Miracle-dz/UniFAR-FTUs huggingface dataset:
Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation.

Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B-lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naïve B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell cycle arrest. Further, short-term Notch2 blockade in vivo reversed division-independent differentiation potential and decreased transcript abundance for numerous mTORC1- and Myc-regulated genes. Myc loss compromised plasma cell differentiation for MZ B cells, and reciprocally induced ectopic mTORC1 signaling in follicular B cells enabled division-independent differentiation and plasma cell-affiliated gene expression. We conclude that ongoing in situ Notch2/mTORC1 signaling in MZ B cells establishes a unique cellular state that enables rapid division-independent plasma cell differentiation.
Ex vivo delivery of regulatory T-cells for control of alloimmune priming in the donor lung

Background Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T-cells (Tregs) are being studied as a cellular therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern. We hypothesised that in vitro-expanded recipient-derived Tregs can be delivered to donor lungs prior to LTx via ex vivo lung perfusion (EVLP), maintaining their immunomodulatory ability. Methods In a rat model, Wistar Kyoto (WKy) CD4+CD25high Tregs were expanded in vitro prior to EVLP. Expanded Tregs were administered to Fisher 344 (F344) donor lungs during EVLP; left lungs were transplanted into WKy recipients. Treg localisation and function post-transplant were assessed. In a proof-of-concept experiment, cryopreserved expanded human CD4+CD25+CD127low Tregs were thawed and injected into discarded human lungs during EVLP. Results Rat Tregs entered the lung parenchyma and retained suppressive function. Expanded Tregs had no adverse effect on donor lung physiology during EVLP; lung water as measured by wet-to-dry weight ratio was reduced by Treg therapy. The administered cells remained in the graft at 3 days post-transplant where they reduced activation of intra-graft effector CD4+ T-cells; these effects were diminished by day 7. Human Tregs entered the lung parenchyma during EVLP where they expressed key immunoregulatory molecules (CTLA4+, 4-1BB+, CD39+ and CD15s+). Conclusions Pre-transplant Treg administration can inhibit alloimmunity within the lung allograft at early time points post-transplant. Our organ-directed approach has potential for clinical translation. A recipient-derived lung allograft-directed regulatory T-cell therapy administered prior to transplantation is feasible in rat and human lungs and demonstrates evidence of immune regulation post-transplant https://bit.ly/3D8MCBo
Carrelizumab combined with anlotinib in the treatment of extensive-stage small cell lung cancer

Abstract Rationale: The emergence of immune checkpoint inhibitors has brought new breakthroughs in the treatment of small cell lung cancer (SCLC). Programmed cell death-ligand 1 inhibitors combined with chemotherapy have been approved for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). However, programmed death 1 inhibitors have limited efficacy in the treatment of SCLC. The reason may be related to the abnormal vascular state in the tumor microenvironment. Patient concerns: A 55-year-old male patient, presenting cough and sputum for 1 month. Diagnoses: The patient was clinically diagnosed with SCLC and staged as ES-SCLC. Interventions: Etoposide combined with lobaplatin treatment every 3 weeks for 4 cycles, evaluate as progressive disease. On the basis of the original plan, combined with camrelizumab for 2 cycles, evaluation as progressive disease. Then, the patient was treated with intravenous infusion of camrelizumab plus oral anlotinib. After 4 cycles, evaluation as partial response. Then we continued to use camrelizumab combined with anlotinib treatment for the patient. At the end of 26 cycles, the chest computed tomography examination revealed that the patient had achieved complete remission. Outcomes: After treated with carrelizumab combined with anlotinib for 26 cycles, the curative effect was evaluated as complete remission, progression-free survival was 24 months and there was no immune-related adverse reaction during treatment period. Besides, the patient developed complicated hand–foot syndrome, but this symptom was significantly relieved after reducing the dosage of anlotinib. Lessons: In this case, antiangiogenesis combined with programmed death 1 inhibitors significantly inhibited tumor progression. It also indicated that anlotinib concurrent carrelizumab may be a superior choice for ES-SCLC. Further clinical trials required to confifirm its effificacy and safety.
To mix or not to mix in allergy immunotherapy vaccines

Purpose of review European and US allergists generally do not agree on the approach to subcutaneous allergy immunotherapy in patients with multiple allergies. The North American approach is to treat with a mixture that contains all the allergen extracts to which the patient has evident clinical sensitivity, whereas the European approach is to select for treatment the one or at the most two allergens that are clinically most important for the patient. Recent findings Recent society guidelines continue to recommend these differing practices of treating the polyallergic patient and reviews of prescribing practices indicate these divergent recommendations are followed in Europe and the USA. Summary The objections by European allergists to the practice by US allergists are that multiallergen immunotherapy leads to dilution of allergens to less than effective doses, that proteases in some extracts can degrade allergens in other extracts, that there is a problem of safety and inability to determine which component extract caused a systemic reaction, and finally that there is alack of convincing studies demonstrating efficacy of multiallergen mixtures. Each of these contentions is addressed.
Tackling the ‘digital pandemic’: The effectiveness of psychological intervention strategies in problematic Internet and smartphone use—A meta-analysis

Objective: Problematic Internet and smartphone use is associated with serious mental health problems. We thus investigated the effectiveness of psychological interventions on problematic Internet and smartphone use. Methods: We conducted a systematic review and meta-analysis and searched in PubMed, PsyArticles, PsycInfo, Medline and Google Scholar for peer-reviewed experimental and quasi-experimental research published between 2008 and 2021. Results: A total of 10 studies accompanied by 14 effect sizes were included in the meta-analyses for problematic Internet use and 3 studies accompanied by 4 effect sizes for problematic smartphone use. The total sample size was n = 1439 with a mean age of 20.34 (SD = 6.63) years. Psychological interventions were effective for both problematic Internet use (g = −1.41, 95% confidence interval = [−1.90, −0.91], p < 0.001) and problematic smartphone use (g = −0.40, 95% confidence interval = [−0.79, −0.01], p < 0.001). Conclusion: Current evidence indicates that psychological interventions can be effective in reducing problematic Internet use/problematic smartphone use. However, the results must be considered preliminary due to the limited number of studies available in the respective fields.
Course of postoperative relapse in non‐small cell lung cancer is strongly associated with post‐progression survival

For early‐stage non‐small cell lung cancer (NSCLC), surgical resection is considered the most effective treatment strategy and curative treatment. Unfortunately, even after complete resection, almost half of all patients with stage I–IIIA NSCLC relapse and die. Although the possibility of a cure for postoperative recurrence of NSCLC is significantly low, the course of subsequent treatment can possibly affect overall survival (OS). Here, we examined the association of relapse‐free survival (RFS) and post‐progression survival (PPS) with OS in patients with postoperative recurrence of NSCLC.
Metal-Clad Waveguide Resonance Sensor Using a Mesoporous TiO2 Thin Film as the Chemical Sensitive Core Layer

A metal-clad optical waveguide sensor based on guided-mode resonance spectroscopy has been developed using a mesoporous TiO2 film as the chemical-sensitive core layer. The sol–gel block copolymer templated mesoporous TiO2 films are ∼275 nm thick, supporting both the transverse electric (TE) and transverse magnetic (TM) modes and thus providing the sensor with the TE- and TM-related dual sensitivities. Both the TE- and TM-mode resonance wavelengths (λR) at the same incident angle were obtained by broadband attenuated total reflection spectroscopy. The film porosity was determined to be ∼0.535 by using the combination of Fresnel formula and Bruggeman approximation to fit the measured values of λR. The TE- and TM-related sensitivities of the sensor to the two analytes of elaidic acid (EA) and Cr6+ were measured at the same incident angle. For each analyte, the TM-related sensitivity is higher than that with the TE-related one. The two sensitivities can be calibrated with each other. Moreover, by adjusting th.
Impact of Sitagliptin in Non-Diabetic Covid-19 Patients.

OBJECTIVE In Coronavirus disease 2019 (Covid-19), SARS-CoV-2 may use dipeptidyl peptidase 4 (DPP4) as an entry-point in different tissues expressing these receptors. DPP4 inhibitors (DPP4Is), also named gliptins like sitagliptin, have anti-inflammatory and antioxidant effects; thereby lessen inflammatory and oxidative stress in diabetic Covid-19 patients. Therefore, the present study aimed to illustrate the potential beneficial effect of sitagliptin in managing Covid-19 in non-diabetic patients. METHODS A total number of 89 patients with Covid-19 were recruited from a single-center at the time of diagnosis. The recruited patients were assigned according to the standard therapy for Covid-19 and our interventional therapy into two groups; Group A: Covid-19 patients on the standard therapy (n=40) and Group B: Covid-19 patients on the standard therapy plus sitagliptin (n=49). The duration of this interventional study was 28 days according to the guideline in management patients with Covid-19. Routine laboratory investigations, serological tests, complete blood count (CBC), C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), and serum ferritin were measured to observed Covid-19 severity and complications. Lung computed tomography (CT) and clinical scores were evaluated. RESULTS The present study illustrated that sitagliptin add-on standard therapy improved clinical outcomes, radiological scores, and inflammatory biomarkers than standard therapy alone in non-diabetic patients with Covid-19 (P<0.01). CONCLUSIONS Sitagliptin add-on standard therapy in managing non-diabetic Covid-19 patients may have a robust beneficial effect by modulating inflammatory cytokines with subsequent good clinical outcomes.
Development of lower limb training interventions that promote an external focus of attention in people with stroke: a modified Delphi survey

ABSTRACT Objective To produce guidance and validated examples of tasks that promote an external focus of attention, for use in lower limb rehabilitation in an inpatient stroke care setting. Design Electronic survey, using e-Delphi methodology. Participants A multi-professional expert panel of 14 clinicians and researchers, with expertise in stroke rehabilitation and/or motor learning. Method Each survey round consisted of two parts: 1) classification of specific exercise examples, shown using video and 2) the categorization of specific tratement adjuncts. The panel was asked to comment on: likely focus of attention of the performer; instructions that would promote an external focus of attention; and how the task set-up could be modified to promote an external focus of attention. Rounds 2 and 3 included a summary of results from the previous round, and revised/new examples. The panel were also asked to state their level of agreement with a series of statements that arose from the free text. Three rounds of survey were completed and the a priori threshold for agreement was set at 80%. Results Eighteen iterations of exercises were presented, and 12 were accepted as promoting an external focus of attention. In addition, six additional statements were generated based on open responses, leading to further specific guidance on facilitating an external focus of attention in clinical practice. Conclusions Commonly used rehabilitation exercises can be adapted to promote an external focus of attention, by altering the therapist’s use of instructions and/or altering the task set up. Treatment principles and examples of tasks that promote an external focus have been produced.
Management of a multiple endocrine neoplasia type 1 during pregnancy: a case with primary hypertension

Abstract Multiple endocrine neoplasia type 1 (MEN 1) is a rare hereditary disease which transmitted as autosomal dominant disorder with high penetrance. MEN1 includes vary combinations of more than 20 endocrine and non-endocrine tumors. Clinically, MEN1 is characterized by tumor or hyperplasia in two or more endocrine tissues (parathyroid, pituitary, pancreas, adrenal glands). Since it is a rare condition, there are no guidelines with respect to the follow-up of pregnant women with MEN 1, here we the first Asian case of a 32-year-old primigravida with a confirmed diagnosis of MEN1 and primary hypertension prior to conception, cesarean section was performed at 34+2 weeks for severe preeclampsia and potential risks, both the patient and fetus recovered well.
Deep-time climate legacies affect origination rates of marine genera

Significance The effect of climate change on biodiversity is dependent on previous climatic trends. For example, climate warming is more deleterious when added to a long-term warming trend. We tested how the interaction of short- and long-term climate change affects origination rates through time. Using data from the marine fossil record, we show that origination rates in the last 485 million years tend to increase when climate cooling is superimposed on longer-term cooling trends. These findings might clarify the ongoing debate on the relationship between climate and origination and underline the complexity of evolutionary dynamics and the presence of intricate interactions in Earth’s system. Biodiversity dynamics are shaped by a complex interplay between current conditions and historic legacy. The interaction of short- and long-term climate change may mask the true relationship of evolutionary responses to climate change if not specifically accounted for. These paleoclimate interactions have been demonstrated for extinction risk and biodiversity change, but their importance for origination dynamics remains untested. Here, we show that origination probability in marine fossil genera is strongly affected by paleoclimate interactions. Overall, origination probability increases by 27.8% [95% CI (27.4%, 28.3%)] when a short-term cooling adds to a long-term cooling trend. This large effect is consistent through time and all studied groups. The mechanisms of the detected effect might be manifold but are likely connected to increased allopatric speciation with eustatic sea level drop caused by sustained global cooling. We tested this potential mechanism through which paleoclimate interactions can act on origination rates by additionally examining a proxy for habitat fragmentation. This proxy, continental fragmentation, has a similar effect on origination rates as paleoclimate interactions, supporting the importance of allopatric speciation through habitat fragmentation in the deep-time fossil record. The identified complex nature of paleoclimate interactions might explain contradictory conclusions on the relationship between temperature and origination in the previous literature. Our results highlight the need to account for complex interactions in evolutionary studies both between and among biotic and abiotic factors.
External treatment of traditional Chinese medicine for constipation after thoracolumbar compression fractures

Abstract Background: Constipation is one of the common complications of thoracolumbar compression fractures, which seriously affects the quality of life and increases pain of patients. External treatment of traditional Chinese medicine (TCM) has been widely used clinically for constipation after thoracolumbar compression fractures, but there are no systematic review and meta-analysis of its efficacy. Therefore, we will conduct this study to systematically evaluate the clinical effects of external treatment of TCM for patients with constipation after thoracolumbar compression fractures. Methods: We will search the following electronic databases: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infastructure, Chinese Biomedical Literatures Database, Chinese Scientific Journal Database, and Wanfang Database. Randomized controlled trials on the treatment of constipation after thoracolumbar compression fractures with external treatment of TCM published from inception to May 2021 will be included in the search scope. The observation group was treated with Simple external treatment of TCM (such as external application of Chinese medicine, Chinese drugs at the acupoint, acupuncture, moxibustion, etc) or external treatment of TCM combined with conventional treatment/nursing of Western medicine, while the control group only was treated by conventional treatment/nursing of Western medicine. After screening literatures, extracting data, and assessing the risk of bias in the included studies, meta-analysis will be performed by Revman 5.3 software. Results: This study is expected to provide an evidence of the efficacy of external treatment of TCM for constipation after thoracolumbar compression fractures. Conclusion: The results of this meta-analysis may help provide evidence to determine whether external treatment of TCM can be effective interventions for thoracolumbar compression fractures patients with constipation. Trial registration number: INPLASY202150005
Using interview surveys and multispecies occupancy models to inform vertebrate conservation

Species distribution data are an essential biodiversity variable requiring robust monitoring to inform wildlife conservation. Yet, such data remain inherently sparse because of the logistical challenges of monitoring biodiversity across broad geographic extents. Surveys of people knowledgeable about the occurrence of wildlife provide an opportunity to evaluate species distributions and the ecology of wildlife communities across large spatial scales. We analyzed detection histories of 30 vertebrate species across the Western Ghats biodiversity hotspot in India, obtained from a large‐scale interview survey of 2318 people who live and work in the forests of this region. We developed a multispecies occupancy model that simultaneously corrected for false‐negative (non‐detection) and false‐positive (misidentification) errors that interview surveys can be prone to. Using this model, we integrated data across species in composite analyses of the responses of functional species groups (based on disturbance tolerance, diet, and body mass traits) to spatial variation in environmental variables, protection, and anthropogenic pressures. We observed a positive association between forest cover and the occurrence of species with low tolerance of human disturbance. Protected areas were associated with higher occurrence for species across different functional groups compared with unprotected lands. We also observed the occurrence of species with low disturbance tolerance, herbivores, and large‐bodied species was negatively associated with developmental pressures, such as human settlements, energy production and mining, and demographic pressures, such as biological resource extraction. For the conservation of threatened vertebrates, our work underscores the importance of maintaining forest cover and reducing deforestation within and outside protected areas, respectively. In addition, mitigating a suite of pervasive human pressures is also crucial for wildlife conservation in one of the world's most densely populated biodiversity hotspots.
Physical Activity and Its Association with Traditional Outcome Measures in Pulmonary Arterial Hypertension.

Rationale Limitation of physical activity is a common presenting complaint for patients with pulmonary arterial hypertension (PAH). Physical activity is thought to be determined by cardiopulmonary function, yet there are limited data that investigate this relationship. Objective We aimed to study the relationship between right ventricular function and daily activity and its impact on health-related quality of life (HRQoL) in PAH. Methods Baseline data for 55 patients enrolled in PHANTOM, an ongoing multicenter randomized controlled trial of anastrozole in PAH were used. Post-menopausal women and men were eligible and underwent six-minute walk testing, echocardiography and completed HRQoL questionnaires. Each patient wore an accelerometer for 7-days. Multivariable linear regression models were used to study the association between tricuspid annular plane systolic excursion (TAPSE) and vector magnitude counts, and between daily activity and HRQoL. Principal component analysis and K-means clustering were used to identify activity-based phenotypes. K-nearest neighbors' classification was applied to an independent cross-sectional cohort from the University of Pennsylvania. Results The mean age of patients in PHANTOM was 61 years. 67% were women with idiopathic PAH as the most common etiology. A 0.4 cm increase in TAPSE was associated with an increase in daily vector magnitude counts (ß:34000, 95%CI:900-67000, p=0.004) after adjustment for age, sex, body mass index, etiology of PAH and wear time. A 1-standard deviation increase in vector magnitude counts was associated with higher six-minute walk distance (ß: 56.1 meters, 95%CI:28.6-83.7, p<0.001) and lower emPHasis-10 scores (ß:-3.3, 95%CI:0.3-6.4, p=0.03). Three activity phenotypes, low, medium, and high, were identified. The most active phenotype had greater six-minute walk distances (p=0.001) and lower emPHasis-10 scores (p=0.009) after adjustment for age, sex, body mass index, WHO functional class and parenteral prostacyclin use. Phenotypes of physical activity were reproduced in the second cohort and were independently associated with six-minute walk distance. Conclusion Better right ventricular systolic function was associated with increased levels of activity in PAH. Increased daily activity was associated with greater six-minute walk distance and better HRQoL. Distinct activity-based phenotypes may be helpful in risk stratification of PAH patients or provide novel endpoints for clinical trials.