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Background: Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) is the second-most common cause of CMS. However, data on pharmacological treatments are limited. Objective: In this study, we reviewed related reports to determine the most appropriate pharmacological strategy for CMS caused by COLQ mutations. A literature review and meta-analysis were also performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched to identify studies published in English before July 22, 2022. Results: A total of 42 studies including 164 patients with CMS due to 72 different COLQ mutations were selected for evaluation. Most studies were case reports, and none were randomized clinical trials. Our meta-analysis revealed evidence that β-adrenergic agonists, including salbutamol and ephedrine, can be used as first-line pharmacological treatments for CMS patients with COLQ mutations, as 98.7% of patients (74/75) treated with β-adrenergic agonists showed positive effects. In addition, AChEIs should be avoided in CMS patients with COLQ mutations, as 90.5% (105/116) of patients treated with AChEIs showed either no or negative effects. Conclusion: (1) β-adrenergic agonist therapy is the first pharmacological strategy for treating CMS with COLQ mutations. (2) AChEIs should be avoided in patients with CMS with COLQ mutations.

This study analyzed the impact of COVID-19 outbreak and targeted required reserve ratio cut policy on stock returns of Chinese listed companies. This paper uses the data of 3,449 A-share listed companies from February 3, 2020 to December 31, 2020 for research, the empirical results showed that stock prices of private enterprises with stronger debt-paying ability and looser financing constraints, and state-owned enterprises with less supply chain credit risks performed better, in the central and western regions, enterprises with stronger solvency and looser financing constraints have better stock price performance during the early stages of pandemic. After the implementation of the targeted RRR cut policy, the stock prices of enterprises with poor solvency, private enterprises, and enterprises in central and western regions with strong financing constraints, state-owned enterprises, and enterprises in eastern region with high credit risks all showed significant reversals, and the stock prices reflected the effect of the targeted RRR cut policy in the short and medium term. Over time, the pandemic has been controlled, and the resumption of work and production has freed most enterprises from financial difficulties. However, due to sporadic outbreaks, large private enterprises and eastern enterprises with strong risk resistance and loose financing constraints enjoy better stock price performance. This study is helpful for enterprises to understand the value of financial flexibility and solvency and provides a reference for enterprises to make financial decisions: how to balance the benefits and costs of solvency.

Background: Malnutrition is a severe but modifiable risk factor for cancers. However, the relationship between malnutrition and the survival of patients with brain metastases has not been fully revealed. We aimed to evaluate the prevalence of malnutrition and assess its prognostic value on patients with brain metastases Methods: We retrospectively recruited 2,633 patients with brain metastases between January 2014 and September 2020. Three malnutrition scores were used to evaluate patients’ malnutrition status at their first admission, including controlling nutritional status, the nutritional risk index, and the prognostic nutritional index. The association between malnutrition and overall survival (OS) was estimated. Results: The three malnutrition scores were associated with each other and with body mass index (BMI). Malnutrition assessed by any of the three scores was significantly associated with poor OS. All three malnutrition scores were better indicators than BMI, and adding malnutrition scores to the Graded Prognostic Assessment (GPA) scoring system could significantly improve the accuracy of prognosis prediction. Conclusions: Malnutrition monitoring using any of the three malnutrition scores on patients’ first admission could be a better survival indicator for patients with brain metastases compared with BMI alone. Impact: Malnutrition is a more significant indicator of survival stratification compared with BMI. Adding malnutrition to the GPA score system achieves better survival prediction.

Study of genomic aberrations leading to immortalization of epithelial cells has been technically challenging due to the lack of isogenic models. To address this, we used healthy primary breast luminal epithelial cells of different genetic ancestry and their hTERT-immortalized counterparts to identify transcriptomic changes associated with immortalization. Elevated expression of TONSL (Tonsoku-like, DNA repair protein) was identified as one of the earliest events during immortalization. TONSL, which is located on chromosome 8q24.3, was found to be amplified in approximately 20% of breast cancers. TONSL alone immortalized primary breast epithelial cells and increased telomerase activity, but overexpression was insufficient for neoplastic transformation. However, TONSL-immortalized primary cells overexpressing defined oncogenes generated estrogen receptor–positive adenocarcinomas in mice. Analysis of a breast tumor microarray with approximately 600 tumors revealed poor overall and progression-free survival of patients with TONSL-overexpressing tumors. TONSL increased chromatin accessibility to pro-oncogenic transcription factors, including NF-κB and limited access to the tumor-suppressor p53. TONSL overexpression resulted in significant changes in the expression of genes associated with DNA repair hubs, including upregulation of several genes in the homologous recombination (HR) and Fanconi anemia pathways. Consistent with these results, TONSL-overexpressing primary cells exhibited upregulated DNA repair via HR. Moreover, TONSL was essential for growth of TONSL-amplified breast cancer cell lines in vivo, and these cells were sensitive to TONSL–FACT complex inhibitor CBL0137. Together, these findings identify TONSL as a regulator of epithelial cell immortalization to facilitate cancer initiation and as a target for breast cancer therapy. Significance: The chr.8q24.3 amplicon-resident gene TONSL is upregulated during the initial steps of tumorigenesis to support neoplastic transformation by increasing DNA repair and represents a potential therapeutic target for treating breast cancer.

Background Dynamic interpersonal therapy (DIT) is a brief, structured psychodynamic psychotherapy with demonstrated efficacy in treating major depressive disorder (MDD). The aim of the study was to determine whether DIT is an acceptable and efficacious treatment for MDD patients in China. Method Patients were randomized to 16-week treatments with either DIT plus antidepressant medication (DIT + ADM; n = 66), general supportive therapy plus antidepressant medication (GST + ADM; n = 75) or antidepressant medication alone (ADM; n = 70). The Hamilton Depression Rating Scale (HAMD) administered by blind raters was the primary efficacy measure. Assessments were completed during the acute 16-week treatment and up to 12-month posttreatment. Results The group × time interaction was significant for the primary outcome HAMD (F = 2.900, df1 = 10, df2 = 774.72, p = 0.001) in the acute treatment phase. Pairwise comparisons showed a benefit of DIT + ADM over ADM at weeks 12 [least-squares (LS) mean difference = −3.161, p = 0.007] and 16 (LS mean difference = −3.237, p = 0.004). Because of the unexpected high attrition during the posttreatment follow-up phase, analyses of follow-up data were considered exploratory. Differences between DIT + ADM and ADM remained significant at the 1-, 6-, and 12-month follow-up (ps range from 0.001 to 0.027). DIT + ADM had no advantage over GST + ADM during the acute treatment phase. However, at the 12-month follow-up, patients who received DIT remained less depressed. Conclusions Acute treatment with DIT or GST in combination with ADM was similarly efficacious in reducing depressive symptoms and yielded a better outcome than ADM alone. DIT may provide MDD patients with long-term benefits in symptom improvement but results must be viewed with caution.

Objectives Fluoxetine has been used as the first line for the therapy of depression. However, lack of therapeutic efficacy and time lag still limit the application of fluoxetine. Gap junction dysfunction is a potentially novel pathogenic mechanism for depression. To clarify the mechanism underlying these limitations, we investigated whether gap junction was related to the antidepressant effects of fluoxetine. Methods and key findings After chronic unpredictable stress (CUS), animals showed decreases in gap junction intracellular communication (GJIC). Treatment with fluoxetine 10 mg/kg significantly improved GJIC and anhedonia of rats until six days. These results indicated that fluoxetine improved gap junction indirectly. Furthermore, to test the role of gap junction on antidepressant effects of fluoxetine, we blocked gap junction using carbenoxolone (CBX) infusion in the prefrontal cortex. CBX dampened fluoxetine-induced decrease in immobility time of mice in tail suspension test (TST). Conclusions Our study suggested that gap junction dysfunction blocks antidepressant effects of fluoxetine, contributing to understanding the mechanism underlying the time lag of fluoxetine.

Background: The impact of diet on breast cancer survival remains inconclusive. We assessed associations of all-cause mortality with adherence to the four diet quality indices: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH). Methods: Dietary intake data were evaluated for 6,157 North American women enrolled in the Breast Cancer Family Registry who had been diagnosed with invasive breast cancer from 1993 to 2011 and were followed through 2018. Pre-diagnosis (n = 4,557) or post-diagnosis (n = 1,600) dietary intake was estimated through a food frequency questionnaire. During a median follow-up time of 11.3 years, 1,265 deaths occurred. Cox proportional hazards models were used to estimate multivariable-adjusted HR and 95% confidence intervals (CI). Results: Women in the highest versus lowest quartile of adherence to the HEI-2015, AHEI, aMED, and DASH indices had a lower risk of all-cause mortality. HR (95% CI) were 0.88 (0.74–1.04; Ptrend = 0.12) for HEI-2015; 0.82 (0.69–0.97; Ptrend = 0.02) for AHEI; 0.73 (0.59–0.92; Ptrend = 0.02) for aMED; and 0.78 (0.65–0.94; Ptrend = 0.006) for DASH. In subgroup analyses, the associations with higher adherence to the four indices were similar for pre- or post-diagnosis dietary intake and were confined to women with a body mass index Conclusions: Higher adherence to the HEI-2015, AHEI, aMED, and DASH indices was associated with lower mortality among women with breast cancer. Impact: Adherence to a healthy diet may improve survival of women with breast cancer.

Prior evidence suggests that physical activity may reduce the risk of multiple diseases and mortality. However, whether and how physical activity affects the aging process remains largely unexplored. We included 284 479 UK Biobank participants and computed leukocyte telomere length (LTL) deviation (ie, the difference between genetically determined and observed LTL) and biological age acceleration (defined as the discrepancy between the phenotypic age of a person and the average phenotypic age in the cohort of individuals with the same age and sex) as the indexes for aging acceleration. Linear and logistic models were used to estimate the associations of self-reported physical activity items and patterns (identified by principal component analysis), as well as accelerometer-assessed physical activity, with aging acceleration. Analyses of physical activity patterns indicated, a higher level of adherence to activity patterns predominated by strenuous sports, other exercises, walking for pleasure, heavy and light housework, and public transportation use was associated with a lower risk of aging acceleration, whereas a higher level of adherence to patterns predominated by job-related activities was associated with a higher risk of aging acceleration. Analysis among 62 418 participants with accelerometer-measured physical activity corroborated these results. Physical activity, such as strenuous sports and other exercises in leisure time and the use of public transportation, was associated with reduced biological aging. Besides highlighting the importance of engaging in physical activity for healthy aging, our results provide further evidence for the beneficial effect of physical activity on the telomere attrition process.

OBJECTIVE Produce prescriptions have shown promise in improving diabetes care, although most studies have used small samples or lacked controls. Our objective was to evaluate the impacts of a produce prescription program on glycemic control for patients with diabetes. RESEARCH DESIGN AND METHODS Participants included a nonrandom enrollment of 252 patients with diabetes who received a produce prescription and 534 similar control participants from two clinics in Hartford, Connecticut. The start of the COVID-19 pandemic in March 2020 coincided with program implementation. Produce prescription enrollees received vouchers ($60 per month) for 6 months to purchase produce at grocery retail. Controls received usual care. The primary outcome was change in glycated hemoglobin (HbA1c) between treatment and control at 6 months. Secondary outcomes included 6-month changes in systolic (SBP) and diastolic blood pressure (DBP), BMI, hospitalizations, and emergency department admissions. Longitudinal generalized estimating equation models, weighted with propensity score overlap weights, assessed changes in outcomes over time. RESULTS At 6 months, there was no significant difference in change in HbA1c between treatment and control groups, with a difference of 0.13 percentage points (95% CI −0.05, 0.32). No significant difference was observed for change in SBP (3.85 mmHg; −0.12, 7.82), DBP (−0.82 mmHg; −2.42, 0.79), or BMI (−0.22 kg/m2; −1.83, 1.38). Incidence rate ratios for hospitalizations and emergency department visits were 0.54 (0.14, 1.95) and 0.53 (0.06, 4.72), respectively. CONCLUSIONS A 6-month produce prescription program for patients with diabetes, implemented during the onset of the COVID-19 pandemic, was not associated with improved glycemic control.

Acetaminophen (AP) is a commonly used drug that has been detected in groundwater systems in many countries, and has received much attention from researchers in recent years due to its potential environmental impact. In this research, uniformly distributed boron nitride quantum dots (BNQDs) were prepared by a simple ultrasound-solvothermal method. Electrochemical luminescence (ECL) spectroscopy confirmed that BNQDs can act as an effective coreactant to create excellent efficiency in amplifying the ECL intensity of ruthenium-based ECL system. Based on the excited state of Ru bpy 3 2 + ∗ and the energy transfer quenching of AP oxidation products in the luminescent system, an AP concentration-quenched drug sensor was successfully constructed. For this sensor, a wide linear dynamic range and low detection limits (5.0 × 10−7−1.0 × 10−5 mol/L and 4.8 × 10−9 mol/L, respectively) were achieved. This ECL drug sensor has excellent performance in the accurate determination of AP content, relieving the stress of the previous AP detection process, and has good reproducibility and recovery in actual sample measurements.

Objective: Amyotrophic lateral sclerosis (ALS) is a clinically heterogenous disease, typically presenting with focal motor weakness that eventually generalizes. Weather there is a correlation between focal motor weakness and metabolic alterations in specific areas of the brain has not been thoroughly explored. This study aims to systematically investigate this by using fluorodeoxyglucose-positron emission tomography (FDG-PET), including longitudinal imaging. Methods: This observational imaging study included 131 ALS patients diagnosed and examined with FDG-PET at the ALS Clinical Research Center at the Karolinska University Hospital in Stockholm, Sweden. Thirteen ALS patients had a second scan and were analyzed longitudinally. The findings were compared to 39 healthy controls examined at the University Medical Center of Gröningen, the Netherlands. Results: There was a general pattern of brain metabolic alterations consistent with previously reported findings in ALS, namely hypometabolism in frontal regions and hypermetabolism in posterior regions. A higher symptom burden was associated with increased hypometabolism and decreased hypermetabolism. However, there was no clear correlation between focal motor weakness and specific metabolic alterations, neither when analyzing focal motor weakness with concomitant upper motor neuron signs or when including all focal motor weakness. Longitudinal FDG-PET imaging showed inconsistent results with little correlation between progression of motor weakness and metabolic alterations. Conclusion: Our results support the disease model of ALS as a diffuse process since no clear correlation was seen between focal motor weakness and specific metabolic alterations. However, there is need for further research on a larger number of patients, particularly including longitudinal imaging.

Soluble microbial products (SMPs), dissolved organic matter excreted by activated sludge, can interact with antibiotics in wastewater and natural water bodies. Interactions between SMPs and antibiotics can influence antibiotic migration, transformation, and toxicity but the mechanisms involved in such interactions are not fully understood. In this study, integrated spectroscopy approaches were used to investigate the mechanisms involved in interactions between SMPs and a representative antibiotic, trimethoprim (TMP), which has a low biodegradation rate and has been detected in wastewater. The results of liquid chromatography-organic carbon detection-organic nitrogen detection indicated that the SMPs used in the study contained 15% biopolymers and 28% humic-like substances (based on the total dissolved organic carbon concentration) so would have contained sites that could interact with TMP. A linear relationship of fluorescent intensities of tryptophan protein-like substances in SMP was observed (R

The ongoing COVID-19 pandemic has had an unprecedented impact on the lives of people globally and is expected to have profound effects on mental health. Here we aim to describe the mental health burden experienced in Sweden using baseline data of the Omtanke2020 Study.We analysed self-reported, cross-sectional baseline data collected over a 12-month period (June 9, 2020-June 8, 2021) from the Omtanke2020 Study including 27,950 adults in Sweden. Participants were volunteers or actively recruited through existing cohorts and, after providing informed consent, responded to online questionnaires on socio-demographics, mental and physical health, as well as COVID-19 infection and impact. Poisson regression was fitted to assess the relative risk of demonstrating high level symptoms of depression, anxiety, and COVID-19 related distress.The proportion of persons with high level of symptoms was 15.6 %, 9.5 % and 24.5 % for depression, anxiety, and COVID-19 specific post-traumatic stress disorder (PTSD), respectively. Overall, 43.4 % of the participants had significant, clinically relevant symptoms for at least one of the three mental health outcomes and 7.3 % had significant symptoms for all three outcomes. We also observed differences in the prevalence of these outcomes across strata of sex, age, recruitment type, COVID-19 status, region, and seasonality.While the proportion of persons with high mental health burden remains higher than the ones reported in pre-pandemic publications, our estimates are lower than previously reported levels of depression, anxiety, and PTSD during the pandemic in Sweden and elsewhere.

Rapid detection of a threat or its symbol (e.g., fearful face), whether visible or invisible, is critical for human survival. This function is suggested to be enabled by a subcortical pathway to the amygdala independent of the cortex. However, conclusive electrophysiological evidence in humans is scarce. Here, we explored whether the amygdala can rapidly encode invisible fearful faces. We recorded intracranial electroencephalogram (iEEG) responses in the human (both sexes) amygdala to faces with fearful, happy, and neutral emotions rendered invisible by backward masking. We found that a short-latency intracranial event-related potential (iERP) in the amygdala, beginning 88 ms poststimulus onset, was preferentially evoked by invisible fearful faces relative to invisible happy or neutral faces. The rapid iERP exhibited selectivity to the low spatial frequency (LSF) component of the fearful faces. Time-frequency iEEG analyses further identified a rapid amygdala response preferentially for LSF fearful faces at the low gamma frequency band, beginning 45 ms poststimulus onset. In contrast, these rapid responses to invisible fearful faces were absent in cortical regions, including early visual areas, the fusiform gyrus, and the parahippocampal gyrus. These findings provide direct evidence for the existence of a subcortical pathway specific for rapid fear detection in the amygdala and demonstrate that the subcortical pathway can function without conscious awareness and under minimal influence from cortical areas.SIGNIFICANCE STATEMENTAutomatic detection of biologically relevant stimuli, such as threats or dangers, has remarkable survival value. Here, we provide direct intracranial electrophysiological evidence that the human amygdala preferentially responds to fearful faces at a rapid speed, despite the faces being invisible. This rapid, fear-selective response is restricted to faces containing low spatial frequency information transmitted by magnocellular neurons and does not appear in cortical regions. These results support the existence of a rapid subcortical pathway independent of cortical pathways to the human amygdala.

New remedies are required for the treatment of diabetic neuropathic pain (DNP) due to insufficient efficacy of available therapies. Here, we used chemogenetic approaches combined with in vivo pharmacology to elucidate the role of basolateral amygdala (BLA) astrocytes in DNP pathogenesis and provide new insights into therapeutic strategies for DNP.A streptozotocin-induced DNP model was established. Designer receptors exclusively activated by designer drugs (DREADDs) were used to regulate astrocyte activity. Mechanical hyperalgesia was assessed using the electronic von Frey test. Anxiety-like behaviors were detected using open field and elevated plus maze tests. Astrocytic activity was detected by immunofluorescence, and cytokine content was determined by ELISA.BLA astrocytes were regulated by DREADDs, and inhibition of BLA astrocytes attenuated mechanical allodynia and pain-related negative emotions in DNP rats. Contrastively, temporary activation of BLA astrocytes induced allodynia without anxious behaviors in naive rats. In addition, koumine (KM) alleviated mechanical allodynia and anxiety-like behaviors in DNP rats, inhibited the activation of BLA astrocytes and suppressed the inflammatory response. Furthermore, persistent activation of BLA astrocytes through chemogenetics mimicked chronic pain, and KM alleviated its pain hypersensitivity and anxiety-like behaviors.DREADDs bidirectionally regulate the activity of BLA astrocytes, which proves for the first time the role of BLA astrocyte activation in the pathogenesis of DNP and represents a novel therapeutic strategy for DNP. KM ameliorates DNP, perhaps by inhibiting the activation of BLA astrocytes and reveal KM as a potential candidate for treating DNP.

Ischemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischemic stroke was performed on 1,333 individuals with SCD from Brazil (178 cases, 1,155 controls). Via a novel Cox proportional hazards analysis, we searched for variants associated with ischemic stroke occurring at younger ages. Variants at genome wide significance (P

Idiopathic Pulmonary Fibrosis (IPF) is identifiable by the excessive increase of mesenchyme paired with the loss of epithelium. Total flavonoids of Astragalus (TFA), the main biologically active ingredient of the traditional Chinese medicine, Astragalus membranaceus (Huangqi), shows outstanding effects on treating pulmonary disorders, including COVID-19-associated pulmonary dysfunctions. This study was designed to evaluate the efficacy of TFA on treating pulmonary fibrosis and the possible mechanisms behind these effects. A549 cells were treated with TGF-[Formula: see text]1 and TFA to observe the potential effects of TFA on regulating alveolar epithelial cell proliferation, TGF-[Formula: see text]1-induced EMT, and the underlying mechanisms in vitro. Then, mouse pulmonary fibrosis was induced with a single intra-tracheal injection of bleomycin, and TFA was administrated by i.p. injection. Lung fibrosis was evaluated through histological and molecular analyses, and the possible mechanisms were explored using immunological methods. The results demonstrated that TFA could promote cell proliferation but inhibit TGF-[Formula: see text]1-induced EMT on A549 cells. TFA attenuated BLM-induced pulmonary fibrosis in mice by modulating inflammatory infiltration and M2 macrophage polarization; it furthermore modulated EMT through regulating the TGF-[Formula: see text]1/Smad pathway. In addition, TFA augmented the expression of the Wnt7b protein, which plays an important role in alveolar epithelium reparation. In conclusion, TFA alleviated bleomycin-induced mouse lung fibrosis by preventing the fibrotic response and increasing epithelium regeneration.