Central Channelopathies in Obesity.

As obesity has raised heightening awareness, researchers have attempted to identify potential targets that can be treated for therapeutic intervention. Focusing on the central nervous system (CNS), the key organ in maintaining energy balance, a plethora of ion channels that are expressed in the CNS have been inspected and determined through manipulation in different hypothalamic neural subpopulations for their roles in fine-tuning neuronal activity on energy state alterations, possibly acting as metabolic sensors. However, a remaining gap persists between human clinical investigations and mouse studies. Despite having delineated the pathways and mechanisms of how the mouse study-identified ion channels modulate energy homeostasis, only a few targets overlap with the obesity-related risk genes extracted from human genome-wide association studies. Here, we present the most recently discovered CNS-specific metabolism-correlated ion channels using reverse and forward genetics approaches in mice and humans, respectively, in the hope of illuminating the prospects for future therapeutic development.

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. Methods: We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Results: Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Conclusion: Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

Real-world characterisation of patients with chronic rhinosinusitis with nasal polyps with and without surgery in England.

OBJECTIVES: To characterise the real-world burden of chronic rhinosinusitis with nasal polyps (CRSwNP) in the UK, stratified by number of surgeries. DESIGN: Retrospective cohort study. SETTING: UK Clinical Practice Research Datalink Aurum database with Hospital Episodes Statistics linkage (2007-2019). PARTICIPANTS: Adults ≥18 years of age with a first NP diagnosis (index) and 365 days of baseline and ≥180 days of follow-up data. Follow-up continued until disenrollment, death or end of data collection. MAIN OUTCOME MEASURES: Primary: primary care physician prescribed CRSwNP-related treatments, and all-cause healthcare resource utilisation (HCRU) in 90 days post-index, stratified by surgeries during follow-up. Secondary: rate of surgery and CRSwNP point prevalence. Baseline patient demographics, clinical characteristics and comorbidities were also assessed. RESULTS: Of the 33 107 patients included, 23.5% and 2.2% had ≥1 and ≥2 surgeries during follow-up, respectively (mean follow-up: 5.3 years). Patients with more surgeries (≥2/≥1/0) during follow-up were more likely to be male (67.3%/69.0%/58.0%), have asthma (37.8%/28.2%/20.2%) and have baseline blood eosinophil counts ≥300 cells/µL (68.5%/66.0%/51.5%). During the first 90-days post-index as surgery number increased, the proportion of patients using oral corticosteroids (25.8%/20.7%/14.2%) and mean (SD) number of all-cause healthcare visits (5.9 [4.2]/5.4 [4.0]/4.9 [4.2]) increased. Time between surgeries was shorter among patients with more surgeries. CRSwNP prevalence on 31 December 2018 was 476 cases per 100 000 persons. CONCLUSION: A small proportion of patients in the UK required multiple surgeries for CRSwNP and this was associated with increasing comorbidity burden, baseline blood eosinophil counts, CRSwNP-related treatment and HCRU use.

The complete chloroplast genome sequence of Rubus irritans Focke 1910 (Rosaceae).

Rubus irritans Focke is a type of tonifying kidney-essence herb used in China. We present the complete chloroplast (cp) genome of R. irritans, a member of the genus Rubus. The complete cp genome of R. irritans was 155,286 bp long and consisted of an 84,613 bp long large single-copy (LSC) region, an 18,697 bp long SSC region, and a pair of 25,988 bp long inverted repeats (IR). Furthermore, the plastid genome contained 130 genes, including 85 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The overall GC content of the genome was 37.29%. Based on the complete cp genome, phylogenetic analysis revealed that R. irritans is closely related to R. amabilis.

Distinct features of the host-parasite interactions between nonadherent and adherent Trichomonas vaginalis isolates.

Cytoadherence of Trichomonas vaginalis to human vaginal epithelial cells (hVECs) was previously shown to involve surface lipoglycans and several reputed adhesins on the parasite. Herein, we report some new observations on the host-parasite interactions of adherent versus nonadherent T. vaginalis isolates to hVECs. The binding of the TH17 adherent isolate to hVECs exhibited an initial discrete phase followed by an aggregation phase inhibited by lactose. T. vaginalis infection immediately induced surface expression of galectin-1 and -3, with extracellular amounts in the spent medium initially decreasing and then increasing thereafter over the next 60 min. Extracellular galectin-1 and -3 were detected on the parasite surface but only the TH17 adherent isolate could uptake galectin-3 via the lysosomes. Only the adherent isolate could morphologically transform from the round-up flagellate with numerous transient protrusions into a flat amoeboid form on contact with the solid surface. Cytochalasin D challenge revealed that actin organization was essential to parasite morphogenesis and cytoadherence. Real-time microscopy showed that parasite exploring and anchoring on hVECs via the axostyle may be required for initial cytoadherence. Together, the parasite cytoskeleton behaviors may collaborate with cell surface adhesion molecules for cytoadherence. The nonadherent isolate migrated faster than the adherent isolate, with motility transiently increasing in the presence of hVECs. Meanwhile, differential histone acetylation was detected between the two isolates. Also, TH17 without Mycoplasma symbiosis suggests that symbiont might not determine TH17 innate cytoadherence. Our findings regarding distinctive host-parasite interactions of the isolates may provide novel insights into T. vaginalis infection.

First report of bacterial soft rot caused by Enterobacter mori affecting host watermelon.

In June 2021, bacterial stem rot-like symptoms were observed on the stems and leaves of watermelon (Citrullus lanatus cv. 'Zaojia') in Pingyu County, Zhumadian City, Henan Province, China (32.44N 114.24E), which showed brown to dark brown lesions on the stems (Fig. 1A). The stems then became scorched, and the leaves showed necrotic lesions with small water-soaked spots (Fig. 1B). Watermelon is a very important economic plant in this small county, where the watermelon planting area accounts for about 15% of the arable land area. Approximately 2 hectares of 'Zaojia' have been investigated, and the disease incidence rates were almost 20~30%, thus, causing severe economic losses. Ten symptomatic watermelon stems and leaves were randomly collected based on the typical symptoms, brought into the Lab and used to isolate the pathogen. Each infected tissue was excised and cut into small pieces (about 5 mm×5 mm) and surface disinfected with 1% NaClO for 3 min. The pieces were then rinsed three times in sterile distilled water (SDW) and dried by airing. These pieces (4-5 pieces per sample) were macerated in 200 µL SDW for 60 s in a sterile mortar and pestle. A volume of 5 µL suspensions of each sample were streaked onto two LB agar plates and incubated for 48 h at 28 °C in the dark. After incubation, the colonies on LB agar plate were small, round, raised, white to cream-colored, and had smooth margins (Fig. 2). Two strains from each plate were selected. The genomic DNA of all 40 strains was extracted using a Bacterial Genomic DNA Extraction Kit D1600 (Beijing Solarbio Science & Technology Co., Ltd., Beijing, China) according to the manufacturer's instructions. The 16S ribosomal RNA gene (27F:5'-AGA GTT TGA TCC TGG CTC AG-3', /1492R: 5'-CTA CGG CTA CCT TGT TAC GA-3'), and the three housekeeping genes, including gyrB (Trantas et al., 2013), icdA and proA (Ma et al., 2007), were amplified. Sequence analysis showed that 40 strains shared the same sequence, so only one sequence was submitted into GenBanK.The 16s rDNA partial sequences (SUB12134746) shared 100% similarity with E.mori (CP084692.1), and the gyrB (OP676246), icdA (OP676248) and proA (OP676247) genes shared 98.67%, 99.39% and 97.99% homology with those of E. mori (CP084692.1), respectively. Besides, the phylogenetic tree analysis based on multi-housekeeping gene joint gryB-icdA-proA showed that E.mori（OP676246-OP676248- OP676247）from watermelon was culsterd with the E.mori (CP084692.1) from South Korea and E.mori (CP055276.1) from kiwifruit (Fig. 3). Thus, E.mori was confirmed to be the pathogen responsible for bacterial soft rot of watermelon in this study. To confirm the pathogenicity, 15-day-old healthy cv. 'Zaojia' watermelon seedlings were inoculated by spraying all the seedlings with a bacterial suspension (1×10 8 CFU mL-1) at an incubation temperature of 28 °C and 70% relative humidity, and sterile distilled liquid LB medium was applied as a negative control treatment. Three times were conducted for the isolate, and each time included nine watermelon plants. After 10 days, only the inoculated cotyledons and leaves with the bacterial suspension showed bacterial leaf spots that resembled those observed on naturally infected watermelon cotyledons and leaves (Fig. 4A-C), whereas the control plants remained asymptomatic (Fig. 4D). Simultaneously, the watermelon stems were inoculated with the bacterium in vitro. Each stem was slightly wounded with a metal sponge and then sprayed with the bacterial suspension (108 CFU mL-1) of each isolate, and the experiment was repeated three times. Water-soaked symptoms were visible on the stems (Fig. 4E), while the control plants remained asymptomatic (Fig. 4F). The strains were then successfully re-isolated and identified by sequence analyses of their 16S ribosomal RNA gene and gyrB, icdA and proA genes. Therefore, the inoculation experiment of the isolatedbacterium fulfilled Koch's postulates. Previously, E. mori has been reported to cause bacterial wilt on white mulberry (Morus alba L.) (Zhu et al. 2022), peach fruit (Prunus persica) (Ahmad et al. 2021) and kiwifruit (Actinidia deliciosa [A. Chev.] CF Liang et AR Ferguson) (Zhang et al. 2021). To our knowledge, this is the first report of E. mori causing bacterial soft rot on watermelon in world.

Elucidating the Real-World Burden of Chronic Rhinosinusitis With Nasal Polyps in Patients in the USA.

Objective: To characterize healthcare burden, treatment patterns, and clinical characteristics associated with chronic rhinosinusitis with nasal polyps (CRSwNP). Study Design: Retrospective cohort. Setting: Real-world study using US health insurance claims database. Methods: Adults with ≥1 CRSwNP diagnosis (index date: first claim for nasal polyps [NPs] between January 1, 2008, and March 31, 2019) and continuous health insurance coverage for ≥180 days preindex (baseline) and postindex were included. Follow-up spanned from index to the earliest of disenrollment, death, or data end. Assessments included patient demographics, comorbidities, and blood eosinophil count at baseline, healthcare resource utilization (HCRU), and costs during follow-up in the overall population and stratified by number of surgeries. Results: Of the 119,357 patients who met the inclusion criteria, 33,748 (28%) had ≥1 surgery during follow-up, among whom 3262 (9.7%) had ≥2 surgeries. At baseline, patients with ≥1 vs no NP surgeries had a greater comorbidity burden; a higher proportion of patients had comorbid asthma (37.8% vs 21.8%) and blood eosinophil count ≥300 cells/µL (42.6% vs 38.1%). During follow-up, patients with NP surgeries had higher all-cause and CRSwNP-related HCRU and costs than patients without NP surgery. All-cause healthcare costs per person per year increased with the number of surgeries during follow-up (no surgery, $10,628; ≥1 surgery, $20,747; ≥2 surgeries, $26,969). Conclusion: Patients with CRSwNP and surgery had a greater disease burden than those without surgery, with higher HCRU and costs, and were more likely to have comorbid conditions (most commonly asthma) and elevated blood eosinophil count, indicating a subset of patients with recalcitrant CRSwNP.

pH-Dependence of Glucose-Dependent Activity of Beta Cell Networks in Acute Mouse Pancreatic Tissue Slice.

Extracellular pH has the potential to affect various aspects of the pancreatic beta cell function. To explain this effect, a number of mechanisms was proposed involving both extracellular and intracellular targets and pathways. Here, we focus on reassessing the influence of extracellular pH on glucose-dependent beta cell activation and collective activity in physiological conditions. To this end we employed mouse pancreatic tissue slices to perform high-temporally resolved functional imaging of cytosolic Ca2+ oscillations. We investigated the effect of either physiological H+ excess or depletion on the activation properties as well as on the collective activity of beta cell in an islet. Our results indicate that lowered pH invokes activation of a subset of beta cells in substimulatory glucose concentrations, enhances the average activity of beta cells, and alters the beta cell network properties in an islet. The enhanced average activity of beta cells was determined indirectly utilizing cytosolic Ca2+ imaging, while direct measuring of insulin secretion confirmed that this enhanced activity is accompanied by a higher insulin release. Furthermore, reduced functional connectivity and higher functional segregation at lower pH, both signs of a reduced intercellular communication, do not necessary result in an impaired insulin release.

Reduction in asthma exacerbation rate after mepolizumab treatment initiation in patients with severe asthma: A real-world database study in Japan.

OBJECTIVE: To investigate the changes in asthma exacerbation, as well as in oral corticosteroid (OCS) use, exacerbation-related healthcare resource utilization (HRU), and healthcare costs before and after mepolizumab treatment initiation in patients with severe asthma who started treatment with mepolizumab in a real-world clinical setting in Japan. METHODS: A retrospective, observational, self-controlled study was conducted in Japan using a hospital-based administrative claims database. Patients who were diagnosed with asthma and who were new users of mepolizumab were included in the study. The primary outcome was the incidence rate of any asthma exacerbation/patient-year during the 12-month period before (baseline period) and after (follow-up period) the first mepolizumab prescription. Secondary outcome measures included the proportion of patients with ≥1 any asthma exacerbation, patients with exacerbation requiring hospitalization, the incidence rate of exacerbations requiring hospitalization/patient-year, the median daily OCS dose (OCS sparing effect), exacerbation-related HRU (hospitalization length, the proportion of patients with emergency visits, and the number of emergency/outpatient visits), and associated costs. RESULTS: Of the 377 patients included, 56.2% were ≥65 years of age. Following the first mepolizumab prescription, incidence rates for any asthma exacerbation were reduced by 40.6% (4.00/patient-year to 2.38/patient-year; the incidence rate ratio [95% confidence interval]: 0.60 [0.53-0.67]; p < 0.0001) from the baseline to follow-up periods. The incidence rate of exacerbations requiring hospitalization was reduced by 55.8% (0.37/patient-year to 0.16/patient-year) from the baseline to follow-up periods. The proportion of patients experiencing any exacerbation decreased from 84.4% to 57.8% and those requiring hospitalization decreased from 23.9% to 10.3% both from the baseline to follow-up periods. The median daily OCS dose decreased by 44.6% (median [interquartile range]: 6.7 [4.7-9.9] mg/day to 3.3 [0.9-5.6] mg/day) from the last baseline quarter to the 4th quarter of the follow-up period. All exacerbation-related HRUs decreased from the baseline to follow-up periods. Inpatient cost reduced by >50% (123,279 Japanese Yen [JPY]/patient-year vs. 57,283 JPY/patient-year), reducing the total cost by 80,716 JPY from the baseline to follow-up periods. CONCLUSION: Mepolizumab was effective in treating patients with severe asthma by reducing the incidence rates of exacerbations and exacerbation requiring hospitalization, OCS dose, exacerbation-related HRU, and cost in routine clinical practice in Japan.

Allosteric coupling between transmembrane segment 4 and the selectivity filter of TALK1 potassium channels regulates their gating by extracellular pH.

Opening of two-pore domain K+ channels (K2Ps) is regulated by various external cues, such as pH, membrane tension, or temperature, which allosterically modulate the selectivity filter (SF) gate. However, how these cues cause conformational changes in the SF of some K2P channels remains unclear. Herein, we investigate the mechanisms by which extracellular pH affects gating in an alkaline-activated K2P channel, TALK1, using electrophysiology and molecular dynamics (MD) simulations. We show that R233, located at the N-terminal end of transmembrane segment 4, is the primary pHo sensor. This residue distally regulates the orientation of the carbonyl group at the S1 potassium-binding site through an interacting network composed of residues on transmembrane segment 4, the pore helix domain 1, and the SF. Moreover, in the presence of divalent cations, we found the acidic pH-activated R233E mutant recapitulates the network interactions of protonated R233. Intriguingly, our data further suggested stochastic coupling between R233 and the SF gate, which can be described by an allosteric gating model. We propose that this allosteric model could predict the hybrid pH sensitivity in heterodimeric channels with alkaline-activated and acidic-activated K2P subunits.

Kv1.1 preserves the neural stem cell pool and facilitates neuron maturation during adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is critical for learning and memory, and aberrant adult neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases [J. T. Gonçalves, S. T. Schafer, F. H. Gage, Cell 167, 897­914 (2016)]. In previous studies, we observed that the delayed-rectifier voltage-gated potassium channel Kv1.1 controls the membrane potential of neural stem and progenitor cells and acts as a brake on neurogenesis during neonatal hippocampal development [S. M. Chou et al., eLife 10, e58779 (2021)]. To assess the role of Kv1.1 in adult hippocampal neurogenesis, we developed an inducible conditional knockout mouse to specifically remove Kv1.1 from adult neural stem cells via tamoxifen administration. We determined that Kv1.1 deletion in adult neural stem cells causes overproliferation and depletion of radial glia-like neural stem cells, prevents proper adult-born granule cell maturation and integration into the dentate gyrus, and moderately impairs hippocampus-dependent contextual fear learning and memory. Taken together, these findings support a critical role for this voltage-gated ion channel in adult neurogenesis.

Carbamazepine promotes surface expression of mutant Kir6.2-A28V ATP-sensitive potassium channels by modulating Golgi retention and autophagy.

Pancreatic ß-cells express ATP-sensitive potassium (KATP) channels, consisting of octamer complexes containing four sulfonylurea receptor 1 (SUR1) and four Kir6.2 subunits. Loss of KATP channel function causes persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a rare but debilitating condition if not treated. We previously showed that the sodium-channel blocker carbamazepine (Carb) corrects KATP channel surface expression defects induced by PHHI-causing mutations in SUR1. In this study, we show that Carb treatment can also ameliorate the trafficking deficits associated with a recently discovered PHHI-causing mutation in Kir6.2 (Kir6.2-A28V). In human embryonic kidney 293 or INS-1 cells expressing this mutant KATP channel (SUR1 and Kir6.2-A28V), biotinylation and immunostaining assays revealed that Carb can increase surface expression of the mutant KATP channels. We further examined the subcellular distributions of mutant KATP channels before and after Carb treatment; without Carb treatment, we found that mutant KATP channels were aberrantly accumulated in the Golgi apparatus. However, after Carb treatment, coimmunoprecipitation of mutant KATP channels and Golgi marker GM130 was diminished, and KATP staining was also reduced in lysosomes. Intriguingly, Carb treatment also simultaneously increased autophagic flux and p62 accumulation, suggesting that autophagy-dependent degradation of the mutant channel was not only stimulated but also interrupted. In summary, our data suggest that surface expression of Kir6.2-A28V KATP channels is rescued by Carb treatment via promotion of mutant KATP channel exit from the Golgi apparatus and reduction of autophagy-mediated protein degradation.

Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polyps.

OBJECTIVE: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. DATA SOURCES: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. STUDY SELECTIONS: Randomized, controlled phase III trials of biologics approved for CRSwNP. RESULTS: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. CONCLUSION: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.

Fragment-Directed Random Mutagenesis by the Reverse Kunkel Method.

Two fundamentally different approaches are routinely used for protein engineering: user-defined mutagenesis and random mutagenesis, each with its own strengths and weaknesses. Here, we invent a unique mutagenesis protocol, which combines the advantages of user-defined mutagenesis and random mutagenesis. The new method, termed the reverse Kunkel method, allows the user to create random mutations at multiple specified regions in a one-pot reaction. We demonstrated the reverse Kunkel method by mimicking the somatic hypermutation in antibodies that introduces random mutations concentrated in complementarity-determining regions. Coupling with the phage display and yeast display selections, we successfully generated dramatically improved antibodies against a model protein and a neurotransmitter peptide in terms of affinity and immunostaining performance. The reverse Kunkel method is especially suitable for engineering proteins whose activities are determined by multiple variable regions, such as antibodies and adeno-associated virus capsids, or whose functional domains are composed of several discontinuous sequences, such as Cas9 and Cas12a.

Potential cross-species correlations in social hierarchy and memory between mice and young children.

Social hierarchy is associated with various phenotypes. Although memory is known to be important for hierarchy formation, the difference in memory abilities between dominant and subordinate individuals remains unclear. In this study, we examined memory performance in mice with different social ranks and found better memory abilities in dominant mice, along with greater long-term potentiation and higher memory-related gene expression in the hippocampus. Daily injection of memory-improving drugs could also enhance dominance. To validate this correlation across species, through inventory, behavioral and event-related potential studies, we identified better memory abilities in preschool children with higher social dominance. Better memory potentially helped children process dominance facial cues and learn social strategies to acquire higher positions. Our study shows a remarkable similarity between humans and mice in the association between memory and social hierarchy and provides valuable insight into social interactions in young animals, with potential implications for preschool education.

Real-life effectiveness of mepolizumab in severe asthma: a systematic literature review.

OBJECTIVE: The efficacy and safety of mepolizumab in patients with severe eosinophilic asthma in randomized controlled trials is well established. Following approval of mepolizumab as add-on therapy for severe eosinophilic asthma in multiple regions worldwide, it is now important to determine its impact in real-world settings in which patients are not subject to stringent eligibility criteria. This systematic literature review assessed published evidence of clinical outcomes, safety, and healthcare resource use among patients with severe asthma receiving mepolizumab in real-world settings. DATA SOURCES: Searches were conducted in Embase, MEDLINE, and MEDLINE In-Process via Ovid. STUDY SELECTIONS: Eligible studies were observational, and enrolled ≥10 patients with asthma who received mepolizumab 100 mg subcutaneously. Data extracted included annualized exacerbation rate, mean daily oral corticosteroid (OCS) dose, proportion of patients using OCS, several measures of lung function, patient-reported asthma control and health-related quality of life (HRQoL), safety, and economic burden. RESULTS: Twenty-three articles (22 unique studies; 2,040 patients with severe asthma on mepolizumab) were identified. Mepolizumab use was associated with a reduction in annualized exacerbation rates (requiring OCS) of 54-97% (p < 0.05 in all studies), reduced mean/median daily OCS doses, and OCS discontinuation during follow-up (27-84% of patients). Improvements in lung function, asthma control, and HRQoL were also observed. The most commonly reported adverse events included headache and arthralgia; discontinuation of mepolizumab due to adverse events occurred in 0-10.6% of patients. CONCLUSION: Findings show that patients with severe asthma consistently demonstrate clinically relevant benefits with mepolizumab treatment in a real-world setting.Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Cost-effectiveness analysis of anti-IL-5 therapies of severe eosinophilic asthma in Spain.

AIM: To analyse the cost-effectiveness of MEP with standard of care (SoC) versus other anti-IL-5 therapies approved for the treatment of severe eosinophilic asthma (SEA) patients, within the Spanish National Health System (NHS) perspective. METHODS: A Markov model with a 4-week cycle length was used to compare MEP with BEN and RES as therapies added to SoC in the management of SEA, in terms of cost per QALY gained and incremental cost-effectiveness ratio (ICER). Costs (€2019) were obtained from public sources, while utilities and transition probabilities were retrieved from literature, e.g. network meta-analysis. Continuation criteria for biological treatment and reduction of oral corticosteroids (OCS) was set at 50% minimum reduction of exacerbation rate. Adverse events related to chronic OCS use included diabetes, osteoporosis, cataracts, acute myocardial infarct, and peptic ulcer. The analysis was performed over a 5-year time horizon from the National Healthcare System (NHCS) perspective, with a yearly discount rate of 3% applied to both costs and QALYs. Probabilistic sensitivity analysis and univariate deterministic sensitivity analysis were performed to address uncertainty around the cost-effectiveness results. RESULTS: On top of SoC, the model indicates that MEP is dominant (lower cost, higher benefit) compared to BEN and RES: For BEN and RES, respectively, treatment with MEP had a point estimate of 0.076 and 0.075 additional QALYs, and savings of €3,173.47 and €7,772.95 per patient. The findings were robust to variation as estimated using sensitivity analysis. CONCLUSIONS: MEP is a cost-effective treatment in comparison with BEN and RES added to SoC for patients with SEA in the Spanish setting.

Kv1.1 channels regulate early postnatal neurogenesis in mouse hippocampus via the TrkB signaling pathway.

In the postnatal brain, neurogenesis occurs only within a few regions, such as the hippocampal sub-granular zone (SGZ). Postnatal neurogenesis is tightly regulated by factors that balance stem cell renewal with differentiation, and it gives rise to neurons that participate in learning and memory formation. The Kv1.1 channel, a voltage-gated potassium channel, was previously shown to suppress postnatal neurogenesis in the SGZ in a cell-autonomous manner. In this study, we have clarified the physiological and molecular mechanisms underlying Kv1.1-dependent postnatal neurogenesis. First, we discovered that the membrane potential of neural progenitor cells is highly dynamic during development. We further established a multinomial logistic regression model for cell-type classification based on the biophysical characteristics and corresponding cell markers. We found that the loss of Kv1.1 channel activity causes significant depolarization of type 2b neural progenitor cells. This depolarization is associated with increased tropomyosin receptor kinase B (TrkB) signaling and proliferation of neural progenitor cells; suppressing TrkB signaling reduces the extent of postnatal neurogenesis. Thus, our study defines the role of the Kv1.1 potassium channel in regulating the proliferation of postnatal neural progenitor cells in mouse hippocampus.