Kaohsiung Medical University Chung-Ho Memorial Hospital

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

BACKGROUND: Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. METHODS: A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. CONCLUSIONS: In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.

OBJECTIVE: To summarize the current world position on laparoscopic liver surgery. SUMMARY BACKGROUND DATA: Multiple series have reported on the safety and efficacy of laparoscopic liver surgery. Small and medium sized procedures have become commonplace in many centers, while major laparoscopic liver resections have been performed with efficacy and safety equaling open surgery in highly specialized centers. Although the field has begun to expand rapidly, no consensus meeting has been convened to discuss the evolving field of laparoscopic liver surgery. METHODS: On November 7 to 8, 2008, 45 experts in hepatobiliary surgery were invited to participate in a consensus conference convened in Louisville, KY, US. In addition, over 300 attendees were present from 5 continents. The conference was divided into sessions, with 2 moderators assigned to each, so as to stimulate discussion and highlight controversies. The format of the meeting varied from formal presentation of experiential data to expert opinion debates. Written and video records of the presentations were produced. Specific areas of discussion included indications for surgery, patient selection, surgical techniques, complications, patient safety, and surgeon training. RESULTS: The consensus conference used the terms pure laparoscopy, hand-assisted laparoscopy, and the hybrid technique to define laparoscopic liver procedures. Currently acceptable indications for laparoscopic liver resection are patients with solitary lesions, 5 cm or less, located in liver segments 2 to 6. The laparoscopic approach to left lateral sectionectomy should be considered standard practice. Although all types of liver resection can be performed laparoscopically, major liver resections (eg, right or left hepatectomies) should be reserved for experienced surgeons facile with more advanced laparoscopic hepatic resections. Conversion should be performed for difficult resections requiring extended operating times, and for patient safety, and should be considered prudent surgical practice rather than failure. In emergent situations, efforts should be made to control bleeding before converting to a formal open approach. Utilization of a hand assist or hybrid technique may be faster, safer, and more efficacious. Indications for surgery for benign hepatic lesions should not be widened simply because the surgery can be done laparoscopically. Although data presented on colorectal metastases did not reveal an adverse effect of the laparoscopic approach on oncological outcomes in terms of margins or survival, adequacy of margins and ability to detect occult lesions are concerns. The pure laparoscopic technique of left lateral sectionectomy was used for adult to child donation while the hybrid approach has been the only one reported to date in the case of adult to adult right lobe donation. Laparoscopic liver surgery has not been tested by controlled trials for efficacy or safety. A prospective randomized trial appears to be logistically prohibitive; however, an international registry should be initiated to document the role and safety of laparoscopic liver resection. CONCLUSIONS: Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery. National and international societies, as well as governing boards, should become involved in the goal of establishing training standards and credentialing, to ensure consistent standards and clinical outcomes.

BACKGROUND: Patients with advanced biliary tract cancer have a poor prognosis, and first-line standard of care (gemcitabine plus cisplatin) has remained unchanged for more than 10 years. The TOPAZ-1 trial evaluated durvalumab plus chemotherapy for patients with advanced biliary tract cancer. METHODS: In this double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease 1:1 to receive durvalumab or placebo in combination with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess overall survival. Secondary end points included progression-free survival, objective response rate, and safety. RESULTS: Overall, 685 patients were randomly assigned to durvalumab (n=341) or placebo (n=344) with chemotherapy. As of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. The hazard ratio for overall survival was 0.80 (95% confidence interval [CI], 0.66 to 0.97; P=0.021). The estimated 24-month overall survival rate was 24.9% (95% CI, 17.9 to 32.5) for durvalumab and 10.4% (95% CI, 4.7 to 18.8) for placebo. The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates were 26.7% with durvalumab and 18.7% with placebo. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. CONCLUSIONS: Durvalumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy and showed improvements versus placebo plus chemotherapy in prespecified secondary end points including progression-free survival and objective response rate. The safety profiles of the two treatment groups were similar. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03875235.)

Hydrogels are crosslinked polymer chains with three-dimensional (3D) network structures, which can absorb relatively large amounts of fluid. Because of the high water content, soft structure, and porosity of hydrogels, they closely resemble living tissues. Research in recent years shows that hydrogels have been applied in various fields, such as agriculture, biomaterials, the food industry, drug delivery, tissue engineering, and regenerative medicine. Along with the underlying technology improvements of hydrogel development, hydrogels can be expected to be applied in more fields. Although not all hydrogels have good biodegradability and biocompatibility, such as synthetic hydrogels (polyvinyl alcohol, polyacrylamide, polyethylene glycol hydrogels, etc.), their biodegradability and biocompatibility can be adjusted by modification of their functional group or incorporation of natural polymers. Hence, scientists are still interested in the biomedical applications of hydrogels due to their creative adjustability for different uses. In this review, we first introduce the basic information of hydrogels, such as structure, classification, and synthesis. Then, we further describe the recent applications of hydrogels in 3D cell cultures, drug delivery, wound dressing, and tissue engineering.

Internet addiction is a newly emergent disorder. It has been found to be associated with a variety of psychiatric disorders. Information about such coexisting psychiatric disorders is essential to understand the mechanism of Internet addiction. In this review, we have recruited articles mentioning coexisting psychiatric disorders of Internet addiction from the PubMed database as at November 3, 2009. We describe the updated results for such disorders of Internet addiction, which include substance use disorder, attention-deficit hyperactivity disorder, depression, hostility, and social anxiety disorder. We also provide discussion for possible mechanisms accounting for the coexistence of psychiatric disorders and Internet addiction. The review might suggest that combined psychiatric disorders mentioned above should be evaluated and treated to prevent their deteriorating effect on the prognosis of Internet addiction. On the other hand, Internet addiction should be paid more attention to when treating people with these coexisting psychiatric disorders of Internet addiction. Additionally, we also suggest future necessary research directions that could provide further important information for the understanding of this issue.

Lysophosphatidylcholine (LPC) is increasingly recognized as a key marker/factor positively associated with cardiovascular and neurodegenerative diseases. However, findings from recent clinical lipidomic studies of LPC have been controversial. A key issue is the complexity of the enzymatic cascade involved in LPC metabolism. Here, we address the coordination of these enzymes and the derangement that may disrupt LPC homeostasis, leading to metabolic disorders. LPC is mainly derived from the turnover of phosphatidylcholine (PC) in the circulation by phospholipase A₂ (PLA₂). In the presence of Acyl-CoA, lysophosphatidylcholine acyltransferase (LPCAT) converts LPC to PC, which rapidly gets recycled by the Lands cycle. However, overexpression or enhanced activity of PLA₂ increases the LPC content in modified low-density lipoprotein (LDL) and oxidized LDL, which play significant roles in the development of atherosclerotic plaques and endothelial dysfunction. The intracellular enzyme LPCAT cannot directly remove LPC from circulation. Hydrolysis of LPC by autotaxin, an enzyme with lysophospholipase D activity, generates lysophosphatidic acid, which is highly associated with cancers. Although enzymes with lysophospholipase A₁ activity could theoretically degrade LPC into harmless metabolites, they have not been found in the circulation. In conclusion, understanding enzyme kinetics and LPC metabolism may help identify novel therapeutic targets in LPC-associated diseases.

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics - from epidemiology, awareness, care and treatment to public health policies and leadership - that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.

The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B*1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B*1502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc=1.6x10, odds ratio (OR)=1357; 95% confidence interval (CI)=193.4-8838.3]. By contrast to CBZ-SJS/TEN, HLA-B*1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (Pc=2.2x10, OR=17.5; 95% CI=4.6-66.5), and HSS with SNPs in the motilin gene (Pc=0.0064, OR=7.11; 95% CI=3.1-16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B*1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotype-specific.

Novel Coronavirus disease (COVID-19) is a newly discovered contagious disease caused by severe acute respiratory syndrome (SARS)–coronavirus (CoV)-2 virus, primarily manifesting as an acute respiratory illness with interstitial and alveolar pneumonia, but it can affect multiple organs such as the kidney, heart, digestive tract, blood, and nervous system.1Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. https://doi.org/10.1001/jama.2020.1585. Accessed March 2, 2020.Google Scholar The rapidly spreading outbreak, which first emerged in Wuhan, Hubei Province, China, in December 2019, has since been declared a global pandemic. As of March 16, 2020, 167,511 cases of COVID-19 have been reported worldwide in 151 countries (and a cruise ship), with 6606 deaths.2World Health OrganizationCoronavirus disease (COVID-2019) situation reports.https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reportsDate accessed: March 16, 2020Google Scholar In recent days, the number of cases has risen rapidly in South Korea, Japan, Europe, and the United States. SARS-CoV-2 has been identified as a bat-origin CoV. The full-length genome sequence of the COVID-19 virus shows a close relationship with the bat SARS-like coronavirus strain BatCov RaTG13 belonging to the Betacoronavirus genus.3World Health OrganizationReport of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19).https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdfDate accessed: March 2, 2020Google Scholar Previous coronavirus infections, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-Co-V), have infected more than 10,000 people in the past 2 decades, with mortality rates of 10% and 37%, respectively.4World Health OrganizationSummary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003.https://www.who.int/csr/sars/country/table2004_04_21/en/Date accessed: January 27, 2020Google Scholar,5World Health OrganizationMiddle East respiratory syndrome coronavirus (MERS-CoV). November 2019.http://www.who.int/emergencies/mers-cov/en/Date accessed: February 27, 2020Google Scholar COVID-19 is more contagious than these illnesses, spreads by human-to-human transmission via droplets, fecal, or direct contact, and has an incubation period estimated at 1 to 14 days (usually 3 to 7 days). Infection has been reported in all ages, including children. The majority of infections are mild, presenting with a flu-like illness. The common clinical presentations of COVID-19 are fever (98%), cough (76%), and myalgia and fatigue (18% each),6Huang C. Wang Y. Li X. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.The Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (33292) Google Scholar with accompanying leucopenia (25%) and lymphopenia (63%). Symptoms of upper respiratory infection with rhinorrhea and productive cough are uncommon, except in children. About 16% to 20% cases have been classified as severe or critical. Of the 41 patients described by Huang et al.,6Huang C. Wang Y. Li X. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.The Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (33292) Google Scholar all had pneumonia with abnormalities on computerized tomographic examination of the chest (bilateral lobular and subsegmental areas of consolidation), and 32% required care from the intensive care unit. Higher plasma cytokine levels (interleukin [IL]-2, IL-7, IL-10, granulocyte-colony stimulating factor, interferon-inducing protein-10, monocyte chemoattractant protein 1, macrophage inflammatory protein-1a, tumor necrosis factor α) were present in patients requiring intensive care unit admission. Limited reports suggest that severe complications are uncommon in children.7Center for Disease Control and PreventionFrequently asked questions and answers: Coronavirus Disease-2019 (COVID-19) and children.https://www.cdc.gov/coronavirus/2019-ncov/specific-groups/children-faq.htmlDate accessed: March 2, 2020Google Scholar The diagnosis is mainly based on epidemiological factors (history of contact), clinical manifestations, and laboratory examination (hemogram, chest computed tomography, and virological examination).8Ling L. Taisheng L. The National Health Commission of PRC Guideline for diagnosis and treatment of novel coronavirus disease (version 6).Natl Med J China. 2020; 100: E001Google Scholar Of note, there are recent cases without any travel history or apparent contact with infected individuals. Several COVID-19 nucleic acid detection assays have been developed, both in-house and commercial. They use fluorescence polymerase chain reaction and probe anchoring polymerization techniques. Gene sequencing has also been used. The World Health Organization has appointed referral laboratories in different countries.9World Health OrganizationSpecimen referral for 2019nCoV - operational details of referral laboratories.https://www.who.int/docs/default-source/coronaviruse/who-appointed-2019-ncov-referral-laboratories-7-february-2020.pdf?sfvrsn&equals;c3fa3ec3_4Date accessed: March 2, 2020Google Scholar A serological test has been developed and allowed detection of a cluster of cases in Singapore.10Normile D. Singapore claims first use of antibody test to track coronavirus infections.https://www.sciencemag.org/news/2020/02/singapore-claims-first-use-antibody-test-track-coronavirus-infectionsDate accessed: March 2, 2020Google Scholar More sensitive and convenient detection methods continue to be developed. In previous reports of SARS and MERS-CoV infections, acute kidney injury (AKI) developed in 5% to 15% cases and carried a high (60%–90%) mortality rate. Early reports suggested a lower incidence (3%–9%) of AKI in those with COVID-19 infection.1Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. https://doi.org/10.1001/jama.2020.1585. Accessed March 2, 2020.Google Scholar,11Chen N. Zhou M. Dong X. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (14520) Google Scholar, 12Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China [e-pub ahead of print]. N Engl J Med. https://doi.org/10.1056/NEJMoa2002032. Accessed March 2, 2020.Google Scholar, 13Cheng Y, Luo R, Wang K, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients [e-pub ahead of print]. medRxiv 2020.02.18.20023242. https://doi.org/10.1101/2020.02.18.20023242. Accessed March 2, 2020.Google Scholar Recent reports, however, have shown higher frequency of renal abnormalities. A study of 59 patients with COVID-19 found that 34% of patients developed massive albuminuria on the first day of admission, and 63% developed proteinuria during their stay in hospital.14Li Z. Wu M. Guo J. et al.Caution on kidney dysfunctions of 2019-nCoV patients. medRxiv 2020.02.08.20021212.Date accessed: March 2, 2020Google Scholar Blood urea nitrogen was elevated in 27% overall and in two-thirds of patients who died. Computed tomography scan of the kidneys showed reduced density, suggestive of inflammation and edema. Cheng et al.13Cheng Y, Luo R, Wang K, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients [e-pub ahead of print]. medRxiv 2020.02.18.20023242. https://doi.org/10.1101/2020.02.18.20023242. Accessed March 2, 2020.Google Scholar recently reported that amongst 710 consecutive hospitalized patients with COVID-19, 44% had proteinuria and hematuria and 26.7% had hematuria on admission. The prevalence of elevated serum creatinine and blood urea nitrogen was 15.5% and 14.1%, respectively. AKI was an independent risk factor for patients’ in-hospital mortality.13Cheng Y, Luo R, Wang K, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients [e-pub ahead of print]. medRxiv 2020.02.18.20023242. https://doi.org/10.1101/2020.02.18.20023242. Accessed March 2, 2020.Google Scholar,14Li Z. Wu M. Guo J. et al.Caution on kidney dysfunctions of 2019-nCoV patients. medRxiv 2020.02.08.20021212.Date accessed: March 2, 2020Google Scholar The exact mechanism of kidney involvement is unclear: postulated mechanisms include sepsis leading to cytokine storm syndrome or direct cellular injury due to the virus. Angiotensin-converting enzyme and dipeptidyl peptidase-4, both expressed on renal tubular cells, were identified as binding partners for SARS-CoV and MERS-CoV, respectively.15Li W. Moore M.J. Vasilieva N. et al.Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426: 450-454Crossref PubMed Scopus (4580) Google Scholar,16Raj V.S. Mou H. Smits S.L. et al.Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC.Nature. 2013; 495: 251-254Crossref PubMed Scopus (1588) Google Scholar Viral RNA has been identified in kidney tissue and urine in both infections.17Peiri J.S.M. Chu C.M. Cheng V.C.C. et al.Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.Lancet. 2003; 361: 1767-1772Abstract Full Text Full Text PDF PubMed Scopus (1998) Google Scholar,18Ding Y. He L. Zhang Q. et al.Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways.J Pathol. 2004; 203: 622-630Crossref PubMed Scopus (841) Google Scholar Recently, Zhong’s lab in Guangzhou successfully isolated SARS-CoV-2 from the urine sample of an infected patient, suggesting the kidney as the target of this novel coronavirus.19The team of Zhong Nanshan responded that the isolation of SARS-CoV-2 from urine remind us to pay more attention to the cleaning of individuals and families.Guangzhou Daily. Published February 22, 2020; Google Scholar The current treatment of COVID-19 with AKI includes general and supportive management and kidney replacement therapy. There is no effective antiviral therapy available at present. All patients with confirmed COVID-19 need to be quarantined. An N95 fit-tested respirator and protective clothes and equipment are essential. Early admission to intensive care units in designated hospitals is recommended for severely ill patients. Supportive care, namely bed rest, nutritional and fluid support, and maintenance of blood pressure and oxygenation are important measures, as for all critically ill patients. Other measures include prevention and treatment of complications by providing organ support, maintaining hemodynamic stability, and preventing secondary infection. There is no specific effective antiviral drug for COVID-19 at present. The guidelines of the Chinese National Health Commission recommend aerosolized inhalation of interferon α and lopinavir/ritonavir. The specific therapeutic value and safety of lopinavir/ritonavir in patients with COVID-19 are under investigation (ChiCTR2000029308).20Expert Team of Chinese Society of NephrologyExpert consensus on diagnosis and treatment of 2019 novel coronavirus (2019 - nCoV) infection with acute kidney injury.Chin J Nephrol. 2020; 3https://doi.org/10.3760/cma.j.cn441217-20200222-00035Google Scholar Successful treatment with remdesivir has been reported in a patient with COVID-19; a clinical trial on the efficacy of remdesivir in patients with COVID-19 is currently underway in China (NCT0425266; NCT04257656) and is expected to be completed in April 2020. Chloroquine phosphate has been shown to have some efficacy against COVID-19–associated pneumonia in multicenter clinical trials conducted in China.21Gao J. Tian Z. Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.Biosci Trends. 2020; 14: 72-73Crossref PubMed Google Scholar Continuous renal replacement therapy (CRRT) has been successfully applied in the treatment of SARS, MERS, and sepsis.22Chu K.H. Tsang W.K. Tang C.S. et al.Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.Kidney Int. 2005; 67: 698-705Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar,23Arabi Y.M. Arifi A.A. Balkhy H.H. et al.Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection.Ann Intern Med. 2014; 160: 389-397Crossref PubMed Google Scholar High-volume hemofiltration in a dose of 6 l/h removed inflammatory cytokines (IL-6) and improved the Sequential Organ Failure Assessment scores at day 7 in patients with sepsis.24Ghani R.A. Zainudin S. Ctkong N. et al.Serum IL-6 and IL-1-ra with sequential organ failure assessment scores in septic patients receiving high-volume haemofiltration and continuous venovenous haemofiltration.Nephrology (Carlton). 2006; 11: 386-393Crossref PubMed Scopus (83) Google Scholar Therefore, CRRT may play a role in patients with COVID-19 and sepsis syndrome. The potential role of extracorporeal therapy techniques needs to be evaluated, however. In a retrospective study of patients with SARS-CoV and sepsis, steroids, at a mean daily dose of 105.3 ± 86.1 mg in 147 of 249 noncritical patients (59.0%), reduced mortality rate and shortened duration of hospitalization, whereas 121 of 152 critical patients (79.6%) received corticosteroids at a mean daily dose of 133.5 ± 102.3 mg, and 25 died.25Chen R.C. Tang X.P. Tan S.Y. et al.Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience.Chest. 2006; 129: 1441-1452Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar A subsequent retrospective, observational study of 309 patients with MERS showed that those who received high-dose steroids were more likely to require mechanical ventilation, vasopressors, and renal replacement therapy (RRT).26Arabi Y.M. Mandourah Y. Al-Hameed F. et al.Corticosteroid therapy for critically ill patients with middle east respiratory syndrome.Am J Respir Crit Care Med. 2018; 197: 757-767Crossref PubMed Scopus (838) Google Scholar In a meta-analysis of corticosteroid use in patients with SARS, 4 studies provided conclusive evidence of harm (psychosis, diabetes, avascular necrosis, and delayed viral clearance).27Stockman L.J. Bellamy R. Garner P. SARS: systematic review of treatment effects.PLoS Med. 2006; 3: e343Crossref PubMed Scopus (986) Google Scholar Therefore, the use of steroids is controversial and not recommended by the World Health Organization because of potential inhibition of viral clearance and prolongation of the duration of viremia.28Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020; 395: 473-475Abstract Full Text Full Text PDF PubMed Scopus (1542) Google Scholar Preliminary clinical studies in China have shown that early application of convalescent plasma in patients with COVID-19 could accelerate clinical recovery.6Huang C. Wang Y. Li X. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.The Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (33292) Google Scholar Currently 2 trials, an open-label, nonrandomized clinical trial (NCT04264858) and a multicenter, randomized, and parallel-controlled trial (ChiCTR2000029757) on the efficacy of convalescent plasma in patients with COVID-19, are underway in China. Monoclonal antibody directed against the Ras-binding domain of the S protein of MERS-CoV has been found to have neutralizing activities in plaque assays in vitro.29Park B.K. Maharjan S. Lee S.I. et al.Generation and characterization of a monoclonal antibody against MERS-CoV targeting the spike protein using a synthetic peptide epitope-CpG-DNA-liposome complex.BMB Rep. 2019; 52: 397-402Crossref PubMed Scopus (20) Google Scholar A monoclonal antibody against COVID-19 has not yet been developed. Tocilizumab, a monoclonal antibody against the IL-6 receptor, has achieved encouraging preliminary clinical results. The safety and efficacy of tocilizumab in COVID-19 infection are undergoing evaluation by a multicenter randomized controlled trial (ChiCTR2000029765). Pregnant women, newborns, the elderly, and patients with comorbidities like diabetes mellitus, hypertension, and cardiovascular disease are susceptible to COVID-19 infection and are likely to have more severe illness often requiring care from an intensive care unit. The impact of COVID-19 on chronic kidney disease has not been reported.30Ma Y. Diao B. Lv X. et al.2019 novel coronavirus disease in hemodialysis (HD) patients: report from one HD center in Wuhan, China.https://www.medrxiv.org/content/10.1101/2020.02.24.20027201v2Date accessed: March 2, 2020Google Scholar COVID-19 infection presents a special threat to patients on dialysis. There are 7184 patients on hemodialysis (HD) in 61 treatment centers in Wuhan City. At a single HD center in Renmin Hospital, Wuhan University, 37 out of 230 patients on HD and 4 of 33 staff members developed COVID-19 infection between January 14 and February 17, 2020.30Ma Y. Diao B. Lv X. et al.2019 novel coronavirus disease in hemodialysis (HD) patients: report from one HD center in Wuhan, China.https://www.medrxiv.org/content/10.1101/2020.02.24.20027201v2Date accessed: March 2, 2020Google Scholar A total of 7 patients on HD died, of whom 6 had COVID-19 infection. However, the deaths were deemed to be due to cardiovascular causes and not directly to the COVID-19 infection. Patients on HD with COVID-19 had less lymphopenia, lower serum levels of inflammatory cytokines, and milder clinical disease than other patients with COVID-19 infection. COVID-19 infection presents particular challenges for patients on dialysis, in particular, those in in-center HD. Patients with uremia are particularly to infection and may in clinical and HD the risk of transmission of including to staff and patients and all The Chinese Society of Team of Chinese for prevention and of novel coronavirus infection in blood center from Chinese J Nephrol. 2020; Scholar and the Society of Guideline for during COVID-19 Society of accessed: March 16, 2020Google Scholar have recently developed guidelines for units during the COVID-19 A of these guidelines is provided team of and in clinical of COVID-19, of infection at prevention and guidelines from the and The of staff be and by on and cluster history of patient, their of the and at be and care and be and to all care as can be or including and be is recommended that staff members have at different to and be removed and with during be to the of their and the team in or their members suggestive of COVID-19 and of people at risk of of or the and be and accompanying be the Patients and during dialysis. They can such as to with or confirmed COVID-19 infection be to a isolation of the of the isolation is the Care is recommended for patients under the period of for contact with of patients continue HD at the HD center and not to and not and staff to and infection. the who need be for novel coronavirus the on patients with confirmed or novel coronavirus infection be carried out in a designated with for not be used. 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Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m 2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m 2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

BACKGROUND AND OBJECTIVES: Dialysis patients have a high burden of co-existing diseases, poor health-related quality of life (HR-QOL), and are prescribed many medications. There are no data on daily pill burden and its relationship to HR-QOL and adherence to therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Two hundred and thirty-three prevalent, chronic dialysis patients from three units in different geographic areas in the United States underwent a single, cross-sectional assessment of total daily pill burden and that from phosphate binders. HR-QOL, adherence to phosphate binders, and serum phosphorus levels were the three main outcome measures studied. RESULTS: The median daily pill burden was 19; in one-quarter of subjects, it exceeded 25 pills/d. Higher pill burden was independently associated with lower physical component summary scale scores on HR-QOL on both univariate and multivariate analyses. Phosphate binders accounted for about one-half of the daily pill burden; 62% of the participants were nonadherent. There was a modest relationship between pill burden from phosphate binders and adherence and serum phosphorus levels; these associations persisted on multivariate analyses. There was no relationship between adherence and serum phosphorus levels. CONCLUSIONS: The daily pill burden in dialysis patients is one of the highest reported to date in any chronic disease state. Higher pill burden is associated with lower HR-QOL. There are many reasons for uncontrolled serum phosphorus levels; increasing the number of prescribed pills does not seem to improve control and may come at the cost of poorer HR-QOL.

IMPORTANCE: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS: EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS: Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS: No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE: Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01035229.

Fecal microbiota transplantation (FMT) is a method to directly change the recipient's gut microbiota to normalize the composition and gain a therapeutic benefit. The history of FMT has been traced back to the 4th century and has been highly regarded since 2013, when the United States Food and Drug Administration approved FMT for treating recurrent and refractory Clostridium difficile infection. Since then, the range of FMT applications extended rapidly and broadly not only in gastrointestinal disorders, but also in extra-gastrointestinal diseases. Donor selection with questionnaire, interview, blood tests, and stool examinations should be strictly performed before FMT to reduce and prevent occurrence of any adverse events. Step-by-step cautious fecal and recipient preparation along with adequately choosing delivery methods based on individual clinical situations are key points of the FMT process. Although current evidence deems FMT as a generally safe therapeutic method with few adverse effects, the long-term outcomes of FMT have not been completely elucidated. Therefore, establishing periodicity and length of regular follow-up after FMT to monitor the clinical efficacy and long-term adverse events are other essential issues. In the future, we will look forward to personalized FMT for different patients and conditions according to varied hosts and diseases.

The early onset breast cancer patients (age ≤ 40) often display higher incidence of axillary lymph node metastasis, and poorer five-year survival than the late-onset patients. To identify the genes and molecules associated with poor prognosis of early onset breast cancer, we examined gene expression profiles from paired breast normal/tumor tissues, and coupled with Gene Ontology and public data base analysis. Our data showed that the expression of GAS7b gene was lower in the early onset breast cancer patients as compared to the elder patients. We found that GAS7 was associated with CYFIP1 and WAVE2 complex to suppress breast cancer metastasis via blocking CYFIP1 and Rac1 protein interaction, actin polymerization, and β1-integrin/FAK/Src signaling. We further demonstrated that p53 directly regulated GAS7 gene expression, which was inversely correlated with p53 mutations in breast cancer specimens. Our study uncover a novel regulatory mechanism of p53 in early onset breast cancer progression through GAS7-CYFIP1-mediated signaling pathways.

Carbapenems are considered as last-resort antibiotics for the treatment of infections caused by multidrug-resistant gram-negative bacteria. With the increasing use of carbapenems in clinical practice, the emergence of carbapenem-resistant pathogens now poses a great threat to human health. Currently, antibiotic options for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) are very limited, with polymyxins, tigecycline, fosfomycin, and aminoglycosides as the mainstays of therapy. The need for new and effective anti-CRE therapies is urgent. Here, we describe the current understanding of issues related to CRE and review potential therapeutic strategies for CRE infections, including high-dose tigecycline, high-dose carbapenem, double carbapenem, and combination therapies. We also review the newly available antibiotics which will play important roles in the future treatment of CRE infections: ceftazidime/avibactam, which is active against KPC and OXA-48 producers, and meropenem/vaborbactam, which is active against KPC producers. Although direct evidence for CRE treatment is still lacking and the development of resistance is a concern, these antibiotics provide promising therapeutic options for CRE infections. Finally, we review other potential anti-CRE antibiotics in development: plazomicin, imipenem/relebactam, cefiderocol, and eravacycline. Currently, high-dose and combination strategies should be considered in severe CRE infections to maximize treatment success. In the future, when more treatment options are available, therapy for CRE infections should be individualized and based on molecular phenotypes of resistance, susceptibility profiles, disease severity, and patient characteristics. More high-quality studies are needed to guide effective treatment for infections caused by CRE.

OBJECTIVE: The goal was to investigate the efficacy of orally administered probiotics in preventing necrotizing enterocolitis for very low birth weight preterm infants. METHODS: A prospective, blinded, randomized, multicenter controlled trial was conducted at 7 NICUs in Taiwan, to evaluate the beneficial effects of probiotics in necrotizing enterocolitis among very low birth weight infants (birth weight: <1500 g). Very low birth weight infants who survived to start enteral feeding were eligible and were assigned randomly to 2 groups after parental informed consent was obtained. Infants in the study group were given Bifidobacterium bifidum and Lactobacillus acidophilus, added to breast milk or mixed feeding (breast milk and formula), twice daily for 6 weeks. Infants in the control group were fed with breast milk or mixed feeding. The clinicians caring for the infants were blinded to the group assignment. The primary outcome measurement was death or necrotizing enterocolitis (Bell's stage >or=2). RESULTS: Four hundred thirty-four infants were enrolled, 217 in the study group and 217 in the control group. The incidence of death or necrotizing enterocolitis (stage >or=2) was significantly lower in the study group (4 of 217 infants vs 20 of 217 infants). The incidence of necrotizing enterocolitis (stage >or=2) was lower in the study group, compared with the control group (4 of 217 infants vs 14 of 217 infants). No adverse effect, such as sepsis, flatulence, or diarrhea, was noted. CONCLUSION: Probiotics, in the form of Bifidobacterium and Lactobacillus, fed enterally to very low birth weight preterm infants for 6 weeks reduced the incidence of death or necrotizing enterocolitis.

In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.

The aim of the study is to examine the differences in the diversity of family factors between adolescents with and without Internet addiction and substance use experience. A total of 3662 students (2328 boys and 1334 girls) were recruited from seven junior high schools, six senior high schools, and four vocational high schools in southern Taiwan. Internet addiction and substance experience were classified according to the score of Chen Internet Addiction Scale Questionnaires for Experience of Substance use. The family factors assessed included perceived family satisfaction, family economic status, parents' marriage status, care-givers, the frequency of intra-family conflict, families' habitual alcohol use, and perceived parents' or care givers' attitude toward adolescents' substance use. This study demonstrated that the characteristics of higher parent-adolescent conflict, habitual alcohol use of siblings, perceived parents' positive attitude to adolescent substance use, and lower family function could be used develop a predictive model for Internet addiction in the multiple logistic regression analysis. The former three family factors were also sufficient in themselves to develop a predictive model for substance use experience. The results revealed that adolescent Internet addiction and substance use experience shared similar family factors, which indicate that Internet addiction and substance use should be considered in the group of behavioral problem syndromes. A family-based preventive approach for Internet addiction and substance use should be introduced for adolescents with negative family factors.