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Abstract Objectives This study aimed to analyse the value of pre-operative 18F-fluorodeoxyglucose positron emission tomography (PET)-computed tomography that can predict tumour pathological complete response, tumour histology grade, overall survival, and recurrence-free survival in patients with locally advanced oesophageal squamous cell carcinoma who underwent neoadjuvant chemoradiotherapy (NCRT) followed by surgery. Methods We retrospectively reviewed the cases of patients with locally advanced oesophageal squamous cell carcinoma undergoing NCRT followed by surgery. Patients who did not undergo PET within 3 months of surgery were excluded. We set a pre-operative PET maximum standardised uptake value (SUVmax) of > 5 as the threshold and classified the patients into two groups. We analysed the tumour response and histology grade, and compared the overall survival and recurrence-free survival between the two groups. Results This cohort included 92 patients with oesophageal squamous cell carcinoma who underwent NCRT followed by surgery; 49 patients had a pre-operative PET SUVmax 5. The patients’ pre-operative PET SUVmax correlated with tumour histology, ypT stage, and tumour response. Patients with a pre-operative SUVmax 5. Conclusions Pre-operative SUVmax may be useful to predict tumour response, survival, and recurrence in patients with locally advanced oesophageal squamous cell carcinoma who undergo NCRT followed by surgery.

Abstract Purpose The present study aimed to propose a modified intra-articular transtendinous looped biceps tenodesis (mTLBT) using a suture anchor and to compare the functional outcomes and incidence of Popeye deformities between biceps tenotomy and mTLBT. Methods Medical records of patients who underwent either tenotomy or mTLBT for the long head of the biceps tendon (LHBT) lesion between January 2016 and April 2021 were retrospectively reviewed. The inclusion criteria were patients aged 40–70 years with LHBT pathologies, such as superior labrum anterior to posterior (SLAP) lesions > type II, LHBT pulley system rupture with bicipital instability, and intra-articular LHBT tear. The exclusion criteria were full-thickness supraspinatus tears, frozen shoulder, shoulder fracture, and postoperative traumatic events that affected the operated shoulder. All patients were followed up for at least 1 year. Popeye deformity, bicipital cramping pain, visual analog scale (VAS) pain score, and functional outcome scores (University of California at Los Angeles [UCLA] and American Shoulder and Elbow Surgeons [ASES] scores) were recorded. Fisher’s exact test and Chi-square test were used for categorical variables, whereas the Mann–Whitney U test was used for nonparametric variables. Results The mTLBT and tenotomy groups included 15 and 40 patients, respectively. The incidence of Popeye deformity and biceps cramping pain in the tenotomy group (52.5% and 50%, respectively) was significantly higher than that in the mTLBT group (13.3% and 20%, respectively) (p = 0.009 and p = 0.045, respectively). The postoperative VAS, UCLA, and ASES scores were not significantly different between the two groups. One patient in the tenodesis group experienced metallic-anchor pullout. Conclusion mTLBT is an arthroscopic intra-articular top of the groove tenodesis that can be performed completely in the intra-articular space and is especially suitable for patients with an intact or partially torn rotator cuff. This technique is reliable for treating biceps pathologies as it results in similar functional outcome scores, lesser biceps cramping pain, and less frequent Popeye deformity compared to biceps tenotomy. Level of Evidence III.

Abstract Background An eye injury that causes no light perception (NLP) typically carries an unfavorable prognosis, and NLP because of trauma is a common indication for enucleation. With advances in vitreoretinal surgical techniques, however, the indication for enucleation is no longer determined by posttrauma NLP vision alone. There are limited studies in the literature to analyse the outcome of NLP eyes following open globe injury. The current study was aimed to evaluate the outcome of surgical repair of severely traumatized eyes with no light perception vision as preoperative visual acuity. Secondary objective was to possibly predict the factors affecting the final vision outcome in this eyes. Methods Retrospective case analysis of patients with surgical repair of open globe injury over last ten years at a tertiary referral eye care centre in Singapore. Results Out of one hundred and seventy two eyes with open globe injury 27 (15.7%) eyes had no light perception (NLP). After surgical repair, final visual acuity remained NLP in 18 (66.7%) eyes. Final vision improved to Light perception/ Hand movement (LP/HM) in 2(7.4%) eyes, 1/200 to 19/200(11.1%) in 3 eyes and 20/50-20/200(14.8%) in 4 eyes. The median follow up was 18.9 months (range: 4–60 months). The factors contributing to poor postoperative outcome were presence of RAPD (p = 0.014), wound extending into zone III (p = 0.023) and associated vitreoretinal trauma (p = 0.008). Conclusions One third of eyes had ambulatory vision or better though two third of eyes still remained NLP. Pre-operative visual acuity of NLP should not be an indication for primary enucleation or evisceration for severely traumatized eyes. Presence of afferent papillary defect, wound extending posterior to rectus insertion and associated vitreoretinal trauma can adversely affect the outcome in severely traumatized eyes with NLP. Timely intervention and state of art surgery may restore useful vision in severely traumatized eyes.

Abstract Objectives Health-Significant Quality of Life Measure (Health-SigQOLM) provides a generic and dynamic assessment of Health-related quality of life (HRQOL). This study aims to assess the HRQOL among healthy and non-healthy participants with varying chronic diseases. Results Comparisons between healthy and non-healthy participants revealed statistically significant differences (p

Abstract Background The low tube-voltage technique (e.g., 80 kV) can efficiently reduce the radiation dose and increase the contrast enhancement of vascular and parenchymal structures in abdominal CT. However, a high tube current is always required in this setting and limits the dose reduction potential. This study investigated the feasibility of a deep learning iterative reconstruction algorithm (Deep IR) in reducing the radiation dose while improving the image quality for abdominal computed tomography (CT) with low tube voltage and current. Methods Sixty patients (male/female, 36/24; Age, 57.72 ± 10.19 years) undergoing the abdominal portal venous phase CT were randomly divided into groups A (100 kV, automatic exposure control [AEC] with reference tube-current of 213 mAs) and B (80 kV, AEC with reference of 130 mAs). Images were reconstructed via hybrid iterative reconstruction (HIR) and Deep IR (levels 1–5). The mean CT and standard deviation (SD) values of four regions of interest (ROI), i.e. liver, spleen, main portal vein and erector spinae at the porta hepatis level in each image serial were measured, and the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. The image quality was subjectively scored by two radiologists using a 5-point criterion. Results A significant reduction in the radiation dose of 69.94% (5.09 ± 0.91 mSv vs. 1.53 ± 0.37 mSv) was detected in Group B compared with Group A. After application of the Deep IR, there was no significant change in the CT value, but the SD gradually increased. Group B had higher CT values than group A, and the portal vein CT values significantly differed between the groups (P

Abstract Introduction Intestinal obstruction is a common complication in patients with advanced malignancies, often attributed to the disease itself or as a side effect of opioid analgesics used for pain management. However, the occurrence of intestinal obstruction following antituberculosis therapy is rare. Case presentation We report a unique case of a 58-year-old Asian male diagnosed with stage IV pancreatic carcinoma and pulmonary tuberculosis. The patient was initiated on a regimen of ethambutol hydrochloride, pyrazinamide, rifampicin, and isoniazid tablets (II) for tuberculosis, alongside morphine for the management of severe cancer-related pain. Subsequently, he developed symptoms indicative of intestinal obstruction. Despite discontinuation of morphine, the patient’s symptoms persisted until he autonomously ceased all medications, leading to a rapid improvement in his condition. This unexpected resolution highlighted the antituberculosis drugs as the probable cause of his intestinal obstruction. Conclusions This case underscores the importance of considering antituberculosis drugs as a potential cause of intestinal obstruction, especially in patients who do not respond to conventional management strategies for drug-induced gastrointestinal side effects. It also emphasizes the need for heightened vigilance and monitoring when prescribing these medications to patients with advanced malignancies, to promptly identify and address rare but significant side effects.

Abstract Background Chronic kidney disease (CKD) is a significant risk factor for pulmonary hypertension (PH), a complication that adversely affects patient prognosis. However, the mechanisms underlying this association remain poorly understood. A major obstacle to progress in this field is the lack of a reliable animal model replicating CKD-PH. Methods This study aimed to establish a stable rat model of CKD-PH. We employed a combined approach, inducing CKD through a 5/6 nephrectomy and concurrently exposing the rats to a high-salt diet. The model's hemodynamics were evaluated dynamically, alongside a comprehensive assessment of pathological changes in multiple organs. Lung tissues and serum samples were collected from the CKD-PH rats to analyze the expression of angiotensin-converting enzyme 2 (ACE2), evaluate the activity of key vascular components within the renin–angiotensin–aldosterone system (RAAS), and characterize alterations in the serum metabolic profile. Results At 14 weeks post-surgery, the CKD-PH rats displayed significant changes in hemodynamic parameters indicative of pulmonary arterial hypertension. Additionally, right ventricular hypertrophy was observed. Notably, no evidence of pulmonary vascular remodeling was found. Further analysis revealed RAAS dysregulation and downregulated ACE2 expression within the pulmonary vascular endothelium of CKD-PH rats. Moreover, the serum metabolic profile of these animals differed markedly from the sham surgery group. Conclusions Our findings suggest that the development of pulmonary arterial hypertension in CKD-PH rats is likely a consequence of a combined effect: RAAS dysregulation, decreased ACE2 expression in pulmonary vascular endothelial cells, and metabolic disturbances. Graphical Abstract

Abstract Objective The “Health” element is one of the elements in Significant Quality of Life Measure (SigQOLM) that measures quality of life and well-being of people. This study aims to evaluate the Health element (Health-SigQOLM) as a generic and dynamic scale to measure health-related quality of life (HRQOL) with a broader spectrum of coverage. This study used a secondary data that developed SigQOLM. Only the “Health” element with 33 items is used for analysis. Results The construct of Health-SigQOLM has a minimum factor loading of 0.425 with excellent model fit. The health status among healthcare workers is significantly associated with the Health-SigQOLM (p

Abstract Background Cystic echinococcosis (CE) is a widespread zoonosis caused by the infection with Echinococcus granulosus sensu lato (E. granulosus s.l.). CE cysts mainly develop in the liver of intermediate hosts, characterized by the fibrotic tissue that separates host organ from parasite. However, precise mechanism underlying the formation of fibrotic tissue in CE remains unclear. Methods To investigate the potential impact of ubiquitin-conjugating enzymes on liver fibrosis formation in CE, two members of ubiquitin-conjugating (UBC) enzyme of Echinococcus granulosus (EgE2D2 and EgE2N) were recombinantly expressed in Escherichia coli and analyzed for bioinformatics, immunogenicity, localization, and enzyme activity. In addition, the secretory pathway and their effects on the formation of liver fibrosis were also explored. Results Both rEgE2D2 and rEgE2N possess intact UBC domains and active sites, exhibiting classical ubiquitin binding activity and strong immunoreactivity. Additionally, EgE2D2 and EgE2N were widely distributed in protoscoleces and germinal layer, with differences observed in their distribution in 25-day strobilated worms. Further, these two enzymes were secreted to the hydatid fluid and CE-infected sheep liver tissues via a non-classical secretory pathway. Notably, TGFβ1-induced LX-2 cells exposed to rEgE2D2 and rEgE2N resulted in increasing expression of fibrosis-related genes, enhancing cell proliferation, and facilitating cell migration. Conclusions Our findings suggest that EgE2D2 and EgE2N could secrete into the liver and may interact with hepatic stellate cells, thereby promoting the formation of liver fibrosis. Graphical Abstract

Abstract Background Clinical practicums are a core component of baccalaureate nursing education. Following the coronavirus pandemic, there have been extensive changes in the workforce environment that may potentially affect nursing students’ experience and readiness for clinical practicums. Methods A qualitative study was conducted to explore final-year nursing students’ experiences and readiness for their final clinical practicum before becoming a registered nurse. A purposive sample of 24 final-year baccalaureate nursing students was included in this study. Individual semi-structured interviews were conducted face-to-face via Zoom. The data was analysed using an inductive thematic analysis approach. Results Three themes depicting students’ experiences and clinical readiness were elucidated. The themes included: (1) Experiencing multiple concerns, (2) requiring a network of support, and (3) easing the transition to professional practice. Students considered the final clinical practicum as challenging and demanding which evoked numerous concerns. Conclusions Considering the stress that final-year nursing students experience, it will be important to devise strategies ranging from personal, relational, and environmental protective factors to enable their successful transition and completion of clinical practice.

Abstract Background Generalizability of predictive models for pathological complete response (pCR) and overall survival (OS) in breast cancer patients requires diverse datasets. This study employed four machine learning models to predict pCR and OS up to 7.5 years using data from a diverse and underserved inner-city population. Methods Demographics, staging, tumor subtypes, income, insurance status, and data from radiology reports were obtained from 475 breast cancer patients on neoadjuvant chemotherapy in an inner-city health system (01/01/2012 to 12/31/2021). Logistic regression, Neural Network, Random Forest, and Gradient Boosted Regression models were used to predict outcomes (pCR and OS) with fivefold cross validation. Results pCR was not associated with age, race, ethnicity, tumor staging, Nottingham grade, income, and insurance status (p > 0.05). ER−/HER2+ showed the highest pCR rate, followed by triple negative, ER+/HER2+, and ER+/HER2− (all p 0.05). Machine learning models ranked tumor stage, pCR, nodal stage, and triple-negative subtype as top predictors of OS (AUC = 0.83–0.85). When grouping race and ethnicity by tumor subtypes, neither OS nor pCR were different due to race and ethnicity for each tumor subtype (p > 0.05). Conclusion Tumor subtypes and imaging characteristics were top predictors of pCR in our inner-city population. Insurance status, race, tumor subtypes and pCR were associated with OS. Machine learning models accurately predicted pCR and OS.

Abstract Background G-protein coupled receptors (GPCRs) are recognized as attractive targets for drug therapy. However, it remains poorly understood how GPCRs, except for a few chemokine receptors, regulate the progression of liver fibrosis. Here, we aimed to reveal the role of GPR65, a proton-sensing receptor, in liver fibrosis and to elucidate the underlying mechanism. Methods The expression level of GPR65 was evaluated in both human and mouse fibrotic livers. Furthermore, Gpr65-deficient mice were treated with either bile duct ligation (BDL) for 21 d or carbon tetrachloride (CCl4) for 8 weeks to investigate the role of GPR65 in liver fibrosis. A combination of experimental approaches, including Western blotting, quantitative real-time reverse transcription‑polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and rescue studies, were used to explore the underlying mechanisms of GPR65’s action in liver fibrosis. Additionally, the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated. Results We found that hepatic macrophages (HMs)-enriched GPR65 was upregulated in both human and mouse fibrotic livers. Moreover, knockout of Gpr65 significantly alleviated BDL- and CCl4-induced liver inflammation, injury and fibrosis in vivo, and mouse bone marrow transplantation (BMT) experiments further demonstrated that the protective effect of Gpr65 knockout is primarily mediated by bone marrow-derived macrophages (BMMs). Additionally, in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited, while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-β (TGF-β), all of which subsequently promoted the activation of hepatic stellate cells (HSCs) and the damage of hepatocytes (HCs). Mechanistically, GPR65 overexpression, the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-α and IL-6 via the Gαq-Ca2+-JNK/NF-κB pathways, while promoted the expression of TGF-β through the Gαq-Ca2+-MLK3-MKK7-JNK pathway. Notably, pharmacological GPR65 inhibition retarded the development of inflammation, HCs injury and fibrosis in vivo. Conclusions GPR65 is a major regulator that modulates the progression of liver fibrosis. Thus, targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis.

Abstract Background Hepatic fibrosis is a common consequence of chronic liver diseases without approved antifibrotic therapies. Long noncoding RNAs (lncRNAs) play an important role in various pathophysiological processes. However, the functions of certain lncRNAs involved in mediating the antifibrotic role remain largely unclear. Methods The RNA level of lnc-High Expressed in Liver Fibrosis (Helf) was detected in both mouse and human fibrotic livers. Furthermore, lnc-Helf-silenced mice were treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL) to investigate the function of lnc-Helf in liver fibrosis. Results We found that lnc-Helf has significantly higher expression in human and mouse fibrotic livers as well as M1 polarized hepatic macrophages (HMs) and activated hepatic stellate cells (HSCs). In vivo studies showed that silencing lnc-Helf by AAV8 vector alleviates CCl4- and BDL-induced hepatic inflammation and fibrosis. Furthermore, in vitro experiments revealed that lnc-Helf promotes HSCs activation and proliferation, as well as HMs M1 polarization and proliferation in the absence or presence of cytokine stimulation. Mechanistically, our data illustrated that lnc-Helf interacts with RNA binding protein PTBP1 to promote its interaction with PIK3R5 mRNA, resulting in increased stability and activating the AKT pathway, thus promoting HSCs and HMs activation and proliferation, which augments hepatic inflammation and fibrosis. Conclusion Our results unveil a lnc-Helf/PTBP1/PIK3R5/AKT feedforward, amplifying signaling that exacerbates the process of hepatic inflammation and fibrosis, thus providing a possible therapeutic strategy for hepatic fibrosis.

Abstract Background The relationship between sleep disturbances and lung cancer is complex and bidirectional. This meta-epidemiological study aimed to explore the potential association between sleep disruption and the risk of pulmonary cancer. Methods We conducted a comprehensive literature search of the PubMed, Embase, Cochrane Library, and Web of Science databases to retrieve relevant studies. We employed the Newcastle–Ottawa Scale to assess the quality of the observational studies. Stata 17.0 was used to synthesize and conduct a meta-analysis of odds ratios (ORs) and corresponding 95% confidence intervals (CIs). We used funnel plot analysis and Egger’s regression test to evaluate potential publication bias. Results A total of 11 studies were included with 469,691 participants. The methodological quality of the included studies ranged from moderate to high. Compared with 7–8 h of sleep time, short sleep duration was associated with a 13% higher lung cancer risk [OR, 1.13; 95%CI: 1.02–1.25; I2 = 67.6%; P = 0.018] and long sleep duration with a 22% higher risk [OR, 1.22; 95%CI: 1.12–1.33; I2 = 6.9%; P

Abstract Right heart failure is the leading cause of death in pulmonary hypertension (PH), and echocardiography is a commonly used tool for evaluating the risk hierarchy of PH. However, few studies have explored the dynamic changes in the structural and functional changes of the right heart during the process of PH. Previous studies have found that pulmonary circulation coupling right ventricular adaptation depends on the degree of pressure overload and other factors. In this study, we performed a time-dependent evaluation of right heart functional changes using transthoracic echocardiography in a SU5416 plus hypoxia (SuHx)-induced PH rat model. Rats were examined in 1-, 2-, 4-, and 6-week using right-heart catheterization, cardiac echocardiography, and harvested heart tissue. Our study found that echocardiographic measures of the right ventricle (RV) gradually worsened with the increase of right ventricular systolic pressure, and right heart hypofunction occurred at an earlier stage than pulmonary artery thickening during the development of PH. Furthermore, sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2), a marker of myocardial damage, was highly expressed in week 2 of SuHx-induced PH and had higher levels of expression of γ-H2AX at all timepoints, as well as higher levels of DDR-related proteins p-ATM and p53/p-p53 and p21 in week 4 and week 6. Our study demonstrates that the structure and function of the RV begin to deteriorate with DNA damage and cellular senescence during the early stages of PH development.

Abstract Background L-type Ca2+ channel CaV1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac CaV1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of CaV1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how CaV1.2 channels are alternatively spliced in diabetic heart remains unknown. Methods Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac CaV1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca2+ concentration was monitored by using Fluo-4 AM. Results We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased CaV1.2 channel with alternative exon 9* (CaV1.2E9*), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of CaV1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates CaV1.2E9* channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac CaV1.2 channels. Moreover, GS treatment raises K+-triggered intracellular Ca2+ concentration ([Ca2+]i), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates CaV1.2E9* channel, shifts CaV1.2 window currents to hyperpolarization, increases [Ca2+]i and induces cardiomyocyte hypertrophy. Conclusions AGEs, not glucose, dysregulates Rbfox2 which thereby increases CaV1.2E9* channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca2+]i in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for CaV1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced CaV1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.

Abstract Background Human babesiosis is a worldwide disease caused by intraerythrocytic protozoa of the genus Babesia. It is transmitted by bites from ixodid ticks, and mechanically transmitted by blood transfusion. It is primarily treated with quinine and/or atovaquone, which are not readily available in China. In this study, we developed a novel treatment regimen involving doxycycline monotherapy in a patient with severe Babesia venatorum infection as an alternative therapeutic medication. The aim of our study is to provide a guidance for clinical practice treatment of human babesiosis. Case presentation A 73-year-old man who had undergone splenectomy and blood transfusion 8 years prior, presented with an unexplained fever, headache, and thrombocytopenia, and was admitted to the Fifth Medical Center of the PLA General Hospital. He was diagnosed with B. venatorum infection by morphological review of thin peripheral blood smears, which was confirmed by multi-gene polymerase chain reaction (PCR), and sequencing of the entire 18s rRNA and partial β-tubulin encoding genes, as well as isolation by animal inoculation. The doxycycline monotherapy regimen (peros, 0.1 g bisindie) was administered following pharmacological guidance and an effective outcome was observed. The patient recovered rapidly following the doxycycline monotherapy. The protozoan load in peripheral blood samples decreased by 88% in hematocrit counts after 8 days, and negative PCR results were obtained after 90 days of follow-up at the hospital. The treatment lasted for 3 months without any side effects or sequelae. The nine-month follow-up survey of the patient did not reveal any signs of recrudescence or anti-babesial tolerance. Conclusions We have reported a clinical case of successful doxycycline monotherapy for human babesiosis caused by B. venatorum, which provides an optional medical intervention for human babesiosis. Graphical Abstract

Abstract Background There is an increasing focus over time on the discovery and validation of biomarkers in cancer medicine, which can inform the identification of patients that are most likely to benefit from treatment, which therapy is most likely to be effective, and treatments that may not be safe. Body Creating the necessary evidence base for biomarker-informed management is a different challenge to developing a new therapy, and many biomarkers have been adopted into routine clinical practice without phase III randomised studies where the primary endpoint was to evaluate the direct impact of a biomarker-informed approach. This has generated a robust discussion in the research and clinical community regarding the most appropriate trial methodologies for biomarker validation, and the level of evidence required to support the incorporation of individual biomarker-driven approaches as a standard of care. This ongoing debate is key to optimising clinical trial design and ultimately delivering the best possible care to patients in an environment increasingly focused on personalised and patient-focused management. Conclusion Ongoing deliberation as to the optimal design of biomarker-driven clinical trials is critical to informing future clinical trial design and will ultimately greatly benefit patients and the clinicians that care for them.

Abstract Despite ongoing debate, the amyloid β-protein (Aβ) remains the prime therapeutic target for the treatment of Alzheimer’s disease (AD). However, rational drug design has been hampered by a lack of knowledge about neuroactive Aβ. To help address this deficit, we developed live-cell imaging of iPSC-derived human neurons (iNs) to study the effects of the most disease relevant form of Aβ-oligomeric assemblies (oAβ) extracted from AD brain. Of ten brains studied, extracts from nine caused neuritotoxicity, and in eight cases this was abrogated by Aβ immunodepletion. Here we show that activity in this bioassay agrees relatively well with disruption of hippocampal long-term potentiation, a correlate of learning and memory, and that measurement of neurotoxic oAβ can be obscured by more abundant non-toxic forms of Aβ. These findings indicate that the development of novel Aβ targeting therapeutics may benefit from unbiased activity-based discovery. To test this principle, we directly compared 5 clinical antibodies (aducanumab, bapineuzumab, BAN2401, gantenerumab, and SAR228810) together with an in-house aggregate-preferring antibody (1C22) and established relative EC50s in protecting human neurons from human Aβ. The results yielded objective numerical data on the potency of each antibody in neutralizing human oAβ neuritotoxicity. Their relative efficacies in this morphological assay were paralleled by their functional ability to rescue oAβ-induced inhibition of hippocampal synaptic plasticity. This novel paradigm provides an unbiased, all-human system for selecting candidate antibodies for advancement to human immunotherapy.

Abstract Background Neural stem cells (NSCs) are considered as candidates for cell replacement therapy in many neurological disorders. However, the propensity for their differentiation to proceed more glial rather than neuronal phenotypes in pathological conditions limits positive outcomes of reparative transplantation. Exogenous physical stimulation to favor the neuronal differentiation of NSCs without extra chemical side effect could alleviate the problem, providing a safe and highly efficient cell therapy to accelerate neurological recovery following neuronal injuries. Results With 7-day physiological electric field (EF) stimulation at 100 mV/mm, we recorded the boosted neuronal differentiation of NSCs, comparing to the non-EF treated cells with 2.3-fold higher MAP2 positive cell ratio, 1.6-fold longer neuronal process and 2.4-fold higher cells ratio with neuronal spontaneous action potential. While with the classical medium induction, the neuronal spontaneous potential may only achieve after 21-day induction. Deficiency of either PI3Kγ or β-catenin abolished the above improvement, demonstrating the requirement of the PI3K/Akt/GSK-3β/β-catenin cascade activation in the physiological EF stimulation boosted neuronal differentiation of NSCs. When transplanted into the spinal cord injury (SCI) modelled mice, these EF pre-stimulated NSCs were recorded to develop twofold higher proportion of neurons, comparing to the non-EF treated NSCs. Along with the boosted neuronal differentiation following transplantation, we also recorded the improved neurogenesis in the impacted spinal cord and the significantly benefitted hind limp motor function repair of the SCI mice. Conclusions In conclusion, we demonstrated physiological EF stimulation as an efficient method to boost the neuronal differentiation of NSCs via the PI3K/Akt/GSK-3β/β-catenin activation. Pre-treatment with the EF stimulation induction before NSCs transplantation would notably improve the therapeutic outcome for neurogenesis and neurofunction recovery of SCI.

Abstract Background Pregnant women with pulmonary hypertension (PH) have higher mortality rates and poor foetal/neonatal outcomes. Tools to assess these risk factors are not well established. Methods Predictive and prognostic nomograms were constructed using data from a “Development” cohort of 420 pregnant patients with PH, recorded between January 2009 and December 2018. Logistic regression analysis established models to predict the probability of adverse maternal and foetal/neonatal events and overall survival by Cox analysis. An independent “Validation” cohort comprised data of 273 consecutive patients assessed from January 2019 until May 2022. Nomogram performance was evaluated internally and implemented with online software to increase the ease of use. Results Type I respiratory failure, New York Heart Association functional class, N-terminal pro-brain natriuretic peptide $$\ge$$ ≥ 1400 ng/L, arrhythmia, and eclampsia with pre-existing hypertension were independent risk factors for maternal mortality or heart failure. Type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, New York Heart Association functional class, and N-terminal pro-brain natriuretic peptide $$\ge$$ ≥ 1400 ng/L were independent predictors of pulmonary hypertension survival during pregnancy. For foetal/neonatal adverse clinical events, type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, parity, platelet count, fibrinogen, and left ventricular systolic diameter were important predictors. Nomogram application for the Development and Validation cohorts showed good discrimination and calibration; decision curve analysis demonstrated their clinical utility. Conclusions The nomogram and its online software can be used to analyse individual mortality, heart failure risk, overall survival prediction, and adverse foetal/neonatal clinical events, which may be useful to facilitate early intervention and better survival rates.

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases. The dysregulation of liver sinusoidal endothelial cell (LSEC) phenotype is a critical early event in the fibrotic process. However, the biological function of lncRNAs in LSEC still remains unclear. Methods The expression level of lncRNA Airn was evaluated in both human fibrotic livers and serums, as well as mouse fibrotic livers. Gain- and loss-of-function experiments were performed to detect the effect of Airn on LSEC differentiation and hepatic stellate cell (HSC) activation in liver fibrosis. Furthermore, RIP, RNA pull-down-immunoblotting, and ChIP experiments were performed to explore the underlying mechanisms of Airn. Results We have identified Airn was significantly upregulated in liver tissues and LSEC of carbon tetrachloride (CCl4)-induced liver fibrosis mouse model. Moreover, the expression of AIRN in fibrotic human liver tissues and serums was remarkably increased compared with healthy controls. In vivo studies showed that Airn deficiency aggravated CCl4- and bile duct ligation (BDL)-induced liver fibrosis, while Airn over-expression by AAV8 alleviated CCl4-induced liver fibrosis. Furthermore, we revealed that Airn maintained LSEC differentiation in vivo and in vitro. Additionally, Airn inhibited HSC activation indirectly by regulating LSEC differentiation and promoted hepatocyte (HC) proliferation by increasing paracrine secretion of Wnt2a and HGF from LSEC. Mechanistically, Airn interacted with EZH2 to maintain LSEC differentiation through KLF2-eNOS-sGC pathway, thereby maintaining HSC quiescence and promoting HC proliferation. Conclusions Our work identified that Airn is beneficial to liver fibrosis by maintaining LSEC differentiation and might be a serum biomarker for liver fibrogenesis.

Abstract Background The Ministry of Civil Affairs of the People’s Republic of China reported that in 2018, 6.97 million left-behind children (LBC), children who live in rural areas away from their parents, were being cared for by grandparents, relatives, elder siblings, or often living alone. Their parents have migrated to cities for better income opportunities. While a number of studies have detailed elevated depressive symptoms among LBC, relatively little is known about the causes of poorer mental health in LBC. Methods This study used longitudinal data to examine associations between peer victimization, stressful life events, and depressive symptom severity in LBC from four randomly-selected middle schools in Guizhou Province, China. A total of 862 children aged 11–18 years, with 472 LBC (54.76%) and 390 non-left-behind children (NLBC) (45.24%), were included in the analysis. T-test was used to compare the depressive symptoms, peer victimization, and stressful life events between LBC and NLBC at baseline and follow-up (6 months later). Multivariable linear regression models were used to examine the mediation effect of follow-up stressful life events on the relationship between baseline peer victimization and follow-up depressive symptoms among LBC. Results Results suggested that LBC had higher peer victimization and stressful life events than NLBC (β = 1.28, p = 0.04), and peer victimization and stressful life events at baseline were associated with increased follow-up depressive symptoms among LBC (Peer victimization: β = 0.25, p

Abstract Background The roles and clinical values of synaptojanin 2 (SYNJ2) in lung squamous cell carcinoma (LUSC) remain unclear. Methods A total of 2824 samples from multi-center were collected to identify the expression of SYNJ2 in LUSC by using Wilcoxon rank-sum test, t-test, and standardized mean difference (SMD), and 194 in-house samples were also included to validate SYNJ2 expression in LUSC. The clinical roles of SYNJ2 were investigated via receiver operating characteristic (ROC) curves, univariate Cox regression analysis, and Kaplan–Meier plots. The underlying mechanisms of SYNJ2 in LUSC were explored by gene set enrichment analysis and immune correlation analysis. Further, a pan-cancer analysis based on 10,238 sapiens was performed to promote the understating of the expression and clinical significance of SYNJ2 in multiple human cancers. Results SYNJ2 was found to be significantly upregulated in LUSC at both mRNA and protein levels (p

Abstract Background To perform virtual re-executions of a breast cancer clinical trial with a time-to-event outcome to demonstrate what would have happened if the trial had used various Bayesian adaptive designs instead. Methods We aimed to retrospectively “re-execute” a randomised controlled trial that compared two chemotherapy regimens for women with metastatic breast cancer (ANZ 9311) using Bayesian adaptive designs. We used computer simulations to estimate the power and sample sizes of a large number of different candidate designs and shortlisted designs with the either highest power or the lowest average sample size. Using the real-world data, we explored what would have happened had ANZ 9311 been conducted using these shortlisted designs. Results We shortlisted ten adaptive designs that had higher power, lower average sample size, and a lower false positive rate, compared to the original trial design. Adaptive designs that prioritised small sample size reduced the average sample size by up to 37% when there was no clinical effect and by up to 17% at the target clinical effect. Adaptive designs that prioritised high power increased power by up to 5.9 percentage points without a corresponding increase in type I error. The performance of the adaptive designs when applied to the real-world ANZ 9311 data was consistent with the simulations. Conclusion The shortlisted Bayesian adaptive designs improved power or lowered the average sample size substantially. When designing new oncology trials, researchers should consider whether a Bayesian adaptive design may be beneficial.

Abstract Background Chronic obstructive pulmonary disease (COPD) is a respiratory disease that causes a wide range of cognitive impairments. Although COPD-Smoking comorbidity is common, the relationship between smoking and cognitive function in COPD-Smoking comorbidity remains unclear. This study aimed to investigate the effect of smoking on cognitive function like attention in COPD-Smoking patients. Methods In this study, we used the Montreal Cognitive Assessment (MoCA) scale and resting-state functional magnetic resonance imaging (fMRI) to explore the effect of smoking on attention in patients with COPD. Results Behavioral analysis revealed that among patients with COPD the smokers had a shorter course of COPD and showed a worse attention performance than the non-smokers. Resting-state fMRI analysis revealed that among patients with COPD smokers showed lower regional homogeneity (ReHo) value of the fusiform gyrus than non-smokers. Importantly, the ReHo of the fusiform gyrus is positively associated with attention and mediates the effect of smoking on attention in COPD. Conclusions In summary, our study provides behavioral and neurobiological evidence supporting the positive effect of smoking on attention in COPD. This may be helpful for understanding and treating COPD and even other diseases comorbid with smoking.

Abstract Granulomatous lobular mastitis (GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions, etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology. The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidence-based consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.

Abstract Background Brain-derived neurotrophic factor (BDNF) is a known regulator of the development and maintenance of chronic pain in various chronic disorders. Together with its high-affinity tyrosine kinase type B (TrKB) receptor, BDNF is extensively expressed in the mammalian female reproductive system. However, BDNF and TrKB expression in different stages of endometriosis and the relationship between the expression of each in ectopic lesions and endometriosis pain remain unclear. Methods Sixty-two women who underwent laparoscopic surgery were enrolled in this study: forty-six diagnosed with ovarian endometrioma (study group) and sixteen diagnosed with ovarian benign tumours (control group). Samples from eutopic endometrium and ovarian endometriotic lesions were obtained at laparoscopic surgery. BDNF and TrKB messenger RNA (mRNA) and proteins levels in the eutopic and ectopic endometrium of both groups were measured by real-time PCR and immunohistochemical staining, respectively. Before the surgery the visual analogue scale (VAS) was used to measure dysmenorrhoea. Results BDNF and TrKB expression levels were higher in ovarian endometriotic lesions than in eutopic endometrium and normal endometrium (P 0.05). Additionally, correlation coefficients for the association analysis between the mRNA expression of BDNF or TrKB in eutopic endometrium and the dysmenorrhoea VAS score were r = 0.52 and r = 0.56 for BDNF and TrKB, respectively (P

Abstract Novel advances in the field of brain imaging have enabled the unprecedented clinical application of various imaging modalities to facilitate disease diagnosis and treatment. Electrical impedance tomography (EIT) is a functional imaging technique that measures the transfer impedances between electrodes on the body surface to estimate the spatial distribution of electrical properties of tissues. EIT offers many advantages over other neuroimaging technologies, which has led to its potential clinical use. This qualitative review provides an overview of the basic principles, algorithms, and system composition of EIT. Recent advances in the field of EIT are discussed in the context of epilepsy, stroke, brain injuries and edema, and other brain diseases. Further, we summarize factors limiting the development of brain EIT and highlight prospects for the field. In epilepsy imaging, there have been advances in EIT imaging depth, from cortical to subcortical regions. In stroke research, a bedside EIT stroke monitoring system has been developed for clinical practice, and data support the role of EIT in multi-modal imaging for diagnosing stroke. Additionally, EIT has been applied to monitor the changes in brain water content associated with cerebral edema, enabling the early identification of brain edema and the evaluation of mannitol dehydration. However, anatomically realistic geometry, inhomogeneity, cranium completeness, anisotropy and skull type, etc., must be considered to improve the accuracy of EIT modeling. Thus, the further establishment of EIT as a mature and routine diagnostic technique will necessitate the accumulation of more supporting evidence.

Abstract Background Soil microbes exist throughout the soil profile and those inhabiting topsoil (0–20 cm) are believed to play a key role in nutrients cycling. However, the majority of the soil microbiology studies have exclusively focused on the distribution of soil microbial communities in the topsoil, and it remains poorly understood through the subsurface soil profile (i.e., 20–40 and 40–60 cm). Here, we examined how the bacterial community composition and functional diversity changes under intensive fertilization across vertical soil profiles [(0–20 cm (RS1), 20–40 cm (RS2), and 40–60 cm (RS3)] in the red soil of pomelo orchard, Pinghe County, Fujian, China. Results Bacterial community composition was determined by 16S rRNA gene sequencing and interlinked with edaphic factors, including soil pH, available phosphorous (AP), available nitrogen (AN), and available potassium (AK) to investigate the key edaphic factors that shape the soil bacterial community along with different soil profiles. The most dominant bacterial taxa were Proteobacteria, Acidobacteria, Actinobacteria, Chloroflexi, Crenarchaeota, and Bacteriodetes. Bacterial richness and diversity was highest in RS1 and declined with increasing soil depth. The distinct distribution patterns of the bacterial community were found across the different soil profiles. Besides, soil pH exhibited a strong influence (pH ˃AP ˃AN) on the bacterial communities under all soil depths. The relative abundance of Proteobacteria, Actinobacteria, Crenarchaeota, and Firmicutes was negatively correlated with soil pH, while Acidobacteria, Chloroflexi, Bacteriodetes, Planctomycetes, and Gemmatimonadetes were positively correlated with soil pH. Co-occurrence network analysis revealed that network topological features were weakened with increasing soil depth, indicating a more stable bacterial community in the RS1. Bacterial functions were estimated using FAPROTAX and the relative abundance of functional bacterial community related to metabolic processes, including C-cycle, N-cycle, and energy production was significantly higher in RS1 compared to RS2 and RS3, and soil pH had a significant effect on these functional microbes. Conclusions This study provided the valuable findings regarding the structure and functions of bacterial communities in red soil of pomelo orchards, and highlighted the importance of soil depth and pH in shaping the soil bacterial population, their spatial distribution and ecological functioning. These results suggest the alleviation of soil acidification by adopting integrated management practices to preserve the soil microbial communities for better ecological functioning.

Abstract Chromatin accessibility is essential for transcriptional activation of genomic regions. It is well established that transcription factors (TFs) and histone modifications (HMs) play critical roles in chromatin accessibility regulation. However, there is a lack of studies that quantify these relationships. Here we constructed a two-layer model to predict chromatin accessibility by integrating DNA sequence, TF binding, and HM signals. By applying the model to two human cell lines (GM12878 and HepG2), we found that DNA sequences had limited power for accessibility prediction, while both TF binding and HM signals predicted chromatin accessibility with high accuracy. According to the HM model, HM features determined chromatin accessibility in a cell line shared manner, with the prediction power attributing to five core HM types. Results from the TF model indicated that chromatin accessibility was determined by a subset of informative TFs including both cell line-specific and generic TFs. The combined model of both TF and HM signals did not further improve the prediction accuracy, indicating that they provide redundant information in terms of chromatin accessibility prediction. The TFs and HM models can also distinguish the chromatin accessibility of proximal versus distal transcription start sites with high accuracy.

Abstract Background Childhood asthma is a common respiratory disease characterized by airway inflammation. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been found to be involved in the progression of asthma. This study aimed to explore the role of TIPE2 in the regulation of airway smooth muscle cells (ASMCs), which are one of the main effector cells in the development of asthma. Materials and methods ASMCs were transfected with pcDNA3.0-TIPE2 or si-TIPE2 for 48 h and then treated with platelet-derived growth factor (PDGF)-BB. Cell proliferation of ASMCs was measured using the MTT assay. Cell migration of ASMCs was determined by a transwell assay. The mRNA expression levels of calponin and smooth muscle protein 22α (SM22α) were measured using qRT-PCR. The levels of TIPE2, calponin, SM22α, PI3K, p-PI3K, Akt, and p-Akt were detected by Western blotting. Results Our results showed that PDGF-BB treatment significantly reduced TIPE2 expression at both the mRNA and protein levels in ASMCs. Overexpression of TIPE2 inhibited PDGF-BB-induced ASMC proliferation and migration. In addition, overexpression of TIPE2 increased the expression of calponin and SM22α in PDGF-BB-stimulated ASMCs. However, an opposite effect was observed with TIPE2 knockdown. Furthermore, TIPE2 overexpression blocked PDGF-BB-induced phosphorylation of PI3K and Akt, whereas the expression of p-PI3K and p-Akt were aggravated by TIPE2 knockdown. Additionally, the effects of TIPE2 overexpression and TIPE2 knockdown were altered by IGF-1 and LY294002 treatments, respectively. Conclusions Our findings demonstrate that TIPE2 inhibits PDGF-BB-induced ASMC proliferation, migration, and phenotype switching via the PI3K/Akt signaling pathway. Thus, TIPE2 may be a potential therapeutic target for the treatment of asthma.

Abstract Background Biofilm formation is one of the main reasons for persistent bacterial infections. Recently, pH-sensitive copolymers have fascinated incredible attention to tackle biofilm-related infections. However, the proper incorporation of pH-sensitive segments in the polymer chains, which could significantly affect the biofilms targeting ability, has not been particularly investigated. Herein, we synthesized three types of pH-sensitive copolymers based on poly (β-amino ester) (PAE), poly (lactic-co-glycolic acid) (PLA) and polyethylene glycol (PEG), PAE-PLA-mPEG (A-L-E), PLA-PAE-mPEG (L-A-E) and PLA-PEG-PAE (L-E-A) to address this issue. Results The three copolymers could self-assemble into micelles (MA-L-E, ML-A-E and ML-E-A) in aqueous medium. Compared with MA-L-E and ML-A-E, placing the PAE at the distal PEG end of PLA-PEG to yield PLA-PEG-PAE (ML-E-A) was characterized with proper triggering pH, fully biofilm penetration, and high cell membrane binding affinity. Further loaded with Triclosan (TCS), ML-E-A/TCS could efficiently kill the bacteria either in planktonic or biofilm mode. We reasoned that PAE segments would be preferentially placed near the surface and distant from the hydrophobic PLA segments. This would increase the magnitude of surface charge-switching capability, as the cationic PAE+ would easily disassociate from the inner core without conquering the additional hydrophobic force arising from covalent linkage with PLA segments, and rapidly rise to the outermost layer of the micellar surface due to the relative hydrophilicity. This was significant in that it could enable the micelles immediately change its surface charge where localized acidity occurred, and efficiently bind themselves to the bacterial surface where they became hydrolyzed by bacterial lipases to stimulate release of encapsulated TCS even a relatively short residence time to prevent rapid wash-out. In vivo therapeutic performance of ML-E-A/TCS was evaluated on a classical biofilm infection model, implant-related biofilm infection. The result suggested that ML-E-A/TCS was effective for the treatment of implant-related biofilm infection, which was proved by the efficient clearance of biofilm-contaminated catheters and the recovery of surrounding infected tissues. Conclusions In summary, elaboration on the architecture of pH-sensitive copolymers was the first step to target biofilm. The ML-E-A structure may represent an interesting future direction in the treatment of biofilm-relevant infections associated with acidity. Graphic abstract

Abstract Lung cancer is one of the most common malignant tumours worldwide. however, emerging immunotherapy and targeted therapies continue to show limited efficacy. In the search for new targets for lung cancer treatment, exosomes have become a major focus of research. Exosomes play an important role in the tumour microenvironment (TME) of lung cancer and affect invasion, metastasis, and treatment responses. This review describes our current understanding of the release of exosomes derived from different cells in the TME, the effects of exosomes on T/Tregs, myeloid-derived suppressor cells, tumour-associated macrophages, dendritic cells, and natural killer cells, and the role of exosomes in the endothelial–mesenchymal transition, angiogenesis, and cancer-associated fibroblasts. In particular, this review focuses on the potential clinical applications of exosomes in the lung cancer microenvironment and their prognostic and diagnostic value.

Abstract Radiation pneumonia (RP) is a common adverse reaction to radiation therapy in patients with chest tumors. Recent studies have shown that diabetes mellitus (DM), which can cause systemic multisystem damage, specifically targets lungs, and the incidence of RP in patients with a history of diabetes is higher than that in other patients with tumors who have undergone radiotherapy. DM is an important risk factor for RP in tumor patients undergoing RT, and patients with DM should be treated with caution. This article reviews research on the clinical aspects, as well as the mechanism, of the effects of diabetes on RP and suggests future research needed to reduce RP.

Abstract Bacterial biofilm is the complicated clinical issues, which usually results in bacterial resistance and reduce the therapeutic efficacy of antibiotics. Although micelles have been drawn attention in treatment of the biofilms, the micelles effectively permeate and retain in biofilms still facing a big challenge. In this study, we fabricated on-demand pH-sensitive surface charge-switchable azithromycin (AZM)-encapsulated micelles (denoted as AZM-SCSMs), aiming to act as therapeutic agent for treating Pseudomonas aeruginosa (P. aeruginosa) biofilms. The AZM-SCSMs was composed of poly(l-lactide)-polyetherimide-hyd-methoxy polyethylene glycol (PLA-PEI-hyd-mPEG). It was noteworthy that the pH-sensitive acylhydrazone bond could be cleaved in acidic biofilm microenvironment, releasing the secondary AZM-loaded cationic micelles based on PLA-PEI (AZM-SCMs) without destroying the micellar integrity, which could tailor drug-bacterium interaction using micelles through electrostatic attraction. The results proved that positively charged AZM-SCMs could facilitate the enhanced penetration and retention inside biofilms, improved binding affinity with bacterial membrane, and added drug internalization, thus characterized as potential anti-biofilm agent. The excellent in vivo therapeutic performance of AZM-SCSMs was confirmed by the targeting delivery to the infected tissue and reduced bacterial burden in the abscess-bearing mice model. This study not only developed a novel method for construction non-depolymerized pH-sensitive SCSMs, but also provided an effective means for the treatment of biofilm-related infections.

Abstract Background The quantity–quality trade-off theory indicates that an increase in siblings might decrease a child’s well-being, but little is known about the impacts of sibling number on children’s oral health-related quality of life (OHRQoL). This study aims to investigate the effects of presence of siblings on children’s OHRQoL, and to further test whether there is an interaction effect between siblings’ presence and locations on children’s OHRQoL. Methods Data were obtained from an oral-health survey of 12-year-old children in Beijing, China, which was a part of the 4th National Oral Health Survey in the Mainland of China (2015–2016). This study included 2158 children data for analysis. OHRQoL was assessed by the child’s Oral Impacts on Daily Performance (OIDP). OIDP prevalence served as an indicator of OHRQoL. Children with and without siblings were recorded as non-single and single children, respectively. Dental variables, including active caries, gingival bleeding, and calculus, were reported. A logistic regression model was applied to investigate the association of siblings’ presence and OIDP prevalence. A synergy index was used to assess the possible interaction effect between siblings’ presence and location on OIDP prevalence. Results Sixty percent of Chinese children reported suffering OIDP in the previous six months. OIDP prevalence for non-single and single children were 68.3% and 56.9%, respectively. The adjusted odds ratio (OR) of OIDP for non-single children was 1.31 (95% CI: 1.05, 1.63), and the adjusted OR of OIDP for non-single and rural children was 2.03 (95% CI: 1.47, 2.81). The synergy index between siblings’ presence and location on OIDP was 2.18 (85% CI: 1.30, 3.67), which indicates that an excessive risk increase for OIDP was observed among non-single and rural children. Conclusions Children with siblings are more likely to report OIDP and have lower OHRQoL, especially those from rural areas. These findings indicate that oral-health interventions should be given priority for non-single and rural children.

Abstract Background A significant number of COVID-19 patients have been treated using invasive mechanical ventilation (IMV). The ability to evaluate functional status of COVID-19 survivors early on at ICU and hospital discharge may enable identification of patients who may need medical and rehabilitation interventions. Methods The modified “Mental Status”, ICU Mobility, and Barthel Index scores at ICU and hospital discharge were tabulated for 118 COVID-19 survivors treated with invasive mechanical ventilation (IMV). These functional scores were compared with pre-admission functional status, discharge durable medical equipment, discharge medical follow-up recommendation, duration on IMV, duration post-IMV, demographics, comorbidities, laboratory tests, and vital signs at ICU and hospital discharge. Results The majority of COVID-19 IMV patients were not functionally independent at hospital discharge (22% discharged with cane or rolling walker, 49% discharged with durable medical equipment, and 14% admitted to a rehabilitation facility), although 94% of these patients were functionally independent prior to COVID-19 illness. Half of the patients were discharged with supplemental oxygen equipment. The most prevalent medical follow-up recommendations were cardiology, vascular medicine, pulmonology, endocrinology, and neurology with many patients receiving multiple medical follow-up recommendations. Functional status improved from ICU discharge to hospital discharge (p < 0.001). Worse functional status at hospital discharge was associated with longer IMV duration, older age, male sex, higher number of comorbidities, and the presence of pre-existing comorbidities including hypertension, diabetes, chronic obstructive pulmonary disease, and immunosuppression (p < 0.05, ANOVA). Conclusions The majority of IMV COVID-19 survivors were not functionally independent at discharge and required significant follow-up medical care. The COVID-19 circumstance has placed constraints on access to in-hospital rehabilitation. These findings underscore the need for prospective studies to ascertain the short- and long-term sequela in COVID-19 survivors.

Abstract Background Non-small-cell lung cancer (NSCLC) is usually diagnosed at an advanced stage, and chemotherapy is the main treatment for this disease. Kanglaite injections (KLTi) have been widely used for the treatment of cancer in China. KLTi combined with chemotherapy could improve the short-term efficacy, quality of life, and performance status for NSCLC compared with chemotherapy alone. This trial aims to assess the long-term efficacy and safety of KLTi in combination with chemotherapy for the treatment of advanced NSCLC. Methods This will be an investigator-initiated multicenter open-label randomized controlled trial. We will randomly assign 334 eligible participants with stage IIIA-IV NSCLC to the treatment or control groups in a 1:1 ratio. Patients in both groups will be administered 4–6 cycles of first-line platinum-based double chemotherapy regimens. Patients with complete response, partial response, or stable disease after 4–6 cycles will receive non-platinum single-agent chemotherapy. Patients in the treatment group are to receive intravenous KLTi 200 ml per day continuously for 14 days, commencing on the first day of chemotherapy. The treatment will be discontinued at the time of disease progression or until unacceptable toxicity is noted. The follow-up will be conducted every 2 months until death, loss of follow-up, or 12 months from randomized enrollment. The primary outcome will be progression-free survival (PFS). The secondary outcomes will be the objective response rate, 1-year survival rate, quality of life, living ability, and blood lipids. The safety outcome will be the rate of adverse events. Discussion This study will be the first randomized controlled trial in which PFS is used as the primary outcome to test whether KLTi combined with first-line chemotherapy has superior efficacy and reduced toxicity compared to chemotherapy alone in advanced NSCLC. This will also be the first clinical study to observe the effects of KLTi on blood lipids. Trial registration ClinicalTrials.gov NCT03986528 . Prospectively registered on 30 May 2019.

Abstract The outbreak of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed significant threats to international health. The genetic traits as well as evolutionary processes in this novel coronavirus are not fully characterized, and their roles in viral pathogenesis are yet largely unknown. To get a better picture of the codon architecture of this newly emerging coronavirus, in this study we perform bioinformatic analysis, based on publicly available nucleotide sequences of SARS-CoV-2 along with those of other members of human coronaviruses as well as non-human coronaviruses in different hosts, to take a snapshot of the genome-wide codon usage pattern of SARS-CoV-2 and uncover that all over-represented codons end with A/U and this newly emerging coronavirus has a relatively low codon usage bias, which is shaped by both mutation pressure and natural selection. Additionally, there is slight variation in the codon usage pattern among the SARS-CoV-2 isolates from different geo-locations. Furthermore, the overall codon usage pattern of SARS-CoV-2 is generally similar to that of its phylogenetic relatives among non-human betacoronaviruses such as RaTG13. Taken together, we comprehensively analyze the characteristics of codon usage pattern in SARS-CoV-2 via bioinformatic approaches. The information from this research may not only be helpful to get new insights into the evolution of SARS-CoV-2, but also have potential value for developing coronavirus vaccines.

Abstract Background Statins are the most widely used drugs in elderly patients; the most common clinical application of statins is in aged hyperlipemia patients. There are few studies on the effects and mechanisms of statins on bone in elderly mice with hyperlipemia. The study is to examine the effects of atorvastatin on bone phenotypes and metabolism in aged apolipoprotein E-deficient (apoE–/–) mice, and the possible mechanisms involved in these changes. Methods Twenty-four 60-week-old apoE–/– mice were randomly allocated to two groups. Twelve mice were orally gavaged with atorvastatin (10 mg/kg body weight/day) for 12 weeks; the others served as the control group. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone metabolism was assessed by serum analyses, qRT-PCR, and Western blot. Bone marrow-derived mesenchymal stem cells (BMSCs) from apoE–/– mice were differentiated into osteoblasts and treated with atorvastatin and silent information regulator 1 (Sirt1) inhibitor EX-527. Results The results showed that long-term administration of atorvastatin increases bone mass and improves bone microarchitecture in trabecular bone but not in cortical bone. Furthermore, the serum bone formation marker osteocalcin (OCN) was ameliorated by atorvastatin, whereas the bone resorption marker tartrate-resistant acid phosphatase 5b (Trap5b) did not appear obviously changes after the treatment of atorvastatin. The mRNA expression of Sirt1, runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and OCN in bone tissue were increased after atorvastatin administration. Western blot showed same trend in Sirt1 and Runx2. The in vitro study showed that when BMSCs from apoE–/– mice were pretreated with EX527, the higher expression of Runx2, ALP, and OCN activated by atorvastatin decreased significantly or showed no difference compared with the control. The protein expression of Runx2 showed same trend. Conclusions Accordingly, the current study validates the hypothesis that atorvastatin can increase bone mass and promote osteogenesis in aged apoE−/− mice by regulating the Sirt1–Runx2 axis.

Abstract Background Bartonella bacteria have been associated with an increasingly wide range of human and animal diseases. These emerging pathogens have been identified as being globally dispersed. Ticks and small rodents are known hosts of Bartonella and play a significant role in the preservation and circulation of Bartonella in nature. This study investigated the occurrence of hoist spp. in ticks (Acari: Ixodidae) and plateau pikas (Ochotona curzoniae) in Shiqu County, which is located on the eastern Qinghai-Tibetan Plateau in China. Shiqu County is spread over approximately 26,000 km2, with an average altitude of above 4200 m and a vast area of pastureland. Results A total of 818 ticks (Dermacentor everestianus, 79.0%, 646/818; Haemaphysalis qinghaiensis, 21.0%, 172/818) were collected from yaks in 4 villages of Shiqu County. Only Bartonella melophagi was detected in tick samples, with a total prevalence of 30.1% (246/818). The infection rates of B. melophagi in ticks from Arizha, Maga, Derongma, and Changxgma were 4.8, 76.8, 12.5, and 18.0%, respectively. The infection rate of B. melophagi in Maga was higher (p 0.05) in the infection rates between these study sites. Conclusion To date, only D. everestianus and H. qinghaiensis were found in Shiqu County with high infection of Bartonella spp. in the ticks and plateau pika. The threats of Bartonella species to public health should be closely monitored.

Abstract Background Recent study found that vitamin D before conception was considered as a potential additional determinant for achieving pregnancy and live births. The study aimed to evaluate the serum 25 hydroxyvitamin D (25(OH)D) levels and its affecting factors among preconception fertile women. Methods This cross-sectional study enrolled 410 women aged 22–44 years who attended a preconception genetic counseling clinic from January 2018 to May 2019. Sociodemographic characteristics and reproductive history of women were collected, and height and weight were measured. Serum 25(OH)D concentration was assayed with chemiluminescence immunoassay. Descriptive statistics were used to examine serum 25(OH)D concentration, and socio-demographic characteristics and reproductive history among preconception women. Determinants of vitamin D deficiency and its affecting factors were assessed using χ2 test and logistic regression. Results Findings showed 84.4% of women had serum 25(OH)D concentration below 20 ng/mL. Women working indoors as well as without a history of childbirth had significantly lower 25(OH)D levels compared with those non-working individuals and having delivered a previous child (both P

Abstract Emerging evidence has revealed significant roles for small nucleolar RNAs (snoRNAs) in tumorigenesis. However, the genetic and pharmacogenomic landscape of snoRNAs has not been characterized. Using the genotype and snoRNA expression data from The Cancer Genome Atlas, we characterized the effects of genetic variants on snoRNAs across 29 cancer types and further linked related alleles with patient survival as well as genome-wide association study risk loci. Furthermore, we characterized the impact of snoRNA expression on drug response in patients to facilitate the clinical utility of snoRNAs in cancer. We also developed a user-friendly data resource, GPSno ( http://hanlab.uth.edu/GPSno ), with multiple modules for researchers to visualize, browse, and download multi-dimensional data. Our study provides a comprehensive genetic and pharmacogenomic landscape of snoRNAs, which will shed light on future clinical considerations for the development of snoRNA-based targeted therapies.

Abstract Background The human myxovirus resistance 2 (Mx2/MxB) protein was originally found to regulate cytoplasmic-nuclear transport but was recently reported to restrict HIV-1 replication by binding to HIV-1 capsid (CA), preventing uncoating, the nuclear import of pre-integration complex (PIC) and viral DNA integration. This work explores the mechanisms of MxB-mediated HIV-1 inhibition. Results We demonstrated that MxB represses NUP358-mediated PIC nuclear import and HIV-1 replication. Moreover, MxB’s effects on PIC nuclear import and HIV-1 replication depend critically on cofactor cleavage and polyadenylation specificity factor subunit 6 (CPSF6). MxB binds nucleoporin NUP358, blocks NUP358-CA interaction, thereby impeding the nuclear import of HIV-1 PIC with CPSF6 binding to PIC. More intriguingly, CPSF6’s role in nuclear import depends on MxB, being a facilitator of HIV-1 nuclear import on its own, but becoming an inhibitor when MxB is present. Conclusions Our work establishes that MxB impedes the NUP358-mediated HIV-1 nuclear import and viral replication cooperatively with CPSF6.

Abstract Background Uterine leiomyomas are common benign tumours found in women of reproductive age that are rarely associated with intra-abdominal haemorrhage. The aetiology behind this relationship is poorly understood and the aforementioned association poorly recognized from a patient’s clinical presentation. Available information in the literature is limited to case reports. The aim of this systematic review is to document and highlight the occurrence of intra-abdominal haemorrhage from uterine fibroids, and determine associated morbidity and mortality. Methods A systematic review of Medline, EMBASE, Web of Science, Scopus, and The Cochrane Library – CENTRAL was performed from the databases inception through to December 2018 for case report and series of patients who experienced intra-abdominal haemorrhage from uterine fibroids. Findings were presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Results We identified 115 publications reporting on 125 original case reports. The documented intra-abdominal haemorrhage were commonly due to the rupture of superficial blood vessels over the surface of a fibroid, followed by rupture and avulsion of the fibroid involved. A clinical picture of sudden and profound hypovolemic shock with severe abdominal pain was often the presenting complaint, with a correct pre-operative diagnosis only made in 7 cases on computed tomography imaging. Hysterectomy and myomectomy were the most common surgery performed. Mortality was reported in 4 cases which were directly related to complications of uterine fibroids. Conclusion Intra-abdominal haemorrhage secondary to uterine fibroids remained a rare phenomenon which is poorly recognized among clinicians. While this association is not representative of the population of interest, it highlights the pathophysiological spectrum of uterine fibroids and its relevance to emergency physicians, surgeons and gynaecologists during clinical practice.

Abstract Background Previous in vitro studies demonstrated that suppression of microRNAs might protect cardiomyocytes and neurons against oxygen–glucose deprivation and reoxygenation (OGD/R)-induced cell apoptosis. However, whether the protective effect of miR-153-inhibition on cardiomyocytes can be observed in the animal model is unknown. We aimed to address this question using a rat model of ischemia–reperfusion (I/R). Methods Rats were received the intramyocardial injection of saline or adenovirus-carrying target or control gene, and the rats were subjected to ischemia/reperfusion (I/R) treatment. The effects of miR-153 on I/R-induced inflammatory response and oxidative stress in the rat model were assessed using various assays. Results We found that suppression of miR-153 decreased cleaved caspase-3 and Bcl-2-associated X (Bax) expression, and increased B cell lymphoma 2 (Bcl-2) expression. We further confirmed that Nuclear transcription factor erythroid 2-like 2 (Nrf2) is a functional target of miR-153, and Nrf2/Heme oxygenase-1 (HO-1) signaling was involved in miR-153-regulated I/R-induced cardiomyocytes apoptosis. Inhibition of miR-153 reduced I/R-induced inflammatory response and oxidative stress in rat myocardium. Conclusion Suppression of miR-153 exerts a cardioprotective effect against I/R-induced injury through the regulation of Nrf2/HO-1 signaling, suggesting that targeting miR-153, Nrf2, or both may serve as promising therapeutic targets for the alleviation of I/R-induced injury.