trivialized by noise, making them susceptible to classical computation spoofing. Here, by implementing an algorithm for random circuit sampling, we demonstrate experimentally that two phase transitions are observable with cross-entropy benchmarking, which we explain theoretically with a statistical model. The first is a dynamical transition as a function of the number of cycles and is the continuation of the anti-concentration point in the noiseless case. The second is a quantum phase transition controlled by the error per cycle; to identify it analytically and experimentally, we create a weak-link model, which allows us to vary the strength of the noise versus coherent evolution. Furthermore, by presenting a random circuit sampling experiment in the weak-noise phase with 67 qubits at 32 cycles, we demonstrate that the computational cost of our experiment is beyond the capabilities of existing classical supercomputers. Our experimental and theoretical work establishes the existence of transitions to a stable, computationally complex phase that is reachable with current quantum processors.

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

The Sec1-Munc18 protein VPS33B forms a uniquely bidirectional complex with VPS16B.

Loss-of-function variants of vacuolar protein sorting proteins VPS33B and VPS16B (VIPAS39) are causative for arthrogryposis, renal dysfunction, and cholestasis syndrome, where early lethality of patients indicates that VPS33B and VPS16B play essential cellular roles. VPS33B is a member of the Sec1-Munc18 protein family and thought to facilitate vesicular fusion via interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, like its paralog VPS33A in the homotypic fusion and vacuole sorting complex. VPS33B and VPS16B are known to associate, but little is known about the composition, structure, or function of the VPS33B-VPS16B complex. We show here that human VPS33B-VPS16B is a high molecular weight complex, which we expressed in yeast to perform structural, composition, and stability analysis. Circular dichroism data indicate VPS33B-VPS16B has a well-folded α-helical secondary structure, and size-exclusion chromatography-multiangle light scattering revealed a molecular weight of ∼315 kDa. Quantitative immunoblotting indicated a VPS33B:VPS16B ratio of 2:3. Expression of arthrogryposis, renal dysfunction, and cholestasis syndrome-causing VPS33B missense variants showed L30P disrupts complex formation but not S243F or H344D. Truncated VPS16B (amino acids 143 to 316) was sufficient to form a complex with VPS33B. Small-angle X-ray scattering and negative-staining EM revealed a two-lobed shape for VPS33B-VPS16B. Avidin tagging indicated that each lobe contains a VPS33B molecule, and they are oriented in opposite directions. We propose a structure for VPS33B-VPS16B that allows the VPS33B at each end to interact with separate SNARE bundles and/or SNAREpins, plus associated membrane components. These observations reveal the only known potentially bidirectional Sec1-Munc18 protein complex.

Hybridization and reticulate evolution in Diphasiastrum (flat-branched clubmosses, Lycopodiaceae) - New data from the island of Taiwan and Vietnam.

In the species groups related to Diphasiastrum multispicatum and D. veitchii, hybridization was investigated in samples from northern and southern Vietnam and the island of Taiwan, including available herbarium specimens from southeast Asia. The accessions were analyzed using flow cytometry (living material only), Sanger sequencing and multiplexed inter-simple sequence repeat genotyping by sequencing. We detected two cases of ancient hybridization involving different combinations of parental species; both led via subsequent duplication to tetraploid taxa. A cross D. multispicatum × D. veitchii from Malaysia represents D. wightianum, a tetraploid taxon according to reported DNA content measurements of dried material (genome formulas MM, VV and MMVV, respectively). The second case involves D. veitchii and an unknown diploid parent (genome formula XX). Three hybridogenous taxa (genome formulas VVX, VVXX, VVVX) were discernable by a combination of flow cytometry and molecular data. Taxon I (VVX, three clones found on Taiwan island) is apparently triploid. Taxon II represents another genetically diverse and sexual tetraploid species (VVXX) and can be assigned to D. yueshanense, described from Taiwan island but occurring as well in mainland China and Vietnam. Taxon III is as well most likely tetraploid (VVVX) and represented by at least one, more likely two, clones from Taiwan island. Taxa I and III are presumably asexual and new to science. Two independently inherited nuclear markers recombine only within, not between these hybrids, pointing towards reproductive isolation. We present an evolutionary scheme which explains the origin of the hybrids and the evolution of new and fully sexual species by hybridization and subsequent allopolyploidization in flat-branched clubmosses.

The Discovery of Gut Microbial Metabolites as Modulators of Host Susceptibility to Acetaminophen-Induced Hepatotoxicity.

The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is a major organ exposed to gut microbial metabolites, and it serves as the nexus for maintaining healthy interactions between the gut microbiota and the host. At the same time, the liver is the primary target of potentially harmful gut microbial metabolites. In this review, we provide an up-to-date list of gut microbial metabolites that have been identified to either increase or decrease host susceptibility to acetaminophen (APAP)-induced liver injury. The signaling pathways and molecular factors involved in the progression of APAP-induced hepatotoxicity are well-established, and we propose that the mouse model of APAP-induced hepatotoxicity serves as a model system for uncovering gut microbial metabolites with previously unknown functions. Furthermore, we envision that gut microbial metabolites identified to alter APAP-induced hepatotoxicity likely have broader implications in other liver diseases. SIGNIFICANCE STATEMENT: This review provides an overview of the role of the gut microbiota in modulating the host susceptibility to acetaminophen (APAP)-induced liver injury. It focuses on the roles of gut bacterial small molecule metabolites as mediators of the interaction between the gut microbiota and the liver. It also illustrates the utility of APAP-induced liver injury as a model to identify gut microbial metabolites with biological function.

Retinoic Acid Differentially Regulates the Migration of Innate Lymphoid Cell Subsets to the Gut.

Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2, and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to migration to the intestine ILCs first undergo a "switch" in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term population and effector function of ILCs in the intestine. Only ILC1 and ILC3, but not ILC2, undergo the RA-dependent homing receptor switch in gut-associated lymphoid tissues. In contrast, ILC2 acquire gut homing receptors in a largely RA-independent manner during their development in the bone marrow and can migrate directly to the intestine. Thus, distinct programs regulate the migration of ILC subsets to the intestine for regulation of innate immunity.

Cutting Edge: The Expression of Transcription Inhibitor GFI1 Is Induced by Retinoic Acid to Rein in Th9 Polarization.

IL-9, produced mainly by specialized T cells, mast cells, and group 2 innate lymphoid cells, regulates immune responses, including anti-helminth and allergic responses. Polarization of naive CD4 T cells into IL-9-producing T cells (Th9s) is induced by IL-4 and TGF-ß1 or IL-1ß. In this article, we report that the transcription factor growth factor-independent 1 transcriptional repressor (GFI1) plays a negative role in mouse Th9 polarization. Moreover, the expression of GFI1 is controlled by liganded RARα, allowing GFI1 to mediate the negative effect of retinoic acid on IL-9 expression. The Gfi1 gene has multiple RARα binding sites in the promoter region for recruiting nuclear coactivator steroid receptor coactivator-3 and p300 for histone epigenetic modifications in a retinoic acid-dependent manner. Retinoic acid-induced GFI1 binds the Il9 gene and suppresses its expression. Thus, GFI1 is a novel negative regulator of Il9 gene expression. The negative GFI1 pathway for IL-9 regulation provides a potential control point for Th9 activity.

Quantum control of surface acoustic-wave phonons.

One of the hallmarks of quantum physics is the generation of non-classical quantum states and superpositions, which has been demonstrated in several quantum systems, including ions, solid-state qubits and photons. However, only indirect demonstrations of non-classical states have been achieved in mechanical systems, despite the scientific appeal and technical utility of such a capability1,2, including in quantum sensing, computation and communication applications. This is due in part to the highly linear response of most mechanical systems, which makes quantum operations difficult, as well as their characteristically low frequencies, which hinder access to the quantum ground state3-7. Here we demonstrate full quantum control of the mechanical state of a macroscale mechanical resonator. We strongly couple a surface acoustic-wave8 resonator to a superconducting qubit, using the qubit to control and measure quantum states in the mechanical resonator. We generate a non-classical superposition of the zero- and one-phonon Fock states and map this and other states using Wigner tomography9-14. Such precise, programmable quantum control is essential to a range of applications of surface acoustic waves in the quantum limit, including the coupling of disparate quantum systems15,16.

Scoping Review: Anesthesiologist Involvement in Alternative Payment Models, Value Measurement, and Nonclinical Capabilities for Success in the United States of America.

The US healthcare sector is undergoing significant payment reforms, leading to the emergence of Alternative Payment Models (APMs) aimed at improving clinical outcomes and patient experiences while reducing costs. This scoping review provides an overview of the involvement of anesthesiologists in APMs as found in published literature. It specifically aims to categorize and understand the breadth and depth of their participation, revolving around 3 main axes or "Aims": (1) shaping APMs through design and implementation, (2) gauging the value and quality of care provided by anesthesiologists within these models, and (3) enhancing nonclinical abilities of anesthesiologists for promoting more value in care. To map out the existing literature, a comprehensive search of relevant electronic databases was conducted, yielding a total of 2173 articles, of which 24 met the inclusion criteria, comprising 21 prospective or retrospective cohort studies, 2 surveys, and 1 case-control cohort study. Eleven publications (45%) discussed value-based, bundled, or episode-based payments, whereas the rest discussed non-payment-based models, such as Enhanced Recovery After Surgery (7 articles, 29%), Perioperative Surgical Home (4 articles, 17%), or other models (3 articles, 13%).The review identified key themes related to each aim. The most prominent themes for aim 1 included protocol standardization (16 articles, 67%), design and implementation leadership (8 articles, 33%), multidisciplinary collaboration (7 articles, 29%), and role expansion (5 articles, 21%). For aim 2, the common themes were Process-Based & Patient-Centric Metrics (1 article, 4%), Shared Accountability (3 articles, 13%), and Time-Driven Activity-Based Costing (TDABC) (3 articles, 13%). Furthermore, we identified a wide range of quality metrics, spanning 8 domains that were used in these studies to evaluate anesthesiologists' performance. For aim 3, the main extracted themes included Education on Healthcare Transformation and Policies (3 articles, 13%), Exploring Collaborative Leadership Skills (5 articles, 21%), and Embracing Advanced Analytics and Data Transparency (4 articles, 17%).Findings revealed the pivotal role of anesthesiologists in the design, implementation, and refinement of these emerging delivery and payment models. Our results highlight that while payment models are shifting toward value, patient-centered metrics have yet to be widely accepted for use in measuring quality and affecting payment for anesthesiologists. Gaps remain in understanding how anesthesiologists assess their direct impact and strategies for enhancing the sustainability of anesthesia practices. This review underscores the need for future research contributing to the successful adaptation of clinical practices in this new era of healthcare delivery.

Estimating Model-Based Marginal Societal Health Benefits of Air Pollution Emission Reductions in the United States and Canada.

We developed spatially detailed source-impact estimates of population health burden measures of air pollution for the United States and Canada by quantifying sources-receptor relationships using the benefit-per-ton (BPT1) metric. We calculated BPTs as the valuations of premature mortality counts due to fine particulate matter (PM2.5; particulate matter ≤2.5 µm in aerodynamic diameter) exposure resulting from emissions of one ton of a given pollutant. Our BPT estimates, while accounting for a large portion of societal impact, do not include morbidity, acute exposure mortality, or chronic exposure mortality due to exposure to other pollutants such as ozone.The adjoint version of a widely used chemical transport model (CTM) allowed us to calculate location-specific BPTs at a high level of granularity for source-impact characterization. Location-specific BPTs provides a means for exploiting the disparities in source impact of emissions at different locations. For instance, estimated BPTs show that 20% of primary PM2.5 and ammonia emissions in the United States account for approximately 50% and 60% of the burden of each species, respectively, for an estimated burden of $370B USD. Similarly, 10% of the most harmful emissions of primary PM2.5 and ammonia emissions in Canada account for approximately 60% and 50% of their burden, respectively. By delineating differences and disparities in source impacts, adjoint-based BPT provides a direct means for prioritizing and targeting emissions that are most damaging.Sensitivity analyses evaluated the impact of our assumptions and study design on the estimated BPTs. The choice of concentration-response function had a substantial impact on the estimated BPTs and is likely to constitute the largest source of uncertainty in those estimates. Our method for constructing annual BPT estimates based on episodic simulations introduces low uncertainty, while uncertainties associated with the spatial resolution of the CTM were evaluated to be of medium importance. Finally, while recognizing that the use of BPTs entails an implied assumption of linearity, we show that BPTs for primary PM2.5 emissions are stable across different emission levels in North America. While BPTs for precursors of secondary inorganic aerosols showed sensitivity to emission levels in the past, we found that those have stabilized with lower emissions and pollutant concentrations in the North American atmosphere.We used BPTs to provide location-specific and sectoral estimates for the cobenefits of reducing carbon dioxide emissions from a range of combustion sources. Cobenefit estimates rely heavily on the emission characteristics of the sector and therefore exhibit more pronounced sectoral fingerprints than do BPTs. We provide cobenefit estimates for various subsectors of on-road transportation, thermal electricity generation, and off-road engines. Off-road engines and various heavy-duty diesel vehicles had the largest cobenefits, which in most urban locations far exceeded estimates of the social cost of carbon. Based on our cobenefit estimations, we also provide per-vehicle burden estimates for different vintages of vehicle subsectors such as transit buses and short-haul trucks in major US cities.

Digital Health in Diabetes and Cardiovascular Disease.

BACKGROUND: Digital health technologies are rapidly evolving and transforming the care of diabetes and cardiovascular disease (CVD). PURPOSE OF THE REVIEW: In this review, we discuss emerging approaches incorporating digital health technologies to improve patient outcomes through a more continuous, accessible, proactive, and patient-centered approach. We discuss various mechanisms of potential benefit ranging from early detection to enhanced physiologic monitoring over time to helping shape important management decisions and engaging patients in their care. Furthermore, we discuss the potential for better individualization of management, which is particularly important in diseases with heterogeneous and complex manifestations, such as diabetes and cardiovascular disease. This narrative review explores ways to leverage digital health technology to better extend the reach of clinicians beyond the physical hospital and clinic spaces to address disparities in the diagnosis, treatment, and prevention of diabetes and cardiovascular disease. CONCLUSION: We are at the early stages of the shift to digital medicine, which holds substantial promise not only to improve patient outcomes but also to lower the costs of care. The review concludes by recognizing the challenges and limitations that need to be addressed for optimal implementation and impact. We present recommendations on how to navigate these challenges as well as goals and opportunities in utilizing digital health technology in the management of diabetes and prevention of adverse cardiovascular outcomes.

The Butyrate-Producing Bacterium Clostridium butyricum Suppresses Clostridioides difficile Infection via Neutrophil- and Antimicrobial Cytokine-Dependent but GPR43/109a-Independent Mechanisms.

Short-chain fatty acids, such as butyrate, are major gut microbial metabolites that are beneficial for gastrointestinal health. Clostridium butyricum MIYAIRI588 (CBM588) is a bacterium that produces a robust amount of butyrate and therefore has been used as a live biotherapeutic probiotic in clinical settings. Clostridioides difficile causes life-threatening diarrhea and colitis. The gut resident microbiota plays a critical role in the prevention of C. difficile infection (CDI), as the disruption of the healthy microbiota by antibiotics greatly increases the risk for CDI. We report that CBM588 treatment in mice significantly improved clinical symptoms associated with CDI and increased the number of neutrophils and Th1 and Th17 cells in the colonic lamina propria in the early phase of CDI. The protective effect of CBM588 was abolished when neutrophils, IFN-γ, or IL-17A were depleted, suggesting that induction of the immune reactants is required to elicit the protective effect of the probiotic. The administration of tributyrin, which elevates the concentration of butyrate in the colon, also increased the number of neutrophils in the colonic lamina propria, indicating that butyrate is a potent booster of neutrophil activity during infection. However, GPR43 and GPR109a, two G protein-coupled receptors activated by butyrate, were dispensable for the protective effect of CBM588. These results indicate that CBM588 and butyrate suppress CDI, in part by boosting antimicrobial innate and cytokine-mediated immunity.

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies.

OBJECTIVE: To evaluate the utility of prenatal exome sequencing (pES) in fetuses with central nervous system (CNS) abnormalities. METHODS: This was a retrospective cohort study of fetuses identified to have CNS abnormality on prenatal ultrasound and/or magnetic resonance imaging. All fetuses were first analyzed by chromosomal microarray analysis (CMA). Fetuses with a confirmed aneuploidy or causal pathogenic copy-number variant (CNV) on CMA did not undergo pES analysis and were excluded, while those with a negative CMA result were offered pES testing. RESULTS: Of the 167 pregnancies included in the study, 42 (25.1%) were identified to have a pathogenic or likely pathogenic (P/LP) variant. The diagnostic rate was significantly higher in fetuses with a non-isolated CNS abnormality than in those with a single CNS abnormality (35.7% (20/56) vs 14.5% (8/55); P = 0.010). Moreover, when a fetus had three or more CNS abnormalities, the positive diagnostic rate increased to 42.9%. A total of 25/42 (59.5%) cases had de-novo mutations, while, in the remaining cases, mutations were inherited and carried a significant risk of recurrence. Families whose fetus carried a P/LP mutation were more likely to choose advanced pregnancy termination than those with a variant of uncertain significance, secondary/incidental finding or negative pES result (83.3% (25/30) vs 41.3% (38/92); P < 0.001). CONCLUSION: pES improved the identification of genetic disorders in fetuses with CNS anomalies without a chromosomal abnormality or CNV identified on CMA, regardless of the number of CNS anomalies and presence of extracranial abnormality. We also demonstrated that pES findings can significantly impact parental decision-making. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Correlations between H2 Permeation and Physical/Mechanical Properties in Ethylene Propylene Diene Monomer Polymers Blended with Carbon Black and Silica Fillers.

H2 permeation in peroxide-crosslinked EPDM blended with carbon black (CB) and silica fillers was studied at pressures ranging from 1.2 MPa to 90 MPa via the volumetric analysis technique. H2 uptake in the CB-filled EPDM revealed dual-sorption behaviors via Henry's law and the Langmuir model, which were attributed to H2 absorption by the polymer chains and H2 adsorption at the filler interfaces, respectively. Additionally, single-sorption mechanisms were observed for neat EPDM and silica-blended EPDM according to Henry's law, indicating H2 absorption by the polymer chain. The linear decreases in the diffusivity with filler content for the silica-blended EPDMs were attributed to increases in the diffusion paths caused by the filler. Exponential decreases in the diffusivity with increasing filler content and in the permeation with the physical/mechanical properties for CB-filled EPDMs were caused by decreases in the fractional free volume due to increased densities for the EPDM composites. Moreover, good filler-dependent correlations between permeability and density, hardness, and tensile strength were demonstrated for EPDMs used as sealing materials for O-rings. From the resulting equation, we predicted the permeation value without further measurements. Thus, we can select EPDM candidates satisfying the permeation guidelines used in hydrogen infrastructure for the future hydrogen economy.

Optimal ropivacaine concentration for ultrasound-guided erector spinae plane block in patients who underwent video-assisted thoracoscopic lobectomy surgery.

Background: An ultrasound-guided erector spinae plane block (ESPB) has emerged as an effective way to control postoperative pain and may be a good alternative way to an epidural block. However, relevant research on the appropriate concentration of local anesthetics for an ESPB remains scarce. Aims: This study aimed to investigate the optimal concentration of ropivacaine for an ESPB in patients undergoing video-assisted thoracoscopic surgery (VATS). Methods: A total of 68 patients who underwent a VATS lobectomy were enrolled. An ipsilateral ultrasound-guided ESPB was performed with three different ropivacaine concentrations as a local anesthetic: 0.189% (G1), 0.375% (G2), and 0.556% (G3). The total amount of perioperative remifentanil administered, patient-controlled analgesia (PCA) applied, and rescue drugs for postoperative analgesia during the 24 h after surgery were acquired, and numeric rating scale (NRS) scores were obtained. Results: The total amount of intraoperative remifentanil administered was 7.20 ± 3.04 mcg/kg, 5.32 ± 2.70 mcg/kg, and 4.60 ± 1.75 in the G1, G2, and G3 groups, respectively. G2 and G3 had significantly lower amounts of remifentanil administered than the G1 group (P = 0.02 vs. G2; P = 0.003 vs. G3). The G3 group needed more inotropes than the G1 and G2 groups in the perioperative period (P = 0.045). The NRS scores, PCA, and rescue drug were not significantly different in the three groups. Conclusion: The optimal concentration of ropivacaine recommended for an ESPB was 0.375%, which was effective in controlling pain and reducing the intraoperative opioid requirements with minimal adverse reactions such as hypotension.

Risk of skin cancer after ultraviolet phototherapy in patients with vitiligo: a systematic review and meta-analysis.

BACKGROUND: Although ultraviolet (UV) phototherapy is an effective treatment for vitiligo, its effect on the risk of skin cancer remains controversial. AIM: To investigate the association between UV phototherapy and skin cancer risk in patients with vitiligo. METHODS: A systematic review was performed for studies published before 5 May 2021 in the PubMed, Embase, Web of Science and Cochrane Library databases. The primary outcome was the association of UV phototherapy with the risk of skin cancer in patients with vitiligo. A meta-analysis with a random-effects model was conducted. RESULTS: Five retrospective cohort studies covering a total of 228 607 patients with vitiligo (110 038 who had been treated with UV phototherapy and 118 569 patients who had not) were included in the meta-analysis. The risk of nonmelanoma skin cancer [Mantel-Haenszel risk ratio (MHRR) = 0.95; 95% CI 0.44-2.05] and melanoma (MHRR = 1.11; 95% CI 0.33-3.82) did not significantly increase after phototherapy in patients with vitiligo. In the subgroup analysis, we also found no significant association between phototherapy with narrowband UVB phototherapy specifically and risk of skin cancer in patients with vitiligo. There was no significant difference in risk of skin cancer between patients from Europe and those from East Asia and the risk was not affected by the number of narrowband UVB phototherapy sessions. CONCLUSIONS: The findings of this systematic review and meta-analysis suggest that UV phototherapy is a safe treatment for vitiligo with no significant risk of skin cancer.

Differential Risk of Cancer Associated with Glucagon-like Peptide-1 Receptor Agonists: Analysis of Real-world Databases.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1Ra) are commonly used in type 2 diabetes mellitus (T2DM). However, differential risk of various cancers among GLP1Ra recipients is unknown. METHODS: We inquired an aggregated electronic health record database, Explorys, and compared the adjusted odds ratio (aOR) of cancers between GLP1Ra and metformin users. Findings were validated in the FDA Adverse Event Reporting System (FDA FAERS). RESULTS: From 1/2005 to 6/2019, we identified 619 340 and 64 230 patients in the metformin and GLP1Ra group, respectively. Within 5 years of starting antidiabetic medications, GLP1Ra was associated with significantly lower incident risk of prostate (aOR 0.81, p = .03), lung (aOR 0.81, p = .05), and colon cancer (aOR 0.85, p = .03), while the risk of thyroid cancer was significantly higher (aOR 1.65, p < .01). Similar findings were seen in the FDA FAERS database, where GLP1Ra was associated with lower risk of prostate (aOR 0.72, p = .08), lung (aOR 0.52, p < .01), colon cancer (aOR 0.82, p = .31), and higher risk of thyroid cancer (aOR 4.33, p < .01). In addition, with longer duration of GLP1Ra use, the risk of prostate, lung, and colon cancer further decreased, suggesting an exposure duration-response relationship. CONCLUSIONS: GLP1Ra is associated with lower risks of prostate, lung, and colon cancer, but higher risk of thyroid cancer.

Long-term trends in the incidence of congenital anomalies in Central China from 1997 to 2019.

OBJECTIVE: The aim of the study was to investigate the incidence of, and trends in, congenital anomalies in Central China from 1997 to 2019. STUDY DESIGN: This was a descriptive study. METHODS: We collected data describing 4,134,098 births from 75 hospital monitoring sites in Henan Province, Central China, from 1997 to 2019. A joinpoint regression model was used to analyze the continuous changes. RESULTS: There were 4,134,098 births recorded from 1997 to 2019, of which 50,646 noted the presence of congenital anomalies (incidence: 122.5 per 10,000). The incidence of congenital anomalies was found to have increased over time (P-trend <0.05). Congenital anomaly incidence in urban areas was higher than that in rural areas (155.3 per 10,000 vs 100.7 per 10,000; P < 0.001). Moreover, incidence was higher in males than in females (129.1 per 10,000 vs 112.9 per 10,000; P < 0.001). The incidence of neural tube defects significantly reduced from 1997 to 2019 (39.3 per 10,000 in 1997 vs 0.92 per 10,000 in 2019, P-trend <0.001), whereas the incidence of congenital heart disease (CHD) increased (5.56 per 10,000 in 2010 to 136.46 per 10,000 in 2019), which meant that CHD was the most common congenital anomaly post-2013. CONCLUSION: In Henan province, the incidence of congenital anomalies increased by 115% from 1997 to 2019. Notably, the incidence of CHD is rising.

IL-4-BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy.

BACKGROUND: This study group has previously identified IL-9-producing mucosal mast cell (MMC9) as the primary source of IL-9 to drive intestinal mastocytosis and experimental IgE-mediated food allergy. However, the molecular mechanisms that regulate the expansion of MMC9s remain unknown. OBJECTIVES: This study hypothesized that IL-4 regulates MMC9 development and MMC9-dependent experimental IgE-mediated food allergy. METHODS: An epicutaneous sensitization model was used and bone marrow reconstitution experiments were performed to test the requirement of IL-4 receptor α (IL-4Rα) signaling on MMC9s in experimental IgE-mediated food allergy. Flow cytometric, bulk, and single-cell RNA-sequencing analyses on small intestine (SI) MMC9s were performed to illuminate MMC9 transcriptional signature and the effect of IL-4Rα signaling on MMC9 function. A bone marrow-derived MMC9 culture system was used to define IL-4-BATF signaling in MMC9 development. RESULTS: Epicutaneous sensitization- and bone marrow reconstitution-based models of IgE-mediated food allergy revealed an IL-4 signaling-dependent cell-intrinsic effect on SI MMC9 accumulation and food allergy severity. RNA-sequencing analysis of SI-MMC9s identified 410 gene transcripts reciprocally regulated by IL-4 signaling, including Il9 and Batf. Insilico analyses identified a 3491-gene MMC9 transcriptional signature and identified 2 transcriptionally distinct SI MMC9 populations enriched for metabolic or inflammatory programs. Employing an in vitro MMC9-culture model system showed that generation of MMC9-like cells was induced by IL-4 and this was in part dependent on BATF. CONCLUSIONS: IL-4Rα signaling directly modulates MMC9 function and exacerbation of experimental IgE-mediated food allergic reactions. IL-4Rα regulation of MMC9s is in part BATF-dependent and occurs via modulation of metabolic transcriptional programs.

[Endoscopic retrograde cholangiopancreatography in patients after bilioenteric anstomosis].

OBJECTIVE: To distinguish clinical features, safety and efficiency of endoscopic retrograde cholangiopancreatography (ERCP) in patients after bilioenteric anstomosis based on retrospectively analyzed clinical data and endoscopy procedures. METHODS: Data extracted from patients after bilioenteric anstomosis due to biliary disease treated with ERCP from January 2005 to December 2021 in the Department of Gastroenterology, Peking University Third Hospital were retrospectively analyzed. Clinical data and endoscopic pictures were reevaluated and analyzed. The patients were divided into three groups, including the patients with choledochoduodenostomy (CDD), Roux-en-Y hepaticojejunostomy (RYHJ) and Whipple. Differences between ERCP success and failure were conducted. RESULTS: In the study, 89 cases with 132 ERCP procedures were involved, 9-80 years old, median 57 years old, containing 4 CDD, 30 RYHJ, 54 Whipple and 1 bile duct ileocecal anastomosis patients; The time between ERCP and surgery were 30 (1-40), 2.75 (0.5-14), 2 (0.3-19), and 10 years, respectively; The time between surgery and symptom were 240 (3-360), 12 (1-156), 22 (0-216), and 60 months, respectively. Fifty percent of CDD could succeed only under local anaesthesia, RYHJ (96.7%) and Whipple (100.0%) needed under general anaesthesia (P < 0.001). Successful first entry rates of CDD, RYHJ and Whipple were 100.0%, 40.0% and 77.8%, respectively. After changing the endoscopy type, successful entry rate could increase to 43.3% of RYHJ and 83.3% of Whipple. The successful entry rate of different anastomotic methods was significant (P < 0.001). The cannulation success rates of CDD, RYHJ and Whipple were 100.0%, 53.8% and 86.7% respectively, with significant difference between the groups (P=0.031). ERCP success rates of CDD, RYHJ and Whipple were 100.0%, 33.3% and 78.8% respectively, with significant difference between the groups (P < 0.001). Complications were found in 23.9% (21/88) patients, including infection (14.8%), pancreatitis (9.2%), bleeding (3.4%), and perforation (2.3%) ranked by incidence. Causes of ERCP in post bilioenteric anstomosis were anastomotic stenosis (50.0%, benign 39.3%, malignant 10.7%), choledocholithiasis (37.5%) and reflux cholangitis (12.5%). Anastomotic method was the only predicting factor of ERCP success in patients after bilioenteric anstomosis (OR=7, 95%CI: 2.591-18.912, P < 0.001). CONCLUSION: ERCP in post bilioenteric anstomosis patients with gastrointestinal reconstruction need general anaesthe-sia, with good safety and efficiency. The successful rate of RYHJ was significantly lower than Whipple. Anastomotic method was the only predicting factor of ERCP success.