A Randomized Trial of Drug Route in Out-of-Hospital Cardiac Arrest.

BACKGROUND: In patients with out-of-hospital cardiac arrest, the effectiveness of drugs such as epinephrine is highly time-dependent. An intraosseous route of drug administration may enable more rapid drug administration than an intravenous route; however, its effect on clinical outcomes is uncertain. METHODS: We conducted a multicenter, open-label, randomized trial across 11 emergency medical systems in the United Kingdom that involved adults in cardiac arrest for whom vascular access for drug administration was needed. Patients were randomly assigned to receive treatment from paramedics by means of an intraosseous-first or intravenous-first vascular access strategy. The primary outcome was survival at 30 days. Key secondary outcomes included any return of spontaneous circulation and favorable neurologic function at hospital discharge (defined by a score of 3 or less on the modified Rankin scale, on which scores range from 0 to 6, with higher scores indicating greater disability). No adjustment for multiplicity was made. RESULTS: A total of 6082 patients were assigned to a trial group: 3040 to the intraosseous group and 3042 to the intravenous group. At 30 days, 137 of 3030 patients (4.5%) in the intraosseous group and 155 of 3034 (5.1%) in the intravenous group were alive (adjusted odds ratio, 0.94; 95% confidence interval [CI], 0.68 to 1.32; P = 0.74). At the time of hospital discharge, a favorable neurologic outcome was observed in 80 of 2994 patients (2.7%) in the intraosseous group and in 85 of 2986 (2.8%) in the intravenous group (adjusted odds ratio, 0.91; 95% CI, 0.57 to 1.47); a return of spontaneous circulation at any time occurred in 1092 of 3031 patients (36.0%) and in 1186 of 3035 patients (39.1%), respectively (adjusted odds ratio, 0.86; 95% CI, 0.76 to 0.97). During the trial, one adverse event, which occurred in the intraosseous group, was reported. CONCLUSIONS: Among adults with out-of-hospital cardiac arrest requiring drug therapy, the use of an intraosseous-first vascular access strategy did not result in higher 30-day survival than an intravenous-first strategy. (Funded by the National Institute for Health and Care Research; PARAMEDIC-3 ISRCTN Registry number, ISRCTN14223494.).

The transcription factors ZmNAC128 and ZmNAC130 coordinate with Opaque2 to promote endosperm filling in maize.

Endosperm filling in maize (Zea mays), which involves nutrient uptake and biosynthesis of storage reserves, largely determines grain yield and quality. However, much remains unclear about the synchronization of these processes. Here, we comprehensively investigated the functions of duplicate NAM, ATAF1/2, and CUC2 (NAC)-type transcription factors, namely, ZmNAC128 and ZmNAC130, in endosperm filling. The gene-edited double mutant zmnac128 zmnac130 exhibits a poorly filled kernel phenotype such that the kernels have an inner cavity. RNA sequencing and protein abundance analysis revealed that the expression of many genes involved in the biosynthesis of zein and starch is reduced in the filling endosperm of zmnac128 zmnac130. Further, DNA affinity purification and sequencing combined with chromatin-immunoprecipitation quantitative PCR and promoter transactivation assays demonstrated that ZmNAC128 and ZmNAC130 are direct regulators of 3 (16-, 27-, and 50-kD) γ-zein genes and 6 important starch metabolism genes (Brittle2 [Bt2], pullulanase-type starch debranching enzyme [Zpu1], granule-bound starch synthase 1 [GBSS1], starch synthase 1 [SS1], starch synthase IIa [SSIIa], and sucrose synthase 1 [Sus1]). ZmNAC128 and ZmNAC130 recognize an additional cis-element in the Opaque2 (O2) promoter to regulate its expression. The triple mutant zmnac128 zmnac130 o2 exhibits extremely poor endosperm filling, which results in more than 70% of kernel weight loss. ZmNAC128 and ZmNAC130 regulate the expression of the transporter genes sugars that will eventually be exported transporter 4c (ZmSWEET4c), sucrose and glucose carrier 1 (ZmSUGCAR1), and yellow stripe-like2 (ZmYSL2) and in turn facilitate nutrient uptake, while O2 plays a supporting role. In conclusion, ZmNAC128 and ZmNAC130 cooperate with O2 to facilitate endosperm filling, which involves nutrient uptake in the basal endosperm transfer layer (BETL) and the synthesis of zeins and starch in the starchy endosperm (SE).

A genome-wide association study identifies a transporter for zinc uploading to maize kernels.

The Zn content in cereal seeds is an important trait for crop production as well as for human health. However, little is known about how Zn is loaded to plant seeds. Here, through a genome-wide association study (GWAS), we identify the Zn-NA (nicotianamine) transporter gene ZmYSL2 that is responsible for loading Zn to maize kernels. High promoter sequence variation in ZmYSL2 most likely drives the natural variation in Zn concentrations in maize kernels. ZmYSL2 is specifically localized on the plasma membrane facing the maternal tissue of the basal endosperm transfer cell layer (BETL) and functions in loading Zn-NA into the BETL. Overexpression of ZmYSL2 increases the Zn concentration in the kernels by 31.6%, which achieves the goal of Zn biofortification of maize. These findings resolve the mystery underlying the loading of Zn into plant seeds, providing an efficient strategy for breeding or engineering maize varieties with enriched Zn nutrition.

Family history and genetic risk score combined to guide cancer risk stratification: A prospective cohort study.

Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.

Development and validation of a lung cancer polygenic risk score incorporating susceptibility variants for risk factors.

Incorporating susceptibility genetic variants of risk factors has been reported to enhance the risk prediction of polygenic risk score (PRS). However, it remains unclear whether this approach is effective for lung cancer. Hence, we aimed to construct a meta polygenic risk score (metaPRS) of lung cancer and assess its prediction of lung cancer risk and implication for risk stratification. Here, a total of 2180 genetic variants were used to develop nine PRSs for lung cancer, three PRSs for different histopathologic subtypes, and 17 PRSs for lung cancer-related risk factors, respectively. These PRSs were then integrated into a metaPRS for lung cancer using the elastic-net Cox regression model in the UK Biobank (N = 442,508). Furthermore, the predictive effects of the metaPRS were assessed in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial (N = 108,665). The metaPRS was associated with lung cancer risk with a hazard ratio of 1.33 (95% confidence interval: 1.27-1.39) per standard deviation increased. The metaPRS showed the highest C-index (0.580) compared with the previous nine PRSs (C-index: 0.513-0.564) in PLCO. Besides, smokers in the intermediate risk group predicted by the clinical risk model (1.34%-1.51%) with the intermediate-high genetic risk had a 6-year average absolute lung cancer risk that exceeded the clinical risk model threshold (≥1.51%). The addition of metaPRS to the clinical risk model showed continuous net reclassification improvement (continuous NRI = 6.50%) in PLCO. These findings suggest the metaPRS can improve the predictive efficiency of lung cancer compared with the previous PRSs and refine risk stratification for lung cancer.

Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study.

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10-8 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.

DNA Origami Plasmonic Nanoantenna for Programmable Biosensing of Multiple Cytokines in Cancer Immunotherapy.

Herein, we report a DNA origami plasmonic nanoantenna for the programmable surface-enhanced Raman scattering (SERS) detection of cytokine release syndrome (CRS)-associated cytokines (e.g., tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)) in cancer immunotherapy. Typically, the nanoantenna was made of self-assembled DNA origami nanotubes (diameter: ∼19 nm; length: ∼90 nm) attached to a silver nanoparticle-modified silicon wafer (AgNP/Si). Each DNA origami nanotube contains one miniature gold nanorod (AuNR) inside (e.g., length: ∼35 nm; width: ∼7 nm). Intriguingly, TNF-α and IFN-γ logically regulate the opening of the nanotubes and the dissociation of the AuNRs from the origami structure upon binding to their corresponding aptamers. On this basis, we constructed a complete set of Boolean logic gates that read cytokine molecules as inputs and return changes in Raman signals as outputs. Significantly, we demonstrated that the presented system enables the quantification of TNF-α and IFN-γ in the serum of tumor-bearing mice receiving different types of immunotherapies (e.g., PD1/PD-L1 complex inhibitors and STING agonists). The sensing results are consistent with those of the ELISA. This strategy fills a gap in the use of DNA origami for the detection of multiple cytokines in real systems.

Genome-wide identification of a MADS-box transcription factor family and their expression during floral development in Coptis teeta wall.

BACKGROUND: MADS-box transcription factors have been shown to be involved in multiple developmental processes, including the regulation of floral organ formation and pollen maturation. However, the role of the MADS-box gene family in floral development of the alpine plant species Coptis teeta Wall, which is widely used in Traditional Chinese Medicine (TCM), is unknown. RESULTS: Sixty-six MADS-box genes were identified in the C. teeta genome. These genes were shown to be unevenly distributed throughout the genome of C. teeta. The majority of which (49) were classified as type I MADS-box genes and were further subdivided into four groups (Mα, Mß, Mγ and Mδ). The remainder were identified as belonging to the type II MADS-box gene category. It was observed that four pairs of segmental and tandem duplication had occurred in the C. teeta MADS-box gene family, and that the ratios of Ka/Ks were less than 1, suggesting that these genes may have experienced purifying selection during evolution. Gene expression profiling analysis revealed that 38 MADS-box genes displayed differential expression patterns between the M and F floral phenotypes. Sixteen of these MADS-box genes were further verified by RT-qPCR. The 3D structure of each subfamily gene was predicted, further indicating that MADS-box genes of the same type possess structural similarities to the known template. CONCLUSIONS: These data provide new insights into the molecular mechanism of dichogamy and herkogamy formation in C. teeta and establish a solid foundation for future studies of the MADS-box genes family in this medicinal plant species.

A Janus Spectrally Selective Glazing Toward All-Season Energy-Efficient Windows.

Windows offer the most promising avenue for mitigating energy consumption and reducing greenhouse gas emissions. However, the balance between comfortable natural lighting and all-season energy savings is often neglected in extensive explorations of energy-efficient windows. Herein, a Janus glazing is proposed that enables the switch of passive radiative cooling and heating under the precondition of conveying sufficient natural light. Measurement results indicate that the Janus window maintains a visible transmittance of 0.47, while possesses a near-infrared (NIR) reflectivity/absorptivity of 0.75/0.71 and a mid-infrared (MIR) emissivity of 0.94/0.13 for the cooling and heating modes, respectively. As demonstrated by the outdoor test, the Janus window realizes a reduction of 7.1 °C for room cooling and an increase of 0.4 °C for room heating compared with commercial low-e window, potentially conserving 13%-53% of the total building energy consumption across China. Meanwhile, attributed to the photothermal effect, the Janus window can elevate the surface temperature by 6.1 °C compared with the low-e window, which can effectively reduce fogging occurrences on the window surface for ensuring sunlight entrance in the cold-weather conditions. This strategy offers novel prospects for enhancing energy efficiency in diverse applications, including architectural windows, greenhouse cultivation, photovoltaic generation, etc.

Identification and genetic characterization of a recently identified enterovirus C116 in China.

Enterovirus C116 (EV-C116) is a new member of the enterovirus C group which is closely associated with several infectious diseases. Although sporadic studies have detected EV-C116 in clinical samples worldwide, there is currently limited information available. In this study, two EV-C-positive fecal specimens were detected in apparently healthy children, which harbored low abundance, through meta-transcriptome sequencing. Based on the prototypes of several EV-Cs, two lineages were observed. Lineage 1 included many types that could not cause EV-like cytopathic effect in cell culture. Three genogroups of EV-C116 were divided in the maximum likelihood tree, and the two strains in this study (XZ2 and XZ113) formed two different lineages, suggesting that EV-C116 still diffuses worldwide. Obvious inter-type recombination events were observed in the XZ2 strain, with CVA22 identified as a minor donor. However, another strain (XZ113) underwent different recombination situations, highlighting the importance of recombination in the formation of EV-Cs biodiversity. The EV-C116 strains could propagate in rhabdomyosarcoma cell cultures at low titer; however, EV-like cytopathic effects were not observed. HEp-2, L20B, VERO, and 293T cell lines did not provide an appropriate environment for EV-C116 growth. These results challenge the traditional recognition of the uncultured nature of EV-C116 strains and explain the difficulty of clinical detection.

The B3 domain-containing transcription factor ZmABI19 coordinates expression of key factors required for maize seed development and grain filling.

Grain filling in maize (Zea mays) is regulated by a group of spatiotemporally synchronized transcription factors (TFs), but the factors that coordinate their expression remain unknown. We used the promoter of the grain filling-specific TF gene Opaque2 (O2) to screen upstream regulatory factors and identified a B3 domain TF, ZmABI19, that directly binds to the O2 promoter for transactivation. zmabi19 mutants displayed developmental defects in the endosperm and embryo, and mature kernels were opaque and reduced in size. The accumulation of zeins, starch and lipids dramatically decreased in zmabi19 mutants. RNA sequencing revealed an alteration of the nutrient reservoir activity and starch and sucrose metabolism in zmabi19 endosperms, and plant phytohormone signal transduction and lipid metabolism in zmabi19 embryos. Chromatin immunoprecipitation followed by sequencing coupled with differential expression analysis identified 106 high-confidence direct ZmABI19 targets. ZmABI19 directly regulates multiple key grain filling TFs including O2, Prolamine-box binding factor 1, ZmbZIP22, NAC130, and Opaque11 in the endosperm and Viviparous1 in the embryo. A number of phytohormone-related genes were also bound and regulated by ZmABI19. Our results demonstrate that ZmABI19 functions as a grain filling initiation regulator. ZmABI19 roles in coupling early endosperm and embryo development are also discussed.

Nuclear Structure Effects on Hyperfine Splittings in Ordinary and Muonic Deuterium.

Precision spectroscopy of hyperfine splitting (HFS) is a crucial tool for investigating the structure of nuclei and testing quantum electrodynamics. However, accurate theoretical predictions are hindered by two-photon exchange (TPE) effects. We propose a novel formalism that accounts for nuclear excitations and recoil in TPE, providing a model-independent description of TPE effects on HFS in light ordinary and muonic atoms. Combining our formalism with pionless effective field theory at next-to-next-to-leading order, the predicted TPE effects on HFS are 41.7(4.4) kHz and 0.117(13) meV for the 1S state in deuterium and the 2S state in muonic deuterium. These results align within 1σ and 1.3σ from recent measurements and highlight the importance of nuclear structure effects on HFS and indicate the value of more precise measurements in future experiments.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in patients from China mainland, Taiwan, and South Korea with moderate to severe plaque psoriasis: a phase 3 randomized clinical trial.

BACKGROUND: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the United States, European Union, Japan, South Korea, China, and other countries for treatment of moderate-to-severe plaque psoriasis. OBJECTIVE: To evaluate the efficacy and safety of deucravacitinib in Asian patients with moderate to severe plaque psoriasis. METHODS: In the 52-week, blinded, phase 3 POETYK PSO-3 trial (NCT04167462), patients were randomized 1 : 2 to placebo (n = 74) or deucravacitinib 6 mg once daily (n = 146) for 16 weeks followed by deucravacitinib alone. Coprimary endpoints were achievement of ≥ 75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) and static Physician Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1) at Week 16. Efficacy and safety were evaluated throughout. RESULTS: At Week 16, significantly higher proportions of patients receiving deucravacitinib versus placebo achieved PASI 75 (68.8% vs. 8.1%; P < 0.0001) and sPGA 0/1 (55.6% vs. 6.8%; P < 0.0001). Response rates with deucravacitinib were maintained through Week 52. Common adverse events included upper respiratory tract infection and nasopharyngitis. Serious adverse event and discontinuation rates were low. CONCLUSIONS: Deucravacitinib was efficacious and well tolerated in Asian patients with moderate to severe plaque psoriasis.

Predictive nomograms of repeat intrahepatic recurrence and overall survival after radiofrequency ablation of recurrent colorectal liver metastases.

OBJECTIVES: This study was conducted to develop nomograms for predicting repeat intrahepatic recurrence (rIHR) and overall survival (OS), after radiofrequency ablation (RFA), treatment in patients with recurrent colorectal liver metastases (CLMs) after hepatectomy based on clinicopathologic features. METHODS: A total of 160 consecutive patients with recurrent CLMs after hepatectomy who were treated with ultrasound-guided percutaneous RFA from 2012 to 2022 were retrospectively included. Patients were randomly divided into a training cohort and a validation cohort, with a ratio of 8:2. Potential prognostic factors associated with rIHR and OS, after RFA, were identified by using the competing-risks and Cox proportional hazard models, respectively, and were used to construct the nomogram. The nomogram was evaluated by Harrell's C-index and a calibration curve. RESULTS: The 1-, 2-, and 3-year rIHR rates after RFA were 58.8%, 70.2%, and 74.2%, respectively. The 1-, 3- and 5-year OS rates were 96.3%, 60.4%, and 38.5%, respectively. In the multivariate analysis, mutant RAS, interval from hepatectomy to intrahepatic recurrence ≤ 12 months, CEA level >5 ng/ml, and ablation margin <5 mm were the independent predictive factors for rIHR. Mutant RAS, largest CLM at hepatectomy >3 cm, CEA level >5 ng/ml, and extrahepatic disease were independent predictors of poor OS. Two nomograms for rIHR and OS were constructed using the respective significant variables. In both cohorts, the nomogram demonstrated good discrimination and calibration. CONCLUSIONS: The established nomograms can predict individual risk of rIHR and OS after RFA for recurrent CLMs and contribute to improving individualized management.

Endovascular thrombectomy in wake-up stroke guided by arterial spin-labeling and fluid-attenuated inversion recovery versus diffusion-weighted imaging mismatch on MRI.

OBJECTIVE: This purpose of this study is to investigate the effectiveness and safety of utilizing the arterial spin-labeling (ASL) combined with diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) combined with DWI double mismatch in the endovascular treatment of patients diagnosed with wake-up stroke (WUS). METHODS: In this single-center trial, patients diagnosed with WUS underwent thrombectomy if acute ischemic lesions were observed on DWI indicating large precerebral circulation occlusion. Patients with no significant parenchymal hypersignal on FLAIR and ASL imaging showing a hypoperfusion tissue to infarct core volume ratio of at least 1.2 were included. The participants were divided into groups receiving endovascular thrombectomy plus medical therapy or medical therapy alone, based on their subjective preference. Functional outcomes were assessed using the ordinal score on the modified Rankin scale (mRs) at 90 days, along with the rate of functional independence. RESULTS: In this study, a total of 77 patients were included, comprising 38 patients in the endovascular therapy group and 39 patients in the medical therapy group. The endovascular therapy group exhibited more favorable changes in the distribution of functional prognosis measured by mRs at 90 days, compared to the medical therapy group (adjusted common odds ratio, 3.25; 95% CI, 1.03 to 10.26; P < 0.01). Additionally, the endovascular therapy group had a higher proportion of patients achieving functional independence (odds ratio, 4.0; 95% CI, 1.36 to 11.81; P < 0.01). Importantly, there were no significant differences observed in the incidence of intracranial hemorrhage or mortality rates between the two groups. CONCLUSION: Guided by the ASL-DWI and FLAIR-DWI double mismatch, endovascular thrombectomy combined with standard medical treatment appears to yield superior functional outcomes in patients with WUS and large vessel occlusion compared to standard medical treatment alone.

Ultra-compact SOI-based higher-order mode pass wavelength demultiplexer.

We propose an ultra-compact mode filtering wavelength demultiplexer design with a footprint of 3µm×3µm. Our device can route input T E 1 mode signals at 1310 nm and 1550 nm to different output ports while simultaneously blocking fundamental transverse electric (T E 0) mode input. Our device is designed based on the topology optimization algorithm, which results in an ultra-compact footprint combining wavelength routing and mode filtering functions for the first time, to the best of our knowledge. Our final optimized devices demonstrated insertion losses of 1.26 dB and 1.47 dB for the C- and O-band output ports, respectively, with inter-port crosstalk as low as -21.25d B and -30.99d B. The extinction ratios between T E 1 mode and T E 0 mode are 24.02 dB and 30.12 dB at the 1310 nm and 1550 nm output ports. The combination of small footprint, broad transmission bandwidth, T E 1 to T E 0 mode selectively filtering, and C- and O-band T E 1 mode demultiplexing functions make this a uniquely versatile device that can play an important role in future high density mode-wavelength multiplexing systems.

Cost-effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-COVID-19 condition after hospitalisation for COVID-19: the REGAIN RCT.

BACKGROUND: Following the COVID-19 pandemic, millions of people continue to experience ongoing physical and mental health sequelae after recovery from acute infection. There is currently no specific treatment for the diverse symptoms associated with post-COVID-19 condition. Physical and mental health rehabilitation may help improve quality of life in such patients. This study reports the cost-effectiveness of a programme of physical and mental health rehabilitation compared to best practice usual care in people with post-COVID-19 condition who were previously hospitalised. METHODS: We conducted an economic evaluation within a randomised controlled trial from the perspective of the UK national health service (NHS) and personnel social services perspective (PSS). Resource used and health-related quality of life were collected using bespoke questionnaire and the EQ-5D-5 L questionnaire at three, six, and 12 months. Incremental costs and quality adjusted life years accrued over the follow-up period were estimated and reported as the incremental cost-effectiveness ratio. Estimate uncertainty was managed by multiple imputation and bootstrapping cost-effectiveness estimates; and displayed graphically on the cost-effectiveness plane. RESULTS: Over a 12-month time horizon, incremental costs and QALYs were £305 (95% CI: -123 to 732) and 0.026 (95% CI: -0.005 to 0.052) respectively. The ICER was £11,941 per QALY indicating cost-effective care. Sensitivity analyses supported the base case findings. The probability of the intervention being cost-effective at a £30,000 per QALY willingness-to-pay threshold was 84%. CONCLUSION: The within-trial economic evaluation suggested that people with post-COVID-19 condition after hospitalisation should be offered a programme of physical and mental health rehabilitation as it likely reflects a cost-effective use of NHS resources. Hospitalisation for COVID-19 has become less commonplace: further evaluation in non-hospitalised patients may be worthwhile. TRIAL REGISTRATION: ISRCTN registry ISRCTN11466448 23rd November 2020.

Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway.

Acute lung injury (ALI) is a severe pulmonary disorder of sepsis with high clinical incidence and mortality. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-cysteinyl aspartate specific proteinase 1-gasdermin D (GSDMD)-dependent pyroptosis of alveolar epithelial cells (AECs) has emerged as a crucial contributor to ALI during sepsis. Phillyrin (PHI), a natural lignan isolated from the traditional Chinese herbal medicine Forsythia suspensa, has been shown to have anti-inflammatory, antioxidant and antiviral properties. However, little is known about the protective role and potential mechanism of PHI in sepsis-induced ALI, and it is uncertain whether the protective effect of PHI in sepsis-induced ALI is connected to pyroptosis. This study aims to examine the preventive effects of PHI on sepsis-induced ALI via the inhibition of NLRP3/caspase-1/GSDMD-mediated pyroptosis in AECs. Our findings demonstrate that preadministration of PHI successfully reduces sepsis-induced pulmonary edema, systemic/pulmonary inflammation, and pulmonary histological damage in lung tissues, bronchoalveolar lavage fluid, and the serum of septic mice. Intriguingly, PHI preadministration suppresses sepsis-induced protein expressions of pyroptosis-specific markers, especially their active forms. In vitro assays show that PHI pretreatment also protects type II AECs (MLE-12) from lipopolysaccharide-induced pyroptosis by preventing the activation of the pyroptosis signaling pathway. The results from molecular docking and surface plasmon resonance reveal that PHI has a significant affinity for direct binding to the GSDMD protein, suggesting that GSDMD is a potential pharmacological target for PHI. In conclusion, PHI can prevent sepsis-triggered ALI by effectively suppressing the activation of the canonical pyroptosis signaling pathway and pyroptosis of AECs.

Dynamin deficiency causes insulin secretion failure and hyperglycemia.

Pancreatic ß cells operate with a high rate of membrane recycling for insulin secretion, yet endocytosis in these cells is not fully understood. We investigate this process in mature mouse ß cells by genetically deleting dynamin GTPase, the membrane fission machinery essential for clathrin-mediated endocytosis. Unexpectedly, the mice lacking all three dynamin genes (DNM1, DNM2, DNM3) in their ß cells are viable, and their ß cells still contain numerous insulin granules. Endocytosis in these ß cells is severely impaired, resulting in abnormal endocytic intermediates on the plasma membrane. Although insulin granules are abundant, their release upon glucose stimulation is blunted in both the first and second phases, leading to hyperglycemia and glucose intolerance in mice. Dynamin triple deletion impairs insulin granule exocytosis and decreases intracellular Ca2+ responses and granule docking. The docking defect is correlated with reduced expression of Munc13-1 and RIM1 and reorganization of cortical F-actin in ß cells. Collectively, these findings uncover the role of dynamin in dense-core vesicle endocytosis and secretory capacity. Insulin secretion deficiency in the absence of dynamin-mediated endocytosis highlights the risk of impaired membrane trafficking in endocrine failure and diabetes pathogenesis.

Inactive Trojan Bacteria as Safe Drug Delivery Vehicles Crossing the Blood-Brain Barrier.

Escherichia coli K1 (EC-K1) can bypass the blood-brain barrier (BBB) and cause meningitis. Excitingly, we find the "dead EC-K1" can safely penetrate the BBB because they retain the intact structure and chemotaxis of the live EC-K1, while losing their pathogenicity. Based on this, we develop a safe "dead EC-K1"-based drug delivery system, in which EC-K1 engulf the maltodextrin (MD)-modified therapeutics through the bacteria-specific MD transporter pathway, followed by the inactivation via UV irradiation. We demonstrate that the dead bacteria could carry therapeutics (e.g., indocyanine green (ICG)) and together bypass the BBB after intravenous injection into the mice, delivering ∼3.0-fold higher doses into the brain than free ICG under the same conditions. What is more, all mice remain healthy even after 14 days of intravenous injection of ∼109 CFU of inactive bacteria. As a proof of concept, we demonstrate the developed strategy enables the therapy of bacterial meningitis and glioblastoma in mice.