Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus.

BACKGROUND: Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and choline in hippocampal transcriptome regulation. To understand the regulatory mechanisms, we investigated epigenetic marks of genes with altered chromatin accessibility (ATAC-seq) or poised to be repressed (H3K9me3 ChIP-seq) in iron-repleted adult rats having experienced fetal-neonatal ID exposure with or without prenatal choline supplementation. RESULTS: Fetal-neonatal ID was induced by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Half of the pregnant dams were given supplemental choline (5.0 g/kg) from G11-18. This resulted in 4 groups at P65 (Iron-sufficient [IS], Formerly Iron-deficient [FID], IS with choline [ISch], and FID with choline [FIDch]). Hippocampi were collected from P65 iron-repleted male offspring and analyzed for chromatin accessibility and H3K9me3 enrichment. 22% and 24% of differentially transcribed genes in FID- and FIDch-groups, respectively, exhibited significant differences in chromatin accessibility, whereas 1.7% and 13% exhibited significant differences in H3K9me3 enrichment. These changes mapped onto gene networks regulating synaptic plasticity, neuroinflammation, and reward circuits. Motif analysis of differentially modified genomic sites revealed significantly stronger choline effects than early-life ID and identified multiple epigenetically modified transcription factor binding sites. CONCLUSIONS: This study reveals genome-wide, stable epigenetic changes and epigenetically modifiable gene networks associated with specific chromatin marks in the hippocampus, and lays a foundation to further elucidate iron-dependent epigenetic mechanisms that underlie the long-term effects of fetal-neonatal ID, choline, and their interactions.

Methylene blue dose-dependently induces cutaneous inflammation and heat hyperalgesia in a novel rat model.

Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1ß and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1ß, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.

Identification of Genes Responding to Iron or Choline Treatment for Early-Life Iron Deficiency in the Male Rat Hippocampal Transcriptomes.

BACKGROUND: Developmental iron deficiency (ID) is associated with long-term cognitive and affective behavioral impairments in humans. Preclinical studies have shown that developmental ID has short- and long-term effects on gene regulation. Prenatal choline supplementation partially rescues early-life ID-induced cognitive deficits in adult male rats. OBJECTIVES: To identify acute and long-term changes in biological processes regulated by developmental ID and modifiable by choline. METHODS: This study compares the hippocampal transcriptomes of postnatal day (P) 15 iron-deficient (acute) and P65 formerly ID (persistent) rats with or without prenatal choline treatment. Pregnant rats were fed an ID (4 mg/kg Fe) or iron-sufficient (IS) (200 mg/kg Fe) diet from gestational day (G) 2 to P7 with or without choline supplementation (5 g/kg choline) from G11 to G18. Hippocampi were collected from P15 or P65 offspring and analyzed for gene expression by RNA sequencing. RESULTS: Developmental ID-induced changes suggested modified activity of oxidative phosphorylation and fatty acid metabolism. Prenatal choline supplementation induced robust changes in gene expression, particularly in iron-deficient animals, where it partially mitigated the early-life ID-dysregulated genes. Choline supplementation also altered the hippocampal transcriptome in the IS rats, with indications for both beneficial and adverse effects. CONCLUSIONS: This study provided global assessments of gene expression regulated by iron and choline. Our new findings highlight genes responding to iron or choline treatments, including a potentially novel choline-regulated transporter (IPO7), with shared effects on neuroinflammation in the male rat hippocampus.

A machine learning approach to robustly determine director fields and analyze defects in active nematics.

Active nematics are dense systems of rodlike particles that consume energy to drive motion at the level of the individual particles. They exist in natural systems like biological tissues and artificial materials such as suspensions of self-propelled colloidal particles or synthetic microswimmers. Active nematics have attracted significant attention in recent years due to their spectacular nonequilibrium collective spatiotemporal dynamics, which may enable applications in fields such as robotics, drug delivery, and materials science. The director field, which measures the direction and degree of alignment of the local nematic orientation, is a crucial characteristic of active nematics and is essential for studying topological defects. However, determining the director field is a significant challenge in many experimental systems. Although director fields can be derived from images of active nematics using traditional imaging processing methods, the accuracy of such methods is highly sensitive to the settings of the algorithms. These settings must be tuned from image to image due to experimental noise, intrinsic noise of the imaging technology, and perturbations caused by changes in experimental conditions. This sensitivity currently limits automatic analysis of active nematics. To address this, we developed a machine learning model for extracting reliable director fields from raw experimental images, which enables accurate analysis of topological defects. Application of the algorithm to experimental data demonstrates that the approach is robust and highly generalizable to experimental settings that are different from those in the training data. It could be a promising tool for investigating active nematics and may be generalized to other active matter systems.

From Plastic Waste to Green Hydrogen and Valuable Chemicals Using Sunlight and Water.

Over 79% of 6.3 billion tonnes of plastics produced from 1950 to 2015 have been disposed in lanfills or found their way to the oceans, where they will reside for up to hundreds of years before being decomposed bringing upon significant dangers to our health and ecosystems. Plastic photoreforming offers an appealing alternative by using solar energy and water to transform plastic waste into value-added chemical commodities, while simultaneously producing green hydrogen via the hydrogen evolution reaction. This review aims to provide an overview of the underlying principles of emerging plastic photoreforming technologies, highlight the challenges associated with experimental protocols and performance assessments, discuss recent global breakthroughs on the photoreforming of plastics, and propose perspectives for future research. A critical assessment of current plastic photoreforming studies shows a lack of standardised conditions, hindering comparison amongst photocatalyst performance. Guidelines to establish a more accurate evaluation of materials and systems are proposed with the aim to facilitate the translation of promising fundamental discovery in photocatalysts design.

Optimal Coatings of Co3 O4 Anodes for Acidic Water Electrooxidation.

Implementation of proton-exchange membrane water electrolyzers for large-scale sustainable hydrogen production requires the replacement of scarce noble-metal anode electrocatalysts with low-cost alternatives. However, such earth-abundant materials often exhibit inadequate stability and/or catalytic activity at low pH, especially at high rates of the anodic oxygen evolution reaction (OER). Here, the authors explore the influence of a dielectric nanoscale-thin oxide layer, namely Al2 O3 , SiO2 , TiO2 , SnO2 , and HfO2 , prepared by atomic layer deposition, on the stability and catalytic activity of low-cost and active but insufficiently stable Co3 O4 anodes. It is demonstrated that the ALD layers improve both the stability and activity of Co3 O4 following the order of HfO2 > SnO2 > TiO2 > Al2 O3 , SiO2 . An optimal HfO2 layer thickness of 12 nm enhances the Co3 O4 anode durability by more than threefold, achieving over 42 h of continuous electrolysis at 10 mA cm-2 in 1 m H2 SO4 electrolyte. Density functional theory is used to investigate the superior performance of HfO2 , revealing a major role of the HfO2 |Co3 O4 interlayer forces in the stabilization mechanism. These insights offer a potential strategy to engineer earth-abundant materials for low-pH OER catalysts with improved performance from earth-abundant materials for efficient hydrogen production.

Understanding the Role of (W, Mo, Sb) Dopants in the Catalyst Evolution and Activity Enhancement of Co3 O4 during Water Electrolysis via In Situ Spectroelectrochemical Techniques.

Unlocking the potential of the hydrogen economy is dependent on achieving green hydrogen (H2 ) production at competitive costs. Engineering highly active and durable catalysts for both oxygen and hydrogen evolution reactions (OER and HER) from earth-abundant elements is key to decreasing costs of electrolysis, a carbon-free route for H2 production. Here, a scalable strategy to prepare doped cobalt oxide (Co3 O4 ) electrocatalysts with ultralow loading, disclosing the role of tungsten (W), molybdenum (Mo), and antimony (Sb) dopants in enhancing OER/HER activity in alkaline conditions, is reported. In situ Raman and X-ray absorption spectroscopies, and electrochemical measurements demonstrate that the dopants do not alter the reaction mechanisms but increase the bulk conductivity and density of redox active sites. As a result, the W-doped Co3 O4 electrode requires ≈390 and ≈560 mV overpotentials to reach ±10 and ±100 mA cm-2 for OER and HER, respectively, over long-term electrolysis. Furthermore, optimal Mo-doping leads to the highest OER and HER activities of 8524 and 634 A g-1 at overpotentials of 0.67 and 0.45 V, respectively. These novel insights provide directions for the effective engineering of Co3 O4 as a low-cost material for green hydrogen electrocatalysis at large scales.

Bending stiffness characterization of Bacillus subtilis' flagellar filament.

The filament of a bacterial flagellum is a tube-like organelle made of a single protein-flagellin-and assembled into multiple polymorphic forms. The filament can be further discretized into four subunit domains (D0, D1, D2, and D3) along the radial direction. However, it remains unclear which subunit domain plays an important role in regulating the rigidity of the filament. In this article, we address how the absence of two outer subunit domains (D2 and D3) affects the bending stiffness of the bacterium B. subtilis' flagellar filament. We first shear off flagellar filaments from the cell body, anchor one of its ends to the wall of a microfluidic channel, and correlate the elongation of the filament with the driving background flow. A numerical model is then applied to determine the bending stiffness of the filament. We find that the bending stiffness does not change drastically when the filament transforms from normal to hyperextended forms, which is estimated to be 2-3 pN⋅µm2. Furthermore, B. subtilis' flagellar filament has similar bending stiffness to Salmonella's, although the radius of the former is almost half of that of the latter, suggesting that the rigidity comes from the inner D0 and D1 subunit domains.

Developmental Iron Deficiency Dysregulates TET Activity and DNA Hydroxymethylation in the Rat Hippocampus and Cerebellum.

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification of 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague Dawley rats were fed iron-deficient diet (ID; 4 mg/kg Fe) from gestational day 2 to generate iron-deficient anemic (IDA) offspring. Control dams were fed iron-sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, the hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p = 0.0105), with a corresponding increase in TET activity (p < 0.0001) and Tet3 expression (p < 0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p = 0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

Overexpression of purple acid phosphatase GmPAP2.1 confers resistance to Soybean mosaic virus in a susceptible soybean cultivar.

A purple acid phosphatase, GmPAP2.1, from the soybean (Glycine max) cultivar L29 may function as a resistance factor acting against specific strains of Soybean mosaic virus (SMV). In this study, we found that overexpression of GmPAP2.1 from L29 conferred SMV resistance to a susceptible cultivar, Lee 74. We determined that GmPAP2.1 interacted with the SMV protein P1 in the chloroplasts, resulting in the up-regulation of the ICS1 gene, which in turn promoted the pathogen-induced salicylic acid (SA) pathway. SA accumulation was elevated in response to the co-expression of GmPAP2.1 and SMV, while transient knockdown of endogenous SA-related genes resulted in systemic infection by SMV strain G5H, suggesting that GmPAP2.1-derived resistance depended on the SA-pathway for the activation of a defense response. Our findings thus suggest that GmPAP2.1 purple acid phosphatase of soybean cultivar L29 functions as an SA-pathway-dependent resistance factor acting against SMV.

Dose- and sex-dependent effects of phlebotomy-induced anemia on the neonatal mouse hippocampal transcriptome.

BACKGROUND: Phlebotomy-induced anemia (PIA) is universal and variable in degree among preterm infants and may contribute to neurodevelopmental risk. In mice, PIA causes brain tissue hypoxia, iron deficiency, and long-term sex-dependent neurobehavioral abnormalities. The neuroregulatory molecular pathways disrupted by PIA underlying these effects are unknown. METHODS: Male and female pups were phlebotomized daily from postnatal day (P)3-P14 via facial venipuncture to target hematocrits of 25% (moderate, mPIA) and 18% (severe, sPIA). P14 hippocampal RNA from non-bled control and PIA mice was sequenced by next-generation sequencing to identify differentially expressed genes (DEGs) that were analyzed using Ingenuity Pathway Analysis. RESULTS: mPIA females showed the least DEGs (0.5% of >22,000 genes) whereas sPIA females had the most (8.6%), indicating a dose-dependent effect. mPIA and sPIA males showed similar changes in gene expression (5.3% and 4.7%, respectively), indicating a threshold effect at mPIA. The pattern of altered genes induced by PIA indicates sex-specific and anemia-dose-dependent effects with increased pro-inflammation in females and decreased neurodevelopment in males. CONCLUSION: These gene-expression changes may underlie the reduced recognition memory function in male and abnormal social-cognitive behavior in female adult mice following neonatal PIA. These results parallel clinical studies demonstrating sex-specific behavioral outcomes as a function of neonatal anemia. IMPACT: Phlebotomy-induced anemia (PIA) in neonatal mice results in an altered hippocampal transcriptome and the severity of changes are dependent upon degree of anemia and sex of neonatal mice. The reported findings provide context to the sex-specific outcomes that have been reported in transfusion threshold clinical trials of preterm infants and therefore may inform treatment strategies that may be based on sex. These data advance the field by showing that consequences of PIA may be based in sex-specific transcriptomic alterations. Such changes may also result from other causes of neonatal anemia that also affect term infants.

Higher blood pressure versus normotension targets to prevent acute kidney injury: a systematic review and meta-regression of randomized controlled trials.

BACKGROUND: Renal hypoperfusion is one of the most common causes of acute kidney injury (AKI), especially in shock and perioperative patients. An optimal blood pressure (BP) target to prevent AKI remains undetermined. We conducted a systematic review and meta-analysis of available randomized clinical trial (RCT) results to address this knowledge gap. METHODS: From inception to May 13, 2022, we searched Ovid Medline, EMBASE, Cochrane Library, SCOPUS, clinicaltrials.gov, and WHO ICTRP for RCTs comparing higher BP target versus normotension in hemodynamically unstable patients (shock, post-cardiac arrest, or surgery patients). The outcomes of interest were post-intervention AKI rate and renal replacement therapy (RRT) rate. Two investigators independently screened the citations and reviewed the full texts for eligible studies according to a predefined form. RESULTS: Twelve trials were included, enrolling a total of 5759 participants, with shock, non-cardiac, and cardiac surgery patients accounting for 3282 (57.0%), 1687 (29.3%) and 790 (13.7%) patients, respectively. Compared to lower mean arterial blood pressure (MAP) targets that served as normotension, targeting higher MAP had no significant effect on AKI rates in shock (RR [95% CI] = 1.10 [0.93, 1.29]), in cardiac-surgery (RR [95% CI] = 0.87 [0.73, 1.03]) and non-cardiac surgery patients (RR [95% CI] = 1.25 [0.98, 1.60]) using random-effects meta-analyses. In shock patients with premorbid hypertension, however, targeting MAP above 70 mmHg resulted in significantly lower RRT risks, RR [95%CI] = 1.20 [1.03, 1.41], p < 0.05. CONCLUSIONS: Targeting a higher MAP in shock or perioperative patients may not be superior to normotension, except in shock patients with premorbid hypertension. Further studies are needed to assess the effects of a high MAP target to preventing AKI in hypertensive patients across common settings of hemodynamic instability. Trial registration This systematic review has been registered on PROSPERO ( CRD42021286203 ) on November 19, 2021, prior to data extraction and analysis.

Quantitative Proteome and Transcriptome Dynamics Analysis Reveals Iron Deficiency Response Networks and Signature in Neuronal Cells.

Iron and oxygen deficiencies are common features in pathophysiological conditions, such as ischemia, neurological diseases, and cancer. Cellular adaptive responses to such deficiencies include repression of mitochondrial respiration, promotion of angiogenesis, and cell cycle control. We applied a systematic proteomics analysis to determine the global proteomic changes caused by acute hypoxia and chronic and acute iron deficiency (ID) in hippocampal neuronal cells. Our analysis identified over 8600 proteins, revealing similar and differential effects of each treatment on activation and inhibition of pathways regulating neuronal development. In addition, comparative analysis of ID-induced proteomics changes in cultured cells and transcriptomic changes in the rat hippocampus identified common altered pathways, indicating specific neuronal effects. Transcription factor enrichment and correlation analysis identified key transcription factors that were activated in both cultured cells and tissue by iron deficiency, including those implicated in iron regulation, such as HIF1, NFY, and NRF1. We further identified MEF2 as a novel transcription factor whose activity was induced by ID in both HT22 proteome and rat hippocampal transcriptome, thus linking iron deficiency to MEF2-dependent cellular signaling pathways in neuronal development. Taken together, our study results identified diverse signaling networks that were differentially regulated by hypoxia and ID in neuronal cells.

Self-Assembled Amphiphilic Starch Based Drug Delivery Platform: Synthesis, Preparation, and Interactions with Biological Barriers.

Core-shell structured nanoparticles (NPs) render the simultaneous coloading capacity of both hydrophobic and hydrophilic drugs and may eventually enhance therapeutic efficacy. In this study, we employed a facile squalenoylation technology to synthesize a new amphiphilic starch derivative from partially oxidized starch, which self-assembled into core-shell starch NPs (StNPs) only at a squalenyl degree of substitution (DoS) of ∼1%. The StNPs characteristics could be tuned as the functions of the polymer molecular weight, DoS, and NPs concentration. The biopharmaceutical features of the StNPs, including colloidal stability, carrier properties, and biocompatibility, were carefully investigated. The interaction study between StNPs and mucin glycoproteins, the main organic component of mucus, revealed a moderate mucin interacting profile. Furthermore, the StNPs also showed good penetration through Pseudomonas aeruginosa biofilms. These results nominate StNPs as a versatile drug delivery platform with potential applications for mucosal drug delivery and the treatment of persistent infections.

Testing early warning and response systems through a full-scale exercise in Vietnam.

BACKGROUND: Simulation exercises can functionally validate World Health Organization (WHO) International Health Regulations (IHR 2005) core capacities. In 2018, the Vietnam Ministry of Health (MOH) conducted a full-scale exercise (FSX) in response to cases of severe viral pneumonia with subsequent laboratory confirmation for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) to evaluate the country's early warning and response capabilities for high-risk events. METHODS: An exercise planning team designed a complex fictitious scenario beginning with one case of severe viral pneumonia presenting at the hospital level and developed all the materials required for the exercise. Actors, controllers and evaluators were trained. In August 2018, a 3-day exercise was conducted in Quang Ninh province and Hanoi city, with participation of public health partners at the community, district, province, regional and national levels. Immediate debriefings and an after-action review were conducted after all exercise activities. Participants assessed overall exercise design, conduction and usefulness. RESULTS: FSX findings demonstrated that the event-based surveillance component of the MOH surveillance system worked optimally at different administrative levels. Detection and reporting of signals at the community and health facility levels were appropriate. Triage, verification and risk assessment were successfully implemented to identify a high-risk event and trigger timely response. The FSX identified infection control, coordination with internal and external response partners and process documentation as response challenges. Participants positively evaluated the exercise training and design. CONCLUSIONS: This exercise documents the value of exercising surveillance capabilities as part of a real-time operational scenario before facing a true emergency. The timing of this exercise and choice of disease scenario was particularly fortuitous given the subsequent appearance of COVID-19. As a result of this exercise and subsequent improvements made by the MOH, the country may have been better able to deal with the emergence of SARS-CoV-2 and contain it.

Non-Periodic Epsilon-Near-Zero Metamaterials at Visible Wavelengths for Efficient Non-Resonant Optical Sensing.

Epsilon-near-zero (ENZ) materials offer unique properties for applications including optical clocking, nonlinear optics, and telecommunication. To date, the fabrication of ENZ materials at visible wavelengths relies mostly on the use of periodic structures, providing some manufacturing and material challenges. Here, we present the engineering of nonperiodic sodium tungsten bronzes (NaxWO3) metamaterials featuring ENZ properties in the visible spectrum. We showcase their use as efficient optical sensors, demonstrating a nonresonant sensing mechanism based on refractive index matching. Our optimized ENZ metamaterials display an unconventional blue-shift of the transmittance maximum to increasing refractive index of the surrounding environment, achieving sensitivity as high as 150 nm/RIU. Our theoretical and experimental investigations provide first insights on this sensing mechanism, establishing guidelines for the future engineering and implementation of efficient ENZ sensors. The unique optoelectronic properties demonstrated by this class of tunable NaxWO3 materials bear potential for various applications ranging from light-harvesting to optical photodetectors.

The False Positive Rate of Transcutaneous Tissue Oximetry Alarms in Microvascular Breast Reconstruction Rises after 24 Hours.

BACKGROUND: Transcutaneous tissue oximetry is widely used as an adjunct for postoperative monitoring after microvascular breast reconstruction. Despite a high sensitivity at detecting vascular issues, alarms from probe malfunctions/errors can generate unnecessary nursing calls, concerns, and evaluations. The purpose of this study is to analyze the false positive rate of transcutaneous tissue oximetry monitoring over the postoperative period and assess changes in its utility over time. METHODS: Consecutive patients undergoing microvascular breast reconstruction at our institution with monitoring using transcutaneous tissue oximetry were assessed between 2017 and 2019. Variables of interest were transcutaneous tissue oximetry alarms, flap loss, re-exploration, and salvage rates. RESULTS: The study included 175 patients (286 flaps). The flap loss rate was 1.0% (3/286). Twelve patients (6.8%) required re-exploration, with 9 patients found to have actual flap compromise (all within 24 hours). The salvage rate was 67.0%. The 3 takebacks after 24 hours were for bleeding concerns rather than anastomotic problems. Within the initial 24-hour postoperative period, 43 tissue oximetry alarms triggered nursing calls; 7 alarms (16.2%) were confirmed to be for flap issues secondary to vascular compromise. After 24 hours, none of the 44 alarms were associated with flap compromise. The false positive rate within 24 hours was 83.7% (36/43) compared with 100% (44/44) after 24 hours (p = 0.01). CONCLUSION: The transcutaneous tissue oximetry false positive rate significantly rises after 24 hours. The benefit may not outweigh the concerns, labor, and effort that results from alarms after postoperative day 1. We recommend considering discontinuing this monitoring after 24 hours.

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain.

To develop non-opioid therapies for postoperative incisional pain, we must understand its underlying molecular mechanisms. In this study, we assessed global gene expression changes in dorsal root ganglia neurons in a model of incisional pain to identify pertinent molecular pathways. Male, Sprague-Dawley rats underwent infiltration of 1% capsaicin or vehicle into the plantar hind paw (n = 6-9/group) 30 min before plantar incision. Twenty-four hours after incision or sham (control) surgery, lumbar L4-L6 dorsal root ganglias were collected from rats pretreated with vehicle or capsaicin. RNA was isolated and sequenced by next generation sequencing. The genes were then annotated to functional networks using a knowledge-based database, Ingenuity Pathway Analysis. In rats pretreated with vehicle, plantar incision caused robust hyperalgesia, up-regulated 36 genes and downregulated 90 genes in dorsal root ganglias one day after plantar incision. Capsaicin pretreatment attenuated pain behaviors, caused localized denervation of the dermis and epidermis, and prevented the incision-induced changes in 99 of 126 genes. The pathway analyses showed altered gene networks related to increased pro-inflammatory and decreased anti-inflammatory responses in dorsal root ganglias. Insulin-like growth factor signaling was identified as one of the major gene networks involved in the development of incisional pain. Expression of insulin-like growth factor -2 and IGFBP6 in dorsal root ganglia were independently validated with quantitative real-time polymerase chain reaction. We discovered a distinct subset of dorsal root ganglia genes and three key signaling pathways that are altered 24 h after plantar incision but are unchanged when incision was made after capsaicin infiltration in the skin. Further exploration of molecular mechanisms of incisional pain may yield novel therapeutic targets.

A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.

INTRODUCTION: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed. METHODS: A cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates. RESULTS: A systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. DISCUSSION: This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment.

A case study of an influenza vaccination program for health care workers in Vietnam.

BACKGROUND: In 2017, the Vietnam Ministry of Health conducted a demonstration project to introduce seasonal influenza vaccination to health care workers. A total of 11,000 doses of influenza vaccine, single-dose prefilled syringes, were provided free to HCWs at 29 selected hospitals, clinics, and research institutes in four provinces: Hanoi, Khanh Hoa, Dak Lak and Ho Chi Minh City. METHODS: Before the campaign, a workshop was organized to discuss an implementation plan including technical requirements, cold chain, uptake reporting, and surveillance for adverse events following immunization. All sites distributed communication materials and encouraged their staff to register for vaccination. Following immunization sessions, sites sent reports on uptake and adverse events following immunization. Left-over vaccine was transferred to other sites to maximize vaccine use. RESULTS: The average uptake was 57% for all health care workers, with 11 sites achieving 90% and above. These 11 sites were small with less than 500 staff, including 5 primary hospitals, 3 preventive medicine units, and 2 referral hospitals. Among the six biggest sites with over 1000 staff, four sites had the lowest uptake (14-47%). Most of the high-uptake sites were from the central to the south; only one site, a referral hospital, was from the north. After redistribution of left-over vaccine, only 130 vaccine doses (1.2%) were not used and destroyed. Based on factors that affected uptake, including registration levels, differing communication strategies, availability of vaccination, and commitment by health facility leaders, we recommended ways to increase health care worker coverage; recommendations to improve reporting adverse events following immunization were also made. CONCLUSIONS: The project demonstrated that it was feasible to conduct influenza vaccination campaigns among health care workers in Vietnam. Improvements in promotion of registration, more intense pre-planning, especially at larger facilities, and wider, more consistent availability of communication materials will result in increased efficiency and coverage in this program's future expansion.