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.

Logistical challenges of CAR T-cell therapy in non-Hodgkin lymphoma: a survey of healthcare professionals.

Aim: Characterize the logistical challenges faced by healthcare professionals (HCPs), patients and caregivers during the chimeric antigen receptor T-cell (CAR T) treatment process for non-Hodgkin lymphoma patients.Materials & methods: HCPs in the US and UK experienced with CAR T administration participated in interviews and completed a web-based survey.Results: A total of 133 (80 US, 53 UK) HCPs participated. Two or more logistical challenges were identified by ≥60% of respondents across all stages of the CAR T process. Commonly reported challenges were lengthy waiting periods, administrative and payer-related barriers, limited healthcare capacity, caregiver support and (particularly in the US) patient out-of-pocket costs.Conclusion: The CAR T treatment process presents numerous challenges, highlighting an unmet need for more convenient therapies.

Chimeric antigen receptor T-cell (CAR T) therapy is a new treatment for patients with non-Hodgkin lymphoma that have not responded to other types of treatment. CAR T therapy uses a person's own immune cells (T cells), which are modified in a laboratory to attack cancer cells. While CAR T therapy has the potential to be effective, there are challenges associated with the treatment process. In this study, we surveyed 133 healthcare professionals (HCPs) in the United States and United Kingdom to understand their experiences with logistical challenges involved in navigating the CAR T process. More than 60% of participants identified two or more logistical challenges at every stage of the CAR T treatment process. The most commonly reported challenges included long waiting periods, limited room at hospitals, availability of caregivers to support patients and issues related to out-of-pocket costs, travel and lodging for patients who are treated at specialized centers. In the United States, challenges related to insurance coverage and out-of-pocket costs for patients were highlighted. More than half of HCPs reported that patients' cancer getting worse while waiting to receive CAR T was a reason why patients may not proceed to treatment. While operational improvements might address some challenges in the CAR T treatment process, these findings highlight the need for more convenient, readily available and easily administered therapies for patients with non-Hodgkin lymphoma.

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.

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.

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.

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.

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.

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 .

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.

Traditional Chinese medicine symptom normalization approach leveraging hierarchical semantic information and text matching with attention mechanism.

Traditional Chinese medicine (TCM) symptom normalization is difficult because the challenges of the symptoms having different literal descriptions, one-to-many symptom descriptions and different symptoms sharing a similar literal description. We propose a novel two-step approach utilizing hierarchical semantic information that represents the functional characteristics of symptoms and develop a text matching model that integrates hierarchical semantic information with an attention mechanism to solve these problems. In this study, we constructed a symptom normalization dataset and a TCM normalization symptom dictionary containing normalization symptom words, and assigned symptoms into 24 classes of functional characteristics. First, we built a multi-label text classifier to isolate the hierarchical semantic information from each symptom description and count the corresponding normalization symptoms and filter the candidate set. Then we designed a text matching model of mixed multi-granularity language features with an attention mechanism that utilizes the hierarchical semantic information to calculate the matching score between the symptom description and the normalization symptom words. We compared our approach with other baselines on real-world data. Our approach gives the best performance with a Hit@ 1, 3, and 10 of 0.821, 0.953, and 0.993, respectively, and a MeanRank of 1.596, thus outperforming significantly regarding the symptom normalization task. We developed an approach for the TCM symptom normalization task and demonstrated its superior performance compared with other baselines, indicating the promise of this research direction.

Real-world mepolizumab in the prospective severe asthma REALITI-A study: initial analysis.

INTRODUCTION: Efficacy of mepolizumab, an anti-interleukin-5 monoclonal antibody, was demonstrated in randomised controlled trials; data on its real-world impact in routine clinical practice are starting to emerge. We assessed the effectiveness and safety of mepolizumab prescribed for patients in the real world. METHODS: REALITI-A is a global, prospective, observational cohort study, collecting data from routine healthcare visits from patients with asthma. Patients newly prescribed mepolizumab for severe asthma with 12 months of relevant medical history pre-mepolizumab (collected retrospectively) were enrolled. An initial analysis of data from early initiators who had completed 1 year of follow-up (as of February 28, 2019) was conducted. The primary objective was to compare the rate of clinically significant exacerbations (requiring oral corticosteroids (OCS) and/or hospitalisation and/or emergency department visit) before and after mepolizumab; exacerbations requiring hospitalisation and/or emergency department visit and change in maintenance OCS use were secondary objectives. Treatment-related adverse events were reported. RESULTS: Overall, 368 mepolizumab-treated patients were included. Rates of clinically significant exacerbations were reduced by 69% from 4.63 per person per year pre-treatment to 1.43 per person per year during follow-up (p<0.001), as were those requiring hospitalisation and/or emergency department visit (from 1.14 to 0.27 per person per year; 77% reduction). In 159 patients with maintenance OCS dose data available during the pre-treatment period, median daily dose decreased from 10.0 (pre-treatment) to 5.0 mg·day-1 by week 21-24 of follow-up, sustained until week 53-56. No new safety signals were reported. CONCLUSION: These data demonstrate that the effectiveness of mepolizumab is consistent with clinical trial results under real-world settings, with significant reductions in exacerbations and daily maintenance OCS dose.

Spindle-F Is the Central Mediator of Ik2 Kinase-Dependent Dendrite Pruning in Drosophila Sensory Neurons.

During development, certain Drosophila sensory neurons undergo dendrite pruning that selectively eliminates their dendrites but leaves the axons intact. How these neurons regulate pruning activity in the dendrites remains unknown. Here, we identify a coiled-coil protein Spindle-F (Spn-F) that is required for dendrite pruning in Drosophila sensory neurons. Spn-F acts downstream of IKK-related kinase Ik2 in the same pathway for dendrite pruning. Spn-F exhibits a punctate pattern in larval neurons, whereas these Spn-F puncta become redistributed in pupal neurons, a step that is essential for dendrite pruning. The redistribution of Spn-F from puncta in pupal neurons requires the phosphorylation of Spn-F by Ik2 kinase to decrease Spn-F self-association, and depends on the function of microtubule motor dynein complex. Spn-F is a key component to link Ik2 kinase to dynein motor complex, and the formation of Ik2/Spn-F/dynein complex is critical for Spn-F redistribution and for dendrite pruning. Our findings reveal a novel regulatory mechanism for dendrite pruning achieved by temporal activation of Ik2 kinase and dynein-mediated redistribution of Ik2/Spn-F complex in neurons.

Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation.

Alzheimer's disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aß and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis.

N-linked glycosylation of Kv1.2 voltage-gated potassium channel facilitates cell surface expression and enhances the stability of internalized channels.

KEY POINTS: Kv1.2 and related voltage-gated potassium channels have a highly conserved N-linked glycosylation site in the first extracellular loop, with complex glycosylation in COS-7 cells similar to endogenous Kv1.2 glycosylation in hippocampal neurons. COS-7 cells expressing Kv1.2 show a crucial role of this N-linked glycosylation in the forward trafficking of Kv1.2 to the cell membrane. Although both wild-type and non-glycosylated mutant Kv1.2 channels that have reached the cell membrane are internalized at a comparable rate, mutant channels are degraded at a faster rate. Treatment of wild-type Kv1.2 channels on the cell surface with glycosidase to remove sialic acids also results in the faster degradation of internalized channels. Glycosylation of Kv1.2 is important with respect to facilitating trafficking to the cell membrane and enhancing the stability of channels that have reached the cell membrane. ABSTRACT: Studies in cultured hippocampal neurons and the COS-7 cell line demonstrate important roles for N-linked glycosylation of Kv1.2 channels in forward trafficking and protein degradation. Kv1.2 channels can contain complex N-linked glycans, which facilitate cell surface expression of the channels. Additionally, the protein stability of cell surface-expressed Kv1.2 channels is affected by glycosylation via differences in the degradation of internalized channels. The present study reveals the importance of N-linked complex glycosylation in boosting Kv1.2 channel density. Notably, sialic acids at the terminal sugar branches play an important role in dampening the degradation of Kv1.2 internalized from the cell membrane to promote its stability.

The Choice of Analytical Strategies in Inverse-Probability-of-Treatment-Weighted Analysis: A Simulation Study.

We sought to explore the impact of intention to treat and complex treatment use assumptions made during weight construction on the validity and precision of estimates derived from inverse-probability-of-treatment-weighted analysis. We simulated data assuming a nonexperimental design that attempted to quantify the effect of statin on lowering low-density lipoprotein cholesterol. We created 324 scenarios by varying parameter values (effect size, sample size, adherence level, probability of treatment initiation, associations between low-density lipoprotein cholesterol and treatment initiation and continuation). Four analytical approaches were used: 1) assuming intention to treat; 2) assuming complex mechanisms of treatment use; 3) assuming a simple mechanism of treatment use; and 4) assuming invariant confounders. With a continuous outcome, estimates assuming intention to treat were biased toward the null when there were nonnull treatment effect and nonadherence after treatment initiation. For each 1% decrease in the proportion of patients staying on treatment after initiation, the bias in estimated average treatment effect increased by 1%. Inverse-probability-of-treatment-weighted analyses that took into account the complex mechanisms of treatment use generated approximately unbiased estimates. Studies estimating the actual effect of a time-varying treatment need to consider the complex mechanisms of treatment use during weight construction.

Changes in body anthropometry and composition in obese adolescents in a lifestyle intervention program.

PURPOSE: Impact of lifestyle modification on obesity control during adolescence, a period of significant physical growth and development, is less quantitatively evaluated. Therefore, we investigated the impact of changes in reported energy intake and physical activity on anthropometrics and body composition in adolescents. METHODS: Participants were obese adolescents aged 11-18 years. All of them have a body mass index (BMI) ≥ 95th percentile specific for age and gender according to the 2000 CDC Growth Charts. The intervention consists of supervised physical activity, structured nutrition education and dietary modification, and behavioral support in 6 months. Hundred and forty-five obese adolescents completed the study. RESULTS: Compared to baseline, significant reductions in body weight (-1.4 kg, p < 0.001) and BMI (-0.1 kg/m(2), p < 0.001) were observed at 6 months. When compared to expected growth trajectories on the 2000 CDC Growth Charts, body weight and BMI were reduced by 3.6 kg and 1.5 kg/m(2), respectively, in boys and 5.6 kg and 1.9 kg/m(2) in girls. Age was inversely associated with changes in weight (ß = -1.48 kg, p < 0.01) and BMI (ß = -0.32 kg/m(2), p = 0.03). There was a dose-response relationship between reduction in energy intake and weight loss. A decrease of 100 kcal/day was significantly associated with reductions in body weight 0.30 kg, BMI 0.09 kg/m(2), and BMI Z score 0.01 (all p < 0.01). Physical activity was not significantly associated with changes in anthropometrics or body composition. CONCLUSIONS: Reduction in energy intake was a significant predictor of obesity reduction in these adolescents. A quantitative evaluation of adolescent weight loss programs should account for natural growth and development.

Application of marginal structural models in pharmacoepidemiologic studies: a systematic review.

PURPOSE: We systematically reviewed pharmacoepidemiologic studies published in 2012 that used inverse probability weighted (IPW) estimation of marginal structural models (MSM) to estimate the effect from a time-varying treatment. METHODS: Potential studies were retrieved through a citation search within Web of Science and a keyword search within PubMed. Eligibility of retrieved studies was independently assessed by at least two reviewers. One reviewer performed data extraction, and a senior epidemiologist confirmed the extracted information for all eligible studies. RESULTS: Twenty pharmacoepidemiologic studies were eligible for data extraction. The majority of reviewed studies did not report whether the positivity assumption was checked. Six studies performed intention-to-treat analyses, but none of them reported adherence levels after treatment initiation. Eight studies chose an as-treated analytic strategy, but only one of them reported modeling the multiphase of treatment use. Almost all studies performing as-treated analyses chose the most recent treatment status as the functional form of exposure in the outcome model. Nearly half of the studies reported that the IPW estimate was substantially different from the estimate derived from a standard regression model. CONCLUSIONS: The use of IPW method to control for time-varying confounding is increasing in medical literature. However, reporting of the application of the technique is variable and suboptimal. It may be prudent to develop best practices in reporting complex methods in epidemiologic research.

Vitamin d deficiency in children with cancer.

A limited number of small studies have examined the vitamin D status of pediatric oncology patients, and the results indicate an increased prevalence of hypovitaminosis. We conducted a cross-sectional study with the primary aim of describing the vitamin D status of our pediatric cancer patients and any associations with demographic characteristics. Our secondary aim was to compare this prevalence to that of a healthy population. We collected data on children seen in our clinic and determined the overall prevalence of hypovitaminosis. We then compared this prevalence to that of healthy populations described in the literature. The prevalence of hypovitaminosis in our study population was 72%. Forty-three percent of our patients were considered deficient with 8% being severely deficient. Our analysis revealed a significant association between the outcome and age in that patients 6 years and above were more likely to have hypovitaminosis after adjustment for other characteristics (AOR = 3.23; 95% CI, 1.11-9.40). When compared with a healthy pediatric population, our patients had a significantly higher prevalence of hypovitaminosis (P-value = 0.003). Vitamin D deficiency is very common in children with cancer, representing a subpopulation of high-risk patients that could benefit most from early detection and supplementation.

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.

Comparisons of treatment outcomes of epcoritamab versus chemoimmunotherapy, polatuzumab-based regimens, tafasitamab-based regimens, or chimeric antigen receptor T-cell therapy, in third-line or later relapsed/refractory large B-cell lymphoma.

Many therapies are available for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥ 2 lines of therapy, albeit with scant evidence on the comparative effectiveness of these therapies. This study used inverse probability of treatment weighting to indirectly compare treatment outcomes of epcoritamab from the EPCORE NHL-1 trial with individual patient data from clinical practice cohorts treated with chemoimmunotherapy (CIT) and novel therapies (polatuzumab-based regimens, tafasitamab-based regimens, and chimeric antigen receptor T-cell [CAR T] therapies) for third-line or later R/R large B-cell lymphoma (LBCL) and DLBCL. In this analysis, epcoritamab demonstrated significantly better response rates and overall survival rates than CIT, polatuzumab-based regimens, and tafasitamab-based regimens. No statistically significant differences in response rates or survival were found for epcoritamab compared with CAR T in R/R LBCL.