Highly pathogenic avian influenza A(H5N1) in animals: A systematic review and meta-analysis.

Introduction: Avian influenza A H5N1 is a significant global public health threat. Although relevant, systematic reviews about its prevalence in animals are lacking. Methods: We performed a systematic literature review in bibliographic databases to assess the prevalence of H5N1 in animals. A meta-analysis with a random-effects model was performed to calculate the pooled prevalence and 95 % confidence intervals (95%CI). In addition, measures of heterogeneity (Cochran's Q statistic and I2 test) were reported. Results: The literature search yielded 1359 articles, of which 33 studies were fully valid for analysis, including 96,909 animals. The pooled prevalence for H5N1 in birds (n = 90,045, 24 studies) was 5.0 % (95%CI: 4.0-6.0 %; I2 = 99.21); in pigs (n = 3,178, 4 studies) was 1.0 % (95%CI: 0.0-1.0 %); in cats (n = 2,911, 4 studies) was 0.0 % (95%CI: 0.0-1.0 %); and in dogs (n = 479, 3 studies) was 0.0 % (95%CI: 0.0-2.0 %). Conclusions: While the occurrence of H5N1 in animals might be comparatively limited compared to other influenza viruses, its impact on public health can be substantial when it transmits to humans. This virus can potentially induce severe illness and has been linked to previous outbreaks. Therefore, it is essential to closely monitor and comprehend the factors influencing the prevalence of H5N1 in both avian and human populations to develop effective disease control and prevention strategies.

A Severe and Prolonged Case of Ocular Monkeypox Without Systemic Manifestations.

PURPOSE: The objective of this study was to present a rare case of prolonged and severe ocular monkeypox virus infection in the absence of systemic manifestations. METHODS: This was a single case report. RESULTS: A 60-year-old man, having been symptomatic for 9 days, presented with several umbilicated, ulcerated papules on the left cheek, left side of the nose, and left upper eyelid, along with marked follicular conjunctivitis and multiple conjunctival ulcerations. Two weeks after presentation, he developed an irregular, 360° circumferential opacity in the peripheral cornea that progressed to a large epithelial defect with corneal thinning. Although the initial eyelid lesions and conjunctivitis quickly resolved, the patient experienced nonresolving corneal inflammation manifest with peripheral corneal thinning, epithelial defects, and stromal keratitis. Four months after presentation, with the presumptive diagnosis of peripheral ulcerative keratitis, the patient was treated with intravenous steroids and immunosuppressive treatment, after which the ocular surface inflammation improved. However, the inflammation recurred 12 weeks later, and the patient developed severe perilimbal necrotizing conjunctivitis, followed by recurrence of ulcerated nodular eyelid lesions. Eight months after presentation, nucleic acid amplification tests from eyelid lesion swabs returned positive for nonvariola Orthopoxviruses, which led to the diagnosis of mpox. Within 2 weeks of beginning antiviral treatment with systemic tecovirimat and cidofovir and topical trifluridine, the eyelid lesions, conjunctivitis, and corneal inflammation resolved. CONCLUSIONS: We present an unusual and challenging case of ocular mpox with severe ocular surface inflammation including peripheral corneal thinning and epithelial defects, without systemic disease. Initiation of antiviral treatment resulted in a quick resolution of the ocular disease.

Serological and molecular detection of dengue virus in animals: A systematic review and meta-analysis.

Introduction: Dengue is a vector-borne disease, especially important in tropical and subtropical areas. The first presentation of many arboviral diseases occurred mainly in animals, including multiple Alphaviruses and Flaviviruses, such as dengue. Objective: To determine the serological and molecular frequency of the dengue virus in animals. Methods: A systematic literature review was carried out in five databases for the proportion of animals infected with dengue, defined by molecular and serological tests. A meta-analysis was performed using a random-effects model to calculate the pooled prevalence and 95% confidence intervals (CI). Cochran?s Q test and the I2 statistic were used to assess the heterogeneity between the two studies. Results: The presence of dengue in bats, primates, birds, sheep, horses, cattle, pigs, rodents and buffaloes, according to serological methods, had a prevalence of 10%, 29%, 8%, 1%, 11%, 0%, 49%, 2%, 7%, respectively. According to molecular methods, the presence of dengue in bats had a seroprevalence of 6.0%. Conclusion: The present study confirms the presence of the Dengue virus in a large group of animal species, with potential implications as possible reservoirs of this virus, raising the possibility of zoonotic transmission.

Neuronal expression of herpes simplex virus-1 VP16 protein induces pseudorabies virus escape from silencing and reactivation.

Alpha herpesvirus (α-HV) particles enter their hosts from mucosal surfaces and efficiently maintain fast transport in peripheral nervous system (PNS) axons to establish infections in the peripheral ganglia. The path from axons to distant neuronal nuclei is challenging to dissect due to the difficulty of monitoring early events in a dispersed neuron culture model. We have established well-controlled, reproducible, and reactivateable latent infections in compartmented rodent neurons by infecting physically isolated axons with a small number of viral particles. This system not only recapitulates the physiological infection route but also facilitates independent treatment of isolated cell bodies or axons. Consequently, this system enables study not only of the stimuli that promote reactivation but also the factors that regulate the initial switch from productive to latent infection. Adeno-associated virus (AAV)-mediated expression of herpes simplex-1 (HSV-1) VP16 alone in neuronal cell bodies enabled the escape from silencing of incoming pseudorabies virus (PRV) genomes. Furthermore, the expression of HSV VP16 alone reactivated a latent PRV infection in this system. Surprisingly, the expression of PRV VP16 protein supported neither PRV escape from silencing nor reactivation. We compared transcription transactivation activity of both VP16 proteins in primary neurons by RNA sequencing and found that these homolog viral proteins produce different gene expression profiles. AAV-transduced HSV VP16 specifically induced the expression of proto-oncogenes including c-Jun and Pim2. In addition, HSV VP16 induces phosphorylation of c-Jun in neurons, and when this activity is inhibited, escape of PRV silencing is dramatically reduced.IMPORTANCEDuring latency, alpha herpesvirus genomes are silenced yet retain the capacity to reactivate. Currently, host and viral protein interactions that determine the establishment of latency, induce escape from genome silencing or reactivation are not completely understood. By using a compartmented neuronal culture model of latency, we investigated the effect of the viral transcriptional activator, VP16 on pseudorabies virus (PRV) escape from genome silencing. This model recapitulates the physiological infection route and enables the study of the stimuli that regulate the initial switch from a latent to productive infection. We investigated the neuronal transcriptional activation profiles of two homolog VP16 proteins (encoded by HSV-1 or PRV) and found distinct gene activation signatures leading to diverse infection outcomes. This study contributes to understanding of how alpha herpesvirus proteins modulate neuronal gene expression leading to the initiation of a productive or a latent infection.

The endocannabinoid anandamide activates pro-resolving pathways in human primary macrophages by engaging both CB2 and GPR18 receptors.

Resolution of inflammation is the cellular and molecular process that protects from widespread and uncontrolled inflammation and restores tissue function in the aftermath of acute immune events. This process is orchestrated by specialized pro-resolving mediators (SPM), a class of bioactive lipids able to reduce immune activation and promote removal of tissue debris and apoptotic cells by macrophages. Although SPMs are the lipid class that has been best studied for its role in facilitating the resolution of self-limited inflammation, a number of other lipid signals, including endocannabinoids, also exert protective immunomodulatory effects on immune cells, including macrophages. These observations suggest that endocannabinoids may also display pro-resolving actions. Interestingly, the endocannabinoid anandamide (AEA) is not only known to bind canonical type 1 and type 2 cannabinoid receptors (CB1 and CB2) but also to engage SPM-binding receptors such as GPR18. This suggests that AEA may also contribute to the governing of resolution processes. In order to interrogate this hypothesis, we investigated the ability of AEA to induce pro-resolving responses by classically-activated primary human monocyte-derived macrophages (MoDM). We found that AEA, at nanomolar concentration, enhances efferocytosis in MoDMs in a CB2- and GPR18-dependent manner. Using lipid mediator profiling, we also observed that AEA modulates SPM profiles in these cells, including levels of resolvin (Rv)D1, RvD6, maresin (MaR)2, and RvE1 in a CB2-dependent manner. AEA treatment also modulated the gene expression of SPM enzymes involved in both the formation and further metabolism of SPM such as 5-lipoxygenase and 15-Prostaglandin dehydrogenase. Our findings show, for the first time, a direct effect of AEA on the regulation of pro-resolving pathways in human macrophages. They also provide new insights into the complex interactions between different lipid pathways in activation of pro-resolving responses contributing to the reestablishment of homeostasis in the aftermath of acute inflammation.

Selective targeting of chemically modified miR-34a to prostate cancer using a small molecule ligand and an endosomal escape agent.

Use of tumor-suppressive microRNAs (miRNAs) as anti-cancer agents is hindered by the lack of effective delivery vehicles, entrapment of the miRNA within endocytic compartments, and rapid degradation of miRNA by nucleases. To address these issues, we developed a miRNA delivery strategy that includes (1) a targeting ligand, (2) an endosomal escape agent, nigericin and (3) a chemically modified miRNA. The delivery ligand, DUPA (2-[3-(1,3-dicarboxy propyl) ureido] pentanedioic acid), was selected based on its specificity for prostate-specific membrane antigen (PSMA), a receptor routinely upregulated in prostate cancer-one of the leading causes of cancer death among men. DUPA was conjugated to the tumor suppressive miRNA, miR-34a (DUPA-miR-34a) based on the ability of miR-34a to inhibit prostate cancer cell proliferation. To mediate endosomal escape, nigericin was incorporated into the complex, resulting in DUPA-nigericin-miR-34a. Both DUPA-miR-34a and DUPA-nigericin-miR-34a specifically bound to, and were taken up by, PSMA-expressing cells in vitro and in vivo. And while both DUPA-miR-34a and DUPA-nigericin-miR-34a downregulated miR-34a target genes, only DUPA-nigericin-miR-34a decreased cell proliferation in vitro and delayed tumor growth in vivo. Tumor growth was further reduced using a fully modified version of miR-34a that has significantly increased stability.

Mpox infection in animals: A systematic review and meta-analysis.

Mpox is a zoonotic disease that became epidemic in multiple countries in 2022. There is a lack of published systematic reviews on natural animal infection due to Mpox. We performed a systematic literature review with meta-analysis to assess animal Mpox prevalence. We performed a random-effects model meta-analysis to calculate the pooled prevalence and 95% confidence interval (95%CI) for prevalence studies. After the screening, 15 reports were selected for full-text assessment and included in qualitative and quantitative analyses. Ten reports assessed Mpox infection by molecular or serological tests (n = 2680), yielding a pooled prevalence of 16.0% (95%CI: 3.0-29.0%) for non-human primates; 8.0% (95%CI: 4.0-12.0%) for rodents and 1.0% (95%CI: 0.0-3.0%) for shrews. Further studies in other animals are required to define the extent and importance of natural infection due to Mpox. These findings have implications for public human and animal health. OneHealth approach is critical for prevention and control.

Association of vitamin B12, folate, and homocysteine with COVID-19 severity and mortality: A systematic review and meta-analysis.

Objective: We aimed to review the available evidence on the association between vitamin B12, folate, and homocysteine levels with worse outcomes among COVID-19 patients. Methods: The search was carried out in ten databases simultaneously run on 10 May 2023, without language restrictions. We included cross-sectional, case-control, and cohort studies. The random-effects meta-analysis was performed using the Sidik-Jonkman method and corrected 95% confidence intervals using the truncated Knapp-Hartung standard errors. Standardized mean difference and 95% CI was used as the measure effect size. Results: Thirteen articles were included in this review (n = 2134). Patients with COVID-19 who did not survive had the highest serum vitamin B12 values (SMD: 1.05; 95% CI: 0.31-1.78; p = 0.01, I2 = 91.22%). In contrast, low serum folate values were associated with patients with severe COVID-19 (SMD: -0.77; 95% CI: -1.35 to -0.19; p = 0.02, I2 = 59.09%). The remaining tested differences did not yield significant results. Conclusion: Elevated serum levels of vitamin B12 were associated with higher mortality in patients with COVID-19. Severe cases of COVID-19 were associated with low serum folate levels. Future studies should incorporate a larger sample size.

Persistent transgene expression in peripheral tissues one year post intravenous and intramuscular administration of AAV vectors containing the alphaherpesvirus latency-associated promoter 2.

Significant progress has been made in enhancing recombinant adeno-associated virus (rAAV) for clinical investigation. Despite its versatility as a gene delivery platform, the inherent packaging constraint of 4.7 kb imposes restrictions on the range of diseases it can address. In this context, we present findings of an exceptionally compact and long-term promoter that facilitates the expression of larger genes compared to conventional promoters. This compact promoter originated from the genome of the alphaherpesvirus pseudorabies virus, latency-associated promoter 2 (LAP2, 404 bp). Promoter driving an mCherry reporter was packaged into single strand (ss) AAV8 and AAV9 vectors and injected into adult C57BL/6 mice at a dose of 5 × 1011 vg/mouse by single intravenous or intramuscular administration. An ssAAV8 and ssAAV9 vector with elongation factor-1α promoter (EF1α, 1264 bp) was injected side-by-side for comparison. After 400 days, we sacrificed the mice and examined mCherry expression in liver, kidney, heart, lung, spleen, pancreas, skeletal muscle, and brain. We found that LAP2 exhibited robust transgene expression across a wide range of cells and tissues comparable to the larger EF1α, which is currently recognized as a rather potent and ubiquitous promoter. The AAV8-LAP2 and AAV9-LAP2 constructs displayed strong transduction and transcription in liver, kidney, and skeletal muscle on both route of administration. However, no expression was detected in the heart, lung, spleen, pancreas, and brain. The outcomes of our investigation propose the viability of LAP2 for gene therapy applications demanding the expression of large or multiple therapeutic genes following a single viralvector administration.

Three dimensional analysis of the exhalation flow in the proximity of the mouth.

The human exhalation flow is characterized in this work from the three-dimensional velocimetry results obtained by using the stereo particle image velocimetry (SPIV) measurement technique on the flow emitted from a realistic airway model. For this purpose, the transient exhalation flow through the mouth of a person performing two different breaths corresponding to two metabolic rates, standing relaxed (SR) and walking active (WA), is emulated and studied. To reproduce the flow realistically, a detailed three-dimensional model obtained from computed tomography measurements on real subjects is used. To cope with the variability of the experimental data, a subsequent analysis of the results is performed using the TR-PIV (time resolved particle image velocimetry) technique. Exhalation produces a transient jet that becomes a puff when flow emission ends. Three-dimensional vector fields of the jet velocity are obtained in five equally spaced transverse planes up to a distance of Image 1 from the mouth at equally spaced time instants Image 2 which will be referred to as phases (φ), from the beginning to the end of exhalation. The time evolution during exhalation of the jet area of influence, the velocity field and the jet air entrainment have been characterized for each of the jet cross sections. The importance of the use of realistic airway models for the study of this type of flow and the influence of the metabolic rate on its development are also analyzed. The results obtained contribute to the characterization of the human exhalation as a pathway of the transmission of pathogens such as SARS-CoV-2 virus.

Snakebite-Associated Infections: A Systematic Review and Meta-Analysis.

Snakebites still constitute a significant public health problem in developing countries and are considered a neglected tropical condition by the WHO. Snake accidents are associated with substantial morbidity and mortality and may produce secondary complications, such as severe infections. The objective of this systematic review was to determine the prevalence of snakebite infections and characterize the bacteria isolated from these infections. A systematic literature review in five databases was carried out to assess the prevalence of snakebite infection. A meta-analysis was performed using a random-effects model to calculate the pooled prevalence and 95% CIs. Cochran's Q test and the I2 statistic were used to assess between-study heterogeneity. The pooled prevalence of infection due to snakebite was 27.0% (95% CI: 22.0-32.0%), with high heterogeneity among studies (I2 = 99.7%). The prevalence was higher in Asia (32%) than in the Americas (21%). Snakebite infections required surgical interventions in 68% (95% CI: 37.0-98.0%). The leading group of pathogens identified corresponded to Gram-negative bacteria (63%), particularly Morganella morganii (32%), but also, Gram-positive cocci (40%), especially Enterococcus spp. (23%) and Staphylococcus aureus (15%). However, multiple other pathogens, including anaerobes, were found. A high prevalence of snakebite-associated infection has been described, primarily due to M. morganii, with the corresponding implications for empirical therapy. Rational use of antimicrobials is recommended, and this should guide initial empirical treatment. Moreover, isolation and identification of the possible bacteria present in snakebite wounds is recommended in all cases to confirm or rule out associated infection.

Confinement tonicity on epidemic spreading.

Emerging and re-emerging pathogens are latent threats in our society with the risk of killing millions of people worldwide, without forgetting the severe economic and educational backlogs. From COVID-19, we learned that self isolation and quarantine restrictions (confinement) were the main way of protection till availability of vaccines. However, abrupt lifting of social confinement would result in new waves of new infection cases and high death tolls. Here, inspired by how an extracellular solution can make water move into or out of a cell through osmosis, we define confinement tonicity. This can serve as a standalone measurement for the net direction and magnitude of flows between the confined and deconfined susceptible compartments. Numerical results offer insights on the effects of easing quarantine restrictions.

Decoupled supercapacitive electrolyzer for membrane-free water splitting.

Green hydrogen production via water splitting is vital for decarbonization of hard-to-abate industries. Its integration with renewable energy sources remains to be a challenge, due to the susceptibility to hazardous gas mixture during electrolysis. Here, we report a hybrid membrane-free cell based on earth-abundant materials for decoupled hydrogen production in either acidic or alkaline medium. The design combines the electrocatalytic reactions of an electrolyzer with a capacitive storage mechanism, leading to spatial/temporal separation of hydrogen and oxygen gases. An energy efficiency of 69% lower heating value (48 kWh/kg) at 10 mA/cm2 (5 cm-by-5 cm cell) was achieved using cobalt-iron phosphide bifunctional catalyst with 99% faradaic efficiency at 100 mA/cm2. Stable operation over 20 hours in alkaline medium shows no apparent electrode degradation. Moreover, the cell voltage breakdown reveals that substantial improvements can be achieved by tunning the activity of the bifunctional catalyst and improving the electrodes conductivity. The cell design offers increased flexibility and robustness for hydrogen production.

Functional EPAS1/HIF2A missense variant is associated with hematocrit in Andean highlanders.

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.

Host genetic regulation of human gut microbial structural variation.

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established1-6, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship.

Treatment of hypopigmented burn hypertrophic scars with short-term topical tacrolimus does not lead to repigmentation.

OBJECTIVES: Dyschromia is an understudied aspect of hypertrophic scar (HTS). The use of topical tacrolimus has successfully shown repigmentation in vitiligo patients through promotion of melanogenesis and melanocyte proliferation. It was hypothesized that HTSs treated with topical tacrolimus would have increased repigmentation compared to controls. METHODOLOGY: Full-thickness burns in red Duroc pigs were either treated with excision and meshed split-thickness skin grafting or excision and no grafting, and these wounds formed hypopigmented HTSs (n = 8). Half of the scars had 0.1% tacrolimus ointment applied to the scar twice a day for 21 days, while controls had no treatment. Further, each scar was bisected with half incurring fractional ablative CO2 laser treatment before topical tacrolimus application to induce laser-assisted drug delivery (LADD). Pigmentation was evaluated using a noninvasive probe to measure melanin index (MI) at Days 0 (pretreatment), 7, 14, and 21. At each timepoint, punch biopsies were obtained and fixed in formalin or were incubated in dispase. The formalin-fixed biopsies were used to evaluate melanin levels by H&E staining. The biopsies incubated in dispase were used to obtain epidermal sheets. The ESs were then flash frozen and RNA was isolated from them and used in quantitative reverse transcription polymerase chain reaction for melanogenesis-related genes: Tyrosinase (TYR), TYR-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). Analysis of variance test with Sídák's multiple comparisons test was used to compare groups. RESULTS: Over time, within the grafted HTS and the NS group, there were no significant changes in MI, except for Week 3 in the -Tacro group. (+Tacro HTS= pre = 685.1 ± 42.0, w1 = 741.0 ± 54.16, w2 = 750.8 ± 59.0, w3 = 760.9 ± 49.8) (-Tacro HTS= pre = 700.4 ± 54.3, w1 = 722.3 ± 50.7, w2 = 739.6 ± 53.2, w3 = 722.7 ± 50.5). Over time, within the ungrafted HTS and the NS group, there were no significant changes in MI. (+Tacro HTS= pre = 644.9 ± 6.9, w1 = 661.6 ± 3.3, w2 = 650.3 ± 6.2, w3 = 636.3 ± 7.4) (-Tacro HTS= pre = 696.8 ± 8.0, w1 = 695.8 ± 12.3, w2 = 678.9 ± 14.0, w3 = 731.2 ± 50.3). LADD did not lead to any differential change in pigmentation compared to the non-LADD group. There was no evidence of increased melanogenesis within the tissue punch biopsies at any timepoint. There were no changes in TYR, TYRP1, or DCT gene expression after treatment. CONCLUSION: Hypopigmented HTSs treated with 0.1% tacrolimus ointment with or without LADD did not show significantly increased repigmentation. This study was limited by a shorter treatment interval than what is known to be required in vitiligo patients for repigmentation. The use of noninvasive, topical treatments to promote repigmentation are an appealing strategy to relieve morbidity associated with dyschromic burn scars and requires further investigation.

Cold atmospheric plasma is bactericidal to wound-relevant pathogens and is compatible with burn wound healing.

Burn wound healing can be significantly delayed by infection leading to increased morbidity and hypertrophic scarring. An optimal antimicrobial agent would have the ability to kill bacteria without negatively affecting the host skin cells that are required for healing. Currently available products provide antimicrobial coverage, but may also cause reductions in cell proliferation and migration. Cold atmospheric plasma is a partially ionized gas that can be produced under atmospheric pressure at room temperature. In this study a novel handheld Aceso Plasma Generator was used to produce and test Aceso Cold Plasma (ACP) in vitro and in vivo. ACP showed a potent ability to eliminate bacterial load in vitro for a number of different species. Deep partial-thickness and full-thickness wounds that were treated with ACP after burning, after excision, after autografting, and at days 5, 7, and 9 did not show any negative effects on their wound healing trajectories. On par with in vitro analysis, bioburden was decreased in treated wounds vs. control. In addition, metrics of hypertrophic scar such as dyschromia, elasticity, trans-epidermal water loss (TEWL), and epidermal and dermal thickness were the same between the two treatment groups.It is likely that ACP can be used to mitigate the risk of bacterial infection during the phase of acute burn injury while patients await surgery for definitive closure. It may also be useful in treating wounds with delayed re-epithelialization that are at risk for infection and hypertrophic scarring. A handheld cold plasma device will be useful in treating all manner of wounds and surgical sites in order to decrease bacterial burden in an efficient and highly effective manner without compromising wound healing.

Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity.

Chronic exposure of the lung to irritants such as allergen is a primary cause of asthma characterized by exaggerated airway constriction, also called hyperreactivity, which can be life-threatening. Aside from immune cells, vagal sensory neurons are important for airway hyperreactivity 1-4 . However, the identity and signature of the downstream nodes of this adaptive circuit remains poorly understood. Here we show that a single population of Dbh + neurons in the nucleus of the solitary tract (nTS) of the brainstem, and downstream neurons in the nucleus ambiguous (NA), are both necessary and sufficient for chronic allergen-induced airway hyperreactivity. We found that repeated exposures of mice to inhaled allergen activates nTS neurons in a mast cell-, interleukin 4 (IL-4)-and vagal nerve-dependent manner. Single-nucleus RNA-seq of the nTS at baseline and following allergen challenges reveals that a Dbh + population is preferentially activated. Ablation or chemogenetic inactivation of Dbh + nTS neurons blunted, while chemogenetic activation promoted hyperreactivity. Viral tracing indicates that Dbh + nTS neurons, capable of producing norepinephrine, project to the NA, and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that then directly drive airway constriction. Focusing on transmitters, delivery of norepinephrine antagonists to the NA blunted allergen-induced hyperreactivity. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. The knowledge opens the possibility of targeted neural modulation as an approach to control refractory allergen-induced airway constriction.

Pre-extensively drug-resistant and extensively drug-resistant tuberculosis in Latin America and the Caribbean: A systematic review and meta-analysis.

BACKGROUND: The growing threat from pre-extensively drug-resistant tuberculosis (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) poses a major public health concern in Latin America and the Caribbean (LAC). Therefore, this study aimed to summarize the available evidence on the prevalence of pre-XDR-TB and XDR-TB among patients with multidrug-resistant tuberculosis in LAC. METHODS: A systematic review was conducted in the following databases on June 3, 2023: PubMed, Scopus, Ovid Medline, Web of Science, Scielo and LILACS. We estimated pooled proportions using a random effects model (Dersimonian and Laird). The 95% confidence intervals (95% CI) were calculated using the binomial exact method (Clopper-Pearson Method). Subgroup (by time period and country) and sensitivity analyses were performed. RESULTS: Twenty-nine studies were eligible for qualitative synthesis and 27 for meta-analysis (n = 15,565). The pooled prevalence of XDR-TB in the study participants was 5% (95% CI: 3%-6%), while that of pre-XDR-TB was 10% (95% CI 7%-14%). Cuba (6%, 95% CI 0%-17%) and Peru (6%, 95% CI 5%-7%) had the highest pooled prevalence of XDR-TB. Regarding pre-XDR-TB, Brazil (16%, 95% CI 11%-22%) and Peru (13%, 95% CI: 9%-16%) showed the highest prevalence. CONCLUSIONS: The pooled prevalence of pre-XDR-TB and XDR-TB in LAC was 10% and 5%, respectively. Governments should strengthen drug-resistance surveillance and TB programs.