Constructing Adsorption Site-Enhanced Vo-BiOCl/rGO Heterostructures for Efficient Response to NO2/NH3 Gases at Room Temperature.

Real-time detection of harmful gases at room temperature has become a serious problem in public health and environmental monitoring. Two-dimensional materials with semiconductor properties BiOCl is a promising gas-sensitive material due to its large specific surface area and adjustable band gap as well as outstanding safety characteristics. However, limited by the weak gas adsorption sites and sluggish charge-transfer ability, the performance of BiOCl could not be fully exploited. Oxygen vacancy (Vo) engineering can introduce lattice defects, thereby significantly increasing the local charge density and enhancing the adsorption of gases, which is an effective strategy to enhance the gas-sensing performance. In this work, we composite BiOCl with a vacancy (Vo-BiOCl) and reduced graphene oxide (rGO) to construct a Vo-BiOCl/rGO heterostructure with enhanced gas adsorption sites. Experimental and theoretical calculations show that Vo can enhance the adsorption of gases and the introduction of rGO forms a high-quality heterostructure with BiOCl, which can effectively reduce the band gap of BiOCl and promote electron transfer, thereby improving the sensitivity of the sensor. Benefiting from above, Vo-BiOCl/rGO achieves the ability to detect low concentrations of NO2/NH3 at room temperature, with high sensitivity (55% at 1 ppm of NO2 and -28% at 1 ppm of NH3), fast response time (40 s at 1 ppm of NO2 and 2 s at 1 ppm of NH3), good stability (over 150 days), and fully recoverable gas sensitivity.

Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.

Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T-cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T-cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor-related protein 10 (Lrp10) cause naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T-cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T-cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T-cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.

Optimizing the Microenvironment in Solid Polymer Electrolytes by Anion Vacancy Coupled with Carbon Dots.

The practical application of solid polymer electrolyte is hindered by the small transference number of Li+, low ionic conductivity and poor interfacial stability, which are seriously determined by the microenvironment in polymer electrolyte. The introduction of functional fillers is an effective solution to these problems. In this work, based on density functional theory (DFT) calculations, it is demonstrated that the anion vacancy of filler can anchor anions of lithium salt, thereby significantly increasing the transference number of Li+ in the electrolyte. Therefore, flower-like SnS2-based filler with abundant sulfur vacancies is prepared under the regulation of functionalized carbon dots (CDs). It is worth mentioning that the CDs dotted on the surface of SnS2 have rich organic functional groups, which can serve as the bridging agent to enhance the compatibility of filler and polymer, leading to superior mechanical performance and fast ion transport pathway. Additionally, the in-situ formed Li2S/Li3N at the interface of Li metal and electrolyte facilitate the fast Li+ diffusion and uniform Li deposition, effectively mitigating the growth of lithium dendrites. As a result, the assembled lithium metal batteries exhibit excellent cycling stability, reflecting the superiority of the carbon dots derived vacancy-rich inorganic filler modification strategy.

Confined Element Distribution with Structure-driven Energy Coupling for Enhanced Prussian Blue Analogue Cathode.

The structural failure of Na2Mn[Fe(CN)6] could not be alleviated with traditional modification strategies through the adjustable composition property of Prussian blue analogues (PBAs), considering that the accumulation and release of stress derived from the MnN6 octahedrons are unilaterally restrained. Herein, a novel application of adjustable composition property, through constructing a coordination competition relationship between chelators and [Fe(CN)6]4- to directionally tune the enrichment of elements, is proposed to restrain structural degradation and induce unconventional energy coupling phenomenon. The non-uniform distribution of elements at the M1 site of PBAs (NFM-PB) is manipulated by the sequentially precipitated Ni, Fe, and Mn according to the Irving-William order. Electrochemically active Fe is operated to accompany Mn, and zero-strain Ni is modulated to enrich at the surface, synergistically mitigating with the enrichment and release of stress and then significantly improving the structural stability. Furthermore, unconventional energy coupling effect, a fusion of the electrochemical behavior between FeLS and MnHS, is triggered by the confined element distribution, leading to the enhanced electrochemical stability and anti-polarization ability. Consequently, the NFM-PB demonstrates superior rate performance and cycling stability. These findings further exploit potentialities of the adjustable composition property and provide new insights into the component design engineering for advanced PBAs.

Bismuth-Containing Quadruple Therapy for Helicobacter pylori Eradication: A Randomized Clinical Trial of 10 and 14 Days.

BACKGROUND: Bismuth-containing quadruple therapy is the first-line treatment for eradicating Helicobacter pylori (H. pylori). The optimal duration for H. pylori eradication using bismuth-containing quadruple therapy remains controversial. Therefore, we aimed to compare the clinical effects of the 10- and 14-day bismuth-containing quadruple treatment regimen to eradicate H. pylori. METHODS: Treatment-naïve patients with H. pylori infection (n = 1300) were enrolled in this multicenter randomized controlled study across five hospitals in China. They were randomized into 10- or 14-day treatment groups to receive bismuth-containing quadruple therapy as follows: vonoprazan 20 mg twice daily; bismuth 220 mg twice daily; amoxicillin 1000 mg twice daily; and either clarithromycin 500 mg twice daily or tetracycline 500 mg four times daily. At least 6 weeks after treatment, we performed a 13C-urea breath test to evaluate H. pylori eradication. RESULTS: The per-protocol eradication rates were 93.22% (564/605) and 93.74% (569/607) (p < 0.001) and the intention-to-treat eradication rates were 88.62% (576/650) and 89.38% (581/650) (p = 0.007) for the 10- and 14-day regimens, respectively. Incidence of adverse effects was lower in patients who received 10- vs. 14 days of treatment (22.59% vs. 28.50%, p = 0.016). We observed no significant differences in the compliance to treatment or the discontinuation of therapy because of severe adverse effects between the groups. CONCLUSION: Compared with the 14-day bismuth-containing quadruple regimens, the 10-day regimen demonstrated a non-inferior efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and tolerated and could be recommended for H. pylori eradication (NCT05049902).

A Novel Hollow Graphene/Polydimethylsiloxane Composite for Pressure Sensors with High Sensitivity and Superhydrophobicity.

Flexible pressure sensors have attracted great interest as they play an important role in various fields such as health monitoring and human-machine interactions. The design of the pressure sensors still faces challenges in achieving a high sensitivity for a wide sensing range, and the interference of water restricts the applications of the sensors. Herein, we developed a graphene-polydimethylsiloxane film combining a hierarchical surface with nanowrinkles on it and a hollow structure. The microstructure design of the composite can be facilely controlled to improve the sensing and hydrophobic performance by tailoring the microsphere building units. Attributed to the irregular surface and hollow structure of the sensing layer, the optimized sensor exhibits a superior sensitivity of 1085 kPa-1 in a 50 kPa linear range. For practical applications, the nanowrinkles on the surface of the microspheres and the polymer coating endow the composite with waterproof properties. Inspired by the dual receptors of the skin, two designed microstructured films can simply integrate into one with double-sided microstructures. The sensing performance and the water-repellence property allow the sensor to detect physiological signals under both ambient and underwater conditions. Furthermore, underwater stimuli detection and communication are demonstrated. This method of fabricating a flexible sensor shows great potential in wearable and robotic fields.

Viable mutations of mouse midnolin suppress B cell malignancies.

In a genetic screen, we identified two viable missense alleles of the essential gene Midnolin (Midn) that were associated with reductions in peripheral B cells. Causation was confirmed in mice with targeted deletion of four of six MIDN protein isoforms. MIDN was expressed predominantly in lymphocytes where it augmented proteasome activity. We showed that purified MIDN directly stimulated 26S proteasome activity in vitro in a manner dependent on the ubiquitin-like domain and a C-terminal region. MIDN-deficient B cells displayed aberrant activation of the IRE-1/XBP-1 pathway of the unfolded protein response. Partial or complete MIDN deficiency strongly suppressed Eµ-Myc-driven B cell leukemia and the antiapoptotic effects of Eµ-BCL2 on B cells in vivo and induced death of Sp2/0 hybridoma cells in vitro, but only partially impaired normal lymphocyte development. Thus, MIDN is required for proteasome activity in support of normal lymphopoiesis and is essential for malignant B cell proliferation over a broad range of differentiation states.

Review on toxicology and activity of tomato glycoalkaloids in immature tomatoes.

Owing to the lack of selection and limited intelligence in mechanical picking, some immature tomatoes that contain alkaloids are thrown away. Tomatine alkaloids are steroidal alkaloids naturally present in Solanaceae plants, which are distributed in small amounts in immature tomato fruits and decrease as the fruits ripen. Tomato glycoalkaloids are harmful to human health. However, in small quantities, there is some evidence that these compounds might be beneficial, as other non-antioxidant bioactivities. This article considers recent research on the biological effects of tomato glycoalkaloids in immature tomatoes, providing reference value for the potential development of these compounds.

Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation.

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis.

Realization of digital twin for dynamic control toward sample variation of ion exchange chromatography in antibody separation.

Digital twin (DT) is a virtual and digital representation of physical objects or processes. In this paper, this concept is applied to dynamic control of the collection window in the ion exchange chromatography (IEC) toward sample variations. A possible structure of a feedforward model-based control DT system was proposed. Initially, a precise IEC mechanistic model was established through experiments, model fitting, and validation. The average root mean square error (RMSE) of fitting and validation was 8.1% and 7.4%, respectively. Then a model-based gradient optimization was performed, resulting in a 70.0% yield with a remarkable 11.2% increase. Subsequently, the DT was established by systematically integrating the model, chromatography system, online high-performance liquid chromatography, and a server computer. The DT was validated under varying load conditions. The results demonstrated that the DT could offer an accurate control with acidic variants proportion and yield difference of less than 2% compared to the offline analysis. The embedding mechanistic model also showed a positive predictive performance with an average RMSE of 11.7% during the DT test under >10% sample variation. Practical scenario tests indicated that tightening the control target could further enhance the DT robustness, achieving over 98% success rate with an average yield of 72.7%. The results demonstrated that the constructed DT could accurately mimic real-world situations and perform an automated and flexible pooling in IEC. Additionally, a detailed methodology for applying DT was summarized.

Comparison of clinical and economic evaluation between selected generic and original febuxostat tablets in Chinese gout patients with hyperuricemia: A real-world multicenter retrospective study.

Generic febuxostat tablets were listed in China's third-round centralized drug procurement program. However, there are no sufficient data available on the use of febuxostat in a real-world setting. This study aimed to compare the efficacy, safety, and cost of selected generic febuxostat with original febuxostat in primary gout and hyperuricemia. Medical records at 3 tertiary hospitals from January 2014 to February 2022 were retrospectively analyzed. Propensity score matching was used to balance the distribution of baseline characteristics. The proportion of patients achieving target serum uric acid (SUA) levels at 12 weeks, the percent changes from baseline in SUA, adverse drug reactions, and the cost of febuxostat therapy were assessed. A total of 221 patients were recruited and 57 pairs of patients were 1:1 matched in the 2 groups. There was no statistically significant difference in the proportion of patients achieving a target SUA levels below 300 µmol/L, the percent changes of SUA decreased from baseline, and the incidence of adverse drug reactions between the 2 groups (all P > .05). The daily febuxostat cost in the generic group were significantly lower than that in original group (P < .05). Based on the results of this study, the clinical efficacy of selected generic febuxostat is comparable to that of original febuxostat for gout with hyperuricemia. No serious adverse reactions were reported in the 2 groups, and generic febuxostat is more economical than the original febuxostat.

Comparing verum and sham acupoint catgut embedding for adults with obesity: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Previous clinical trials have reported that acupoint catgut embedding (ACE) is a useful modality for weight loss. However, no study has specifically investigated the effectiveness and safety of comparing verum and sham ACE in adults with obesity. Thus, this study aimed to evaluate the effectiveness and safety of comparing verum and sham ACE in obese adults. METHODS: A comprehensive literature search was conducted in the electronic databases of PUBMED, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, and China Biomedical Literature Service System from inception to April 1, 2022. Randomized clinical trials that focused on evaluating the effectiveness of comparing verum and sham ACE in adults with obesity were included. The primary outcomes included reduction in body weight, body mass index, hip circumference, and waist circumference. The secondary outcomes consisted of a decrease in body fat percentage and the occurrence rate of adverse events. The methodological quality of the included randomized clinical trials was evaluated using the Cochrane Risk-of-bias tool. Statistical analysis was performed using RevMan 5.4 software. RESULTS: Six trials involving 679 adults with obesity were included in this study and entered in the data analysis of systematic review and meta-analysis. Results of the meta-analysis revealed significant reduction in body weight (mean difference [MD] = -1.68, 95% confidence intervals (CI) [-2.34, -1.01], I2 = 51%, P < .001), body mass index (MD = -0.51, 95% CI [-0.81, -0.21], I2 = 74%, P < .001), hip circumference (MD = -1.11, 95% CI [-1.67, -0.55], I2 = 0%, P < .001), waist circumference (MD = -2.42, 95% CI [-3.38, -1.45], I2 = 68%, P < .001), and decrease in body fat percentage (MD = -0.83, 95% CI [-1.30, -0.36], I2 = 16%, P < .001) in comparing verum and sham ACE. However, no significant difference was identified in AEs (odds ratio = 1.53, 95% CI [0.80, 2.95], I2 = 0%, P = .20) between the 2 groups. CONCLUSION: ACE is effective in the treatment of obesity in adults with safety profile. Further studies with higher quality and larger sample size are warranted to confirm the current findings.

Short-term associations of particulate matter with different aerodynamic diameters with mortality due to mental disorders and dementia in Ningde, China.

Limited evidence is available regarding the impact of ambient inhalable particulate matter (PM) on mental disorder (MD) or dementia-related deaths, particularly PM1, PM1-2.5, and coarse particles (PM2.5-10). Moreover, individual confounders have rarely been considered. In addition, evidence from low-pollution areas is needed but is inadequate. Using death records from the Death Registration System during 2015-2021 in Ningde, a coastal city in southeast China, we combined a conditional quasi-Poisson model with a distributed lag nonlinear model to estimate the nonlinear and lagged associations of PM exposure with MD or dementia-related deaths in Ningde, China, comprehensively controlling for individual time-invariant confounders using a time-stratified case-crossover design. The attributable fraction and number were calculated to quantify the burden of MD or dementia-related deaths that were related to PMs. We found J-shaped relationships between MD or dementia-related deaths and PMs, with different thresholds of 13, 9, 19, 33 and 12 µg/m3 for PM1, PM1-2.5, PM2.5, PM10 and PM2.5-10. An inter-quartile range increase for PM1, PM1-2.5, PM2.5, PM10 and PM2.5-10 above the thresholds led to an increase of 31.8% (95% confidence interval, 14.3-51.9%), 53.7% (22.4-93.1%), 32.6% (15.0-53.0%), 35.1% (17.7-55.0%) and 25.9% (13.0-40.3%) in MD-related deaths at lag 0-3 days, respectively. The associations were significant in the cool season rather than in the warm season and were significantly greater among people aged 75-84 years than in others. The fractions of MD-related deaths attributable to PM1, PM1-2.5, PM2.5, PM10 and PM2.5-10 were 5.55%, 6.49%, 7.68%, 10.66%, and 15.11%, respectively; however, only some of them could be protected by the concentrations recommended by the World Health Organisation or China grade I standard. Smaller associations and similar patterns were observed between PMs and dementia-related death. These findings suggest stricter standards, and provide evidence for the development of relevant policies and measures.

The Jagged-1/Notch1 Signaling Pathway Promotes the Construction of Tissue-Engineered Heart Valves.

Background: Tissue-engineered heart valves (TEHVs) are promising new heart valve substitutes for valvular heart disease. The Notch signaling pathway plays a critical role in the development of congenital heart valves. Objective: To investigate the role of the Notch signaling pathway in the construction of TEHVs. Methods: The induced endothelial cells, which act as seed cells, were differentiated from adipose-derived stem cells and were treated with Jagged-1 (JAG-1) protein and γ-secretase inhibitor (DAPT, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester), respectively. Cell phenotypic changes, the expression of proteins relating to the epithelial-mesenchymal transition (EMT), and changes in paxillin expression were detected. Decellularized valve scaffolds were produced from decellularized porcine aortic valves. The seed cells were them inoculated into Matrigel-coated flap scaffolds for complex culture and characterization. Results: JAG-1 significantly reduced apoptosis and promoted the seeded cells' proliferation and migration ability, in contrast to the treatment of DAPT. In addition, the expression of EMT-related proteins, E-cadherin and N-cadherin, was significantly increased after treatment with JAG-1 and was reduced after the application of DAPT. Meanwhile, the adhesive-related expression of paxillin and fibronectin proteins was increased after the activation of Notch1 signaling and vice versa. Of interest, activation of the Notch1 signaling pathway resulted in more closely arranged cells on the valve surface after recellularization. Conclusion: Activation of the JAG-1/Notch1 signaling pathway increased seeded cells' proliferation and migratory ability and promoted the EMT and adhesion of seed cells, which was conducive to binding to the matrix, facilitating accelerated endothelialization of TEHVs.

An Evidence Map of Clinical Practice Guideline Recommendations and Quality on Venous Leg Ulcer.

Significance: Venous leg ulcers (VLUs) are the most common venous disease, mainly presenting as open skin lesions on the legs or feet and are an important concern in clinical care settings. Recent Advances: Comprehensive tactics were employed to search electronic databases PubMed, Embase, guideline databases, and society websites were searched for Clinical Practice Guidelines (CPGs) on VLU care. The basic information, recommendations for the VLUs, methodological quality, and reporting quality of VLU's CPGs were extracted and captured in Excel. The quality of each CPG was independently assessed by four researchers using AGREE II instrument and the RIGHT checklist. Critical Issues: This study included 19 CPGs with a combined 23 recommendations. The assessment of VLUs was summarized based on the recommendations of VLUs in 11 major items; six on VLU's diagnosis and six on therapeutic strategies of VLUs. The identified CPGs were of mixed quality, and the highest score based on the scope and purpose was 82.85 ± 11.66, whereas the lowest mean score based on the editorial independence by AGREE II was 59.93 ± 21.50. Regarding the RIGHT checklist, field one (basic information) had the highest reporting rate (84.33%), whereas field five (review and quality assurance) had the lowest quality of CPGs (41.11%). Future Directions: This evidence map provided new perspectives in the presentation of evidence. In addition, the evidence map collected and evaluated the characteristics of published CPGs. Thus, the evidence map enhances our knowledge and promotes the development of trustworthy CPGs for VLUs.

Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis.

We detected ENU-induced alleles of Mfsd1 (encoding the major facilitator superfamily domain containing 1 protein) that caused lymphopenia, splenomegaly, progressive liver pathology, and extramedullary hematopoiesis (EMH). MFSD1 is a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified association between MFSD1 and both GLMP (glycosylated lysosomal membrane protein) and GIMAP5 (GTPase of immunity-associated protein 5). Germline knockout alleles of Mfsd1, Glmp, and Gimap5 each caused lymphopenia, liver pathology, EMH, and lipid deposition in the bone marrow and liver. We found that the interactions of MFSD1 and GLMP with GIMAP5 are essential to maintain normal GIMAP5 expression, which in turn is critical to support lymphocyte development and liver homeostasis that suppresses EMH. These findings identify the protein complex MFSD1-GLMP-GIMAP5 operating in hematopoietic and extrahematopoietic tissues to regulate immunity and liver homeostasis.

Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.

Signals emanating from the T cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T cell function. Through forward genetic screening in mice, we discovered that loss-of-function mutations in LDL receptor related protein 10 ( Lrp10 ) caused naïve and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. Lrp10 was induced with T cell activation and its expression post-translationally suppressed IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhanced T cell homeostatic expansion through IL7R signaling. Lrp10 -deficient mice were also intrinsically resistant to syngeneic tumors. This phenotype depended on dense tumor infiltration of CD8 T cells that displayed increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.

Boosting the interfacial dynamics and thermodynamics in polyanion cathode by carbon dots for ultrafast-charging sodium ion batteries.

Ultrafast-charging is the focus of next-generation rechargeable batteries for widespread economic success by reducing the time cost. However, the poor ion diffusion rate, intrinsic electronic conductivity and structural stability of cathode materials seriously hinder the development of ultrafast-charging technology. To overcome these challenges, an interfacial dynamics and thermodynamics synergistic strategy is proposed to synchronously enhance the fast-charging capability and structural stability of polyanion cathode materials. As a case study, a Na3V2(PO4)3 composite (NVP/NSC) is successfully obtained by introducing an interface layer derived from N/S co-doped carbon dots. Density functional theory calculations validate that the interfacial bonding effect of V-N/S-C significantly reduces the Na+ transport energy barrier. D-band center theory analysis confirms the downward shift of the V d-band center enhances the strength of the V-O bond and considerably inhibits irreversible phase transformation. Benefitting from this interfacial synergistic strategy, NVP/NSC achieves a high capability and excellent cycling stability with a surprisingly low carbon content (2.23%) at an extremely high rate of 100C for 10 000 cycles (87.2 mA h g-1, 0.0028% capacity decay per cycle). Furthermore, a superior performance at 5C (115.3 mA h g-1, 92.1% capacity retention after 800 cycles) is exhibited by the NVP/NSC‖HC full cell. These findings provide timely new insights for the systematic design of ultrafast-charging cathode materials.

Evaluation of the efficacy and safety of nirmatrelvir/ritonavir co-administration inpatients with rheumatic disease infected with SARS-CoV-2: a real-world study.

Background: The breakthrough development of novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines and oral antivirals have played a critical role in curtailing the spread of the pandemic and dramatically reducing the morbidity and mortality rates among those infected. Among these oral antivirals, nirmatrelvir/ritonavir (NR) has been repurposed successfully for use against coronavirus disease-2019 (COVID-19) and is now readily available on the market with promising therapeutic effects. The availability of convenient and effective NR treatments for COVID-19 greatly mitigates the severity of the epidemic and contributes to an early end to the pandemic. Furthermore, certain patient subgroups, specifically those with rheumatic disease (RD) who are currently undergoing intensive immunodeficiency and/or immunosuppressive treatments, continue to be vulnerable and at a higher risk of experiencing severe consequences from COVID-19. Additionally, it has also been observed that NR exhibited prevalent drug-drug interactions of clinical significance, and more instances of COVID-19 rebound were being recognized with increasing frequency. Methods: A retrospective cohort study was conducted on a real-world RD population who were infected with SARS-CoV-2 and treated with NR. The time of symptom resolution, length of hospitalization, and response rate were assessed. Results were compared among the standard regimen and non-standard regimen groups, early NR regimen and late NR regimen groups, and the NR indication regimen and NR non-indication regimen groups. During the course, all grades of adverse drug reactions (ADRs) directly associated with NR administration and associated with drug-drug interactions (DDIs) were also monitored. Results: A total of 32 patients with RD, who were infected with SARS-CoV-2 and received NR, were retrospectively identified and divided into different groups. We found that the standard regimen group and the early NR regimen group had a shorter median time of symptom resolution compared to the control group [9.0 (interquartile range [IQR], 8.3-11.3) vs. 21.5 (IQR16.0-24.0) days, p < 0.001 and 9.0 (IQR 8.3-11.3) vs. 23.0 (IQR 18.0-24.0) days, p = 0.0]. We further found that even if the NR administration time exceeds 5 days, patients with RD who receive the NR indication regimen can still derive certain benefits from it. The proportion of patients who showed symptom improvement was higher in the NR indication regimen compared to the NR non-indication regimen group (n = 13/17 vs. 3/6, 76.5% vs. 50.0%) at the end of follow-up, and there was a statistical difference (p = 0.0) in the response rate of patients between the two groups. We also analyzed the effect of comorbidities on patient response rates and found that the percentage of patients who showed symptom improvement was higher in the group with <4 comorbidities compared to the group with ≥ 4 comorbidities (n = 7/7 vs. 16/25, 100.0% vs. 64.0%) at the end of follow-up. During the course, all grades of ADRs and grade ≥3ADRs directly associated with NR administration were not observed in any of the 32 cases. Despite discontinuing warfarin prior to NR application (using NR immediately on the first day of warfarin withdrawal), one patient still experienced an increased international normalized ratio [INR, 5.32(0.90-1.20)] and coagulation disorders (weak positive fecal occult blood test) on the second day after using NR. The INR levels decreased to nearly normal values, and coagulation disorders returned to normal after 2 days of discontinuing NR (the seventh day after the initial administration of NR). Conclusion: We showed NR therapy to be associated with a favorable outcome and an acceptable safety profile in an immunosuppressed population with RD during the Omicron surge. Early use of NR (within 5 days of symptom onset) could improve the prognosis of patients. NR administration for symptoms and confirmed SARS-CoV-2 infection after >5 days may also mitigate progression to severe disease and is a viable strategy. Our results highlight the importance of early utilization and/or NR indication, which may yield clinical advantages for patients with RD infected with SARS-CoV-2.

Essential requirement for IER3IP1 in B cell development.

In a forward genetic screen of mice with N-ethyl-N-nitrosourea-induced mutations for aberrant immune function, we identified animals with low percentages of B220+ cells in the peripheral blood. The causative mutation was in Ier3ip1, encoding immediate early response 3 interacting protein 1 (IER3IP1), an endoplasmic reticulum membrane protein mutated in an autosomal recessive neurodevelopmental disorder termed Microcephaly with simplified gyration, Epilepsy and permanent neonatal Diabetes Syndrome (MEDS) in humans. However, no immune function for IER3IP1 had previously been reported. The viable hypomorphic Ier3ip1 allele uncovered in this study, identical to a reported IER3IP1 variant in a MEDS patient, reveals an essential hematopoietic-intrinsic role for IER3IP1 in B cell development and function. We show that IER3IP1 forms a complex with the Golgi transmembrane protein 167A and limits activation of the unfolded protein response mediated by inositol-requiring enzyme-1α and X-box binding protein 1 in B cells. Our findings suggest that B cell deficiency may be a feature of MEDS.