Phase angle obtained by bioelectrical impedance analysis independently predicts mortality in patients with cirrhosis

AIM To evaluate the prognostic value of the phase angle(PA)obtained from bioelectrical impedance analysis(BIA) for mortality prediction in patients with cirrhosis. METHODS In total, 134 male cirrhotic patients prospectively completed clinical evaluations and nutritional assessment by BIA to obtain PAs during a 36-mo follow-up period. Mortality risk was analyzed by applying the PA cutoff point recently proposed as a malnutrition marker(PA ≤ 4.9°) in Kaplan-Meier curves and multivariate Cox regression models. RESULTS The patients were divided into two groups according to the PA cutoff value(PA > 4.9°, n = 73; PA ≤ 4.9°, n = 61). Weight, height, and body mass index were similar in both groups, but patients with PAs > 4.9° were younger and had higher mid-arm muscle circumference, albumin, and handgrip-strength values and lower severe ascites and encephalopathy incidences, interleukin(IL)-6/IL-10 ratios and C-reactive protein levels than did patients with PAs ≤ 4.9°(P ≤ 0.05). Forty-eight(35.80%) patients died due to cirrhosis, with a median of 18 mo(interquartile range, 3.3-25.6 mo) follow-up until death. Thirty-one(64.60%) of these patients were from the PA ≤ 4.9° group. PA ≤ 4.9° significantly and independently affected the mortality model adjusted for Model for End-Stage Liver Disease score and age(hazard ratio = 2.05, 95%CI: 1.11-3.77, P = 0.021). In addition, Kaplan-Meier curves showed that patients with PAs ≤ 4.9° were significantly more likely to die. CONCLUSION In male patients with cirrhosis, the PA ≤ 4.9° cutoff was associated independently with mortality and identified patients with worse metabolic, nutritional, and disease progression profiles. The PA may be a useful and reliable bedside tool to evaluate prognosis in cirrhosis.

Anti-rods/rings autoantibody generation in hepatitis Cpatients during interferon-α/ribavirin therapy

Chronic inflammation associated with hepatitis C virus(HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α(IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies(ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings(RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings(antiRR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2(IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.

Umbilical cord as a mesenchymal stem cell source for treating joint pathologies

Articular cartilage disorders and injuries often result in life-long chronic pain and compromised quality of life.Regrettably,the regeneration of articular cartilage is a continuing challenge for biomedical research.One of the most promising therapeutic approaches is cellbased tissue engineering,which provides a healthy population of cells to the injured site but requires differentiated chondrocytes from an uninjured site.The use of healthy chondrocytes has been found to have limitations.A promising alternative cell population is mesenchymal stem cells(MSCs),known to possess excellent proliferation potential and proven capability for differentiation into chondrocytes.The“immunosuppressive”property of human MSCs makes them an important candidate for allogeneic cell therapy.The use of allogeneic MSCs to repair large defects may prove to be an alternative to current autologous and allogeneic tissue-grafting procedures.An allogeneic cell-based approach would enable MSCs to be isolated from any donor,expanded and cryopreserved in allogeneic MSC banks,providing a readily available source of progenitors for cell replacement therapy.These possibilities have spawned the current exponential growth in stem cell research in pharmaceutical and biotechnology communities.Our objective in this review is to summarize the knowledge about MSCs from umbilical cord stroma and focus mainly on their applications for joint pathologies.

An automated spring-loaded needle for endoscopic ultrasound-guided abdominal paracentesis in cancer patients

AIM: To evaluate the feasibility of using an automatedspring-loaded needle device for endoscopic ultrasound(EUS)-guided abdominal paracentesis(EUS-P) to see if this would make it easier to puncture the mobile and lax gastric wall for EUS-P.METHODS: The EUS database and electronic medical records at Fukushima Medical University Hospital were searched from January 2001 to April 2011. Patients with a history of cancer and who underwent EUS-P using an automated spring-loaded needle device with a 22-gauge puncture needle were included. The needle was passed through the instrument channel and advanced through the gastrointestinal wall under EUS guidance into the echo-free space in the abdominal cavity and ascitic fluid was collected. The confirmed diagnosis of malignant ascites included positive cytology and results from careful clinical observation for at least 6 mo in patients with negative cytology. The technical success rate, cytology results and complications were evaluated.RESULTS: We found 11 patients who underwent EUS-P with an automated spring-loaded needle device. In 4 cases, ascites was revealed only with EUS but not in other imaging modalities. EUS-P was done in 7 other cases because there was minimal ascitic fluid and no safe window for percutaneous abdominal aspiration. Ascitic fluid was obtained in all cases by EUS-P. The average amount aspirated was 14.1 mL(range 0.5-38 mL) and that was sent for cytological exam. The etiology of ascitic fluid was benign in 5 patients and malignant in 6. In all cases, ascitic fluid was obtained with the first needle pass. No procedure-related adverse effects occurred.CONCLUSION: EUS-P with an automated springloaded needle device is a feasible and safe method for ascites evaluation.

纤维肌痛综合征的治疗

背景：目前尚未明确纤维肌痛综合征（fibromyalgia syndrome，FMS）的最佳疗法，相关的综合性循证指导原则也未见报道。 目的：为FMS的最佳治疗提供最新的循证指导原则。 资料来源、选择与提取：检索Cochrane Collaboration Reviews（1993年至2004年）、MEDLINE（1966年至2004年）、CINAHL（1982年至2004年）、EMBASE（1988年至2004年）、PubMed（1966年至2004年）、Heahhstar（1975年至2000年）、Current Contents（2000年至2004年）、Web of Science（1980年至2004年）、Psychlnfo（1887年至2004年）和Sciece Citation Indexes（1996年至2004年）上有关FMS的所有人群试验（随机对照试验及其汇总分析）。由美国疼痛协会（American Pain Society，APS）挑选出13位不同领域的疼痛治疗专家组成多学科小组，负责对文献进行评审。由APS的工作人员和犹他药品信息服务机构（Utah Drug Information Service）对部分文献进行评审，作为补充。共对505篇文章进行了审核。 数据综合：有关FMS的文献存在着重大缺陷，许多治疗性试验观测时间比较短，而且未经过盲法处理。目前，还没有哪种疗法被美国食品与药物管理局（US Food and Drug Administration）特批用于治疗FMS。但是，目前的证据表明，服用小剂量三环类抗抑郁药、开展心血管适应性锻炼、实施认知行为疗法、对患者进行教育都是有效的。其他几种常用疗法（如触发点注射）尚未经充分评价。 结论：尽管FMS是一种复杂的慢性疾病，但现有的药物干预及非药物干预仍能取得临床疗效。依据目前的证据，我们建议逐一实施患者教育、特定药物治疗、锻炼及认知疗法，必要时四管齐下。

No independent associations between physical activity and clinical outcomes among hospitalized patients with moderate to severe COVID-19

Background:Regular physical activity(PA)has been postulated to improve,or at least maintain,immunity across the life span.However,the link between physical(in)activity and coronavirus disease 2019(COVID-19)remains to be established.This small-scale prospective cohort study is nested within a randomized controlled trial aimed to investigate the possible associations between PA levels and clinical outcomes among hospitalized patients with moderate to severe COVID-19.Methods:Hospitalized patients with COVID-19(mean age:54.9 years)were recruited from the Clinical Hospital of the School of Medicine of the University of Sao Paulo(a quaternary referral teaching hospital)and from Ibirapuera Field Hospital,both located in Sao Paulo,Brazil.PA level was assessed using the Baecke Questionnaire of Habitual Physical Activity.The primary outcome was hospital length of stay.The secondary outcomes were mortality,admission to the intensive care unit(ICU),and mechanical ventilation requirement.Results:The median hospital length of stay was 7.0§4.0 days,median§IQR;3.3%of patients died,13.8%were admitted to the ICU,and 8.6%required mechanical ventilation.Adjusted linear regression models showed that PA indices were not associated with hospital length of stay(work index:b=-0.57(95%confidence interval(95%CI):-1.80 to 0.65),p=0.355;sport index:b=0.43(95%CI:-0.94 to 1.80),p=0.536;leisure-time index:b=1.18(95%CI:-0.22 to 2.59),p=0.099;and total activity index:b=0.20(95%CI:-0.48 to 0.87),p=0.563).None of the PA indices were associated with mortality,admission to the ICU,or mechanical ventilation requirement(all p>0.050).Conclusion:Among hospitalized patients with COVID-19,PA did not independently associate with hospital length of stay or any other clinically relevant outcomes.These findings should be interpreted as meaning that,among already hospitalized patients with more severe forms of COVID-19,being active is a potential protective factor likely outweighed by a cluster of comorbidities(e.g.,type 2 diabetes,hypertension,weight excess)and older age,suggesting that the benefit of PA against the worsening of COVID-19 may vary across stages of the disease.

Familial Eosinophilic Granulomatosis with Polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is an uncommon ANCA associated vasculitic disorder characterized by systemic necrotizing vasculitis of small vessels occurring exclusively among patients with bronchial asthma and tissue eosinophilia. Familial EGPA is extremely rare. Only two case reports have been published so far. We present a Saudi family with 3 cases of EGPA and almost three-fourths of family members affected by asthma. We explored genetic basis of EGPA in this family and found that genes were mutated in four affected siblings suggesting genetic involvement in susceptibility to EGPA.

Ocular Manifestations in Granulomatosis with Polyangiitis Patients from Saudi Arabia

Eye and/or orbit involvement occurs in Granulomatosis with polyangiitis (GPA) patients frequently. The aim of our study was to describe the clinical manifestations, therapy and outcome of ocular involvement in our GPA patients. A retrospective study was conducted including patients with GPA who followed up in Rheumatology clinics during 1990-2016 at King Khalid University Hospital, Riyadh. Information relating to demographics, ocular manifestations, laboratory findings, therapy and outcome of GPA patients were noted. Ocular involvement was detected in 9 (39.1%) of the 23 GPA cases identified. The mean age of ocular GPA patients was 51.8 (range 27 - 62) years, the mean age at onset of disease was 39.6 (range 11 - 57) years and the mean duration of disease was 9.0 (range 2 - 19) years. Concomitant ear, nose, throat and sino-nasal manifestations occurred with ocular symptoms in 77.8% GPA patients. The most frequent manifestations were, eye pain (66.7%), scleritis/episcleritis (55.6%), eye redness and itching (55.6% each). Antineutrophil cytoplasmic antibodies (ANCA) were positive in 88.9% patients, 55.6% had c-ANCA and 33.3% had p-ANCA. Infections were observed in 22.2% of patients, which included pneumonia in one patient and esophageal candidiasis and bacterial meningitis in another. All patients received oral prednisolone, 44.4% received intravenous cyclophosphamide, 22.2% refractory cases received rituximab doses and the disease outcome was good. Comparison of ocular GPA with non-ocular GPA patients showed that 77.8% of ocular GPA patients had concomitant sino-nasal symptoms compared to 42.9% in non-ocular GPA patients and 22.2% of the ocular GPA patients had renal involvement compared to 64.3% in non-ocular GPA patients (p = 0.049). We found that the frequency of ocular manifestations in our GPA patients was similar to reports elsewhere, and the most frequent symptom was eye pain and scleritis/episcleritis.

A Needs-Based Rheumatologist Education Program on Treating to Target in Psoriatic Arthritis and Spondyloarthropathy: Insights and Challenges

Objectives: To determine if comparative practice data and education for rheumatologists would change physician behavior for monitoring and treating psoriatic arthritis (PsA) and spondyloarthritis (SpA). Methods: Participating rheumatologists each performed a chart audit on 20 patients with PsA and SpA. Accredited education (determined by a survey and chart audits) and results of chart audits (comparing to other rheumatologists) were provided for each participant (intervention). Eight months later, a repeat chart audit by each participant was conducted on another 20 PsA and SpA patients. Changes in measurements collected, treatment given and patient characteristics pre and post intervention were analyzed. Results: Nine rheumatologists received the intervention. At baseline, most routinely monitored PsA and SpA for clinical and laboratory markers. In PsA, there was no change post-intervention in performing SJC (96%), TJC (≥91%), ESR (≥70%), CRP (≥73%), and CDAI (25%). In SpA, there were increased measurements of inflammatory markers (54% pre vs. 61% post for CRP), more NSAID use and decreased physical exam measures and HAQ but no significant changes. There were no major treatment differences pre and post intervention including NSAIDs, DMARDs and biologics. Conclusions: The rheumatologists frequently performed measurements of disease activity, did not change significantly with educational intervention so there may have been little room for improvement and many patients were already in a low disease state. Calculation of composite scores did not increase in PsA. The validity of physical exam and BASDAI as a measurement of disease activity were noted as concerns in applying a treat-to-target approach in SpA. Significance and Innovation: This study did not show a significant change in behavior for rheumatologists who had education based on care gaps and needs assessment in psoriatic arthritis and spondyloarthropathy. The rheumatologists identified that disease activity is difficult to determine with usual care in SpA and thought some measures lacked validity.

Assembly of IMPDH2-Based,CTPS-Based,and Mixed Rod/Ring Structures Is Dependent on Cell Type and Conditions of Induction

Inhibition of guanosine triphosphate(GTP)and cytidine triphosphate(CTP)biosynthetic pathways induces cells to assemble rod/ring(RR)structures,also named cytoophidia,which consist of the enzymes cytidine triphosphate synthase(CTPS)and inosine-50-monophosphate dehydrogenase 2(IMPDH2).We aim to explore the interaction of CTPS and IMPDH2 in the generation of RR structures.He La and COS-7 cells were cultured in normal conditions or in the presence of 6-diazo-5-oxo-L-norleucine(DON),ribavirin,or mycophenolic acid(MPA).Over 90%of DON-treated cells presented RR structures.In He La cells,35%of the RR structures were positive for IMPDH2alone,26%were CTPS alone,and 31%were IMPDH2/CTPS mixed,while in COS-7 cells,42%of RR were IMPDH2 alone,41%were CTPS alone,and 10%were IMPDH2/CTPS mixed.Ribavirin and MPA treatments induced only IMPDH2-based RR.Cells were also transfected with an N-terminal hemagglutinin(NHA)-tagged CTPS1 construct.Over 95%of NHA-CTPS1 transfected cells with DON treatment presented IMPDH2-based RR and almost 100%presented CTPS1-based RR;when treated with ribavirin,over 94%of transfected cells presented IMPDH2-based RR and 37%presented CTPS1-based RR,whereas 2%of untreated transfected cells presented IMPDH2-based RR and 28%presented CTPS1-based RR.These results may help in understanding the relationship between CTP and GTP biosynthetic pathways,especially concerning the formation of filamentous RR structures.

Nutritional therapy for hospitalized patients with COVID-19:A narrative and integrative review

Hospitalized patients affected by coronavirus disease 19(COVID-19)have a sustained pro-inflammatory state and recurrent gastrointestinal symptoms that correlate with a decline in the nutritional status,which is directly related to poor immune response and clinical evolution.Nutritional therapy has proven crucial in COVID-19 treatment through the provision of adequate amounts of nutrients.Since the beginning of the pandemic,medical societies have mobilized to provide practical nutritional guidelines to support decision-making;despite this,there are only a few studies dedicated to compiling the most relevant recommendations.In this narrative review,we aimed to summarize and stratify the current scientific literature on nutritional support for hospitalized COVID-19 patients.We carried out a literature review from three databases between January 2020 and July 2021,using nutrition therapy(or medical nutrition or enteral nutrition or parental nutrition or nutritional support)and COVID-19(SARS-CoV-2 infection)as the search terms.Only those studies that evaluated adult hospitalized patients with admissions to wards,specific clinics,or intensive care units were included.The nutritional intervention considered was that of specific nutritional support via oral,enteral,or parenteral modes.A total of 37 articles were included.In general,the nutritional care provided to COVID-19 patients follows the same premises as for other patients,i.e.,it opts for the most physiological route and meets nutritional demands based on the clinical condition.However,some protocols that minimize the risk of contamination exposure for the health team have to be considered.Energy requirements varied from 15 kcal/kg/day to 30 kcal/kg/day and protein goals from 1.2 g/kg/day to 2 g/kg/day.In both cases,the ramp protocol for increased supply should be considered.In cases of enteral therapy,ready-to-use diet and continuous mode are recommended.Attention to refeeding syndrome is essential when parenteral nutrition is used.