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During development, neural progenitors are in proliferative and immature states; however, the molecular machinery that cooperatively controls both states remains elusive. Here, we report that cyclin D1 (CCND1) directly regulates both proliferative and immature states of cerebellar granule cell progenitors (GCPs). CCND1 not only accelerates cell cycle but also upregulates ATOH1 protein, an essential transcription factor that maintains GCPs in an immature state. In cooperation with CDK4, CCND1 directly phosphorylates S309 of ATOH1, which inhibits additional phosphorylation at S328 and consequently prevents S328 phosphorylation‐dependent ATOH1 degradation. Additionally, PROX1 downregulates Ccnd1 expression by histone deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. Moreover, WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT‐PROX1‐CCND1‐ATOH1 signaling cascade cooperatively controls proliferative and immature states of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which are suggested to determine appropriate differentiation rates from GCPs to GCs at distinct developmental stages. This study contributes to understanding the regulatory mechanism of GCPs as well as neural progenitors.

Background Specific data regarding coronavirus disease 2019 (COVID-19) in patients with neuroendocrine neoplasms (NENs) are lacking. The aim of this study is to describe the characteristics of patients with NENs who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive. Material and methods This is a worldwide study collecting cases of patients with NENs along with a positive nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between June 1, 2020, and March 31, 2021. Centres treating patients with NENs were directly contacted by the principal investigator. Patients with NENs of any primary site, grade and stage were included, excluding small-cell lung carcinoma and mixed adenoneuroendocrine carcinoma. Results Among 81 centres directly contacted, 88.8% responded and 48.6% of them declined due to lack of cases or interest. On March 31st, 2021, eight recruiting centres enrolled 89 patients. The median age was 64 years at the time of COVID-19 diagnosis. Most patients had metastatic, non-functioning, low-/intermediate-grade gastroenteropancreatic NENs on treatment with somatostatin analogues and radioligand therapy. Most of them had comorbidities. Only 8% of patients had high-grade NENs and 12% were receiving chemotherapy. Most patients had symptoms or signs of COVID-19, mainly fever and cough. Only 3 patients underwent sub-intensive treatment, whereas most of them received medical therapies, mostly antibiotics. In two third of cases, no changes occurred for the anti-NEN therapy. More than 80% of patients completely recovered without sequelae, whereas 7.8% patients died due to COVID-19. Conclusions Patients included in this study reflect the typical NEN population regardless of SARS-CoV-2. In most cases, they overcome COVID-19 without need of intensive care, short-term sequelae and discontinuation of systemic oncological therapy.

Increasing evidences suggest that circular RNAs (circRNAs) exert crucial functions in regulating gene expression. In this study, we perform RNA‐seq and identify 6,154 distinct circRNAs from human bladder cancer and normal bladder tissues. We find that hundreds of circRNAs are significantly dysregulated in human bladder cancer tissues. We further show that circHIPK3, also named bladder cancer‐related circular RNA‐2 (BCRC‐2), is significantly down‐regulated in bladder cancer tissues and cell lines, and negatively correlates with bladder cancer grade, invasion as well as lymph node metastasis, respectively. Over‐expression of circHIPK3 effectively inhibits migration, invasion, and angiogenesis of bladder cancer cells in vitro and suppresses bladder cancer growth and metastasis in vivo . Mechanistic studies reveal that circHIPK3 contains two critical binding sites for the microRNA miR‐558 and can abundantly sponge miR‐558 to suppress the expression of heparanase (HPSE). Taken together, our findings provide evidence that circRNAs act as “microRNA sponges”, and suggest a new therapeutic target for the treatment of bladder cancer.

Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis‐associated gallbladder cancer lncRNA (lncRNA‐PAGBC), which we find to be an independent prognostic marker in GBC. Functional analysis indicates that lncRNA‐PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA‐PAGBC competitively binds to the tumour suppressive microRNAs miR‐133b and miR‐511. This competitive role of lncRNA‐PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA‐PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC.

PurposeThe objective of this review is to address the barriers limiting access to diagnosis and treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Brazil, specifically for patients in the public healthcare system, arguably those with the least access to innovation.DesignA selected panel of Brazilian experts in SLE/LN were provided with a series of relevant questions to address in a multi-day conference. During the conference, responses were discussed and edited by the entire group through numerous drafts and rounds of discussion until a consensus was achieved.ResultsThe authors propose specific and realistic recommendations for implementing access to innovative diagnostic tools and treatment alternatives for SLE/LN in Brazil. Moreover, in creating these recommendations, the authors strived to address barriers and impediments for technology adoption. The multidisciplinary care required for SLE/LN necessitates the collective participation of all involved stakeholders.ConclusionA great need exists to expand the adoption of innovative diagnostic tools and treatments for SLE/LN not only in Brazil but also in most countries, as access issues remain an urgent demand. The recommendations presented in this article can serve as a strategy for new technology adoption in other countries in a similar situation.

The objective of the study was to describe cellular and molecular markers of radioprotection by anisomycin, focusing on the changes in rat brain tissue. Two-month-old Wistar rats were exposed to a 60Co radiation source at a dose of 6 Gy, with or without radioprotection with anisomycin (150 mg/kg) administered subcutaneously 30 min before or 3 or 6 h after irradiation. Survivors were analyzed 30 days after treatment. Astroglial and microglial responses were investigated based on the expression of glial markers assessed with immunohistochemistry, and quantitative changes in brain biomolecules were investigated by Raman microspectroscopy. In addition, blood plasma levels of pro-inflammatory (interleukin 6 and tumor necrosis factor α) and anti-inflammatory (interleukin 10) cytokines were assessed. We found that application of anisomycin either before or after irradiation significantly decreased the expression of the microglial marker Iba-1. We also found an increased intensity of Raman spectral bands related to nucleic acids, as well as an increased level of cytokines when anisomycin was applied after irradiation. This suggests that the radioprotective effects of anisomycin are by decreasing Iba-1 expression and stabilizing genetic material by increasing the level of nucleic acids.

PURPOSE: Musculoskeletal problems are the leading cause of chronic disability. Most patients in the UK seek initial care from general practitioners (GPs), who are struggling to meet demand. Patient direct access to National Health Service physiotherapy is one possible solution. The purpose of this study was to understand the experiences of patients, GPs, physiotherapists and clinical commissioners on direct access in a region in England with it commissioned. \ud \ud METHODS: The study was informed by Normalisation Process Theory (NTP). Data collection was via semi-structured individual face-to-face and telephone interviews with 22 patients and 20 health care professionals (HCPs). Data were analysed thematically using NPT. \ud \ud RESULTS: Three themes emerged: understanding physiotherapy and the direct access pathway; negotiating the pathway; making the pathway viable. HCPs saw direct access as acceptable. Whilst patients found the concept of direct access, those with complex conditions continued to see their GP as first point of contact. Some GPs and patients reported a lack of clarity around the pathway, reflected in ambiguous paperwork and inconsistent promotion. Operational challenges emerged in cross-disciplinary communication and between HCPs and patients, and lack of adequate resources. \ud \ud CONCLUSION: Direct access to NHS musculoskeletal physiotherapy is acceptable to patients and HCPs. There is need to ensure: effective communication between HCPs and with patients, clarity on the scope of physiotherapy and the direct access pathway, and sufficient resources to meet demand. Patient direct access can free GPs to focus on those patients with more complex health conditions who are most in need of their care.

Aims Two complementary studies were used to assess the real-life use of nalmefene in alcohol-dependent patients and its impact on alcohol use health status. Methods USE-PACT was a prospective cohort study designed to evaluate the real-life effectiveness of nalmefene in the management of alcohol dependence, as assessed by total alcohol consumption (TAC) and number of heavy drinking days (HDD) at 1 year. USE-AM was a cohort study using data from the French nationwide claims database and was used to evaluate the external validity of the population in the prospective study. Results Overall, 256 of 700 new nalmefene users enrolled in the USE-PACT study had valid data at 1 year. After 1 year, patients treated with nalmefene showed a mean ± SD reduction from baseline in TAC (−41.5 ± 57.4 g/day) and number of HDD (−10.7 ± 11.7 days/4 weeks). Patients took a mean ± SD of 20.0 ± 12.0 tablets/4 weeks (median of 1 tablet/day) for the first 3 months and then reduced the dose. The proportion of patients who no longer took nalmefene gradually increased from 5% at 1 month to 52% at 1 year. The USE-AM study identified 486 patients with a first reimbursement for nalmefene in 2016; baseline characteristics confirmed external validity of the USE-PACT study. Overall, 46.3% of initial USE-AM prescriptions were made by GPs; most (91.8%) patients stopped treatment during follow-up. However, 15.2% of patients resumed treatment after stopping. Conclusions In this analysis of French routine practice, patients with alcohol dependence treated with nalmefene showed reduced alcohol consumption, and nalmefene was generally well tolerated., Short Summary: Two studies were used to evaluate how nalmefene is used in the management of alcohol dependence in France. After 1 year, new nalmefene users had substantially reduced alcohol consumption. Insurance data confirmed external validity of the population sample and the observation that patients often discontinue treatment over 1 year.

Objective To evaluate the efficacy and safety of enzalutamide plus androgen deprivation therapy in Japanese men with metastatic hormone-sensitive prostate cancer. Methods A post-hoc analysis of the Japanese subgroup in the phase III, randomized, multinational ARCHES study (NCT02677896) was carried out. Patients with metastatic hormone-sensitive prostate cancer were randomized to receive enzalutamide or a placebo, plus androgen deprivation therapy, stratified by disease volume and prior docetaxel therapy. The primary end-point was radiographic progression-free survival. Secondary end-points included time to prostate-specific antigen progression and overall survival. Results Of 1150 patients, 92 Japanese patients were randomized to enzalutamide (n = 36) or a placebo (n = 56), plus androgen deprivation therapy; none received prior docetaxel. Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression or death in Japanese patients by 61% versus the placebo, similar to the overall population. Similar results were observed with secondary end-points, showing clinical benefit of enzalutamide plus androgen deprivation therapy in Japanese patients. Overall survival data were immature. Grade 3-4 adverse events were reported in 47% and 25% of the enzalutamide and placebo groups, respectively. Nasopharyngitis, hypertension and abnormal hepatic function were reported more frequently in Japanese patients versus the overall population. Conclusions Enzalutamide plus androgen deprivation therapy has clinical benefit with a tolerable safety profile in Japanese men with metastatic hormone-sensitive prostate cancer, consistent with the overall population.

[Objective] The coronavirus disease 2019 (COVID-19) pandemic has affected all healthcare systems. This study aimed to assess the impact of the COVID-19 pandemic on the number and severity of cases of community-acquired pneumonia (CAP) in Japan. [Methods] Using claims data from the Quality Indicator/Improvement Project (QIP) database, urgent cases of inpatients for CAP from 01 August 2018 to 30 July 2020 were included. The monthly ratios of inpatient cases were compared from August 2018 to July 2019 and August 2019 to July 2020 as a year-over-year comparison. These ratios were also compared according to the “A-DROP” severity score, and an interrupted time series (ITS) analysis was performed to evaluate the impact of the COVID-19 pandemic on the monthly number of inpatient cases. [Results] This study included a total of 67, 900 inpatient cases for CAP in 262 hospitals. During the COVID-19 pandemic (defined as the period between March and July 2020) the number of inpatient cases for CAP drastically decreased compared with the same period in the previous year (–48.1%), despite a temporary reduction in the number of other urgent admissions. The number of inpatient cases decreased according to the severity of pneumonia. Milder cases showed a greater decrease in the year-over-year ratio than severe ones: mild –55.2%, moderate –45.8%, severe –39.4%, and extremely severe –33.2%. The ITS analysis showed that the COVID-19 pandemic significantly reduced the monthly number of inpatient cases for CAP (estimated decrease: –1233 cases; 95% CI –521 to –1955). [Conclusions] This study showed a significant reduction in the number of inpatient cases for CAP during the COVID-19 pandemic in Japan. The milder cases showed a greater decrease in the year-over-year ratio of the number of inpatient cases., COVID-19流行が市中肺炎の緊急入院に与えた影響を検証. 京都大学プレスリリース. 2021-05-10.

Antibiotic resistance (ABR) has been identified as a critical threat to global health at the highest policy fora. A leading cause of ABR is the inappropriate use of antibiotics by both patients and healthcare providers. Although countries around the world have committed to developing and implementing national action plans to tackle ABR, there is a considerable gap in evidence about effective behaviour change interventions addressing inappropriate use of antibiotics in low- and middle-income countries (LMICs), where ABR is growing at an alarming rate. We conducted a systematic review to synthesize evidence about the effectiveness and cost-effectiveness of behaviour change interventions to reduce inappropriate use of antibiotics in LMICs. Three databases were searched using a set of predefined search terms and exclusion criteria. The search identified 43 relevant articles. A narrative synthesis of results was conducted using the Behaviour Change Wheel framework to categorize intervention components. The majority of the reviewed studies were set in lower-middle-income or low-income countries located in Sub-Saharan Africa or East Asia and the Pacific. Twenty-four articles evaluated multi-faceted interventions over a period of 12 months or less. Despite the widespread use of antibiotics in the community, interventions were primarily implemented in public health facilities, targeting health professionals such as doctors, nurses, and other allied medical staff. Although education for providers was the most widely used strategy for influencing antibiotic use, it was shown to be most effective when used in conjunction with training or other enabling and supportive measures to nudge behaviour. Six articles included an evaluation of costs of interventions and found a reduction in costs in inpatient and outpatient settings, and one article found a training and guidelines implementation-based intervention to be highly cost-effective. However, the small number of articles conducting an economic evaluation highlights the need for such analyses to be conducted more frequently to support priority setting in resource-constrained environments.

Aims The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes.Methods and results The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age +/- standard deviation, 64.3 +/- 8.0 vs. 62.5 +/- 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all P-difference < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), P-heterogeneity < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all P-difference > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (-0.52% vs. -0.64%, P-heterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all P-heterogeneity > 0.07).Conclusions Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.

Background Health literacy, the ability to access, understand, evaluate and apply health information, was found to contribute to positive health outcomes, possibly via promoting healthy behaviours. However, the specific pathways linking different health literacy skills to health and well-being have remained unclear. Methods A cross-sectional survey with structural questionnaires was administered among 2236 adults in Hong Kong (mean age = 46.10 ± 19.05). Health literacy was measured by HLS-Asian-47. Participants' physical conditions and subjective well-being were predicted by health literacy and health behaviours with structural modelling path analysis. Results Health literacy in finding and understanding information showed a direct effect on enhancing physical health, while applying information capacity had an indirect positive effect via promoting health behaviours, which was moderated by sex. Only among women, this indirect effect predicting fewer physical symptoms and better well-being was significant. Conclusions Different health literacy dimensions showed distinct direct and indirect pathways in influencing health for men and women. Based on the findings, skill trainings should be developed to enhance both gender's abilities of finding and understanding health information, while the ability of applying health information should also be improved for modifying lifestyle and promoting health, particularly for women. Patient or public contribution Two thousand and two hundred thirty-six adults from different districts of Hong Kong participated in the study, and responded to questions on health literacy, behaviours and health status.

To evaluate the effects of probiotic on patient’s respiratory tract infection (RTI), a systematic review was conducted on randomized controlled trials (RCTs). PubMed, Google Scholar, Embase, Scopus, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP) databases were systematically searched for the following keywords from January 2010 to January 2020: including respiratory tract infection, probiotics, viral infection, COVID-19, and clinical trial. A total of 27 clinical trials conducted on 9,433 patients with RTI and 10 ongoing clinical studies of probiotics intervention in COVID-19 were reviewed. In this systematic review, were attempted to study the potency of probiotics for the hindrance and/or treatment of RTI diseases extensively, which may be practical to conflict the new coronavirus (COVID-19). Overall, probiotics could significantly increase the plasma levels of cytokines, the effect of influenzae vaccine, and quality of life as well as reducing the titre of viruses and the incidence and duration of respiratory infections. These antiviral and immune-modulating activities and their ability to stimulate interferon production recommended that to use probiotics as adjunctive therapy to prevent COVID-19. The rapid spread of the virus has affected the entire world socially and economically. Given this extensive research on RCTs, were expected probiotics to be a rational complementary treatment for RTI disease and a viable option for faster recovery.

Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

Background:. The pathogenesis of osteosarcoma (OS) is still unclear, and it is still necessary to find new targets and drugs for anti-OS. This study aimed to investigate the role and mechanism of the anti-OS effects of miR-296-5p. Methods:. We measured the expression of miR-296-5p in human OS cell lines and tissues. The effect of miR-296-5p and its target gene staphylococcal nuclease and tudor domain containing 1 on proliferation, migration, and invasion of human OS lines was examined. The Student's t test was used for statistical analysis. Results:. We found that microRNA (miR)-296-5p was significantly downregulated in OS cell lines and tissues (control vs. OS, 1.802 ± 0.313 vs. 0.618 ± 0.235, t = 6.402, P

Background Although obesity differs according to ethnicity, it is globally established as a solid risk factor for cardiovascular disease. However, it is not fully understood how obesity parameters affect the progression of coronary artery calcification (CAC) in Korean population. We sought to evaluate the association of obesity-related parameters including visceral adipose tissue (VAT) measurement and CAC progression. Methods This retrospective observational cohort study investigated 1,015 asymptomatic Korean subjects who underwent serial CAC scoring by computed tomography (CT) with at least 1-year interval and adipose tissue measurement using non-contrast CT at baseline for a routine checkup between 2003 and 2015. CAC progression, the main outcome, was defined as a difference of ≥2.5 between the square roots of the baseline and follow-up CAC scores using Agatston units. Results During follow-up (median 39 months), 37.5% of subjects showed CAC progression of a total population (56.4 years, 80.6% male). Body mass index (BMI) ≥25 kg/m2, increasing waist circumferences (WC), and higher VAT/subcutaneous adipose tissue (SAT) area ratio were independently associated with CAC progression. Particularly, predominance of VAT over SAT at ≥30% showed the strongest prediction for CAC progression (adjusted hazard ratio, 2.20; P

Aging is the process spontaneously occurred in living organisms. Cardiac fibrosis is a pathophysiological process of cardiac aging. Mangiferin is a well-known C-glucoside xanthone in mango leaves with lots of beneficial properties. In this study, rat model of cardiac fibrosis was induced by injected with 150 mg/kg/d D-galactose for 8 weeks. The age-related cardiac decline was estimated by detecting the relative weight of heart, the serum levels of cardiac injury indicators and the expression of hypertrophic biomakers. Cardiac oxidative stress and local inflammation were measured by detecting the levels of malondialdehyde, enzymatic antioxidant status and proinflammatory cytokines. Cardiac fibrosis was evaluated by observing collagen deposition via masson and sirius red staining, as well as by examining the expression of extracellular matrix proteins via Western blot analysis. The cardiac activity of profibrotic TGF-β1/p38/MK2 signaling pathway was assessed by measuring the expression of TGF-β1 and the phosphorylation levels of p38 and MK2. It was observed that mangiferin ameliorated D-galactose-induced cardiac aging, attenuated cardiac oxidative stress, inflammation and fibrosis, as well as inhibited the activation of TGF-β1/p38/MK2 signaling pathway. These results showed that mangiferin could ameliorate cardiac fibrosis in D-galactose-induced aging rats possibly via inhibiting TGF-β/p38/MK2 signaling pathway.

Summary Primary immunodeficiency disorders (PID) are a group of heterogeneous disorders characterized by recurrent infections, autoimmunity, increased lymphoproliferative disorders and other malignancies. PID is classified into cellular or humoral disorders or a combination of both. We evaluated the clinical differences among adult patients with three variants of PID: common variable immunodeficiency (CVID), idiopathic CD4 lymphopenia (ICL) and combined immunodeficiency (CID). We retrospectively compared demographics, immunological characteristics, clinical presentations and outcomes of CVID, CID and ICL patients followed from 2012 to 2018. In our cohort, we identified 44 adult patients diagnosed with CVID (22), CID (11) and ICL (11). Malignancy was associated with CID, as seven of 11 patients in this group were diagnosed with malignancy compared to CVID (three of 22) or ICL (two of 11) (P = 0·002 and 0·03, respectively). Malignancies were also linked to male gender [odds ratio (OR) = 5, 95% confidence interval (CI) = 1·12–22·18) P = 0·0342] and a low ratio of CD4/CD8

Transcription factor AP‐2 gamma (TFAP2C) is a known regulator of the estrogen receptor, and high expression of TFAP2C is associated with therapy resistance. This study identified PELP1 as a TFAP2C interacting protein. PELP1 is essential for optimal TFAP2C transcriptional functions. TFAP2C interactions with PELP1 confer a growth advantage to breast cancer (BC) cells by activating an oncogenic RET signaling thus contributing to BC progression and therapy resistance., A significant proportion of estrogen receptor‐positive (ER+) breast cancer (BC) initially responds to endocrine therapy but eventually evolves into therapy‐resistant BC. Transcription factor AP‐2 gamma (TFAP2C) is a known regulator of ER activity, and high expression of TFAP2C is associated with a decreased response to endocrine therapies. PELP1 is a nuclear receptor coregulator, commonly overexpressed in BC, and its levels are correlated with poorer survival. In this study, we identified PELP1 as a novel interacting protein of TFAP2C. RNA‐seq analysis of PELP1 knockdown BC cells followed by transcription factor motif prediction pointed to TFAP2C being enriched in PELP1‐regulated genes. Gene set enrichment analysis (GSEA) revealed that the TFAP2C‐PELP1 axis induced a subset of common genes. Reporter gene assays confirmed PELP1 functions as a coactivator of TFAP2C. Mechanistic studies showed that PELP1‐mediated changes in histone methylation contributed to increased expression of the TFAP2C target gene RET. Furthermore, the TFAP2C‐PELP1 axis promoted the activation of the RET signaling pathway, which contributed to downstream activation of AKT and ERK pathways in ER+ BC cells. Concomitantly, knockdown of PELP1 attenuated these effects mediated by TFAP2C. Overexpression of TFAP2C contributed to increased cell proliferation and therapy resistance in ER+ BC models, while knockdown of PELP1 mitigated these effects. Utilizing ZR75‐TFAP2C xenografts with or without PELP1 knockdown, we provided genetic evidence that endogenous PELP1 is essential for TFAP2C‐driven BC progression in vivo. Collectively, our studies demonstrated that PELP1 plays a critical role in TFAP2C transcriptional and tumorigenic functions in BC and blocking the PELP1‐TFAP2C axis could have utility for treating therapy resistance.

Kaori Hisanaga,1 Hiroshi Uchino,1 Naoko Kakisu,1 Masahiko Miyagi,1 Fukumi Yoshikawa,1 Genki Sato,1 Kazutoshi Isobe,2 Kazuma Kishi,2 Sakae Homma,3 Takahisa Hirose1 1Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Tokyo, Japan; 2Department of Respiratory Medicine, Toho University Graduate School of Medicine, Tokyo, Japan; 3Department of Advanced and Integrated Interstitial Lung Disease Research, School of Medicine, Toho University, Tokyo, JapanCorrespondence: Hiroshi UchinoDivision of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-Nishi, Ota-Ku, Tokyo, 143-8541, JapanTel +81-3-3762-4151Fax +81-3-3765-6488Email h.uchino@med.toho-u.ac.jpBackground: Although immune checkpoint inhibitors (ICIs) are promising in the treatment of advanced cancer, their use is associated with immune-related adverse events (irAEs) that affect endocrine organ systems. Although development of irAEs was associated with improved cancer-specific survival, the risk of irAEs is unclear. We investigated the association of pre-ICI comorbidities—including diabetes—with irAEs, overall survival (OS), and progression-free survival (PFS) in advanced lung cancer.Methods: Patients with lung cancer who were treated with ICIs during the period from September 1, 2015 through July 31, 2018 were retrospectively enrolled. All data were collected from the NEPTUNE database of university patients. Hazard ratios were estimated by using Cox regression weighted for propensity scores. Odds ratios were calculated by logistic regression and adjusted for unbalanced variables. The Kaplan–Meier method was used to compare OS, and the generalized Wilcoxon test was used to compare median survival.Results: Among the 88 patients identified, 22 (25.0%) had diabetes (DM) before ICI treatment and 57 (75.0%) did not (non-DM); irAEs developed in 12.2% of patients with DM and in 9.1% of patients in non-DM (p=0.87). Diabetes status was not associated with irAE risk in relation to baseline characteristics (age, sex, TNM staging, thyroid and renal function) or in propensity score–matched analysis (age, TNM staging). During a mean follow-up of 30 months, OS and cancer-specific PFS were significantly higher in patients who developed irAEs (Kaplan–Meier estimates, p=0· 04 and 0· 03, respectively). In propensity score–matched analysis, diabetes was significantly associated with lower OS (multivariate hazard ratio, 0· 36; 95% CI, 0· 13– 0· 98) unrelated to irAEs. Irrespective of irAEs, PFS was also lower among patients with DM than among non-DM patients (Kaplan–Meier estimate, p=0· 04).Conclusion: Pre-existing diabetes was associated with higher mortality in advanced lung cancer, regardless of irAE development during treatment with ICI.Keywords: immune checkpoint inhibitor, diabetes, overall survival, progression-free survival

Background Prosthetic joint infection (PJI) of total hip (THA) or total knee arthroplasty (TKA) after dental procedures is uncommon, and antibiotic prophylaxis remains controversial. For high-risk patients, the American Academy of Orthopedic Surgeons recommends amoxicillin prophylaxis. However, no systematic review of the literature of PJIs associated with dental procedures explores if amoxicillin is suitable for the reported organisms. Methods A librarian-assisted search of the major databases (PubMed, Medline, Embase, Scopus) identified 954 articles. Only case reports, case series, and reviews with patient level data were included. After exclusions, 79 articles were fully reviewed. Results Forty-four PJIs after dental procedures were identified, 22 in primary THA, 20 in primary TKA, one in revision THA, and one in a hip resurfacing procedure. Antibiotic prophylaxis was documented for 5 patients. The dental procedure was invasive in 35 (79.5%). Comorbidities were present in 17 patients (38.7%). The organisms reported were Streptococcus spp. in 44%, other aerobic gram-positives in 27%, anaerobic gram-positives in 18%, and gram-negative organisms in 11%. An estimated 46% of organisms may be resistant to amoxicillin. The outcomes of treatment were reported for 35 patients (79.5%). Twenty-seven patients (61.4%) had no clinical signs of PJI at the final follow-up visit. Conclusions Lower extremity PJI associated with dental procedures is often caused by organisms unlikely to be prevented with amoxicillin. Additional studies are warranted to determine the choice and efficacy of antibiotic prophylaxis to prevent dental-associated PJI in the highest risk patients. Insufficient data exist to recommend the optimal treatment for patients with PJI in THA and TKA associated with dental procedures.

Purpose Diagnostic biomarkers of pancreatic ductal adenocarcinoma (PDAC) have been used for early detection to reduce its dismal survival rate. However, clinically feasible biomarkers are still rare. Therefore, in this study, we developed an automated multi-marker enzyme-linked immunosorbent assay (ELISA) kit using 3 biomarkers (leucine-rich alpha-2-glycoprotein [LRG1], transthyretin [TTR], and CA 19-9) that were previously discovered and proposed a diagnostic model for PDAC based on this kit for clinical usage. Methods Individual LRG1, TTR, and CA 19-9 panels were combined into a single automated ELISA panel and tested on 728 plasma samples, including PDAC (n = 381) and normal samples (n = 347). The consistency between individual panels of 3 biomarkers and the automated multi-panel ELISA kit were accessed by correlation. The diagnostic model was developed using logistic regression according to the automated ELISA kit to predict the risk of pancreatic cancer (high-, intermediate-, and low-risk groups). Results The Pearson correlation coefficient of predicted values between the triple-marker automated ELISA panel and the former individual ELISA was 0.865. The proposed model provided reliable prediction results with a positive predictive value of 92.05%, negative predictive value of 90.69%, specificity of 90.69%, and sensitivity of 92.05%, which all simultaneously exceed 90% cutoff value. Conclusion This diagnostic model based on the triple ELISA kit showed better diagnostic performance than previous markers for PDAC. In the future, it needs external validation to be used in the clinic.

Highlights l Conditional process analysis was conducted to examine the relationship between emotion, cognition, and psychological disorders. l Alienation, potentially induced by social distancing, mediate the development of post-traumatic stress disorder (PTSD) from negative emotions. l Anxiety increased the mediating effect of alienation but weakened the direct effect of negative emotions. l Clinical psychologists would better identify individuals with symptoms implying affective disorders in the early stages to provide more accurate and adequate intervention., Background The social distancing during COVID-19 is likely to cause a feeling of alienation, which may pose a threat to the public's mental health. Our research aims to examine the relationship between negative emotions and Post-Traumatic Stress Disorder (PTSD), considering the mediation effect of alienation and how it is moderated by anxiety and depression. Methods For this, the current study conducted a cross-sectional survey on 7145 participants during the outbreak of COVID-19, via online questionnaires comprised of a self-designed Negative emotions questionnaire, Symptom Check List 90 (SCL-90), PTSD Checklist-civilian version (PCL-C), and Adolescent Students Alienation Scale (ASAS). Results A total of 6666 pieces of data from the general population were included in the statistical analysis. The descriptive statistics showed a relatively mild level of mental disorders. Besides, results of Conditional Process Model analysis supported our hypotheses that negative emotions and alienation were both predictors for PTSD symptoms, and their direct and indirect effects were all moderated by the level of anxiety. Limitations This study was limited by the generality and causality of the conclusion. The moderating effect of depression was left for further study due to the collinearity problem of variables. Conclusions Social distancing may have an impact on individuals’ mental health by the feeling of alienation, which was moderated by affective disorders. Clinical psychologists should identify individuals’ particular cognition and mental disorders to provide a more accurate and adequate intervention for them.

Objective:The aim was to evaluate nurses’ self-efficacy, confidence, and nurse-patient interaction during caring of patients with coronavirus disease 2019 (COVID-19).Methods:A cross-sectional design with online survey was used with a Self-efficacy scale, Self-confidence scale, and Caring nurse-patient interaction scale: 23-item Version-Nurse (CNPI-23 N).Results:A sample of 120 nurses participated in the current study. The results showed that the participants had a moderate level of self-efficacy, self-confidence and interaction (M = 28.84 (SD = 7.7), M = 47.41 (SD = 9.0), and M = 93.59 (SD = 16.3), respectively). Positive relationships were found between nurse’ self-efficacy, self-confidence, and nurse-patient interaction (r = 0.81; P < 0.0001 and 0.79; P < 0.0001, respectively). Significant differences were found in self-efficacy according to years of experience, academic qualifications and position (F = 2.10; P = 0.003; F = 3.60; P = 0.002, and F = 2.60; P =0.007, respectively). Furthermore, the results indicated that there was a significant difference in self-confidence and nurse-patient interaction also.Conclusion:Nurse educators and administrators should develop and implement further strategies, such as continuing education and training, compensatory payment, organizational support, and availability of protective measures to increase their self-efficacy, self-confidence, and interaction with COVID-19 patients.

Veins are easy to obtain, have low immunogenicity, and induce a relatively weak inflammatory response. Therefore, veins have the potential to be used as conduits for nerve regeneration. However, because of the presence of venous valves and the great elasticity of the venous wall, the vein is not conducive to nerve regeneration. In this study, a novel tissue engineered nerve graft was constructed by combining normal dissected nerve microtissue with an autologous vein graft for repairing 10-mm peripheral nerve defects in rats. Compared with rats given the vein graft alone, rats given the tissue engineered nerve graft had an improved sciatic static index, and a higher amplitude and shorter latency of compound muscle action potentials. Furthermore, rats implanted with the microtissue graft had a higher density and thickness of myelinated nerve fibers and reduced gastrocnemius muscle atrophy compared with rats implanted with the vein alone. However, the tissue engineered nerve graft had a lower ability to repair the defect than autogenous nerve transplantation. In summary, although the tissue engineered nerve graft constructed with autologous vein and nerve microtissue is not as effective as autologous nerve transplantation for repairing long-segment sciatic nerve defects, it may nonetheless have therapeutic potential for the clinical repair of long sciatic nerve defects. This study was approved by the Experimental Animal Ethics Committee of Chinese PLA General Hospital (approval No. 2016-x9-07) on September 7, 2016.

Introduction Familial IgA nephropathy (IgAN) has been widely reported. However, its clinicohistologic characteristics and long-term prognosis are not clear. Methods A total of 348 familial IgAN cases from 167 independent families were recruited and their clinicohistologic characteristics as well as lifetime risk of end-stage renal disease (ESRD) were compared to 1116 sporadic IgAN patients from the same geographic region. Results Of all familial IgAN patients, 60 (17%) came from 32 single-generation (SG; all affected individuals are siblings) families, whereas 286 (82%) came from 134 multiple-generation (MG; affected individuals were present in at least 2 consecutive generations) families. The lifetime ESRD risk was significantly higher in familial patients than sporadic ones after adjusting by gender (hazard ratio [HR]=1.40, 95% confidence interval [CI]: 1.12–1.74, P = 0.004), with 5 years younger in median ESRD age (60 years vs. 65 years in familial and sporadic cases separately). Interestingly, among familial patients, we found cases from SG families (vs. MG families: HR = 2.62, 95% CI: 1.59–4.31, P < 0.001) or with early onset (onset age, Graphical abstract

Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction. Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse, and glutamatergic neurotransmission is essential for the formation and maintenance of these memories. In this review, we discuss the mechanisms by which gluta-mate, dopamine, and opioid signaling interact to mediate the primary rewarding effects of opioids, and cover the glutamatergic systems and circuits that mediate the expression, extinc-tion, and reinstatement of opioid seeking over the course of opioid addiction.

Background: Relapses are common in patients with multiple sclerosis (MS) even after the use of disease-modifying therapies. Repository corticotropin injection (RCI), plasmapheresis (PMP), and intravenous immunoglobulin (IVIg) may be utilized as alternative therapies in the management of MS relapse. There is a lack of health economic studies on these alternative therapies for the acute exacerbations of MS. The objective of this study was to estimate the cost per response of RCI compared with PMP or IVIg from the United States (US) commercial payer perspective. Methods: Costs and response rates were sourced from published peer-reviewed observational studies. The cost of care included MS-related inpatient, outpatient, and medication costs. Treatment response was defined as no evidence of additional relapse treatment or procedure claims within 30 days after treatment. The cost per response for each treatment was calculated by dividing the total annual cost of care by the proportion of patients with resolved relapse for each treatment. The incremental cost per response ratio was calculated by dividing the difference in costs and the proportion of responses for RCI versus PMP or IVIg. One-way sensitivity analysis (OWSA) was conducted for both costs and response rates. All included costs were inflated to the 2019 US dollars. Results: With a lower total annual cost of care and a higher response rate, RCI had a lower cost per response (US$141,970) compared with PMP or IVIg (US$253,331). RCI had a lower cost per response even when more stringent estimates for RCI were applied in the OWSA. The annual cost of care had a greater influence on the cost per response in the OWSA. Conclusions: Based on the estimates from the real-world evidence, our economic evaluation suggests that RCI may have real-world clinical and economic benefits for patients with MS relapse who fail on corticosteroid therapy.

Purpose This study assessed the therapeutic efficacy of postoperative magnetic resonance (MR)-guided interstitial 125 I seed implantation for treatment of oral and maxillofacial malignant tumors. Methods and materials A total of 127 patients with oral or maxillofacial malignant tumors were included in this study who received interstitial 125 I treatment after the surgery resection. Before implantation, all the patients received MR scans to assess the lesion scope, extent, and nature. 125 I implantation target regions were based on the pre-operative imaging. 125 I seeds were delivered to target regions via puncture needles under the real-time guidance of MR. Computed tomography (CT)or MR was performed immediately after implantation and again every 3 months later. Results After successful 125 I implantation, all patients were also examined regularly to detect tumor recurrence, lymphatic, and distant metastases. To date, CT or MR verification showed that 13/127 patients experienced tumor recurrence or lymphatic metastasis or distant metastasis. No seeds migration was observed, no serious treatment-related complications affected patient quality of life, and no important organ (such as major cervical vessels, spinal cord, etc.) injuries were observed. Conclusion Our results show that MR-guided 125 I implantation is an effective approach to site-specific treatment for oral and maxillofacial tumor, which could potentially reduce postoperative complications and tumor recurrence rates, increase patient survival, and improve quality of life.

Objective: Positive psychology interventions (PPIs) incorporate principles of personal strengths with the view that mental health recovery transcends symptom relief. Severe psychiatric conditions, such as schizophrenia, may benefit from such interventions. This study aims to gather the current evidence on the impact of PPIs on increasing well-being in patients on the schizophrenia spectrum and assess reductions in negative or positive symptoms. Methods: A systematic review of PPI studies with schizophrenia-spectrum patients was carried out following PRISMA recommendations. The PubMed, PsycINFO, Web of Science, and Scopus databases were searched for relevant publications in order to understand the possible effects of these interventions on well-being measures and psychotic symptoms in this population. Results: Nine studies (four controlled) were included. Meta-analysis of the controlled studies showed a significant effect (p = 0.04) for improvement of well-being (Z = 2.01). Overall, the reviewed evidence suggests well-being improvement. The effect on reduction of negative symptoms was unclear. Conclusion: Used as an adjunctive therapy, PPIs appear to be a promising resource for patients on the schizophrenia spectrum, with possible effects on well-being and symptom reduction.

Introduction A scoring system to determine indications for catheter ablation (CA) in atrial fibrillation (AF) is desired. Methods and Results Among 2898 consecutive patients with AF, CA was performed in 938 (32.4%). A new HEAL‐AF score has been developed by six variables, all of which were independently associated with CA by multivariate analysis and for each 1 point was assigned: heart failure ≥ NYHA II, elderly patients (age ≥75 years), asymptomatic AF, long‐standing persistent AF, atrial dilation (left atrial diameter ≥ 50 mm), and female sex. Low HEAL‐AF score was associated with high incidence of CA performance (52.0% for 0, 36.5% for 1, 15.1% for 2, and 5.6% for ≥ 3) and the predictive capability of this score by AUC of ROC curve was 0.720 (95% CI 0.701‐0.739, P, The HEAL‐AF score consists of six simple clinical variables (1 point for each of heart failure ≥ NYHA II, age ≥ 75 years, asymptomatic AF, and long‐standing persistent AF, left atrial diameter ≥ 50 mm, and female sex). The HEAL‐AF score was significantly associated with not only patient selection for catheter ablation (CA) but also complex ablation strategy and recurrence of AF after CA.

Chronic hand eczema (CHE) is a common and burdensome inflammatory skin condition seen in up to 10% of the population, more often in high-risk occupational workers. Topical therapeutics comprise the standard of care, but up to 65% of cases do not resolve after treatment, and moderate-to-severe cases are often resistant to topical therapeutics and require systemic options instead. To date, there are no systemic therapeutics approved to treat CHE in the United States, but several drugs are under investigation as potential treatments for CHE. The primary focus of this review is on the novel therapeutics, topical and systemic, that are under investigation in recently completed or currently ongoing trials. This review also briefly outlines the existing treatments utilized for CHE, often with limited success or extensive adverse effects. CHE represents a major challenge for physicians and patients alike, and efforts to improve the minimally invasive diagnostic tools and treatment paradigms are ongoing. In the near future, CHE patients may benefit from new topical and systemic therapeutics that specifically target abnormally expressed immune markers.

In spite of multiple program efforts in Ghana, progress in reducing the burden of anemia is slow. The objective was to conduct multilevel assessments of existing childhood (, In Ghana, numerous preventive and management interventions are implemented concurrently to address childhood anemia. Despite existing program efforts, the incidence of childhood anemia remains high. The objectives of our study were to conduct multilevel assessments of existing childhood anemia prevention and treatment programs, to elucidate implementation gaps in Ghana using UNICEF's conceptual framework of malnutrition as a guide.

The blood‐brain barrier is a dynamic and complex neurovascular unit that protects neurons from somatic circulatory factors as well as regulates the internal environmental stability of the central nervous system. Endothelial glycocalyx is a critical component of an extended neurovascular unit that influences the structure of the blood‐brain barrier and plays various physiological functions, including an important role in maintaining normal neuronal homeostasis. Specifically, glycocalyx acts in physical and charge barriers, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation. Since intact glycocalyx is necessary to maintain the stability and integrity of the internal environment of the blood‐brain barrier, damage to glycocalyx can lead to the dysfunction of the blood‐brain barrier. This review discusses the role of glycocalyx in the context of the substantial literature regarding the blood‐brain barrier research, in order to provide a theoretical basis for the diagnosis and treatment of neurological diseases as well as point to new breakthroughs and innovations in glycocalyx‐dependent blood‐brain barrier function., Endothelial glycocalyx as an important factor in composition of blood‐brain barrier and significance.

Yan Liu,1,* Chi Zhang,2,* Chengyu Li,1 Chunxue Bai,3 Hongcai Shang1 1Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Institute for Brain Disorders, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongcai ShangKey Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, 5 Haiyuncang, Dongcheng District, Beijing 100700, People’s Republic of ChinaEmail shanghongcai@126.comBackground: There were few studies on the case mortality of severe community-acquired pneumonia (CAP) in elderly people. Improved outcomes with XueBiJing (XBJ) injection vs placebo have been shown in overall trial populations. We investigated the efficacy and safety of XBJ vs placebo in subjects with severe CAP stratified by age (< 65 and ≥ 65 years).Methods: This post hoc analysis of a large randomized trial compared data from elderly and nonelderly patients with XBJ, 100 mL, q 12 h, or a visually indistinguishable placebo for five-to-seven days.Results: Among subjects ≥ 65 years (n=291), 23 (16.0%) XBJ recipients and 41 (27.9%) placebo recipients (P=0.014) died within 28 days. Among subjects < 65 years (n=360), XBJ still had lower mortality (XBJ 15.6% vs placebo 22.8%; P=0.082), without significantly statistical difference. Total duration of ICU stay and the time of mechanical ventilation were similar in both groups (P> 0.05). XBJ also had a favorable safety profile, with no clinically relevant differences between the two groups. The overall incidence of adverse events was similar in both groups.Conclusion: XBJ was safe and effective for reduction in 28-day mortality among elderly patients with severe CAP. Additional confirmatory trials involving elderly patients are needed to further confirm the present results.Trial Registration: http://www.chictr.org.cn/index.aspx. ChiCTR-TRC-13003534.Keywords: severe community-acquired pneumonia, randomized controlled trial, post hoc analysis, 28-day mortality rate, XueBiJing injection

Aims/Introduction It was reported that fetuses secrete endogenous incretin; however, the stimulants of fetal incretin secretion are not fully understood. To investigate the association between the passage of amniotic fluid through the intestinal tract and fetal secretion of incretin, we analyzed umbilical cord incretin levels of infants with duodenum atresia. Materials and Methods Infants born from July 2017 to July 2019 (infants with duodenum atresia and normal term or preterm infants) were enrolled. We measured and compared the concentrations of glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory peptide/glucose‐dependent insulinotropic polypeptide (GIP) in the umbilical vein and preprandial blood samples after birth. Results A total of 98 infants (47 term, 46 preterm and 5 with duodenum atresia) were included. In patients with duodenum atresia, umbilical vein GLP‐1 and GIP levels were the same as those in normal infants. In postnatal samples, there were positive correlations between the amount of enteral feeding and preprandial serum concentrations of GLP‐1 (r = 0.47) or GIP (r = 0.49). Conclusions Our results show that enteral feeding is important for secretion of GLP‐1 and GIP in postnatal infants, whereas the passage of amniotic fluid is not important for fetal secretion of GLP‐1 and GIP. The effect of ingested material passing through the digestive tract on incretin secretion might change before and after birth. Other factors might stimulate secretion of GLP‐1 and GIP during the fetal period., Enteral feeding is important for secretion of glucagon‐like peptide‐1 and gastric inhibitory peptide/glucose‐dependent insulinotropic polypeptide in postnatal infants, whereas the passage of amniotic fluid is not important for fetal secretion of glucagon‐like peptide‐1 and inhibitory peptide/glucose‐dependent insulinotropic polypeptide. The effect of ingested material passing through the digestive tract on incretin secretion might change before and after birth.

Mitaw Girma,1 Shambel Wodajo,2 Sewunet Ademe,3 Afework Edmealem,3 Mulugeta W/silasie,4 Gebremeskel Mesafint5 1Department of Adult Health Nursing, Wollo University, Dessie, Amhara, Ethiopia; 2Department of Public Health, Wollo University, Dessie, Amhara, Ethiopia; 3Department of Nursing, Wollo University, Dessie, Amhara, Ethiopia; 4Department of Pediatric Nursing, Wollo University, Dessie, Amhara, Ethiopia; 5Department of Nursing, Mizan Tepi University, Mizan Tepi, South Ethiopia, EthiopiaCorrespondence: Sewunet AdemeDepartment of Nursing, Wollo University, Dessie, Amhara, EthiopiaTel +251 918126233Email sewunet.ademe@gmail.comBackground: Diabetes mellitus is a disorder of carbohydrate metabolism and it is highly related with diminished HRQOL in Ethiopia; diabetic related complications especially bring major negative impacts on HRQOL.Objective: To assess HRQOL and associated factors among type two diabetic patients in Dessie Comprehensive Specialized Hospital, north east Ethiopia, 2020.Methods: Institutional-based cross-sectional study design was conducted on 417 patients through systematic random sampling technique from February 08 to April 08, 2020. WHO HRQOL 26 items were used to measure outcome variable. Face-to-face interview, document review and measurement were implemented to collect data. The data were analyzed by IBM SPSS Statistics version 25 and summarized by using tables. Simple linear regression analysis was done and forwarded to multivariable linear regression analysis at p-value < 0.25. Next multivariable linear regression analysis was done and variables whose p-value less than 0.05 with unstandardized B-coefficient were declared significant predictor variables.Results: The mean scores of physical domain, psychological domain, environmental domain and social domain were 48± 6.7 (47– 49), 52± 4.2 (50– 52.3), 48.9± 3.4 (48– 50.4) and 49± 4 (48– 50), respectively. As age increased by one year, patients’ physical HRQOL decreased by 0.031 factor, keeping effect of other variables constant [− 0.031, 95% CI (− 0.050 to-0.013)]. As duration of diabetes increased by one year, patients’ physical HRQOL increased by 0.034 factor, keeping effect of other variables constant [0.034, 95% CI (0.004 to 0.065)]. In general, age, depression, perceived social stigma, self-employed, having two complications, widowed, insulin and oral anti-diabetic medication affected HRQOL negatively and duration of diabetes in physical domain and university level of education in environmental domain affected HRQOL positively.Conclusion and Recommendation: The mean score of health-relatedquality of life in physical health domain, psychological health domain, social health domain and environmental health domain was recorded nearly half score point out of ahundred. Health professionals should follow a holistic approach to management to address negatively associated predictor variables with HRQOL.Keywords: HRQOL, type II diabetes

Six‐Transmembrane Epithelial Antigene of the Prostate 1 (STEAP1) is associated with the occurrence and development of cancer. This study aimed to clarify the role of STEAP1 in gastric cancer tumour growth and metastasis, as well as its molecular mechanism of action.Statistical methods were used for clinical data analysis. Protein expression was detected using immunohistochemistry(IHC). The mRNA and protein expression in the cell cultures were detected using reverse transcription‐polymerase chain reaction(RT‐PCR) and western blot analysis. Overexpression and silencing models were constructed using plasmid and lentivirus transfection. To detect cell proliferation in vitro, Cell Counting Kit‐8(CCK‐8), flow cytometry and colony formation assays were used; transwell and wound healing assays were used to detect cell migration and invasion;For in vivo experiments, nude BALB/c mice were used for detecting subcutaneous tumorigenesis and intraperitoneal implantation. In the results,we found STEAP1 was overexpressed in gastric cancer tissues and cell lines. Single‐factor and Cox analyses showed that STEAP1 gene expression level correlated with poor prognosis. Up‐regulation of STEAP1 increased cell proliferation, migration and invasion, which decreased after STEAP1 was knocked down. These changes were achieved via the activation of the AKT/FoxO1 pathway and epithelial‐mesenchymal transformation (EMT). The in vivo animal experiments showed that STEAP1 knock down, resulted in a decrease in the subcutaneous tumour and peritoneal tumour formation.

Tim-3 is a promising target for antitumor immunotherapy. A number of clinical trials are evaluating the efficacy of anti-Tim-3 therapies as a single agent or combinations in solid tumors and haematologic malignancies. However, there remains a considerable lack of data on Tim-3 signalling, especially the genetic characteristics and immune microenvironment, in diffuse large B cell lymphoma (DLBCL). Herein, we identified three genetic mutations in galectin-9, a major ligand of Tim-3, in six patients with DLBCL (6/188, 3.2%) that were not detected in the COSMIC database. The Oncomine database showed that the mRNA levels of Tim-3 were higher in DLBCL cells than those in normal B cells. Multiplexed immunofluorescence revealed that patients with Tim-3-expressing tumor-infiltrating lymphocytes (Tim-3+ TILs) exhibited poor outcomes than those with Tim-3- TILs ( p = 0.041 ). The median survival times of these patients were 65.0 (95% confidence interval (CI): 71.2–88.6) and 79.9 months (95% CI: 54.4–75.6), respectively. Furthermore, we defined a novel subtype of exhausted T cells, named as exhausted Tim-3+ CD8+ T cells, and found that patients with exhausted Tim-3+ CD8+ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) exhibited shorter survival than those with nonexhausted Tim-3- CD8+ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9; p = 0.034 ). Overall, these findings provide the genetic status of the Tim-3 ligand in DLBCL. Patients with Tim-3+ TILs and exhausted Tim-3+ CD8+ T cells exhibited inferior survival, thus highlighting the possibility of potential therapeutic applications of the inhibition of Tim-3 alone or in combination with other immune checkpoints for treatment of patients with DLBCL.

Most eukaryotic pre-mRNAs must undergo 3′-end cleavage and polyadenylation prior to their export from the nucleus. A large number of proteins in several complexes participate in this 3′-end processing, including cleavage and polyadenylation specificity factor (CPSF) in mammals. The CPSF30 subunit contains five CCCH zinc fingers (ZFs), with ZF2–ZF3 being required for the recognition of the AAUAAA poly(A) signal. ZF4–ZF5 recruits the hFip1 subunit of CPSF, although the details of this interaction have not been characterized. Here we report the crystal structure of human CPSF30 ZF4–ZF5 in complex with residues 161–200 of hFip1 at 1.9 Å resolution, illuminating the molecular basis for their interaction. Unexpectedly, the structure reveals one hFip1 molecule binding to each ZF4 and ZF5, with a conserved mode of interaction. Our mutagenesis studies confirm that the CPSF30–hFip1 complex has 1:2 stoichiometry in vitro. Mutation of each binding site in CPSF30 still allows one copy of hFip1 to bind, while mutation of both sites abrogates binding. Our fluorescence polarization binding assays show that ZF4 has higher affinity for hFip1, with a Kd of 1.8 nM. We also demonstrate that two copies of the catalytic module of poly(A) polymerase (PAP) are recruited by the CPSF30–hFip1 complex in vitro, and both hFip1 binding sites in CPSF30 can support polyadenylation.

The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18 354 mutations in S protein were analyzed, and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3705 mutations in SARS-CoV-2 RBD and 11 324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD–ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.

Aims Heart rate reduction therapy using ivabradine, a selective inhibitor of the funny current of the sinoatrial node, is widely used in the systolic heart failure cohort. However, the optimal target of heart rate remains controversial. The association between heart rate and ‘overlap’ between E‐wave and A‐wave in the pulse wave transmitral flow Doppler echocardiography might be a key to find the ideal heart rate in each individual. Methods and results We performed transthoracic echocardiography in patients with systolic heart failure, and the association between heart rate, deceleration time, and overlap length between E‐wave and A‐wave was assessed. In total, 368 patients with systolic heart failure (median 76 years old, 190 men, median ejection fraction 40%) were included. The measured overlap length was 35 (−72, 115) ms. Given the results of multiple linear regression analyses, we constructed a formula: estimated overlap length (ms) = −589 + 6.2 × heart rate (bpm) + 0.81 × deceleration time (ms), which had a good agreement with actually measured one (r = 0.62). The ideal heart rate, at which the overlap length is ‘zero’ and probably cardiac output is maximized, is calculated as follows: ideal heart rate (bpm) = 93 – 0.13 × deceleration time (ms). Conclusions We proposed a novel formula using deceleration time to estimate ideal heart rate that achieves a zero overlap between E‐wave and A‐wave in patients with systolic heart failure. Prognostic impact of the formula‐guided heart rate optimization should be studied.

Axial SpA (axSpA), encompassing AS, is a multifactorial disease that localizes to sites of high spinal biomechanical stress. Much has been written on T cells and adaptive immunity in axSpA, which is understandable given the very strong HLA-B27 disease association. Extra-axial disease characteristically involves the anterior uveal tract, aortic root, lung apex and terminal ileum. Under recent classification, axSpA is classified as an intermediate between autoimmunity and autoinflammatory disease, with the latter term being synonymous with innate immune dysregulation. The purpose of this review is to evaluate the ‘danger signals’ from both the exogenous intestinal microbiotal adjuvants or pathogen-associated molecular patterns that access the circulation and endogenously derived damaged self-tissue or damage-associated molecular patterns derived from entheses and other sites of high biomechanical stress or damage that may serve as key drivers of axSpA onset, evolution, disease flares and eventual outcomes.

Introduction Although predialysis hemoglobin concentration is affected by interdialytic weight gain (IDWG), the interaction between these parameters is not well understood. Methods Using data from the Dialysis Outcomes and Practice Pattern Study in Japan (J-DOPPS) phases 1, 2, 3, 4, and 5, we analyzed patients who underwent maintenance hemodialysis. The exposure variable was hemoglobin concentration, and the effect modifier was IDWG at baseline. These 2 categorical variables were then combined and analyzed. The primary outcome was major adverse cardiovascular events (MACEs). Hazard ratios (HRs) were estimated using a Cox model for the association between exposure and MACEs after adjusting for potential confounders. We examined additive interactions between hemoglobin concentration and IDWG by calculating the relative excess risk due to interaction (RERI), which is defined as a departure from the additivity of effects. Results A total of 8234 patients were enrolled. During a median follow-up of 2.1 years, 1062 (12.9%) patients developed MACEs. As the IDWG increased, the lowest point estimation in each IDWG category tended to shift to the lower hemoglobin concentration categories. In IDWG categories of ≥6%, point estimation of MACEs with hemoglobin concentration of ≥10.0 g/dl to, Graphical abstract

Type 2 diabetes mellitus (T2DM) is highly prevalent in the general population and especially in patients with heart failure (HF). It is not only a risk factor for incident HF, but is also associated with worse outcomes in prevalent HF. Therefore, antihyperglycaemic management in patients at risk of or with established HF is of importance to reduce morbidity/mortality. Following revision of the drug approval process in 2008 by the Food and Drug Administration and European Medicines Agency, several cardiovascular outcome trials on antihyperglycaemic drugs have recently investigated HF endpoints. Signals of harm in terms of increased risk of HF have been identified for thiazolidinediones and the dipeptidyl peptidase 4 inhibitor saxagliptin, and therefore, these drugs are not currently recommended in HF. Sulfonylureas also have an unfavourable safety profile and should be avoided in patients at increased risk of/with HF. Observational studies have assessed the use of metformin in patients with HF, showing potential safety and potential survival/morbidity benefits. Overall use of glucagon‐like peptide 1 receptor agonists has not been linked with any clear benefit in terms of HF outcomes. Sodium–glucose cotransporter protein 2 inhibitors (SGLT2i) have consistently shown to reduce risk of HF‐related outcomes in T2DM with and without HF and are thus currently recommended to lower risk of HF hospitalization in T2DM. Recent findings from the DAPA‐HF trial support the use of dapagliflozin in patients with HF with reduced ejection fraction and, should ongoing trials with empagliflozin, sotagliflozin, and canagliflozin prove efficacy, will pave the way for SGLT2i as HF treatment regardless of T2DM.

Introduction There is a paucity of information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients undergoing maintenance hemodialysis. We aimed to estimate the cumulative attack rate of SARS-CoV-2 in hemodialysis patients in China using a serological test. Methods We enrolled all hemodialysis patients from 8 hemodialysis facilities in Honghu and Jingzhou of Hubei province and Guangzhou and Foshan of Guangdong province in China. We screened these patients for SARS-CoV-2 infection by both a reverse transcriptase polymerase chain reaction (RT-PCR) test for viral RNA and a serological test for IgG and IgM antibodies. Data on demographics and clinical characteristics were collected by means of case report forms. We also enrolled the health care workers (HCWs) from the participating hospitals and compared the seropositive rate between hemodialysis patients and HCWs in the same region. Results Among 1542 hemodialysis patients, 5 (0.32%) and 51 (3.3%) tested positive by the RT-PCR test and the serological test, respectively. The seropositive rate in Hubei (3.6%) was higher than that in Guangdong (2.8%), although the difference was not statistically significant (P = 0.5). Most of the seropositive patients were asymptomatic. Independent risk factors for SARS-CoV-2 infection were age greater than 65 years, a manifestation of lung infection on imaging examinations, and a lower level of serum albumin. In comparison, the seropositive rate in 3205 health care workers was 1.2%, which was significantly lower than that observed in the hemodialysis patients (P < .001). Conclusion The cumulative rate of SARS-CoV-2 infection in hemodialysis patients in China was high, at 3.3%. The serological test detected 10 times more cases of SARS-CoV-2 infection than the RT-PCR test, and should be the preferred tool for estimating the prevalence of coronavirus disease 2019 (COVID-19)., Graphical abstract

People with chronic disease often have poor comprehension of their disease and medications, which can negatively affect health outcomes. In a randomised‐controlled trial, we found that patients with decompensated cirrhosis who received a pharmacist‐led, patient‐oriented education and medication management intervention (n = 57) had greater knowledge of cirrhosis and key self‐care tasks compared with usual care (n = 59). Intervention patients also experienced improved quality of life. Dedicated resources are needed to support implementation of evidence‐based measures at local centres to improve outcomes.

Lemur tyrosine kinase 3 (LMTK3) is a key member of the serine–threonine tyrosine kinase family. It plays an important role in breast cancer tumorigenesis and progression. However, its biological role in bladder cancer remains elusive. In this study, we demonstrated that LMTK3 was overexpressed in bladder cancer and was positively correlated with bladder cancer malignancy. High LMTK3 expression predicted poor overall survival. Knockdown of LMTK3 in bladder cancer cells triggered cell‐cycle arrest at G2/M phase, suppressed cell growth, and induced cell apoptosis in bladder cancer cells. Furthermore, Transwell assays revealed that reduction of LMTK3 decreased cell migration by regulating the epithelial‐to‐mesenchymal transition pathway. Conversely, LKTM3 overexpression was shown to promote proliferation and migration of bladder cancer cells. We assessed phosphorylation of MEK and ERK1/2 in bladder cancer cells depleted of LMTK3 and demonstrated a reduced phosphorylation status compared with the control group. Using an MAPK signaling‐specific inhibitor, U0126, we could rescue the promotion of proliferation and viability in LMTK3‐overexpressing cells. In conclusion, we extend the status of LMTK3 as an oncogene in bladder cancer and provide evidence for its function via the activation of the ERK/MAPK pathway. Thus, targeting LMTK3 may hold potential as a diagnostic and prognostic biomarker and as a possible future treatment for bladder cancer., Here, we characterise LMTK3 as an oncogene in bladder cancer. LMTK3 was overexpressed in bladder cancer and this increased expression closely correlated with poor survival of bladder cancer patients. LMTK3 overexpression induced cell growth and migration whereas its depletion promoted apoptosis of bladder cancer cells. We found LMTK3 promoted tumorigenesis and progression by activating the ERK/MAPK pathway.

Purified IgG from a patient with progressive encephalopathy with rigidity and myoclonus (PERM) who had raised antibodies to the inhibitory glycine receptor was injected into mice together with lipopolysaccharide to open the blood–brain barrier. The mice developed a motor phenotype, indicated by falling off a rotating cylinder earlier than healthy IgG injected controls. At termination, these mice had deposits of IgG within the brainstem neurons which express glycine receptors, consistent with an antibody‐induced dysfunction of these neurons., Aims Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life‐threatening condition often associated with highly raised serum antibodies to glycine receptors (GlyRs); these bind to the surface of large neurons and interneurons in rodent brain and spinal cord sections and, in vitro, inhibit function and reduce surface expression of the GlyRs. The effects in vivo have not been reported. Methods Purified plasma IgG from a GlyR antibody‐positive patient with PERM, and a healthy control (HC), was injected daily into the peritoneal cavity of mice for 12 days; lipopolysaccharide (LPS) to open the blood–brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48 h post‐LPS on days 5–7 and 10–12. Results The GlyR IgG injected mice showed impaired ability on the rotarod from days 5 to 10 but this normalized by day 12. There were no other behavioural differences but, at termination (d13), the GlyR IgG‐injected mice had IgG deposits on the neurons that express GlyRs in the brainstem and spinal cord. The IgG was not only on the surface but also inside these large GlyR expressing neurons, which continued to express surface GlyR. Conclusions Despite the partial clinical phenotype, not uncommon in passive transfer studies, the results suggest that the antibodies had accessed the GlyRs in relevant brain regions, led to antibody‐mediated internalization and increased GlyR synthesis, compatible with the temporary loss of function.