Addressing Gaps for Health Systems Strengthening: A Public Perspective on Health Systems' Response towards COVID-19.

Strengthening the health systems through gaps identification is necessary to ensure sustainable improvements especially in facing a debilitating outbreak such as COVID-19. This study aims to explore public perspective on health systems' response towards COVID-19, and to identify gaps for health systems strengthening by leveraging on WHO health systems' building blocks. A qualitative study was conducted using open-ended questions survey among public followed by in-depth interviews with key informants. Opinions on Malaysia's health systems response towards COVID-19 were gathered. Data were exported to NVIVO version 12 and analysed using content analysis approach. The study identified various issues on health systems' response towards COVID-19, which were then mapped into health systems' building blocks. The study showed the gaps were embedded among complex interactions between the health systems building blocks. The leadership and governance building block had cross-cutting effects, and all building blocks influenced service deliveries. Understanding the complexities in fostering whole-systems strengthening through a holistic measure in facing an outbreak was paramount. Applying systems thinking in addressing gaps could help addressing the complexity at a macro level, including consideration of how an action implicates other building blocks and approaching the governance effort in a more adaptive manner to develop resilient systems.

Total glucosides of Paeony restores intestinal barrier function through inhibiting Lyn/Snail signaling pathway in colitis mice.

BACKGROUND: Inflammatory bowel disease (IBD) is an autoimmune disease. The pathogenesis of IBD is complicated and intestinal mucosal barrier damage is considered as the trigger factor for the initiation and recurrence of IBD. Total Glucosides of Paeony (TGP) has shown good inhibitory effects on immune-inflammation in clinic studies. However, its effect and mechanism on IBD are largely unknown. PURPOSE: The purpose of this study is to evaluate the effect and mechanism of TGP on IBD. STUDY DESIGN: DSS-induced colitis mouse model was used. TGP was given by gavage. Caco-2 cells were stimulated by outer membrane vesicles (OMV) to establish an in vitro model. METHODS: C57BL/6 mice were divided into normal control group, model group, mesalazine group, paeoniflorin (PA) group, high-dose group of TGP, and low-dose group of TGP. The model was induced with 2.5% DSS for 7 days, and TGP was intragastrically administered for 10 days. The therapeutic effect of TGP was evaluated by symptoms, histochemical analysis, RT-qPCR and ELISA. The mechanism was explored by intestinal permeability, Western blot and immunofluorescence in vivo and in vitro. RESULTS: Our results showed that TGP could significantly improve the symptoms and pathological changes, with reduced levels of TNF-α, IL-17A, IL-23 and IFN-γ in the colon tissues and serum under a dose-dependent manner. TGP also reduced the intestinal permeability and restored the protein expression of tight junction and adherens junction proteins of intestinal epithelial cells in vivo and in vitro. Furthermore, TGP could inhibit the expression of p-Lyn and Snail and prevent Snail nuclear localization, thereby maintaining tight and adherens junctions. CONCLUSION: TGP effectively improves the symptoms of DSS-induced colitis in mice, protects the intestinal epithelial barrier by inhibiting the Lyn/Snail signaling pathway, and maybe a promise therapeutic agent for IBD treatment.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: An evidence-based clinical practice guideline (updated version).

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID-19 patients.

Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: an evidence-based clinical practice guideline (updated version)

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID19 patients

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version).

In December 2019, a new type viral pneumonia cases occurred in Wuhan, Hubei Province; and then named "2019 novel coronavirus (2019-nCoV)" by the World Health Organization (WHO) on 12 January 2020. For it is a never been experienced respiratory disease before and with infection ability widely and quickly, it attracted the world's attention but without treatment and control manual. For the request from frontline clinicians and public health professionals of 2019-nCoV infected pneumonia management, an evidence-based guideline urgently needs to be developed. Therefore, we drafted this guideline according to the rapid advice guidelines methodology and general rules of WHO guideline development; we also added the first-hand management data of Zhongnan Hospital of Wuhan University. This guideline includes the guideline methodology, epidemiological characteristics, disease screening and population prevention, diagnosis, treatment and control (including traditional Chinese Medicine), nosocomial infection prevention and control, and disease nursing of the 2019-nCoV. Moreover, we also provide a whole process of a successful treatment case of the severe 2019-nCoV infected pneumonia and experience and lessons of hospital rescue for 2019-nCoV infections. This rapid advice guideline is suitable for the first frontline doctors and nurses, managers of hospitals and healthcare sections, community residents, public health persons, relevant researchers, and all person who are interested in the 2019-nCoV.

Fuzhenghuayu Decoction ameliorates hepatic fibrosis by attenuating experimental sinusoidal capillarization and liver angiogenesis.

Fuzhenghuayu (FZHY) is a compound extracted from natural plants. Its anti-fibrotic effect has been confirmed in experimental and clinical studies. However, precise effects and underlying mechanisms of FZHY in liver angiogenesis largely remain understood. In this study, we investigated the effects of FZHY on sinusoidal capillarization and angiogenesis with mice challenged for Carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN), in vitro human hepatic sinusoidal endothelial cells (HHSEC) and Human Umbilical Vein Endothelial Cell (HUVEC) 3D fibrin gel model. Besides its anti-fibrotic effect, FZHY ameliorated CCl4 and DMN-induced sinusoidal capillarization, angiogenesis and expression of angiogenesis-associated factors, i.e. CD31, VEGF, VEGF receptor II, phosphor-ERK and HIF-1α. Consistent with the findings based on animal models, inhibitory effects of FZHY on capillarization and angiogenesis were further confirmed in HHSEC and the HUVEC 3D fibrin gel model, respectively. These data suggest that FZHY ameliorates not only liver fibrosis but also vessel remodeling in experimental models. Therefore, FZHY might be a potentially useful drug to treat liver cirrhosis in clinical practice.

Bupleurum polysaccharides ameliorated renal injury in diabetic mice associated with suppression of HMGB1-TLR4 signaling.

Bupleurum polysaccharides (BPs) is isolated from Bupleurum smithii var. parvifolium, a key traditional Chinese medicine. The study was to investigate the effects of BPs on diabetic kidney injury. After two intraperitoneal injections of streptozotozin (STZ) 100 mg·kg-1, renal injury in diabetic mice was induced and BPs was orally administrated at dosages of 30 and 60 mg·kg-1·d-1. The STZ injected mice developed renal function damage, renal inflammation and fibrosis known as diabetic kidney disease (DKD). BPs significantly reduced serum creatinine level and urinary albumin excretion rate, with the attenuated swelling of kidneys. BPs treatment obviously alleviated the pathological damage of renal tissue. The progression of renal injury in BPs treated mice was inhibited with less expression of type IV collagen (Col IV), fibronectin (FN) and α-smooth muscle actin (α-SMA). The inhibition of inflammation in kidney was associated with the reduced level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). BPs administration suppressed the over-expression of toll like receptor 4 (TLR4) and high-mobility group box 1 (HMGB1) with lowered activity of nuclear factor kappa B (NF-κB) in renal tissue of diabetic mice. Oral administration of BPs effectively prevented the development ofrenal injury in diabetic mice. This study suggested that the protection provided by BPs might affect through the interruption of HMGB1-TLR4 pathway, leading to the inhibition of renal inflammation and fibrotic process.

Houttuynia cordata polysaccharide alleviated intestinal injury and modulated intestinal microbiota in H1N1 virus infected mice.

Houttuynia cordata polysaccharide (HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg(kg-1(d-1. H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus, the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1ß in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP.

Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8.

BACKGROUND & AIMS: Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about the mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. METHODS: We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription polymerase chain reaction. We studied mice in which hepatocyte-specific deletion of ß-catenin (Ctnnb1flox/flox mice injected with Adeno-associated virus serotype 8 [AAV8]-TBG-Cre) induces differentiation of LPCs into hepatocytes after a choline-deficient, ethionine-supplemented (CDE) diet. Liver tissues were collected and analyzed by immunohistochemistry and immunoblots. We performed immunohistochemical analyses of liver tissues from patients with compensated or decompensated cirrhosis or acute on chronic liver failure (n = 15). RESULTS: Loss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of ß-catenin impaired differentiation of LPCs into hepatocytes after the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis. CONCLUSIONS: Hdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury after the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.

Taxus chinensis ameliorates diabetic nephropathy through down-regulating TGF-ß1/Smad pathway.

Diabetic nephropathy (DN) is one of the common microvascular complications of diabetes mellitus. Renal fibrosis is closely related to the deterioration of renal function. The present study aimed to investigate protective effect of Taxus chinensis on high-fat diet/streptozotocin-induced DN in rats and explore the underlying mechanism of action. The rat DN model was established via feeding high fat diet for 4 weeks and subsequently injecting streptozotocin (30 mg·kg-1 body weight) intraperitoneally. The rats with blood glucose levels higher than 16.8 mmol·L-1 were selected for experiments. The DN rats were treated with Taxus chinensis orally (0.32, 0.64, and 1.28 g·kg-1) once a day for 8 weeks. Taxus chinensis significantly improved the renal damage, which was indicated by the decreases in 24-h urinary albumin excretion rate, blood serum creatinine, and blood urea nitrogen. Histopathological examination confirmed the protective effect of Taxus chinensis. The thickness of glomerular basement membrane was reduced, and proliferation of mesangial cells and podocytes cells and increase in mesangial matrix were attenuated. Further experiments showed that Taxus chinensis treatment down-regulated the expression of TGF-ß1 and α-SMA, inhibited phosphorylation of Smad2 and Smad3. These results demonstrated that Taxus chinensis alleviated renal injuries in DN rats, which may be associated with suppressing TGF-ß1/Smad signaling pathway.

Long-Term Coffee Consumption and Risk of Gastric Cancer: A PRISMA-Compliant Dose-Response Meta-Analysis of Prospective Cohort Studies.

Association between coffee consumption and gastric cancer risk remains controversial. Hence, we performed a meta-analysis to investigate and quantify the potential dose-response association between long-term coffee consumption and risk of gastric cancer.Pertinent studies were identified by searching PubMed and Embase from January 1996 through February 10, 2015 and by reviewing the reference lists of retrieved publications. Prospective cohort studies in which authors reported effect sizes and corresponding 95% confidence intervals (CIs) of gastric cancer for 3 or more categories of coffee consumption were eligible. Results from eligible studies were aggregated using a random effect model. All analyses were carried out using the STATA 12.0 software.Nine studies involving 15 independent prospective cohorts were finally included. A total of 2019 incident cases of gastric cancer were ascertained among 1,289,314 participants with mean follow-up periods ranging from 8 to 18 years. No nonlinear relationship of coffee consumption with gastric cancer risk was indentified (P for nonlinearity = 0.53; P for heterogeneity = 0.004). The linear regression model showed that the combined relative risk (RR) of every 3 cups/day increment of total coffee consumption was 1.07 (95% CI = 0.95-1.21). Compared with the lowest category of coffee consumption, the RR of gastric cancer was 1.18 (95% CI = 0.90-1.55) for the highest (median 6.5 cups/day) category, 1.06 (95% CI = 0.85-1.32) for the second highest category (median 3.5 cups/day), and 0.97 (95% CI = 0.79-1.20) for the third highest category (median 1.5 cups/day). Subgroup analysis showed an elevated risk in the US population (RR = 1.36, 95% CI = 1.06-1.75) and no adjustment for smoking (RR = 1.67, 95% CI = 1.08-2.59) for 6.5 cups/day.Current evidence indicated there was no nonlinear association between coffee consumption and gastric cancer risk. However, high coffee consumption (more than 6.5 cups/day) might increase the risk of gastric cancer in the US population. More high quality studies were warranted to further investigate the association.

Plasmakinetic resection technology for the treatment of benign prostatic hyperplasia: evidence from a systematic review and meta-analysis.

The aim of this study was to compare plasmakinetic resection of the prostate (PKRP) with transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) in terms of efficacy and safety. Published RCTs were searched from PubMed, Embase, Science Citation Index, and Cochrane Library up to April 10, 2014. After methodological quality assessment and data extraction, meta-analysis was performed using the STATA 12.0 software. 18 reports of 16 RCTs were included in this analysis. Meta-analyses showed that PKRP significantly improved Qmax at 12 months, but no significant difference was found for other efficacy outcomes. In terms of safety, treatment of PKRP was associated with reduced drop in serum sodium, lower TUR syndrome, reduced need of blood transfusion, clot retention, and shorter catheterization time and hospital stay; in contrast, there were no significant differences in the analysis of operative time, postoperative fever, and long-term postoperative complications. In summary, current evidence suggests that, although PKRP and TURP are both effective for BPH, PKRP is associated with additional potential benefits in efficacy and more favorable safety profile. It may be possible that PKRP may replace the TURP in the future and become a new standard surgical procedure.

Holmium laser enucleation versus transurethral resection in patients with benign prostate hyperplasia: an updated systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Holmium laser enucleation (HoLEP) in surgical treatment of benign prostate hyperplasia (BPH) potentially offers advantages over transurethral resection of the prostate (TURP). METHODS: Published randomized controlled trials (RCTs) were identified from PubMed, EMBASE, Science Citation Index, and the Cochrane Library up to October 10, 2013 (updated on February 5, 2014). After methodological quality assessment and data extraction, meta-analysis was performed using STATA 12.0 and Trial Sequential Analysis (TSA) 0.9 software. RESULTS: Fifteen studies including 8 RCTs involving 855 patients met the criteria. The results of meta-analysis showed that: a) efficacy indicators: there was no significant difference in quality of life between the two groups (P>0.05), but compared with the TURP group, Qmax was better at 3 months and 12 months, PVR was less at 6, 12 months, and IPSS was lower at 12 months in the HoLEP, b) safety indicators: compared with the TURP, HoLEP had less blood transfusion (RR 0.17, 95% CI 0.06 to 0.47), but there was no significant difference in early and late postoperative complications (P>0.05), and c) perioperative indicators: HoLEP was associated with longer operation time (WMD 14.19 min, 95% CI 6.30 to 22.08 min), shorter catheterization time (WMD -19.97 h, 95% CI -24.24 to -15.70 h) and hospital stay (WMD -25.25 h, 95% CI -29.81 to -20.68 h). CONCLUSIONS: In conventional meta-analyses, there is no clinically relevant difference in early and late postoperative complications between the two techniques, but HoLEP is preferable due to advantage in the curative effect, less blood transfusion rate, shorter catheterization duration time and hospital stay. However, trial sequential analysis does not allow us to draw any solid conclusion in overall clinical benefit comparison between the two approaches. Further large, well-designed, multicentre/international RCTs with long-term data and the comparison between the two approaches remain open.

IFN-γ inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice.

BACKGROUND & AIMS: Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. METHODS: We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. RESULTS: The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-γ did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1(-/-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. CONCLUSIONS: IFN-γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.