Patch angioplasty carotid endarterectomy versus eversion carotid endarterectomy.

OBJECTIVES: To compare carotid endarterectomy patch angioplasty (p-CEA) with eversion carotid endarterectomy (e-CEA) and associated risks of early cardio-cerebrovascular complications. METHODS: The study was a prospective randomized single-blind trial, monocentric, clinically applicable, descriptive analytical and comparative. From June 2021 to June 2023, 62 consecutive patients with symptomatic and asymptomatic stenosis of the internal carotid artery, admitted to our department and randomized into two groups: carotid endarterectomy with patch angioplasty and eversion carotid endarterectomy. Follow-up for 30 days after surgery. RESULTS: During surgery e-CEA, 70% patients had an arrhythmia, and 24 hours after 66.7%, seven days after 46.7% and month after 13.3%. During surgery p-CEA, 33.3% patients had an arrhythmia, 24 hours later 33.3%, 7 days after 13.3% and 30 days after 13.3% patients. Statistically significant difference observed during surgery (Fishers p=0.004). One day after the surgery rate of patients with arrhythmia that were treated e-CEA has decreased, but it was still higher than after p-CEA (Fishers p=0.010). CONCLUSION: The frequency and categorization of postoperative cardiac arrhythmias after eversion carotid endarterectomy, the clinical implications of various postoperative heart rhythm disturbances and their long-term effects on patients need to be further investigate through sufficiently powered randomized controlled studies.

Patch and matrix striatonigral neurons differentially regulate locomotion.

The striatonigral neurons are known to promote locomotion1,2. These neurons reside in both the patch (also known as striosome) and matrix compartments of the dorsal striatum3-5. However, the specific contribution of patch and matrix striatonigral neurons to locomotion remain largely unexplored. Using molecular identifier Kringle-Containing Protein Marking the Eye and the Nose (Kremen1) and Calbidin (Calb1)6, we showed in mouse models that patch and matrix striatonigral neurons exert opposite influence on locomotion. While a reduction in neuronal activity in matrix striatonigral neurons precedes the cessation of locomotion, fiber photometry recording during self-paced movement revealed an unexpected increase of patch striatonigral neuron activity, indicating an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed locomotion, contrasting with the locomotion-promoting effect of matrix striatonigral neurons. Consistently, patch striatonigral neuron activation markedly inhibited dopamine release, whereas matrix striatonigral neuron activation initially promoted dopamine release. Moreover, the genetic deletion of inhibitory GABA-B receptor Gabbr1 in Aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neurons (DANs) completely abolished the locomotion-suppressing effect caused by activating patch striatonigral neurons. Together, our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting the activity of ALDH1A1+ nigrostriatal DANs.

A flexible and dissolving traditional Chinese medicine microneedle patch for sleep-aid intervention.

About a quarter of the world's population suffers from insomnia, and the number of the insomniacs is gradually increasing. However, the current drug therapy and non-drug therapy sleep-aid methods have certain limitations. In general, the sleep-aid effect of drug therapy is better than that of Non-drug therapy, but western medicine may lead to some side effects and drug abuse. Although the side effects of Chinese Herbal Medicine (CHM) are relatively small, making the herbal decoction is complex and time-consuming. Therefore, exploring a novel sleep-aid method is very significant. In this paper, a flexible and dissolving Traditional Chinese Medicine (TCM) microneedle patch is proposed for sleep-aid intervention. The TCM microneedle patch is a micrometer-scale intrusive object, and the herbal extracts are carried by the patch. The materials, design method, and fabrication process of the microneedle patch have been described in detail. Besides, the mechanical characteristics of the microneedle patch, sleep-aid effect evaluation method, and experimental scheme have been presented. Three microneedle tips with radii of 5 µm, 15 µm, and 22 µm are selected for simulation analysis. Abaqus simulation results indicate that the smaller the radius of the microneedle tip, the smaller the piercing force. Considering that the microneedle should easily penetrate the skin without buckling, that is, the piercing force should be larger than the buckling force, thus 15 µm, instead of 5 µm or 22 µm, is more suitable to be adopted as the radius of the microneedle tip. For the microneedle with the radius of 15 µm, the piercing force is 0.033 N, and the difference between the piercing force and buckling force is 0.036 N. Experimental results demonstrate that the fracture force of the microneedle is about 0.29 N, which is far larger than the piercing force and buckling force. The single-lead EEG signals of the frontal lobe are used to evaluate the sleep-aid effect of the TCM microneedle patch. After sleep-aid intervention on the Anmian and Yintang acupoints using the patches, for most subjects, the ratios of the low-frequency brain wave energies to the high-frequency brain wave energies are increased obviously, indicating that the proposed sleep-aid method is effective.

Surgical approaches to congenital diaphragmatic hernia.

Surgical repair of the diaphragm is essential for survival in congenital diaphragmatic hernia (CDH). There are many considerations surrounding the operation - why the operation matters, optimal timing of repair and its relation to extracorporeal life support (ECLS) use, minimally invasive versus open approaches, and strategies for reconstruction. Surgery is both affected by, and affects, the physiology of these infants and is an important factor in determining long-term outcomes. Here we discuss the evidence and provide insight surrounding this complex decision making, technical pearls, and outcomes in repair of CDH.

Spatial heterogeneity analysis for the transmission of syphilis disease in China via a data-validated reaction-diffusion model.

Based on the distinctive spatial diffusion characteristics observed in syphilis transmission patterns, this paper introduces a novel reaction-diffusion model for syphilis disease dynamics, incorporating general incidence functions within a heterogeneous environment. We derive the basic reproduction number essential for threshold dynamics and investigate the uniform persistence of the model. We validate the model and estimate its parameters by employing the multi-objective Markov Chain Monte Carlo (MCMC) method, using real syphilis data from the years 2004 to 2018 in China. Furthermore, we explore the impact of spatial heterogeneity and intervention measures on syphilis transmission. Our findings reveal several key insights: (1) In addition to the original high-incidence areas of syphilis, Xinjiang, Guizhou, Hunan and Northeast China have also emerged as high-incidence regions for syphilis in China. (2) The latent syphilis cases represent the highest proportion of newly reported cases, highlighting the critical importance of considering their role in transmission dynamics to avoid underestimation of syphilis outbreaks. (3) Neglecting spatial heterogeneity results in an underestimation of disease prevalence and the number of syphilis-infected individuals, undermining effective disease prevention and control strategies. (4) The initial conditions have minimal impact on the long-term spatial distribution of syphilis-infected individuals in scenarios of varying diffusion rates. This study underscores the significance of spatial dynamics and intervention measures in assessing and managing syphilis transmission, which offers insights for public health policymakers.

Integrative Analysis of Long Isoform Sequencing and Functional Data Identifies Distinct Cortical Layer Neuronal Subtypes Derived from Human iPSCs.

Generation of human induced pluripotent stem cells (iPSCs) through reprogramming was a transformational change in the field of regenerative medicine that led to new possibilities for drug discovery and cell replacement therapy. Several protocols have been established to differentiate hiPSCs into neuronal lineages. However, low differentiation efficiency is one of the major drawbacks of these approaches. Here, we compared the efficiency of two methods of neuronal differentiation from iPSCs cultured in two different culture media, StemFlex Medium (SFM) and Essential 8 Medium (E8M). The results indicated that iPSCs cultured in E8M efficiently generated different types of neurons in a shorter time and without the growth of undifferentiated non-neuronal cells in the culture as compared to those generated from iPSCs in SFM. Furthermore, these neurons were validated as functional units immunocytochemically by confirming the expression of mature neuronal markers (i.e., NeuN, Beta tubulin, and Synapsin I), and whole-cell patch-clamp recordings. Long-read single-cell RNA sequencing confirms the presence of upper and deep layer cortical layer excitatory and inhibitory neuronal subtypes in addition to small populations of GABAergic neurons in day 30 neuronal cultures. Pathway analysis indicated that our protocol triggers the signaling transcriptional networks important for the process of neuronal differentiation in vivo.

Clustered synapses develop in distinct dendritic domains in visual cortex before eye opening.

Synaptic inputs to cortical neurons are highly structured in adult sensory systems, such that neighboring synapses along dendrites are activated by similar stimuli. This organization of synaptic inputs, called synaptic clustering, is required for high-fidelity signal processing, and clustered synapses can already be observed before eye opening. However, how clustered inputs emerge during development is unknown. Here, we employed concurrent in vivo whole-cell patch-clamp and dendritic calcium imaging to map spontaneous synaptic inputs to dendrites of layer 2/3 neurons in the mouse primary visual cortex during the second postnatal week until eye opening. We found that the number of functional synapses and the frequency of transmission events increase several fold during this developmental period. At the beginning of the second postnatal week, synapses assemble specifically in confined dendritic segments, whereas other segments are devoid of synapses. By the end of the second postnatal week, just before eye opening, dendrites are almost entirely covered by domains of co-active synapses. Finally, co-activity with their neighbor synapses correlates with synaptic stabilization and potentiation. Thus, clustered synapses form in distinct functional domains presumably to equip dendrites with computational modules for high-capacity sensory processing when the eyes open.

Electrophysiology of human iPSC-derived vascular smooth muscle cells and cell autonomous consequences of Cantu Syndrome mutations.

OBJECTIVE: Cantu Syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by GoF variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels, and is characterized by low systemic vascular resistance, as well as tortuous, dilated vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell-autonomously within vascular smooth muscle cells (VSMCs), or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. APPROACH AND RESULTS: Whole-cell voltage-clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were consistent with those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance, and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae, and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs, suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. CONCLUSIONS: The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs.

Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome-Associated Variants.

BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was generated and independently studied at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values yielded 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.

Management of Cerebrospinal Fluid Leak After Intrathecal Baclofen Pump Procedures in Adolescents With Cerebral Palsy: A Retrospective Study.

STUDY OBJECTIVE:  Epidural blood patches (EBPs) are frequently performed in children with cerebral palsy (CP) to manage post-dural puncture headache (PDPH) due to cerebrospinal fluid (CSF) leak after intrathecal baclofen pump (ITBP) placement or replacement procedures. The purpose of our study was to review the incidence and management of CSF leak following ITBP placement or replacement procedures in children with CP. The study was a retrospective review of 245 patients representing 310 surgical cases of baclofen pump insertion (n=141) or reinsertion (n=169) conducted at a 125-bed children's hospital with prominent specialty orthopedics surgical cases. MEASUREMENTS:  Demographic and clinical information was obtained from the anesthesia pain service database on all new ITBP placement and subsequent replacements over an eight-year period. MAIN RESULTS:  The overall incidence of CSF leak in our population was 16% (50 of 310) and 18% (25 of 141) with a new ITBP placement. Children with diplegia were associated with a threefold risk of developing CSF leak. Of patients who developed CSF leak (n=50), 68% (n=34) were successfully treated conservatively, while 32% (n=16) required EBPs. EBPs were successful in 87.5% (14 of 16) of patients at relieving PDPH on the first attempt.  Conclusions: CSF leak is a known problem after ITBP placement and replacement. Most patients were successfully treated with conservative management and EBPs were successful in patients failing conservative therapy. Diagnosing PDPH in non-verbal patients can be challenging.

Ultrathin silk nanofiber-carbon nanotube skin tattoos for wirelessly triggered and temperature feedbacked transdermal drug delivery.

Transdermal drug delivery has emerged as an alternative to conventional drug delivery systems as it enables painless and convenient drug administration. However, next-generation healthcare systems need to facilitate "on-demand" delivery operations and should be highly efficient to penetrate the physiological barriers in the skin. Here, we report an ultrathin dye-loaded epidermal tattoo (UDET) that allows wirelessly stimulated drug delivery with high efficiency. The UDET consists of an electrospun dye-loaded silk nanofiber mat and a covered carbon nanotube (CNT) layer. UDETs are conformally tattooed on pigskins and show stable operation under mechanical deformation. Biological fluorescence dyes such as vitamin B12, riboflavin, rhodamine B, and sodium fluorescein are applied as model drugs. Illuminating the UDET by a low-power light-emitting diode (< 34.5 mW/cm2) triggers transdermal drug delivery due to heat generation. The CNTs convert the absorbed light into heat, and then the dyes loaded on silk can be diffused through the epidermis. The CNT layer is electrically conductive and can detect the temperature by reading the resistance change (0.1917 Ω/°C). This indicates that the UDET can be used simultaneously to read temperature and deliver the loaded dye molecules, making it a promising on-demand drug delivery strategy for future medicine technology. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00363-6.

Tuck-in tenon patch graft for giant full-thickness macular holes.

PURPOSE: To report the results of using autologous Tenon patch grafts for managing giant full-thickness macular holes (FTMHs) when other alternatives are not applicable. METHODS: The same surgical technique was performed in all three cases. Briefly, a small fragment of Tenon's tissue was collected. The graft was introduced through a 23G trocar and released over the macular hole under a bubble of PFCL. The patch is delicately pushed towards the edges of the hole to slide underneath. The PFCL bubble is then actively aspirated next to the optic disc. Tamponade with gas or silicone oil is subsequently injected, with care taken to minimize fluid turbulence during the procedure. RESULTS: The outcomes of autologous Tenon patch grafts in three giant FTMHs are reported. In the first case, silicone oil tamponade was injected, in the second, C2F6 gas was injected. And in the third case, that of a woman with advanced glaucoma, no tamponade was left in the eye. No adverse effects were observed during or after the procedures. Closure of the macular hole and functional improvement were documented during the follow-up period in all three cases. CONCLUSION: With a follow-up of up to 6 months, the Tenon patch graft appeared to be a promising technique for managing complex cases of FTMH. Additional studies to investigate long-term outcomes and determine the most appropriate indications are warranted.

Changes in hippocampal volume, synaptic plasticity and amylin sensitivity in an animal model of type 2 diabetes are associated with increased vulnerability to amyloid-beta in advancing age.

Type-2 diabetes (T2D) is a metabolic disorder that is considered a risk factor for Alzheimer's disease (AD). Cognitive impairment can arise due to hypoglycemia associated with T2D, and hyperamylinemia associated with insulin resistance can enhance AD pathology. We explored whether changes occur in the hippocampus in aging (6-12 months old) female V-Lep○b-/- transgenic (tg) mice, comprising an animal model of T2D. We also investigated whether an increase in vulnerability to Aß (1-42), a known pathological hallmark of AD, is evident. Using magnetic resonance imaging we detected significant decreases in hippocampal brain volume in female tg-mice compared to wild-type (wt) littermates. Long-term potentiation (LTP) was impaired in tg compared to wt mice. Treatment of the hippocampus with Aß (1-42) elicited a stronger debilitation of LTP in tg compared to wt mice. Treatment with an amylin antagonist (AC187) significantly enhanced LTP in wt and tg mice, and rescued LTP in Aß (1-42)-treated tg mice. Taken together our data indicate that a T2D-like state results in an increased vulnerability of the hippocampus to the debilitating effects of Aß (1-42) and that effects are mediated in part by changes in amylin receptor signaling.

Delayed skin testing for systemic medications: helpful or not?

Cutaneous adverse drug reactions (CADR) collectively are delayed drug reactions such as morbilliform drug eruption (MDE) and severe cutaneous adverse reactions (SCAR). Whereas MDE may wane over time, be the result of drug viral interactions and be amenable to slow reintroduction or rechallenge, SCAR are HLA class I restricted, T-cell mediated reactions that demonstrate durable immunity and warrant lifelong avoidance. SCAR such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and generalized bullous fixed drug eruption (GBFDE) often occur in the setting of multiple drugs dosed together. Collectively, they lead to significant morbidity, mortality and drug safety concerns that could severely limit future treatment options. Currently, no single or combination of diagnostic tests for SCAR such as ex vivo or in vitro testing, in vivo (skin testing) or other adjunctive tests such as HLA typing have 100% negative predictive value. In this "Controversies in Allergy Review Article", we review the current literature on delayed skin testing (patch and delayed prick/intradermal test) and critically assess the evidence base of its utility across different drugs and clinical phenotypes of delayed hypersensitivity reactions.

Probabilistic inference and Bayesian-like estimation in animals: Empirical evidence.

Animals often make decisions without perfect knowledge of environmental parameters like the quality of an encountered food patch or a potential mate. Theoreticians often assume animals make such decisions using a Bayesian updating process that combines prior information about the frequency distribution of resources in the environment with sample information from an encountered resource; such a process leads to decisions that maximize fitness, given the available information. I examine three aspects of empirical work that shed light on the idea that animals can make such decisions in a Bayesian-like manner. First, many animals are sensitive to variance differences in behavioral options, one metric used to characterize frequency distributions. Second, several species use information about the relative frequency of preferred versus nonpreferred items in different populations to make probabilistic inferences about samples taken from populations in a manner that results in maximizing the likelihood of obtaining a preferred reward. Third, the predictions of Bayesian models often match the behavior of individuals in two main approaches. One approach compares behavior to models that make different assumptions about how individuals estimate the quality of an environmental parameter. The patch exploitation behavior of nine species of birds and mammals has matched the predictions of Bayesian models. The other approach compares the behavior of individuals who learn, through experience, different frequency distributions of resources in their environment. The behavior of three bird species and bumblebees exploiting food patches and fruit flies selecting mates is influenced by their experience learning different frequency distributions of food and mates, respectively, in ways consistent with Bayesian models. These studies lend support to the idea that animals may combine prior and sample information in a Bayesian-like manner to make decisions under uncertainty, but additional work on a greater diversity of species is required to better understand the generality of this ability.

Ambient Moisture-Driven Self-Powered Iontophoresis Patch for Enhanced Transdermal Drug Delivery.

Iontophoretic transdermal drug delivery (TDD) devices are known to enhance the transdermal transport of drugs. However, conventional transdermal iontophoretic devices require external power sources, wired connections, or mechanical parts, which reduce the comfort level for patients during extended use. In this work, a self-powered, wearable transdermal iontophoretic patch (TIP) is proposed by harvesting ambient humidity for energy generation, enabling controlled TDD. This patch primarily uses moist-electric generators (MEGs) as its power source, thus obviating the need for complex power management modules and mechanical components. A single MEG unit can produce an open-circuit voltage of 0.80 V and a short-circuit current of 11.65 µA under the condition of 80% relative humidity. Amplification of the electrical output is feasible by connecting multiple generator units in series and parallel, facilitating the powering of certain commercial electronic devices. Subsequently, the MEG array is integrated with the TDD circuit to create the wearable TIP. After 20 min of application, the depth of drug penetration through the skin is observed to increase threefold. The effective promotion effect of TIP on the transdermal delivery of ionized drugs is corroborated by simulations and experiments. This wearable TIP offers a simple, noninvasive solution for TDD.

Eugenol and lidocaine inhibit voltage-gated Na+ channels from dorsal root ganglion neurons with different mechanisms.

Eugenol (EUG) is a bioactive monoterpenoid used as an analgesic, preservative, and flavoring agent. Our new data show EUG as a voltage-gated Na+ channel (VGSC) inhibitor, comparable but not identical to lidocaine (LID). EUG inhibits both total and only TTX-R voltage-activated Na+ currents (INa) recorded from VGSCs naturally expressed on dorsal root ganglion sensory neurons in rats. Inhibition is quick, fully reversible, and dose-dependent. Our biophysical and pharmacological analyses showed that EUG and LID inhibit VGSCs with different mechanisms. EUG inhibits VGSCs with a dose-response relationship characterized by a Hill coefficient of 2, while this parameter for the inhibition by LID is 1. Furthermore, in a different way from LID, EUG modified the voltage dependence of both the VGSC activation and inactivation processes and the recovery from fast inactivated states and the entry to slow inactivated states. In addition, we suggest that EUG, but not LID, interacts with VGSC pre-open-closed states, according to our data.