Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction.

This review presents a comprehensive exploration of the pivotal role played by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, with a particular focus on Nesprin proteins, in cellular mechanics and the pathogenesis of muscular diseases. Distinguishing itself from prior works, the analysis delves deeply into the intricate interplay of the LINC complex, emphasizing its indispensable contribution to maintaining cellular structural integrity, especially in mechanically sensitive tissues such as cardiac and striated muscles. Additionally, the significant association between mutations in Nesprin proteins and the onset of Dilated Cardiomyopathy (DCM) and Emery-Dreifuss Muscular Dystrophy (EDMD) is highlighted, underscoring their pivotal role in disease pathogenesis. Through a comprehensive examination of DCM and EDMD cases, the review elucidates the disruptions in the LINC complex, nuclear morphology alterations, and muscular developmental disorders, thus emphasizing the essential function of an intact LINC complex in preserving muscle physiological functions. Moreover, the review provides novel insights into the implications of Nesprin mutations for cellular dynamics in the pathogenesis of muscular diseases, particularly in maintaining cardiac structural and functional integrity. Furthermore, advanced therapeutic strategies, including rectifying Nesprin gene mutations, controlling Nesprin protein expression, enhancing LINC complex functionality, and augmenting cardiac muscle cell function are proposed. By shedding light on the intricate molecular mechanisms underlying nuclear-cytoskeletal interactions, the review lays the groundwork for future research and therapeutic interventions aimed at addressing genetic muscle disorders.

Phosphorylation of sugar transporter TST2 by protein kinase CPK27 enhances drought tolerance in tomato.

Drought is a major environmental stress threatening plant growth and productivity. Calcium-dependent protein kinases (CPKs) are plant-specific Ca2+ sensors with multifaceted roles in signaling drought responses. Nonetheless, the mechanisms underpinning how CPKs transmit downstream drought signaling remain unresolved. Through genetic investigations, our study unveiled that knocking out CPK27 reduces drought tolerance in tomato (Solanum lycopersicum) plants and impairs abscisic acid (ABA)-orchestrated plant response to drought stress. Proteomics and phosphoproteomics revealed that CPK27-dependent drought-induced proteins were highly associated with the sugar metabolism pathway, which was further verified by reduced soluble sugar content in the cpk27 mutant under drought conditions. Using protein-protein interaction assays and phosphorylation assessments, we demonstrated that CPK27 directly interacts with and phosphorylates Tonoplast Sugar Transporter 2 (TST2), promoting intercellular soluble sugar accumulation during drought stress. Furthermore, Ca2+ and ABA enhanced CPK27-mediated interaction and phosphorylation of TST2, thus revealing a role of TST2 in tomato plant drought tolerance. These findings extend the toolbox of potential interventions for enhancing plant drought stress tolerance and provide a target to improve drought tolerance by manipulating CPK27-mediated soluble sugar accumulation for rendering drought tolerance in a changing climate.

Identification of Skin Lesions by Snapshot Hyperspectral Imaging.

This study pioneers the application of artificial intelligence (AI) and hyperspectral imaging (HSI) in the diagnosis of skin cancer lesions, particularly focusing on Mycosis fungoides (MF) and its differentiation from psoriasis (PsO) and atopic dermatitis (AD). By utilizing a comprehensive dataset of 1659 skin images, including cases of MF, PsO, AD, and normal skin, a novel multi-frame AI algorithm was used for computer-aided diagnosis. The automatic segmentation and classification of skin lesions were further explored using advanced techniques, such as U-Net Attention models and XGBoost algorithms, transforming images from the color space to the spectral domain. The potential of AI and HSI in dermatological diagnostics was underscored, offering a noninvasive, efficient, and accurate alternative to traditional methods. The findings are particularly crucial for early-stage invasive lesion detection in MF, showcasing the model's robust performance in segmenting and classifying lesions and its superior predictive accuracy validated through k-fold cross-validation. The model attained its optimal performance with a k-fold cross-validation value of 7, achieving a sensitivity of 90.72%, a specificity of 96.76%, an F1-score of 90.08%, and an ROC-AUC of 0.9351. This study marks a substantial advancement in dermatological diagnostics, thereby contributing significantly to the early and precise identification of skin malignancies and inflammatory conditions.

Life satisfaction components and all-cause and cause-specific mortality: A large prospective cohort study.

BACKGROUND: Which life satisfaction components could be a target of positive psychological interventions for longevity is largely unknown. We aimed to investigate association of the composite measure of life satisfaction and its individual components with mortality. METHODS: This cohort study included UK Biobank participants who responded to questions concerning five components of life satisfaction at baseline. We generated a composite score representing overall life satisfaction, ranging from 0 (lowest) to 5 (highest). The outcomes were all-cause and cause-specific mortality. We used multivariable Cox regression to estimate hazard ratios (HR) for the associations of interest. RESULTS: Among 165,842 eligible participants, 12,261 all-cause deaths were observed over a median of 12.9-year follow-up. Overall life satisfaction was inversely associated with all-cause mortality (adjusted HR 0.94 [95% CI: 0.93-0.95] per 1 score increment). Health satisfaction showed the strongest association with all-cause mortality, with a fully adjusted HR of 0.52 (95% CI: 0.49-0.55) for high/extreme satisfaction and 0.63 (95% CI: 0.59-0.66) for moderate satisfaction, compared with unsatisfaction (P-trend<0.001), independent of other satisfaction components, regardless of physical health and sociodemographics. The association for family, friendship, work and financial satisfaction was attenuated when adjusted for other life satisfaction components. Similar findings were observed for cause-specific mortality. LIMITATIONS: Observational study with single baseline measurement of life satisfaction precludes the ability to establish causal relationship. CONCLUSIONS: Higher overall life satisfaction was associated with lower mortality. As the major contributor to lower mortality regardless of physical health and sociodemographics, health satisfaction could be an important target of positive psychological interventions for longevity.

The epidemiology of pediatric psoriasis: A nationwide cohort study in Taiwan.

Psoriasis can affect individuals of all age groups. While the epidemiology of psoriasis in adults has been extensively studied, there is limited research specifically investigating pediatric cases. This study aimed to investigate the prevalence and incidence of skin psoriasis (PsO) and psoriatic arthritis (PsA) among pediatric patients in Taiwan. A nationwide cohort of 17 535 patients with psoriatic diseases under the age of 18 was enrolled from the National Health Insurance Research Database for the period 2000-2013, including 16 129 PsO patients and 2022 PsA patients. The age- and sex-standardized prevalence and incidence of pediatric PsO and PsA were calculated. The 2007 yearly reports of age- and sex-specific distribution of the general population was adopted as a standard. The results showed that between 2000 and 2013, the prevalence for pediatric PsO increased from 0.03% to 0.07%, and from 0.003% to 0.014% for pediatric PsA. During the same period, the incidence slightly decreased from 19.81 to 17.55 per 100 000 for pediatric PsO but increased from 1.02 to 5.06 per 100 000 for pediatric PsA. Adolescents (12 to <18 years) had higher prevalence and incidence rates of PsO and PsA than children (aged ≤ 12 years), with no sex difference observed in either age group. PsA preceding PsO was more common among children than adolescents (27.07% vs. 13.46%). This study provides important insights into the prevalence and incidence of psoriatic diseases in the pediatric population. Further research is needed to identify risk factors for pediatric psoriasis and to investigate its long-term health outcomes.

Breast Imaging Reporting and Data System evaluation of breast lesions improved with virtual touch tissue imaging average grayscale values.

BACKGROUND: Early breast cancer diagnosis is of great clinical importance for selecting treatment options, improving prognosis, and enhancing the quality of patients' survival. OBJECTIVE: We investigated the value of virtual touch tissue imaging average grayscale values (VAGV) helper Breast Imaging Reporting and Data System (BI-RADS) in diagnosing breast malignancy. METHODS: We retrospectively analyzed 141 breast tumors in 134 patients. All breast lesions were diagnosed pathologically by biopsy or surgical excision. All patients first underwent conventional ultrasound (US) followed by virtual touch tissue imaging (VTI). The measurement of the VAGV of the lesion was performed by Image J software. BI-RADS classification was performed for each lesion according to the US. We performed a two-by-two comparison of the diagnostic values of VAGV, BI-RADS, and BI-RADS+VAGV. RESULTS: VAGV was lower in malignant tumors than in benign ones (35.82 ± 13.39 versus 73.58 ± 42.69, P< 0.001). The area under the receiver operating characteristic curve (AUC) value, sensitivity, and specificity of VAGV was 0.834, 84.09%, and 69.07%, respectively. Among BI-RADS, VAGV, and BI-RADS+VAGV, BI-RADS+VAGV had the highest AUC (0.926 versus 0.882, P= 0.0066; 0.926 versus 0.834, P= 0.0012). There was perfect agreement between the two radiologists using VAGV (ICC= 0.9796) and substantial agreement using BI-RADS (Kappa= 0.725). CONCLUSION: Our study shows that VAGV can accurately diagnose breast cancer. VAGV effectively improves the diagnostic performance of BI-RADS.

Responses of a common tropical epiphyte, Asplenium nidus, to changes in water and nutrient availability.

Epiphytes are highly dependent on atmospheric inputs of water and nutrients. Reductions in water availability associated with warming and climate change and continual atmospheric nitrogen (N) deposition can affect plant growth but few studies have evaluated the effects of changes in both water and nutrient availabilities on epiphytes. We experimentally tested whether epiphyte growth is more water- or nutrient-limited, if nutrient limitation was stronger for nitrogen or phosphorus, and whether nutrient limitation interacts with water availability. We applied watering (high and low) and nutrient addition (control, +N, +P, +N+P) treatments to greenhouse-grown Asplenium nidus, a common epiphytic fern found in many tropical and subtropical wet forests. We measured leaf area production and leaf elemental concentrations to assess how A. nidus growth and physiology respond to changes in water and nutrient availabilities. We found that leaf growth of A. nidus was more affected by water availability than nutrient addition and the effect of adding nutrients was not fully realized under low-water availability. Among the different nutrient treatments, +N+P had the greatest effects on A. nidus growth and physiology in both watering treatments. Watering treatment changed leaf elemental concentrations but not their ratios (i.e. C:N and N:P). Nutrient addition altered C:N and N:P ratios and increased the concentration of the added elements in leaves, with more pronounced increases in the high-watering treatment. We conclude that the growth of A. nidus is more water- than nutrient-limited. When nutrient limitation occurs (i.e. under high-water availability), nutrient co-limitation is stronger than limitation by N or P alone. This result taken together with studies of other epiphytes suggests greater water than nutrient limitation is likely widespread among epiphytic plants. The limited effects of nutrient addition in the low-water treatment suggest that the effect of atmospheric N deposition on epiphyte growth will be limited when water availability is low.

A Method of Producing Low-Density, High-Strength Thin Cement Sheets: Pilot Run for a Glass-Free Solar Panel.

This paper presents an innovative method of producing a low-density, high-strength, thin cement sheet. A seaweed powder was mixed with Portland cement, a foaming agent, calcium sulfoaluminate (CSA), and a quantity of water to create an A4-sized thin sheet with a thickness of 7 mm, which can withstand 1.5 kg in weight. This sheet was then covered with ethylene vinyl acetate and a backsheet to create a sandwiched cement sheet. The advantages of this sandwiched cement sheet are two-fold. First, it can support up to 13 kg in a static mechanical loading test, without bending, for over eight hours. Second, it can be quickly recovered at the end of its life cycle. This was a preliminary experiment to produce a large cement sheet that could satisfy the loading requirements for a solar panel. The purpose of the large, thin cement sheet is to replace the glass in a conventional solar panel and create a lightweight solar panel of less than 10 kg, which would mean that the installation of solar panels would become a one-person operation rather than a two-person operation. It would also increase the efficiency of the solar panel installation process.

The Relationship between Muscle Ultrasound Parameters and Diabetic Peripheral Neuropathy among Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study.

Background: Muscle dysfunction is an early complication of diabetic peripheral neuropathy (DPN). As a convenient and low-cost tool, muscle ultrasound has been used to assess muscle quality and muscle mass. However, the relationship between different muscle ultrasound parameters and DPN is unclear. Objectives: This study was designed to investigate the relationship between ultrasound parameters of different muscles and DPN among patients with type 2 diabetes mellitus, including the rectus femoris (RF), tibialis anterior (TA), and medial head of gastrocnemius (MG). Materials and Methods: The research enrolled 90 patients with type 2 diabetes mellitus (T2DM). All images were attained from both sides. Muscle measurements contained muscle thickness (MT), cross-sectional area (CSA), echo intensity (EI), and corrected EI. The binary logistic regression and multiple linear regression were used to investigate the association between muscle ultrasound parameters and DPN or vibration perception threshold (VPT). Results: EI, corrected EI, MT of MG, and EI of TA were associated with DPN separately after adjusting other clinical variates. Among these muscle parameters, the EI of MG had a better predictive value (OR: 1.114, 95% CI: 1.039, 1.196) of DPN. Combined with CSA of RF, peripheral artery disease (PAD), and sex, the corrected EI of MG was associated with the vibration perception threshold (VPT) (standard ß = 0.242, p < 0.001), better than the EI of MG (standard ß = 0.215, p = 0.002). Conclusions: MG (MT, EI, and corrected EI) and TA (EI) were associated with DPN, respectively. CSA of RF and corrected EI or EI of MG combined with PAD and sex were associated with VPT significantly, which supported that muscle ultrasound might be a substantial quantitative tool for detecting the exercise benefits for DPN.

Virtual touch tissue imaging for differential diagnosis in ACR TI-RADS category 3-4 thyroid nodules: Conservative and aggressive methods.

PURPOSE: Many Thyroid Imaging Reporting and Data System (TI-RADS) category 3-4 nodules are benign. Our study aimed to add virtual touch tissue imaging (VTI) to TI-RADS using two methods, namely conservative and aggressive, and to explore which method had better diagnostic performance and which method avoided more unnecessary biopsies. METHODS: From January 2016 to December 2021, we included 121 thyroid nodules classified as TI-RADS category 3-4 in 115 consecutive patients in this retrospective study. This study used the reference standard for pathological diagnosis by surgical resection or biopsy. The diagnostic performance of the different methods was evaluated and compared by receiver operating characteristic (ROC) and area under the ROC curve (AUC). RESULTS: In this study, the aggressive approach had the best diagnostic performance among TI-RADS alone, the conservative approach, and the aggressive approach (AUC: 0.863 versus 0.598, P = 0.0007; 0.863 versus 0.755, P = 0.0067). When we used an aggressive approach, 75.44% (43/57) of the 57 false-positive nodes diagnosed by TI-RADS were appropriately downgraded from TI-RADS category 4 to category 3, avoiding unnecessary biopsies. CONCLUSION: VTI improves the diagnostic performance of TI-RADS. The aggressive approach of combining the TI-RADS with VTI would help reduce unnecessary biopsies.

Psoriatic arthritis risk in psoriasis patients prescribed acitretin versus disease-modifying antirheumatic drugs: a nationwide cohort study.

OBJECTIVES: To compare the risk of psoriatic arthritis (PsA) in psoriasis (PsO) patients treated with acitretin vs disease-modifying antirheumatic drugs (DMARDs). METHODS: This retrospective study used Taiwan's National Health Insurance Research Database from 1997 to 2013. Adult PsO patients without PsA prescribed acitretin or DMARDs for ≥30 days within a year were assigned to the acitretin cohort or DMARDs cohort, respectively. Patients in the acitretin cohort prescribed DMARDs for >7 days, or in the DMARDs cohort prescribed acitretin for >7 days, were excluded. Cumulative incidence of PsA were determined within both cohorts using the Kaplan-Meier method. The hazard ratio (HR) comparing acitretin to DMARDs was calculated with Cox regression models, adjusting for demographic and clinical covariates including the use of non-steroidal anti-inflammatory drugs (NSAIDs) and comorbidities. RESULTS: The study included 1,948 patients in each cohort. The 5-year cumulative incidence of PsA in the acitretin cohort was lower than that in the reference cohort (7.52% vs 9.93%; P=0.005), with a more pronounced difference in the subpopulation receiving NSAIDs treatment. However, in subpopulations without NSAIDs treatment, the 5-year cumulative incidence of PsA in the acitretin cohort was comparable to the DMARDs cohort (5.26% vs 6.98%; P = 0.106). Acitretin was not associated with PsA development in PsO (HR 0.83, 95% confidence interval 0.65-1.05). This risk remained consistent regardless of adjustments for NSAID treatment and comorbidities. Other independent risk factors for PsA included female and NSAIDs treatment. CONCLUSION: Compared with DMARDs, acitretin was not associated with increased PsA risk in PsO patients.

Fog and rain water chemistry in a tea plantation of northern Taiwan.

Tea plantations are expanding globally and many are in mountainous areas with frequent fog but few studies have examined fog chemistry in these areas. We examined chemical composition of fog and rain water at a tea plantation in northern Taiwan. Fog water was collected using a Kroneis passive cylindrical fog-water collector and rain water was collected using a 20-cm-diameter funnel. The most abundant ions were Cl- and Na+ in both fog and rain waters due to the proximity of the site to the coast. The order of abundance of other ions was NO3- > Mg2+ > SO42- > Ca2+ > NH4+ > K+ > H+ in fog water and SO42- > K+ > NO3- > NH4+ > Ca2+ > Mg2+ > H+ in rain water. The concentration enrichment ratio (fog to rain) ranged between 2.2 (K+) and 22 (Mg2+) lying between sites near major emission sources and sites in remote areas, possibly because the immediate surrounding landscape is covered with secondary forests although it is near large cities. Factor analysis highlights the influences of sea-salt aerosols on the variation of fog and rain water chemistry. Sea-salt corrections using Na+ as the sea salt tracer led to negative concentrations of Cl- and Mg2+ suggesting that assumptions involved in sea-salt corrections were not satisfied. Agriculture influence is identified as a unique factor for explaining variance of K+, NH4+, and dissolved organic nitrogen (DON) concentrations in fog water but not rain water. Ion concentrations in fog and rain water were generally higher in the weekly samples associated with air trajectories passing through the continental East Asia than those associated with oceanic trajectories pointing to the role of regional pollution sources in affecting local fog and rain water chemistry. Our study highlights greater effects of tea agriculture on fog than rain water chemistry.

Prevalence and practices of immunofluorescent cell image processing: a systematic review.

Background: We performed a systematic review that identified at least 9,000 scientific papers on PubMed that include immunofluorescent images of cells from the central nervous system (CNS). These CNS papers contain tens of thousands of immunofluorescent neural images supporting the findings of over 50,000 associated researchers. While many existing reviews discuss different aspects of immunofluorescent microscopy, such as image acquisition and staining protocols, few papers discuss immunofluorescent imaging from an image-processing perspective. We analyzed the literature to determine the image processing methods that were commonly published alongside the associated CNS cell, microscopy technique, and animal model, and highlight gaps in image processing documentation and reporting in the CNS research field. Methods: We completed a comprehensive search of PubMed publications using Medical Subject Headings (MeSH) terms and other general search terms for CNS cells and common fluorescent microscopy techniques. Publications were found on PubMed using a combination of column description terms and row description terms. We manually tagged the comma-separated values file (CSV) metadata of each publication with the following categories: animal or cell model, quantified features, threshold techniques, segmentation techniques, and image processing software. Results: Of the almost 9,000 immunofluorescent imaging papers identified in our search, only 856 explicitly include image processing information. Moreover, hundreds of the 856 papers are missing thresholding, segmentation, and morphological feature details necessary for explainable, unbiased, and reproducible results. In our assessment of the literature, we visualized current image processing practices, compiled the image processing options from the top twelve software programs, and designed a road map to enhance image processing. We determined that thresholding and segmentation methods were often left out of publications and underreported or underutilized for quantifying CNS cell research. Discussion: Less than 10% of papers with immunofluorescent images include image processing in their methods. A few authors are implementing advanced methods in image analysis to quantify over 40 different CNS cell features, which can provide quantitative insights in CNS cell features that will advance CNS research. However, our review puts forward that image analysis methods will remain limited in rigor and reproducibility without more rigorous and detailed reporting of image processing methods. Conclusion: Image processing is a critical part of CNS research that must be improved to increase scientific insight, explainability, reproducibility, and rigor.

Phenolic compound profile and gastrointestinal action of Solanaceae fruits: Species-specific differences.

In this study, the presence of phenolic compounds derived from four Solanaceae fruits (tomato, pepino, tamarillo, and goldenberry) during gastrointestinal digestion and the effect of these compounds on human gut microbiota was investigated. The results indicated that the total phenolic content of all Solanaceae fruits were increased during digestion. Furthermore, the targeted metabolic analysis identified 296 compounds, of which 71 were changed after gastrointestinal digestion in all Solanaceae fruits. Among these changed phenolic compounds, 51.3% phenolic acids and 91% flavonoids presented higher bioaccessibility in pepino and tamarillo, respectively. Moreover, higher levels of glycoside-formed phenolic acids, including dihydroferulic acid glucoside and coumaric acid glucoside, were found in tomato fruits. In addition, tachioside showed the highest bioaccessibility in goldenberry fruits. The intake of Solanaceae fruits during the in vitro fermentation decreased the Firmicutes/Bacteroidetes ratio (F/B) compared with the control (∼15-fold change on average), and goldenberry fruits showed the best effect (F/B = 2.1). Furthermore, tamarillo significantly promoted the growth of Bifidobacterium and short-chain fatty acids production. Overall, this study revealed that Solanaceae fruits had different phenolic compound profiles and health-promoting effects on the gut microbiota. It also provided relevant information to improve the consumption of Solanaceae fruits, mainly tamarillo and goldenberry fruits, due to their gut health-promoting properties, as functional foods.

COVID-19, Blood Lipid Changes, and Thrombosis.

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC).

Efficacy of SARS-CoV-2 vaccines and the dose-response relationship with three major antibodies: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The efficacy of SARS-CoV-2 vaccines in preventing severe COVID-19 illness and death is uncertain due to the rarity of data in individual trials. How well the antibody concentrations can predict the efficacy is also uncertain. We aimed to assess the efficacy of these vaccines in preventing SARS-CoV-2 infections of different severities and the dose-response relationship between the antibody concentrations and efficacy. METHODS: We did a systematic review and meta-analysis of randomised controlled trials (RCTs). We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, WHO, bioRxiv, and medRxiv for papers published between Jan 1, 2020 and Sep 12, 2022. RCTs on the efficacy of SARS-CoV-2 vaccines were eligible. Risk of bias was assessed using the Cochrane tool. A frequentist, random-effects model was used to combine efficacy for common outcomes (ie, symptomatic and asymptomatic infections) and a Bayesian random-effects model was used for rare outcomes (ie, hospital admission, severe infection, and death). Potential sources of heterogeneity were investigated. The dose-response relationships of neutralising, spike-specific IgG and receptor binding domain-specific IgG antibody titres with efficacy in preventing SARS-CoV-2 symptomatic and severe infections were examined by meta-regression. This systematic review is registered with PROSPERO, CRD42021287238. FINDINGS: 28 RCTs (n=286 915 in vaccination groups and n=233 236 in placebo groups; median follow-up 1-6 months after last vaccination) across 32 publications were included in this review. The combined efficacy of full vaccination was 44·5% (95% CI 27·8-57·4) for preventing asymptomatic infections, 76·5% (69·8-81·7) for preventing symptomatic infections, 95·4% (95% credible interval 88·0-98·7) for preventing hospitalisation, 90·8% (85·5-95·1) for preventing severe infection, and 85·8% (68·7-94·6) for preventing death. There was heterogeneity in the efficacy of SARS-CoV-2 vaccines against asymptomatic and symptomatic infections but insufficient evidence to suggest whether the efficacy could differ according to the type of vaccine, age of the vaccinated individual, and between-dose interval (p>0·05 for all). Vaccine efficacy against symptomatic infection waned over time after full vaccination, with an average decrease of 13·6% (95% CI 5·5-22·3; p=0·0007) per month but can be enhanced by a booster. We found a significant non-linear relationship between each type of antibody and efficacy against symptomatic and severe infections (p<0·0001 for all), but there remained considerable heterogeneity in the efficacy, which cannot be explained by antibody concentrations. The risk of bias was low in most studies. INTERPRETATION: The efficacy of SARS-CoV-2 vaccines is higher for preventing severe infection and death than for preventing milder infection. Vaccine efficacy wanes over time but can be enhanced by a booster. Higher antibody titres are associated with higher estimates of efficacy but precise predictions are difficult due to large unexplained heterogeneity. These findings provide an important knowledge base for interpretation and application of future studies on these issues. FUNDING: Shenzhen Science and Technology Programs.

Risk of Psychiatric Disorders in Patients with Psoriasis Prescribed Acitretin versus Disease-Modifying Antirheumatic Drugs: A Nationwide Matched Cohort Study.

BACKGROUND: Acitretin has been linked to the development of psychiatric disturbance. OBJECTIVES: The aim of this study was to assess the psychiatric hazards in patients with psoriasis prescribed acitretin compared with those prescribed disease-modifying antirheumatic drugs (DMARDs). METHODS: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, adult patients with psoriasis between 1997 and 2013 were screened. Patients prescribed acitretin for at least 30 days per year on average (acitretin cohort) were matched 1:2 with those prescribed DMARDs for at least 30 days per year on average (reference cohort), by means of age, gender, and psoriasis duration. Patients prescribed medication of the corresponding cohort for more than 7 days during the observation period were excluded. Cumulative incidences of psychiatric disorders in both cohorts were plotted with the Kaplan-Meier method. The modified Cox regression models were constructed to estimate hazard ratios (HRs). RESULTS: In total, 1,152 and 2,304 patients in the acitretin and the reference cohorts, respectively, were included. The 4-year cumulative incidence of overall psychiatric disorders (19.62% vs. 12.06%; p < 0.001), mood disorders (12.81% vs. 7.67%; p < 0.001), and psychosis (7.21% vs. 4.63%; p < 0.001) in the acitretin cohort was significantly higher than that in the reference cohort. Acitretin was independently associated with psychiatric disorders (HR 1.51, 95% confidence interval [CI] 1.23-1.85). The risk is more accentuated in the subgroups of comorbid chronic liver disease (HR 2.60, 95% CI: 1.56-4.33) or psoriatic arthritis (HR 3.23, 95% CI: 1.75-5.97). Other independent risk factors included insomnia, acute coronary syndrome, females, and age. CONCLUSIONS: Compared with DMARDs, acitretin was associated with higher hazards of psychiatric disorders among psoriasis patients.

Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein.

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment.