Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.

Anomalous electrons in a metallic kagome ferromagnet.

Ordinary metals contain electron liquids within well-defined 'Fermi' surfaces at which the electrons behave as if they were non-interacting. In the absence of transitions to entirely new phases such as insulators or superconductors, interactions between electrons induce scattering that is quadratic in the deviation of the binding energy from the Fermi level. A long-standing puzzle is that certain materials do not fit this 'Fermi liquid' description. A common feature is strong interactions between electrons relative to their kinetic energies. One route to this regime is special lattices to reduce the electron kinetic energies. Twisted bilayer graphene1-4 is an example, and trihexagonal tiling lattices (triangular 'kagome'), with all corner sites removed on a 2 × 2 superlattice, can also host narrow electron bands5 for which interaction effects would be enhanced. Here we describe spectroscopy revealing non-Fermi-liquid behaviour for the ferromagnetic kagome metal Fe3Sn2 (ref. 6). We discover three C3-symmetric electron pockets at the Brillouin zone centre, two of which are expected from density functional theory. The third and most sharply defined band emerges at low temperatures and binding energies by means of fractionalization of one of the other two, most likely on the account of enhanced electron-electron interactions owing to a flat band predicted to lie just above the Fermi level. Our discovery opens the topic of how such many-body physics involving flat bands7,8 could differ depending on whether they arise from lattice geometry or from strongly localized atomic orbitals9,10.

An electrochemical series for materials.

The electrochemical series is a useful tool in electrochemistry, but its effectiveness in materials chemistry is limited by the fact that the standard electrochemical series is based on a relatively small set of reactions, many of which are measured in aqueous solutions. To address this problem, we have used machine learning to create an electrochemical series for inorganic materials from tens of thousands of entries in the Inorganic Crystal Structure Database. We demonstrate that this series is generally more consistent with oxidation states in solid-state materials than the series based on aqueous ions. The electrochemical series was constructed by developing and parameterizing a physical, human-interpretable model of oxidation states in materials. We show that this model enables the prediction of oxidation states from composition in a way that is more accurate than a state-of-the-art transformer-based neural network model. We present applications of our approach to structure prediction, materials discovery, and materials electrochemistry, and we discuss possible additional applications and areas for improvement. To facilitate the use of our approach, we introduce a freely available website and API.

Drosophila immune priming to Enterococcus faecalis relies on immune tolerance rather than resistance.

Innate immune priming increases an organism's survival of a second infection after an initial, non-lethal infection. We used Drosophila melanogaster and an insect-derived strain of Enterococcus faecalis to study transcriptional control of priming. In contrast to other pathogens, the enhanced survival in primed animals does not correlate with decreased E. faecalis load. Further analysis shows that primed organisms tolerate, rather than resist infection. Using RNA-seq of immune tissues, we found many genes were upregulated in only primed flies, suggesting a distinct transcriptional program in response to initial and secondary infections. In contrast, few genes continuously express throughout the experiment or more efficiently re-activate upon reinfection. Priming experiments in immune deficient mutants revealed Imd is largely dispensable for responding to a single infection but needed to fully prime. Together, this indicates the fly's innate immune response is plastic-differing in immune strategy, transcriptional program, and pathway use depending on infection history.

The circular RNA Edis regulates neurodevelopment and innate immunity.

Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset has been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis (circ_Ect4) causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotor activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Furthermore, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain. Moreover, we provide evidence that Edis encodes a functional protein that associates with and compromises the processing and activation of the immune transcription factor Relish. Importantly, restoring Edis expression or ectopic expression of Edis-encoded protein suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. Thus, our study establishes Edis as a key regulator of neurodevelopment and innate immunity.

Identification of biomarkers for the early detection of non-small cell lung cancer: a systematic review and meta-analysis.

Lung cancer (LC) causes few symptoms in the earliest stages, leading to one of the highest mortality rates among cancers. Low-dose computerised tomography (LDCT) is used to screen high-risk individuals, reducing the mortality rate by 20%. However, LDCT results in a high number of false positives and is associated with unnecessary follow-up and cost. Biomarkers with high sensitivities and specificities could assist in the early detection of LC, especially in patients with high-risk features. Carcinoembryonic antigen (CEA), cytokeratin 19 fragments and cancer antigen 125 have been found to be highly expressed during the later stages of LC but have low sensitivity in the earliest stages. We determined the best biomarkers for the early diagnosis of LC, using a systematic review of eight databases. We identified 98 articles that focussed on the identification and assessment of diagnostic biomarkers and achieved a pooled area under curve of 0.85 (95% CI 0.82-0.088), indicating that the diagnostic performance of these biomarkers when combined was excellent. Of the studies, 30 focussed on single/antigen panels, 22 on autoantibodies, 31 on miRNA and RNA panels, and 15 suggested the use of circulating DNA combined with CEA or neuron-specific enolase (NSE) for early LC detection. Verification of blood biomarkers with high sensitivities (Ciz1, exoGCC2, ITGA2B), high specificities (CYFR21-1, antiHE4, OPNV) or both (HSP90α, CEA) along with miR-15b and miR-27b/miR-21 from sputum may improve early LC detection. Further assessment is needed using appropriate sample sizes, control groups that include patients with non-malignant conditions, and standardised cut-off levels for each biomarker.

Glymphatic fluid transport is suppressed by the aquaporin-4 inhibitor AER-271.

The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain.

How to make a digital reconstruction of the human ribcage.

Up to now, there have been no publication standardizing the digital reconstruction of the modern human ribcage from commingled costo-vertebral material. Consequently, we designed a validated protocol based on anatomical features observed in the literature and the CT scanned ribcages of 10 adult European individuals. After quantifying the shape of these ribcages using 3D geometric morphometrics, we split each vertebra and rib within their corresponding (semi)landmarks. Subsequently, individual bones + (semi)landmarks were imported to LhpFusionBox, commingled and 3D reconstructed. To validate the accuracy of the protocol, we first reconstructed a randomly chosen ribcage three times and then compared these reconstructions to the rest of the sample. Since these reconstructions were closer to their original counterpart than to the others, the remaining sample was reconstructed once. Next, we tested the intra-observer error during reconstructing using the Procrustes distances among the original ribcages and the reconstructions. We observed that first each ribcage reconstruction was clustered to its original counterpart and second there was a learning curve showing an improvement in the reconstruction process over time. Subsequently, we explored general size and shape differences among the original and reconstructed ribcages through a study of centroid size and a permutation test on the Procrustes distances (10,000 permutations), respectively. Specific shape differences between both groups were further examined through a principal component analysis in shape space. None of these analyses found statistical differences between the original and reconstructed ribcages (p > 0.05). Eventually, we extracted the mean shapes of the original ribcages and the reconstructions in order to visualize potential deviations caused by the anatomical considerations of the researcher. These results demonstrate that the protocol is accurate enough to be used when reconstructing a disarticulated human ribcage.

Selection of the Most Suitable Culture Medium for Patient-Derived Lung Cancer Organoids.

INTRODUCTION: Patient-derived organoids have emerged as a promising in vitro model for precision medicine, particularly in cancer, but also in noncancer-related diseases. However, the optimal culture medium for culturing patient-derived lung organoids has not yet been agreed upon. This study aimed to shed light on the optimal selection of a culture media for developing studies using patient-derived lung organoids. METHODS: Tumor and normal paired tissue from 71 resected non-small cell lung cancer patients were processed for organoid culture. Lung cancer organoids (LCOs) were derived from tumor tissue and normal lung organoids (LNOs) from nonneoplastic lung tissue. Three different culture media were compared: permissive culture medium (PCM), limited culture medium (LCM), and minimum basal medium (MBM). We assessed their effectiveness in establishing organoid cultures, promoting organoid growth and viability, and compared their differential phenotypic characteristics. RESULTS: While PCM was associated with the highest success rate and useful for long-term expansion, MBM was the best option to avoid normal organoid overgrowth in the organoid culture. The density, size, and viability of LNOs were reduced using LCM and severely affected with MBM. LNOs cultured in PCM tend to differentiate to bronchospheres, while alveolosphere differentiation can be observed in those cultured with LCM. The morphological phenotype of LCO was influenced by the culture media of election. Mesenchymal cell overgrowth was observed when LCM was used. CONCLUSION: This work highlights the importance of considering the research objectives when selecting the most suitable culture medium for growing patient-derived lung organoids.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

BACKGROUND: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for

Eco-geographic and sexual variation of the ribcage in Homo sapiens.

Up to now, Allen and Bergmann's rules have been studied in modern humans by analyzing differences in limb length, height, or body mass. However, there are no publications studying the effects of latitude in the 3D configuration of the ribcage. To assess this issue, we digitally reconstructed the ribcages of a balanced sample of 109 adult individuals of global distribution. Shape and size of the ribcage was quantified using geometric morphometrics. Our results show that the ribcage belonging to tropical individuals is smaller and slenderer compared to others living in higher latitudes, which is in line with Allen and Bergmann's rules and suggests an allometric relationship between size and shape. Although sexual dimorphism was observed in the whole sample, significant differences were only found in tropical populations. Our proposal is that, apart from potential sexual selection, avoiding heat loss might be the limiting factor for sexual dimorphism in cold-adapted populations.

Outcomes of initially nonoperative management of diverticulitis with abscess formation in immunosuppressed patients. DIPLICAB study COLLABORATIVE group.

AIM: Management of diverticulitis with abscess formation in immunosuppressed patients (IMS) remains unclear. The main objective of the study was to assess short- and long-term outcomes between IMS and immunocompetent patients (IC). The secondary aim was to identify risk factors for emergency surgery. METHODS: A nationwide retrospective cohort study was performed at 29 Spanish referral centres between 2015-2019 including consecutive patients with first episode of diverticulitis classified as modified Hinchey Ib or II. IMS included immunosuppressive therapy, biologic therapy, malignant neoplasm with active chemotherapy and chronic steroid therapy. A multivariate analysis was performed to identify independent risk factors to emergency surgery in IMS. RESULTS: A total of 1395 patients were included; 118 IMS and 1277 IC. There were no significant differences in emergency surgery between IMS and IC (19.5% and 13.5%, p = 0.075) but IMS was associated with higher mortality (15.1% vs. 0.6%, p < 0.001). Similar recurrent episodes were found between IMS and IC (28% vs. 28.2%, p = 0.963). Following multivariate analysis, immunosuppressive treatment, p = 0.002; OR: 3.35 (1.57-7.15), free gas bubbles, p < 0.001; OR: 2.91 (2.01-4.21), Hinchey II, p = 0.002; OR: 1.88 (1.26-2.83), use of morphine, p < 0.001; OR: 3.08 (1.98-4.80), abscess size ≥5 cm, p = 0.001; OR: 1.97 (1.33-2.93) and leucocytosis at third day, p < 0.001; OR: 1.001 (1.001-1.002) were independently associated with emergency surgery in IMS. CONCLUSION: Nonoperative management in IMS has been shown to be safe with similar treatment failure than IC. IMS presented higher mortality in emergency surgery and similar rate of recurrent diverticulitis than IC. Identifying risk factors to emergency surgery may anticipate emergency surgery.

Circumferential exposure of the cavernous sinus and parasellar region through a combined open and endoscopic endonasal transcavernous approach, a morphometric study.

INTRODUCTION: Although recent trends currently favor the endoscopic endonasal transcavernous approach (EETA) over the pretemporal transcavernous approach (PTA) for certain cavernous sinus pathologies, dedicated assessment of the surgical exposure and maneuverability is wanting. Toward this aim, this morphometric study quantifies these variables within four cavernous sinus compartments by comparing the PTA, EETA, and a combined approach to achieve a circumferential dissection (EETA-PTA). MATERIAL: In five latex-injected specimens, exposure volumes of the EETA, PTA, and circumferential EETA-PTA approaches were quantified; the latter combined the most conservative options of both the endoscopic and open approaches. Two clinical cases illustrate the combined approach. RESULTS: EETA-PTA provided the largest volume of exposure (65.6% vs 35% PTA vs 44.6% EETA, P = 0.01) and eliminated the need to mobilize the ICA or cross cranial nerves. Although EETA and PTA approaches afforded comparable exposure volumes along the entire cavernous sinus (34.9 vs 44.6%), the EETA better exposed medial and inferior compartments (whereas the PTA exposed larger volumes in the lateral and superior compartments. The combined EETA-PTA yielded 66% of total cavernous sinus exposure volumes and eliminated the need to mobilize the ICA or cross cranial nerves. CONCLUSIONS: Our methodology aligns with strategies that use a modular concept to divide the skull base into compartments for maximal safe resection. Excluding soft tumors, the EETA is preferred for medial and inferior lesions and the PTA for superior and lateral lesions. A staged combined EETA-PTA may safely yield a 360-degree access for extensive multi-compartment lesions that span neurovascular structures within the cavernous sinus.

Rationale and design of the artificial intelligence scalable solution for acute myocardial infarction (ASSIST) study.

BACKGROUND: Acute coronary syndrome (ACS), specifically ST-segment elevation myocardial infarction is a major cause of morbidity and mortality throughout Europe. Diagnosis in the acute setting is mainly based on clinical symptoms and physician's interpretation of an electrocardiogram (ECG), which may be subject to errors. ST-segment elevation is the leading criteria to activate urgent reperfusion therapy, but a clear ST-elevation pattern might not be present in patients with coronary occlusion and ST-segment elevation might be seen in patients with normal coronary arteries. METHODS: The ASSIST project is a retrospective observational study aiming to improve the ECG-assisted assessment of ACS patients in the acute setting by incorporating an artificial intelligence platform, Willem™ to analyze 12­lead ECGs. Our aim is to improve diagnostic accuracy and reduce treatment delays. ECG and clinical data collected during this study will enable the optimization and validation of Willem™. A retrospective multicenter study will collect ECG, clinical, and coronary angiography data from 10,309 patients. The primary outcome is the performance of this tool in the correct identification of acute myocardial infarction with coronary artery occlusion. Model performance will be evaluated internally with patients recruited in this retrospective study while external validation will be performed in a second stage. CONCLUSION: ASSIST will provide key data to optimize Willem™ platform to detect myocardial infarction based on ECG-assessment alone. Our hypothesis is that such a diagnostic approach may reduce time delays, enhance diagnostic accuracy, and improve clinical outcomes.

First report of a new Carlavirus provisionally named rose virus B and apple mosaic virus in mixed infections of Rosa sp. in Mexico.

Rose (Rosa sp.) is an important ornamental plant in the cut flower industry around the world. This species is prone to hosting several viruses since it is propagated vegetatively, mainly by grafting (Mollov et al., 2013). In 2021, rose plants of unidentified variety with mosaic, vein yellowing, chlorotic line patterns, and interveinal chlorosis were observed in a rose plantation established in open field in Temixco, Morelos (Supplementary Figure 1). To determine the cause of symptoms was due to viral infection, nucleic acids were extracted from leaves by in-house CTAB procedure and DNase treated. A pooled RNA sample extracted from 4 symptomatic plants was sent to BGI Genomics (China) for high-throughput sequencing (HTS). A stranded mRNA library was prepared and sequenced on the DNBSEQ platform (BGI). A total number of 13,646,715 paired 150-bp clean reads were generated. The reads were assembled de novo into 79,309 contigs ranging from 78 to 15,817 nucleotides (nt) using SPAdes (Prjibelskiet et al., 2020). The contigs were subjected to BLASTx and BLASTn for annotation. A contig with a length of 8,842 nt (208x average coverage per nt) showed 90.6% identity to rose virus B (RVB) (MT473961), and was deposited in GenBank under accession number ON165234. Additionally, three contigs (ON165235-ON165237) corresponding to RNA1 (3,443 nt; 154x coverage), RNA2 (2,938 nt; 231x coverage), and RNA3 (1,897 nt; 232x coverage) of apple mosaic virus (ApMV) were identified. These contigs showed up to 98.4%, 89.7%, and 98.6% identity, respectively, to each corresponding RNA sequences of ApMV. No other viral sequence was identified from the constructed contigs. Subsequently, the presence of RVB was confirmed by RT-PCR performed with an aliquot of the pooled RNAspan style="font-family:'Times New Roman'; font-size:11pt"> with specific primers targeting the replicase and CP (Diaz-Lara et al., 2021). For ApMV, a new set of primers were designed: ApMV_RNA1F (5'-AAATCTCCCGAAAGGGCCTG-3')/ApMV_RNA1R (5'-TCACTCGTCGCATGGATGGATAGC-3'), ApMV_RNA2F (5'-TTGGTACGAGTCGTGGTTGGTTGG-3')/ApMV_RNA2R (5'-GGAAAACTGACCGCAAACCC-3'), and ApMV_RNA3F (5'-GGAGGTTAGAGGCCCGAATG-3')/ApMV_RNA3R (5'-CGCACAGGTGGTAACTCACT-3') which amplify segments of 444 bp, 546 bp, and 434 bp, respectively. The amplicons obtained for both viruses were subjected to Sanger sequencing, confirming the identity of RVB and ApMV. The sequences from the RVB replicase (ON165241) and CP (ON165240) showed 93.9% and 97.0% nt identity with an RVB isolate reported in the USA (MT473961). On the other hand, sequences from RNA1 (ON165238), RNA2, (OP413436), and RNA3 (ON165239) of ApMV had 99.2%, 89.2%, and 99% nt identity, respectively. Finally, the four symptomatic plants were individually tested by RT-PCR to identify RVB and ApMV. Interestingly, both viruses were detected in all the plants analyzed. ApMV (genus Ilarvirus) is associated with mosaic and mottling symptoms in rose (Thomas, 1984). It has been accepted that ApMV is present in rose plants in Mexico (Cardenas-Alonso, 1994), with no evidence to confirm it. RVB was identified in rose in USA, and this virus was classified as a new species of the genus Carlavirus (Diaz-Lara et al., 2021). In addition to RVB, rose virus A and rose virus C have also been reported in rose; however, the symptomatology linked to these viruses is unknown (Xing et al. 2021; Diaz-Lara et al., 2020). Recently, RVB and ApMV were reported in rose plants in Taiwan (Chen et al., 2022). To our knowledge, this is the first report of RVB and ApMV in a mixed infection in rose in Mexico.

AMIC achieves sustained clinical improvement in isolated patellar cartilage defects over 5 years, correlating with MRI.

PURPOSE: To evaluate 5-year postoperative clinical outcomes of autologous matrix-induced chondrogenesis (AMIC) for isolated ICRS grade 3-4 patellar cartilage defects and correlate outcomes with magnetic resonance imaging (MRI). The hypothesis was that AMIC would improve clinical symptoms and induce neocartilage formation, visible on MRI, making it a safe and effective option for repairing focal patellar cartilage defects. METHODS: The cohort comprised 13 focal patellar lesions in 12 patients. Pain visual analogue scale (VAS), Knee Injury and Osteoarthritis Outcome Score (KOOS), Kujala score, EuroQol-5D Health Survey questionnaire and MRI data were assessed preoperatively and at 2 and 5 years postoperatively. All MRI scans were evaluated using the Magnetic Resonance Observation of Cartilage Repair Tissue System. Descriptive statistics were calculated on all data. Inferential analysis comparing outcome scores before and after surgery employed the nonparametric Wilcoxon signed-rank test, with the nonparametric Friedman test used to detect differences across multiple test attempts. p < 0.05 was considered statistically significant. RESULTS: Twelve patients (23-52 years old) with patellofemoral chondral full-thickness defects (2-4 cm2) were treated. At a 5-year follow-up, eleven knees showed MRI improvement. Two were asymptomatic and nine showed clear clinical improvement. Only one knee showed no clinical improvement. MRI revealed a defect filling with newly formed cartilage characterized by a less compact and heterogeneous signal. Cartilage degradation or joint damage was observed in two knees, and bone formation within the plate was identified in four. AMIC significantly improved patients' VAS pain, KOOS, EuroQol-5D and Kujala scores compared to preoperative baseline for up to 5 years postoperatively. CONCLUSIONS: Satisfactory clinical outcomes and new cartilage formation, as observed by MRI, are achieved with AMIC at mid-term follow-up for ICRS grade 3-4 in small-to-medium-sized patellar defects in patients under 52 years of age, with improvements maintained for up to 5 years. LEVEL OF EVIDENCE: Level III.

Active shooter in emergency departments in Guanajuato State, Mexico.

Mass violence events, especially in healthcare settings, have devastating consequences and long-lasting effects on the victims and the community. The rate of violent events in Mexico, especially in hospital settings, has increased since 2006, but has become more evident in 2018. Guanajuato State, located in central Mexico, is among the states most affected by the wave of violence, especially active shooter events. The year 2019 had the highest number of incidents. Therefore, the Silver Code and the components of Safe Hospitals, in accordance with the Hartford consensus and PAHO guidelines, were implemented in the hospitals of the Institute of Public Health of the State of Guanajuato, with a focus on the actions of healthcare personnel to prevent collateral damage. Although subsequently there were still fatalities and injuries in the events involving active shooters in the hospitals, there were no casualties among healthcare personnel, according to data from the Institute of Public Health, Guanajuato State. This paper presents information from the data from General Directorate of Epidemiology to describe the hospital mass violence situation in the State of Guanajuato, Mexico and recounts the step taken to effectively manage and prevent these situations moving forward. Specific recommendations based on international consensus and our experience provided include increasing the level of security checks for people entering the hospital premises, training healthcare personnel on violence-related preparedness and improving management of active shooter events consistent with published evidence, to reduce the possibility of casualties.

Probabilistic Method to Fuse Artificial Intelligence-Generated Underground Utility Mapping.

Utility as-built plans, which typically provide information about underground utilities' position and spatial locations, are known to comprise inaccuracies. Over the years, the reliance on utility investigations using an array of sensing equipment has increased in an attempt to resolve utility as-built inaccuracies and mitigate the high rate of accidental underground utility strikes during excavation activities. Adapting data fusion into utility engineering and investigation practices has been shown to be effective in generating information with improved accuracy. However, the complexities in data interpretation and associated prohibitive costs, especially for large-scale projects, are limiting factors. This paper addresses the problem of data interpretation, costs, and large-scale utility mapping with a novel framework that generates probabilistic inferences by fusing data from an automatically generated initial map with as-built data. The probabilistic inferences expose regions of high uncertainty, highlighting them as prime targets for further investigations. The proposed model is a collection of three main processes. First, the automatic initial map creation is a novel contribution supporting rapid utility mapping by subjecting identified utility appurtenances to utility inference rules. The second and third processes encompass the fusion of the created initial utility map with available knowledge from utility as-builts or historical satellite imagery data and then evaluating the uncertainties using confidence value estimators. The proposed framework transcends the point estimation of buried utility locations in previous works by producing a final probabilistic utility map, revealing a confidence level attributed to each segment linking aboveground features. In this approach, the utility infrastructure is rapidly mapped at a low cost, limiting the extent of more detailed utility investigations to low-confidence regions. In resisting obsolescence, another unique advantage of this framework is the dynamic nature of the mapping to automatically update information upon the arrival of new knowledge. This ultimately minimizes the problem of utility as-built accuracies dwindling over time.

Impact of previous percutaneous coronary intervention on angiographic and clinical outcomes in patients with ST-segment elevation myocardial infarction.

BACKGROUND: The prognosis of patients with ST-segment elevation myocardial infarction (STEMI) and previous percutaneous coronary intervention (PCI) is uncertain. OBJECTIVE: To evaluate if previous PCI in patients with STEMI increases the risk of major cardiovascular events, and if final epicardial blood flow differs according to the reperfusion strategy. MATERIAL AND METHODS: Observational, longitudinal, comparative sub-study of the PHASE-MX trial that included patients with STEMI and reperfusion within 12 hours of symptom onset, who were classified according to their history of PCI. The occurrence of the composite primary endpoint (cardiovascular death, re-infarction, congestive heart failure and cardiogenic shock) within 30 days was evaluated using Kaplan-Meier estimates, log-rank test and Cox proportional hazards model. Epicardial blood flow was assessed using the TIMI grading system after reperfusion. RESULTS: A total of 935 patients were included; 85.6% were males and 6.9% had a history of PCI; 53% underwent pharmacoinvasive therapy, and 47%, primary PCI. The incidence of the composite primary endpoint at 30 days in patients with a history of PCI was 9.8% vs 13.3% in those with no previous PCI (p = 0.06). Among the patients with previous PCI, 87.1% reached a final TIMI grade 3 flow after primary PCI vs. 75% in the group with pharmacoinvasive strategy (p = 0.235). CONCLUSIONS: A history of PCI does not increase the risk of major cardiovascular events at 30 days; however, it impacted negatively on the final angiographic blood flow of patients that received pharmacoinvasive therapy (compared to primary PCI).

ANTECEDENTES: El pronóstico de los pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMCEST) y antecedente de intervención coronaria percutánea (ICP) es incierto. Objetivos: Evaluar si la ICP previa en pacientes con IAMCEST incrementa el riesgo de eventos cardiovasculares mayores y si el flujo final epicárdico varía según la estrategia de reperfusión. MATERIAL Y MÉTODOS: Subestudio de PHASE-MX, observacional, longitudinal y comparativo, de pacientes con IAMCEST reperfundidos en menos de 12 horas de iniciados los síntomas, divididos conforme el antecedente de ICP. El acaecimiento del criterio de valoración principal (muerte cardiovascular, reinfarto, insuficiencia cardíaca y choque cardiogénico) dentro de los 30 días se comparó con estimaciones de Kaplan-Meier, prueba de rangos logarítmicos y modelo de riesgos proporcionales de Cox. El flujo epicárdico final se evaluó con el sistema de clasificación del flujo TIMI después de la reperfusión. RESULTADOS: Se incluyeron 935 pacientes, 85.6 % del sexo masculino, 6.9 % de los cuales tenía antecedente de ICP; 53 % recibió terapia farmacoinvasiva y 47 %, ICP primaria. La incidencia del criterio de valoración principal en pacientes con ICP previa fue de 9.8 % versus 13.3 % en aquellos sin ese antecedente (p = 0.06); 87.1 % de los pacientes con ICP previa obtuvo flujo final de grado TIMI 3 versus 75 % del grupo con estrategia farmacoinvasiva (p = 0.235). CONCLUSIONES: El antecedente de ICP no incrementa el riesgo de eventos cardiovasculares mayores a los 30 días en pacientes con IAMCEST; sin embargo, impacta negativamente en el flujo sanguíneo angiográfico final de los pacientes que recibieron terapia farmacoinvasiva (en comparación con ICP primaria).

Isothermal Phase Transitions in Liquid Crystals Driven by Dynamic Covalent Chemistry.

The dynamic nature of calamitic liquid crystals is exploited to perform isothermal phase transitions driven by dynamic covalent chemistry. For this purpose, nematic (N) arrays based on aldehyde 1 were treated with different amines (A-E) in an on-surface process, which resulted in different isothermal phase transitions. These phase transformations were caused by in situ imination reactions and are dependent on the nature of the added amine. Transitions from the N to crystal (1A, 1E), isotropic (1B), and smectic (Sm) (1C, 1D) phases were achieved, while the resulting materials feature thermotropic liquid crystal behavior. A sequential transformation from the N 1 to the Sm 1C and then to the N 1B was achieved by coupling an imination to a transimination processes and adjusting the temperature. All of these processes were well characterized by microscopic, spectroscopic, and X-ray techniques, unlocking not only the constitutional but also the structural aspects of the phase transitions. This work provides new insights into designing constitutionally and structurally adaptable liquid crystal systems, paving the way toward the conception of programable evolutive pathways and adaptive materials.