OpenChemIE: An Information Extraction Toolkit for Chemistry Literature.

Information extraction from chemistry literature is vital for constructing up-to-date reaction databases for data-driven chemistry. Complete extraction requires combining information across text, tables, and figures, whereas prior work has mainly investigated extracting reactions from single modalities. In this paper, we present OpenChemIE to address this complex challenge and enable the extraction of reaction data at the document level. OpenChemIE approaches the problem in two steps: extracting relevant information from individual modalities and then integrating the results to obtain a final list of reactions. For the first step, we employ specialized neural models that each address a specific task for chemistry information extraction, such as parsing molecules or reactions from text or figures. We then integrate the information from these modules using chemistry-informed algorithms, allowing for the extraction of fine-grained reaction data from reaction condition and substrate scope investigations. Our machine learning models attain state-of-the-art performance when evaluated individually, and we meticulously annotate a challenging dataset of reaction schemes with R-groups to evaluate our pipeline as a whole, achieving an F1 score of 69.5%. Additionally, the reaction extraction results of OpenChemIE attain an accuracy score of 64.3% when directly compared against the Reaxys chemical database. OpenChemIE is most suited for information extraction on organic chemistry literature, where molecules are generally depicted as planar graphs or written in text and can be consolidated into a SMILES format. We provide OpenChemIE freely to the public as an open-source package, as well as through a web interface.

The myriad roles of RNA structure in the flavivirus life cycle.

As positive-sense RNA viruses, the genomes of flaviviruses serve as the template for all stages of the viral life cycle, including translation, replication, and infectious particle production. Yet, they encode just 10 proteins, suggesting that the structure and dynamics of the viral RNA itself helps shepherd the viral genome through these stages. Herein, we highlight advances in our understanding of flavivirus RNA structural elements through the lens of their impact on the viral life cycle. We highlight how RNA structures impact translation, the switch from translation to replication, negative- and positive-strand RNA synthesis, and virion assembly. Consequently, we describe three major themes regarding the roles of RNA structure in flavivirus infections: 1) providing a layer of specificity; 2) increasing the functional capacity; and 3) providing a mechanism to support genome compaction. While the interactions described herein are specific to flaviviruses, these themes appear to extend more broadly across RNA viruses.

Developmental trajectory of cortical somatostatin interneuron function.

GABAergic inhibition is critical to the proper development of neocortical circuits. However, GABAergic interneurons are highly diverse and the developmental roles of distinct inhibitory subpopulations remain largely unclear. Dendrite-targeting, somatostatin-expressing interneurons (SST-INs) in the mature cortex regulate synaptic integration and plasticity in excitatory pyramidal neurons (PNs) and exhibit unique feature selectivity. Relatively little is known about early postnatal SST-IN activity or impact on surrounding local circuits. We examined juvenile SST-INs and PNs in mouse primary visual cortex. PNs exhibited stable visual responses and feature selectivity from eye opening onwards. In contrast, SST-INs developed visual responses and feature selectivity during the third postnatal week in parallel with a rapid increase in excitatory synaptic innervation. SST-INs largely exerted a multiplicative effect on nearby PN visual responses at all ages, but this impact increased over time. Our results identify a developmental window for the emergence of an inhibitory circuit mechanism for normalization.

Real-World Clinical Profile of Patients Prescribed Evolocumab in Japan.

BACKGROUND: Real-world utilization data for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be introduced in Japan in 2016, to date are limited. This study aimed to clarify the current real-world patient user profiles of evolocumab based on large-scale health claims data.Methods and Results: This retrospective database study examined patients from a health administrative database (MDV database) who initiated evolocumab between April 2016 (baseline) and November 2021. Characteristics and clinical profiles of this patient population are described. In all, 4,022 patients were included in the final analysis. Most evolocumab prescriptions occurred in the outpatient setting (3,170; 78.82%), and 940 patients (23.37%) had a recent diagnosis of familial hypercholesterolemia. Common recent atherosclerotic cardiovascular disease events at baseline included myocardial infarction (1,633; 40.60%), unstable angina (561; 13.95%), and ischemic stroke (408; 10.14%). Comorbidity diseases included hypertension (2,504; 62.26%), heart failure (1,750; 43.51%), diabetes (1,199; 29.81%), and chronic kidney disease (297; 7.38%). Among the lipid-lowering regimens concomitant with evolocumab, ezetimibe+statin was used most frequently (1,281; 31.85%), followed by no concomitant lipid-lowering regimen (1,190; 29.59%), statin (950; 23.62%), and ezetimibe (601; 14.94%). The median evolocumab treatment duration for all patients was 260 days (interquartile range 57-575 days). CONCLUSIONS: This study provides real-world insights into evolocumab utilization in Japan for optimizing patient care and adherence to guideline-based therapies to better address hypercholesterolemia in Japan.

Enhancing Visual Grounding in Vision-Language Pre-Training With Position-Guided Text Prompts.

Vision-Language Pre-Training (VLP) has demonstrated remarkable potential in aligning image and text pairs, paving the way for a wide range of cross-modal learning tasks. Nevertheless, we have observed that VLP models often fall short in terms of visual grounding and localization capabilities, which are crucial for many downstream tasks, such as visual reasoning. In response, we introduce a novel Position-guided Text Prompt (PTP) paradigm to bolster the visual grounding abilities of cross-modal models trained with VLP. In the VLP phase, PTP divides an image into N x N blocks and employs a widely-used object detector to identify objects within each block. PTP then reframes the visual grounding task as a fill-in-the-blank problem, encouraging the model to predict objects in given blocks or regress the blocks of a given object, exemplified by filling "[P]" or "[O]" in a PTP sentence such as "The block [P] has a [O]." This strategy enhances the visual grounding capabilities of VLP models, enabling them to better tackle various downstream tasks. Additionally, we integrate the seconda-order relationships between objects to further enhance the visual grounding capabilities of our proposed PTP paradigm. Incorporating PTP into several state-of-the-art VLP frameworks leads to consistently significant improvements across representative cross-modal learning model architectures and multiple benchmarks, such as zero-shot Flickr30 k Retrieval (+5.6 in average recall@1) for ViLT baseline, and COCO Captioning (+5.5 in CIDEr) for the state-of-the-art BLIP baseline. Furthermore, PTP attains comparable results with object-detector-based methods and a faster inference speed, as it discards its object detector during inference, unlike other approaches.

Catch of the Day: New Serum Amyloid A (SAA) Antibody Is a Valuable Tool to Study Fish Health in Salmonids.

Serum amyloid A (SAA) proteins belong to a family of acute-phase reactants, playing an integral role in defending the organism from pathological damage. Despite a wealth of data on the regulation of SAA transcripts in teleosts, there is only limited information on these proteins' abundance in fish. The aim of this study is to characterise SAA protein levels in salmonids using a newly developed antibody specific to salmonid SAA. The salmonid SAA antibody detected SAA and accurately discriminated between stimulated and control specimens from rainbow trout macrophage cell line (RTS-11) in vitro, as well as rainbow trout challenged with Aeromonas salmonicida- or flagellin-stimulated Atlantic salmon in vivo. The presence of SAA protein was analysed in RTS-11 cell line supernatants, liver, and spleen samples using ELISA, immunoblotting, and immunohistochemistry. This study is the first to characterise SAA protein levels in salmonids in vivo and in vitro. The newly developed salmonid SAA antibody was able to discriminate between stimulated and unstimulated specimens, showing that it can be used to study the acute-phase response in salmonids with the potential to be further developed into assays to monitor and evaluate health in wild and farmed fish.

Robotic-assisted Posterior Urethroplasty: Outcomes From 105 Men in a Single-center Experience.

OBJECTIVE: To determine surgical outcomes in a large of cohort men undergoing robotic-assisted posterior urethroplasty (RPU), which has been described in small series as a viable option. MATERIALS AND METHODS: We performed a retrospective review of all 105 men who underwent RPU from October 2014 to August 2022 at a single institution. We evaluated postoperative outcomes, including complications; surgical success defined as no need for reintervention; and incontinence requiring artificial urinary sphincter placement. We performed descriptive statistics and chi-square testing to determine if outcomes were associated with certain posterior urethral disease etiologies. RESULTS: Mean follow-up time was 18.7months. Over half of patients (57.1%) received prior pelvic radiation. The most common reconstructive techniques were excision and primary anastomosis (n = 45, 30.0%), resitting of the bladder neck (n = 26, 24.8%), Y-V plasty (n = 21, 20.0%), and buccal mucosal graft urethroplasty (n = 14, 13.3%). Forty-one patients (39.0%) required a combined abdominoperineal approach. Seven patients (6.7%) had ≥CD grade 3 complications within 30days. Thirty patients (28.6%) developed incontinence with subsequent artificial urinary sphincter placement. One-quarter (24.8%) of patients required at least one subsequent surgical reintervention. CONCLUSION: In the largest RPU cohort to date, surgical success rates were similar and continence rates were improved compared to open surgery and align with existing robotic series, adding to the growing body of evidence demonstrating advantages of RPU.

Herpes zoster vaccine safety in the Aotearoa New Zealand population: a self-controlled case series study.

In Aotearoa New Zealand, zoster vaccine live is used for the prevention of zoster and associated complications in adults. This study assessed the risk of pre-specified serious adverse events following zoster vaccine live immunisation among adults in routine clinical practice. We conducted a self-controlled case series study using routinely collected national data. We compared the incidence of serious adverse events during the at-risk period with the control period. Rate ratios were estimated using Conditional Poisson regression models. Falsification outcomes analyses were used to evaluate biases in our study population. From April 2018 to July 2021, 278,375 received the vaccine. The rate ratio of serious adverse events following immunisation was 0·43 (95% confidence interval [CI]: 0·37-0·50). There was no significant increase in the risk of cerebrovascular accidents, acute myocardial infarction, acute pericarditis, acute myocarditis, and Ramsay-Hunt Syndrome. The herpes zoster vaccine is safe in adults in Aotearoa New Zealand.

Zika virus NS3 and NS5 proteins determine strain-dependent differences in dsRNA accumulation in a host cell type-dependent manner.

For positive-sense RNA viruses, initiation of viral RNA replication represents a major target of antiviral responses to infection. Despite this, the interplay between viral replication and the innate antiviral response at early steps in the Zika virus (ZIKV) life cycle is not well understood. We have previously identified ZIKV isolates with differing levels of dsRNA accumulation, ZIKVPR (high dsRNA per infected cell) and ZIKVCDN (low dsRNA per infected cell), and we hypothesized that we could use reverse genetics to investigate how host and viral factors contribute to the establishment of viral RNA replication. We found that both the ZIKV NS3 and NS5 proteins as well as host factors were necessary to determine the dsRNA accumulation phenotype. Additionally, we show that dsRNA correlates with viral negative-strand RNA measured by strand-specific RT-qPCR, suggesting that dsRNA is an accurate readout of viral RNA replication. Interestingly, although we did not observe NS3- and NS5-dependent differences in cells with defects in interferon (IFN) production, differences in RNA accumulation precede induction of the IFN response, suggesting that RNA sensing pathways or intrinsic restriction factors may differentially restrict ZIKV in an NS3- and NS5-dependent manner. This work expands our understanding of the interplay of early steps of viral RNA replication and the induction of the innate antiviral response to ZIKV infection.

Acute Mania in a Patient With Primary Adrenal Insufficiency Due to Autoimmune Adrenalitis: A Case Report.

We describe a rare case of acute mania in the setting of autoimmune adrenalitis. A 41-year-old male with no previous psychiatric diagnoses presented with impulsivity, grandiosity, delusions of telepathy, and hyperreligiosity following a previous hospitalization for an acute adrenal crisis and 2 subsequent days of low-dose corticosteroid treatment. Workups for encephalopathy and lupus cerebritis were negative, raising concern that this presentation might represent steroid-induced psychosis. However, discontinuation of corticosteroids for 5 days did not resolve the patient's manic episode, suggesting that his clinical presentation was more likely new onset of a primary mood disorder or a psychiatric manifestation of adrenal insufficiency itself. The decision was made to restart corticosteroid treatment for the patient's primary adrenal insufficiency (formerly known as Addison disease), coupled with administration of both risperidone and valproate for mania and psychosis. Over the following 2 weeks, the patient's manic symptoms resolved, and he was discharged home. His final diagnosis was acute mania secondary to autoimmune adrenalitis. Although acute mania in adrenal insufficiency is quite rare, clinicians should be aware of the range of psychiatric manifestations associated with Addison disease so that they can pursue the optimal course of both medical and psychiatric treatment for these patients.

BDNF signaling in correlation-dependent structural plasticity in the developing visual system.

During development, patterned neural activity instructs topographic map refinement. Axons with similar patterns of neural activity converge onto target neurons and stabilize their synapses with these postsynaptic partners, restricting exploratory branch elaboration (Hebbian structural plasticity). On the other hand, non-correlated firing in inputs leads to synapse weakening and increased exploratory growth of axons (Stentian structural plasticity). We used visual stimulation to control the correlation structure of neural activity in a few ipsilaterally projecting (ipsi) retinal ganglion cell (RGC) axons with respect to the majority contralateral eye inputs in the optic tectum of albino Xenopus laevis tadpoles. Multiphoton live imaging of ipsi axons, combined with specific targeted disruptions of brain-derived neurotrophic factor (BDNF) signaling, revealed that both presynaptic p75NTR and TrkB are required for Stentian axonal branch addition, whereas presumptive postsynaptic BDNF signaling is necessary for Hebbian axon stabilization. Additionally, we found that BDNF signaling mediates local suppression of branch elimination in response to correlated firing of inputs. Daily in vivo imaging of contralateral RGC axons demonstrated that p75NTR knockdown reduces axon branch elongation and arbor spanning field volume.

Herpes zoster vaccine effectiveness against herpes zoster and postherpetic neuralgia in New Zealand: a retrospective cohort study.

Background: Herpes zoster (HZ) and associated complications cause significant burden to older people. A HZ vaccination programme was introduced in Aotearoa New Zealand in April 2018 with a single dose vaccine for those aged 65 years and a four-year catch up for 66-80 year-olds. This study aimed to assess the 'real-world' effectiveness of the zoster vaccine live (ZVL) against HZ and postherpetic neuralgia (PHN). Methods: We conducted a nationwide retrospective matched cohort study from 1 April 2018 to 1 April 2021 using a linked de-identified patient level Ministry of Health data platform. A Cox proportional hazards model was used to estimate ZVL vaccine effectiveness (VE) against HZ and PHN adjusting for covariates. Multiple outcomes were assessed in the primary (hospitalised HZ and PHN - primary diagnosis) and secondary (hospitalised HZ and PHN: primary and secondary diagnosis, community HZ) analyses. A sub-group analysis was carried out in, adults ≥ 65 years old, immunocompromised adults, Maori, and Pacific populations. Findings: A total of 824,142 (274,272 vaccinated with ZVL matched with 549,870 unvaccinated) New Zealand residents were included in the study. The matched population was 93.4% immunocompetent, 52.2% female, 80.2% European (level 1 ethnic codes), and 64.5% were 65-74 years old (mean age = 71.1±5.0). Vaccinated versus unvaccinated incidence of hospitalised HZ was 0.16 vs. 0.31/1,000 person-years and 0.03 vs. 0.08/1000 person-years for PHN. In the primary analysis, the adjusted overall VE against hospitalised HZ and hospitalised PHN was 57.8% (95% CI: 41.1-69.8) and 73.7% (95% CI:14.0-92.0) respectively. In adults ≥ 65 years old, the VE against hospitalised HZ was 54.4% (95% CI: 36.0-67.5) and VE against hospitalised PHN was 75·5% (95% CI: 19.9-92.5). In the secondary analysis, the VE against community HZ was 30.0% (95% CI: 25.6-34.5). The ZVL VE against hospitalised HZ for immunocompromised adults was 51.1% (95% CI: 23.1-69.5), and PHN hospitalisation was 67.6% (95% CI: 9.3-88.4). The VE against HZ hospitalisation for Maori was 45.2% (95% CI: -23.2-75.6) and for Pacific Peoples was 52.2% (95% CI: -40.6 -83·7). Interpretation: ZVL was associated with a reduction in risk of hospitalisation from HZ and PHN in the New Zealand population. Funding: Wellington Doctoral Scholarship awarded to JFM.

Minimizing opioids after gender affirming orchiectomy - a multimodal pain pathway.

INTRODUCTION: To evaluate the effectiveness of a standardized multimodal pain pathway for gender affirming orchiectomy (GAO) in adequately addressing postoperative pain while reducing the prescribing of unnecessary opioids. MATERIALS AND METHODS: A standardized discharge pain pathway for GAO +/- scrotectomy or testicular implants was implemented between May 2020 and March 2022. A retrospective analysis was performed on all consecutive patients who underwent GAO with a single surgeon. Patients answered five questions on postoperative pain management at their 3 week follow up. RESULTS: A total of 69 patients were included in the study. Mean age was 34.3 years (SD ± 10.5; IQR 26-39) with a mean body mass index (BMI) of 27.1 (SD ± 7.5; IQR 22.3-31). No patients were taking narcotics preoperatively. Mean 4.7 tablets (SD ± 4.5; range 0-30) oxycodone tablets taken by GAO patients without concurrent procedures, with 33 patients (47.8%) taking fewer than 4 tablets. Thirteen patients (18.8%) required no narcotics. Four patients (5.8%) requested an additional narcotic prescription, none of whom underwent a concurrent procedure. There was no significant association between BMI and the number of oxycodone tablets taken. All patients used at least one recommended alternative therapy (acetaminophen, ibuprofen and ice packs) with 41 patients (59.4%) using all three. CONCLUSION: Most patients achieved adequate postoperative pain control as requests for additional narcotic prescriptions were low. Almost half of patients used < 4 tablets, and all patients employed at least one alternative non-narcotic analgesic. Based on these findings, we plan to decrease the quantity of opioids on discharge.

Risks of decoupling from China on low-carbon technologies.

For most technologies, the cure is likely worse than the disease.

Nucleation of the destruction complex on the centrosome accelerates degradation of ß-catenin and regulates Wnt signal transmission.

Wnt signal transduction is controlled by the destruction complex (DC), a condensate comprising scaffold proteins and kinases that regulate ß-catenin stability. Overexpressed DC scaffolds undergo liquid-liquid phase separation (LLPS), but DC mesoscale organization at endogenous expression levels and its role in ß-catenin processing were previously unknown. Here, we find that DC LLPS is nucleated by the centrosome. Through a combination of CRISPR-engineered custom fluorescent tags, finite element simulations, and optogenetic tools that allow for manipulation of DC concentration and multivalency, we find that centrosomal nucleation drives processing of ß-catenin by colocalizing DC components to a single reaction crucible. Enriching GSK3ß partitioning on the centrosome controls ß-catenin processing and prevents Wnt-driven embryonic stem cell differentiation to mesoderm. Our findings demonstrate the role of nucleators in controlling biomolecular condensates and suggest tight integration between Wnt signal transduction and the cell cycle.

A Mouse Holder for Awake Functional Imaging in Unanesthetized Mice: Applications in 31P Spectroscopy, Manganese-Enhanced Magnetic Resonance Imaging Studies, and Resting-State Functional Magnetic Resonance Imaging.

Anesthesia is often used in preclinical imaging studies that incorporate mouse or rat models. However, multiple reports indicate that anesthesia has significant physiological impacts. Thus, there has been great interest in performing imaging studies in awake, unanesthetized animals to obtain accurate results without the confounding physiological effects of anesthesia. Here, we describe a newly designed mouse holder that is interfaceable with existing MRI systems and enables awake in vivo mouse imaging. This holder significantly reduces head movement of the awake animal compared to previously designed holders and allows for the acquisition of improved anatomical images. In addition to applications in anatomical T2-weighted magnetic resonance imaging (MRI), we also describe applications in acquiring 31P spectra, manganese-enhanced magnetic resonance imaging (MEMRI) transport rates and resting-state functional magnetic resonance imaging (rs-fMRI) in awake animals and describe a successful conditioning paradigm for awake imaging. These data demonstrate significant differences in 31P spectra, MEMRI transport rates, and rs-fMRI connectivity between anesthetized and awake animals, emphasizing the importance of performing functional studies in unanesthetized animals. Furthermore, these studies demonstrate that the mouse holder presented here is easy to construct and use, compatible with standard Bruker systems for mouse imaging, and provides rigorous results in awake mice.

Engineering Modular 3D Liver Culture Microenvironments In Vitro to Parse the Interplay between Biophysical and Biochemical Microenvironment Cues on Hepatic Phenotypes.

In vitro models of human liver functions are used across a diverse range of applications in preclinical drug development and disease modeling, with particular increasing interest in models that capture facets of liver inflammatory status. This study investigates how the interplay between biophysical and biochemical microenvironment cues influence phenotypic responses, including inflammation signatures, of primary human hepatocytes (PHH) cultured in a commercially available perfused bioreactor. A 3D printing-based alginate microwell system was designed to form thousands of hepatic spheroids in a scalable manner as a comparator 3D culture modality to the bioreactor. Soft, synthetic extracellular matrix (ECM) hydrogel scaffolds with biophysical properties mimicking features of liver were engineered to replace polystyrene scaffolds, and the biochemical microenvironment was modulated with a defined set of growth factors and signaling modulators. The supplemented media significantly increased tissue density, albumin secretion, and CYP3A4 activity but also upregulated inflammatory markers. Basal inflammatory markers were lower for cells maintained in ECM hydrogel scaffolds or spheroid formats than polystyrene scaffolds, while hydrogel scaffolds exhibited the most sensitive response to inflammation as assessed by multiplexed cytokine and RNA-seq analyses. Together, these engineered 3D liver microenvironments provide insights for probing human liver functions and inflammatory response in vitro.

A highly sensitive strand-specific multiplex RT-qPCR assay for quantitation of Zika virus replication.

Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) is widely used to quantify viral RNA genomes for diagnostics and research, yet conventional RT-qPCR protocols are unable to accurately distinguish between the different viral RNA species that exist during infection. Here we show that false-priming and self-priming occur during reverse transcription with several published Zika virus (ZIKV) primer sets. We developed a RT-qPCR assay using tagged primers and thermostable reverse transcriptase, which greatly reduced the occurrence of nonspecific cDNA products. Furthermore, we optimized the assay for use in multiplex qPCR which allows for simultaneous quantitative detection of positive-strand and negative-strand ZIKV RNA along with an internal control from both human and mosquito cells. Importantly, this assay is sensitive enough to study early stages of virus infection in vitro. Strikingly, using this assay, we detected ZIKV negative-strand RNA as early as 3 h post-infection in mammalian cell culture, at a time point prior to the onset of positive-strand RNA synthesis. Overall, the strand-specific RT-qPCR assay developed herein is a valuable tool to quantify ZIKV RNA and to study viral replication dynamics during infection. The application of these findings has the potential to increase accuracy of RNA detection methods for a variety of viral pathogens.

Perinatal outcomes of women with gestational breast cancer in Australia and New Zealand: A prospective population-based study.

OBJECTIVE: To determine the epidemiology, clinical management, and outcomes of women with gestational breast cancer (GBC). METHODS: A population-based prospective cohort study was conducted in Australia and New Zealand between 2013 and 2014 using the Australasian Maternity Outcomes Surveillance System (AMOSS). Women who gave birth with a primary diagnosis of breast cancer during pregnancy were included. Data were collected on demographic and pregnancy factors, GBC diagnosis, obstetric and cancer management, and perinatal outcomes. The main outcome measures were preterm birth, maternal complications, breastfeeding, and death. RESULTS: Forty women with GBC (incidence 7.5/100 000 women giving birth) gave birth to 40 live-born babies. Thirty-three (82.5%) women had breast symptoms at diagnosis. Of 27 women diagnosed before 30 weeks' gestation, 85% had breast surgery and 67% had systemic therapy during pregnancy. In contrast, all 13 women diagnosed from 30 weeks had their cancer management delayed until postdelivery. There were 17 preterm deliveries; 15 were planned. Postpartum complications included the following: hemorrhage (n = 4), laparotomy (n = 1), and thrombocytopenia (n = 1). There was one late maternal death. Eighteen (45.0%) women initiated breastfeeding, including 12 of 23 women who had antenatal breast surgery. There were no perinatal deaths or congenital malformations, but 42.5% of babies were preterm, and 32.5% were admitted for higher-level neonatal care. CONCLUSIONS: Gestational breast cancer diagnosed before 30 weeks' gestation was associated with surgical and systemic cancer care during pregnancy and planned preterm birth. In contrast, cancer treatment was deferred to postdelivery for women diagnosed from 30 weeks, reflecting the complexity of managing expectant mothers with GBC in multidisciplinary care settings.