Etiological Analysis of 3 Cases of Gonorrhea with Spectinomycin Treatment Failure

Objectives: To report three cases of gonorrhea withspectinomycin treatment failure, and to analyze thepossible causes.Methods: Identification of the three Neisseriagonorrhoeae isolates was made by an oxidase test anda rapid carbohydrate utilization test. The sensitivitytesting was performed by an agar dilution method.Results: All three isolates were identified as Ngonorrhoeae strains by positive oxidase test andbecause they only utilized glucose in the carbohydrateutilization test. All three strains were resistant tociprofloxacin and susceptible to ceftriaxoneSpectinomycin-resistant strains were found in onlytwo of the three patients, including one penicillinase-producing N. gonorrhoeae (PPNG). The third patienthad a spectinomycin sensitive strain, which was alsoPPNG and tetracycline resistant (TRNG). Based onthe medical history, spectinomycin treatment failurefor the third patient was due to inadequate injection.Conclusion: The causes of spectinomycin treatmentfailure of gonorrhea include spectinomycin resistanceand inadequate injection.

Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures

AIM:To evaluate the efficacy and safety of tenofovir disoproxil fumarate(TDF) for chronic hepatitis B(CHB) patients after multiple failures.METHODS:A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue(NA) treatments were included.Study subjects were treated with TDF alone(n = 13) or in combination with lamivudine(LAM,n = 12) or entecavir(ETV,n = 4) for ≥ 6 mo.Complete virologic response(CVR) was defined as an achievement of serum hepatitis B virus(HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment.Safety assessment was based on serum creatinine and phosphorus level.Eleven patients had histories of LAM and adefovir dipivoxil(ADV) treatment and 18 patients were exposed to LAM,ADV,and ETV.Twenty-seven patients(93.1%) were hepatitis B e antigen(HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL.The median treatment duration was 16 mo(range 7 to 29 mo).RESULTS:All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it.Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV.One patient had a resistance to both ADV and ETV.The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%,respectively.Although one patient failed to achieve CVR,serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL,achieving near CVR.No patients in this study showed viral breakthrough or primary non-response during the follow-up period.The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%,12%,and 27% at 6,12,and 18 mo of treatment,respectively.Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations.History of prior exposure to specific antiviral agents did not make a difference to treatment outcome.Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV.No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed.There were no other adverse events related to TDF therapy observed in the study subjects.CONCLUSION:TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.

Risk of Treatment Failure in Patients with Drug-susceptible Pulmonary Tuberculosis in China

The objective of this prospective study of the risks of treatment failure in patients with drug-susceptible pulmonary tuberculosis （PTB） was to provide reference data to help develop a disease control strategy. Participants were recruited in eight provinces of China from October 2008 to December 2010. A total of 1447 patients with drug-susceptible PTB and older than 15 years of age were enrolled.

Effect of treatment failure on the Cag A EPIYA motif in Helicobacter pylori strains from Colombian subjects

AIM To evaluate effect of treatment failure on cag A and vac A genotypes in Helicobacter pylori(H. pylori) isolates from Colombia.METHODS One hundred and seventy-six participants infected with H. pylori from Colombia were treated during 14 d with the triple-standard therapy. Six weeks later, eradication was evaluated by 13C-Urea breath test. Patients with treatment failure were subjected to endoscopy control; biopsies obtained were used for histopathology and culture. DNA from H. pylori isolates was amplified using primers specific for cag A and vac A genes. The phylogenetic relationships among isolates obtained before and after treatment were established by conglomerate analysis based on random amplified polymorphic DNA(RAPD) fingerprinting.RESULTS Treatment effectiveness was at 74.6%. Of the par-ticipants with treatment failure, 25 accepted subjected to a second endoscopy. Prevalence of posttreatment infection was 64%(16/25) and 40%(10/25) by histology and culture, respectively. Upon comparing the cag A and vac A genotypes found before and after therapy, multiple cag A genotypes(cag A-positive and cag A-negative) were found before treatment; in contrast, cag A-negative genotypes decreased after treatment. vac A s1m1 genotype was highly prevalent in patients before and after therapy. The 3'cag A region was successfully amplified in 95.5%(21/22) of the isolates obtained before and in 81.8%(18/22) of the isolates obtained after treatment. In the isolates obtained from patients with treatment failure, it was found that 72.7%(16/22) presented alterations in the number of EPIYA motifs, compared to isolates found before treatment.CONCLUSION Unsuccessful treatment limits colonization by lowvirulence strains resulting in partial and selective eradication in mixed infections, and acts on the cag A-positive strains inducing genetic rearrangements in cag A variable region that produces a loss or gain of EPIYA repetitions.

Hepatitis C virus treatment failure:Clinical utility for testing resistance-associated substitutions

The hepatitis C virus has a high mutation capacity that leads to the emergence of resistance-associated substitutions(RAS).However,the consequence of resistance selection during new direct-acting antiviral drug(DAA)treatment is not necessarily the therapeutic failure.In fact,DAA treatment has shown a high rate(>95%)of sustained virological response even when high baseline RAS prevalence has been reported.In the context of RAS emergence and high rates of sustained viral response,the clinical relevance of variants harboring RAS is still controversial.Therefore,in order to summarize the data available in international guidelines,we have reviewed the clinical utility of testing RAS in the era of new pangenotypic DAA drugs.

Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients

AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a first direct-acting antiviral （DAA） regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defned as： （1） non-response [HCV-RNA remained detectable during treatment, at end of treatment （EOT）]; and （2） relapse （HCV-RNA suppressed at EOT but detectable thereafter）. Sequencing analysis was performed to describe prevalence of drug class-specifc RAS. Factors associated with failure were determined using logistic regression models.RESULTSAmong 559 patients, 77% had suppressed plasmaHIV-RNA 〈 50 copies/mL at DAA treatment initiation41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in22 patients and were mainly relapses （17, 77%） thenundefined failures （3, 14%） and non-responses （29%）. Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5A or NS5B RAS were detected in10/14 patients with samples available for sequencinganalysis. After adjustment for age, sex, ribavirin useHCV genotype and treatment duration, low platelecount was the only factor signifcantly associated with ahigher risk of failure （OR： 6.5; 95%CI： 1.8-22.6）. CONCLUSIONOnly 3.9% HIV-HCV coinfected patients failed DAAregimens and RAS were found in 70% of those failingLow platelet count was independently associated withvirological failure.

Factors influencing syphilis treatment failure and/or re-infection in HIV co-infected patients： immunosuppression or behaviors

Background Recent studies have reported overall increasing rates of syphilis with a high rate of human immunodeficiency virus （HIV） co-infection. However, there is little information about factors influencing syphilis treatment failure and/or re-infection in HIV co-infected patients. We conducted a study to evaluate factors associated with syphilis treatment failure/re-infection in HIV co-infected patients.Methods We reviewed 3542 medical records of HIV-infected patients from January 2005 to December 2007 followed up at HIV Clinic in New York City. Patients were categorized by rapid plasma regain titer （RPR） into success/serofast （4-fold decrease in RPR by 12 months after treatment, RPR conversion to nonreactive, persistently stable reactive RPR with no 4-fold increase）, and failure/re-infection （failure to decrease 4 folds in RPR by 12 months after treatment, 4-fold increase in RPR from baseline）.Results Among a total of 156 patients who met the eligibility criteria, 122 （78.2％） were under success/serofast category,and 34 （21.8％） were under failure/re-infection category. HIV viral load, CD4 cell count, and use of highly active antiretroviral therapy （HAART） were not associated with syphilis treatment failure/re-infection. However, early syphilis stage （OR：11.036, 95％ CI： 2.499-48.740, P=0.002） and high （＞1∶64） RPR titers （OR： 715.921, 95％ CI： 422.175-23 113.396, P ＜0.001） were significantly associated.Conclusions No correlations were seen with depressed immune states with syphilis treatment failure and/or re-infection. However, association with early stage syphilis suggests that risky psychological sexual behaviors may be the most important leading factor, emphasizing needs for safe sex education.

Factors Associated with Antiretroviral Treatments Failure among HIV-Positive Patients in Congo: A Retrospective Cohort Study

Background: Viral load is the key indicator of the effectiveness of antiretroviral treatment in HIV patients. Study aimed to determine antiretroviral treatments failure rates and associated risk factors among HIV-infected adult patients in Congo. Methods: Data from the Congolese AIDS and Epidemics Control Council were combined to create a historical cohort. Patients were followed up between 2003 to 2017. Mixed logistic regression was used to identify treatment failure associated-factors. Intercooled Stata 10 (StataCorp LP, College Station, Texas, USA) software packages was used for analysis. Results: Over 14 years of follow-up, a total of 25,500 visits for 6391 adult patients were reported. Among them, 88% i.e. 22,328 visits (for a total of 6127 patients) were visits with treatment failure. In the multivariate analysis, being aged >26 years, having primary education level, being student, others nationality, unspecifiedmarital status and being worker in informal sector were found associated with a higher risk of treatment failure. Conversely, being pensioners, receiving second line therapeutic protocols and having good adherence to treatment were found significantly associated with a lower risk of treatment failure. Conclusion: Antiretroviral treatments failure among HIV-treated patients is common in Congo. Developing treatment adherence-centered interventions with focus in patients who have low socio-economic status needed to reduced treatments failure. As treatment failure is not only determined by individual factors, psychosocial supports and availability of antiretroviral drugs needs to be taken into account.

Current concept in the diagnosis,treatment and rehabilitation of patients with congestive heart failure

Heart failure(HF)is a major public health problem with a prevalence of 1%-2%in developed countries.The underlying pathophysiology of HF is complex and as a clinical syndrome is characterized by various symptoms and signs.HF is classified according to left ventricular ejection fraction(LVEF)and falls into three groups:LVEF≥50%-HF with preserved ejection fraction(HFpEF),LVEF<40%-HF with reduced ejection fraction(HFrEF),LVEF 40%-49%-HF with mid-range ejection fraction.Diagnosing HF is primarily a clinical approach and it is based on anamnesis,physical examination,echocardiogram,radiological findings of the heart and lungs and laboratory tests,including a specific markers of HF-brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide as well as other diagnostic tests in order to elucidate possible etiologies.Updated diagnostic algorithms for HFpEF have been recommended(H2FPEF,HFA-PEFF).New therapeutic options improve clinical outcomes as well as functional status in patients with HFrEF(e.g.,sodium-glucose cotransporter-2-SGLT2 inhibitors)and such progress in treatment of HFrEF patients resulted in new working definition of the term“HF with recovered left ventricular ejection fraction”.In line with rapid development of HF treatment,cardiac rehabilitation becomes an increasingly important part of overall approach to patients with chronic HF for it has been proven that exercise training can relieve symptoms,improve exercise capacity and quality of life as well as reduce disability and hospitalization rates.We gave an overview of latest insights in HF diagnosis and treatment with special emphasize on the important role of cardiac rehabilitation in such patients.

The role of B-type natriuretic peptide in the diagnosis and treatment of decompensated heart failure

Heart failure (HF) is a common disease associated with increasing age. B-type natriuretic peptide (BNP), is a cardiac neurohormone, and is released as prepro BNP and then enzyrnatically cleaved to the Ntenninal-proBNP (NT-proBNP) and BNP upon ventricular myocyte stretch. Blood measurements of BNP have been used to identify patients with I-IF. The BNP assay is currently used as a diagnostic and prognostic aid in HF. In general, a BNP level below 100 pg/mL excludes acutely decompensated HF and levels ＞ 500 pg/ml indicate decompensation. Recombinant human BNP (hBNP, nesiritide) is an approved intravenous treatment for acute,decompensated -HF. Nesiritide given in supraphysiologic doses causes vasodilation, natriuresis, diuresis, and improved symptoms over the course of a 48-hour infusion. This paper will sort out the literature concerning the use of this peptide both as a diagnostic test and as an intravenous therapy.

Diabetes and tuberculosis:An emerging dual threat to healthcare

Tuberculosis(TB)remains a huge global healthcare challenge even in the 21^(st) century though the prevalence has dropped in developed countries in recent decades.Diabetes mellitus(DM)is an important risk factor for the development and perpetuation of TB owing to the immune dysfunction in patients with DM.The coexistence of both diseases in the same individual also aggravates disease severity,complications,and chance of treatment failure because of gross immune alterations posed by DM as well as TB.Various complex cellular and humoral immunological factors are involved in the dangerous interaction between TB and DM,some of which remain unknown even today.It is highly important to identify the risk factors for TB in patients with DM,and vice versa,to ensure early diagnosis and management to prevent complications from this ominous coexistence.In their research study published in the recent issue of the World Journal of Diabetes,Shi et al elaborate on the factors associated with the development of TB in a large cohort of DM patients from China.More such research output from different regions of the world is expected to improve our knowledge to fight the health devastation posed by TB in patients with diabetes.

Personalized medicine and opioid use disorder

Opioid use disorder(OUD)is a major public health problem affecting millions of people worldwide.Although OUD is a chronic and relapsing disorder,a variety of pharmacological and non-pharmacological interventions are available.Medication-assisted treatment of OUD generally relies on competition for opioid receptors against the addictive substance.The mechanisms of this competition are to block or inactivate the opioid receptor or activate the receptor with a substance that is intermittent or long acting.Methadone and buprenorphine are two United States Food and Drug Administration-approved medications that have long-term positive effects on the health of opioid-dependent individuals.Although clinical studies of drugs generally demonstrate efficacy in thousands of people and toxicity is excluded,it cannot be predicted whether the given drug will cause side effects in one of the patients at the treatment dose.Individual differences can be explained by many biological and environmental factors.Variations in genes encoding drug metabolism or cellular drug targets significantly explain the variability in drug response between individuals.Therefore,for the effects of candidate genes to be accepted and included in individual treatment protocols,it is important to repeat studies on individuals of different ethnic backgrounds and prove a similar effect.

Second and third line treatment options for Helicobacter pylori eradication

Helicobacter pylori is a highly successful bacterium with a high global prevalence and the infection carries significant disease burden. It is also becoming increasingly difficult to eradicate and the main reason for this is growing primary antibiotic resistance rates in a world where antibiotics are frequently prescribed and readily available. Despite knowing much more about the bacterium since its discovery, such as its genomic makeup and pathogenesis, we have seen declining treatment success. Therefore, clinicians today must be prepared to face one, two or even multiple treatment failures, and should be equipped with sufficient knowledge to decide on the appropriate salvage therapy when this happens. This article discusses the factors contributing to treatment failure and reviews the second and thirdline treatment strategies that have been investigated. Established empiric second line treatment options include both bismuth based quadruple therapy and levofloxacin based triple therapy. Antibiotic testing is recommended prior to initiating third line treatment. In the event that antibiotic susceptibility testing is unavailable, third line treatment options include rifabutin, rifaximin and sitafloxacin based therapies.

Properties and feasibility of using cancer stem cells in clinical cancer treatment

Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells(CSCs). The characteristics of this subgroup of cells include self-renewal, tumorigenesis, multiple differentiation and high invasiveness, metastasis, and drug resistance potential. Many studies have demonstrated that CSCs play important roles in tumor growth, spread and metastatic relapse after treatment, and are closely related to the prognosis of patients.From a therapeutic viewpoint, deep insights into the CSCs biology, development of specific therapeutic strategies for targeting CSCs, and characterization of their microenvironment could be an ideal way to combat cancer.

Quo vadis cardiac rehabilitation;the role of comprehensive cardiac rehabilitation in modern cardiology

In accordance with the guidelines established by prominent European and global cardiology associations,comprehensive cardiac rehabilitation(CR)stands as an officially endorsed and highly recommended therapeutic approach(class I recommendations;level of evidence A)for a diverse spectrum of cardiac patients.Nevertheless,it is a cause for concern to observe that fewer than 50%of eligible patients are being effectively referred for CR,whether in an outpatient or in-patient setting.Concurrently,studies reveal that a substantial proportion of individuals with atherosclerotic cardiovascular disease maintain unhealthy lifestyles and exhibit suboptimal management of modifiable cardiovascular risk factors,including hypertension,lipid levels,and diabetes.Beyond the conven-tional patient profile encompassing those recovering from acute coronary syndrome with or without percutaneous coronary intervention,as well as patients who have undergone coronary or valvular surgery,contemporary CR now emphasizes specialized subgroups of patients.These include frail elderly patients,the female population with its unique considerations,individuals burdened by multiple cardiovascular comorbidities,those who have developed psychological consequences due to a cardiac illness and particularly those grappling with chronic heart failure.This editorial seeks to offer a state-of-the-art assessment of the significance and role of comprehensive CR within modern cardiology.

Treatment of hepatic failure with artificial liver support system

Objective To assess the effectiveness of artificial liver support system (ALSS) treatment in patients with hepatic failure. Methods 235 cases of hepatic failure were treated with ALSS in our hospital. All data were analyzed by SPSS. The effectiveness of ALSS treatment was compared according to different stages (i.e., early, middle and end stages). Results 108 patients survived after therapy of ALSS. After each ALSS treatment, the liver function of these patients was greatly improved, the serum endotoxin and HBV-DNA concentrations were significantly decreased, and the serum concentration of aromatic amino acids (AAA) such as methionine decreased while the ratio of branched chain amino acids and aromatic amino acids (BCAA/AAA ratio) increased; patients treated with ALSS in the early or middle stages of disease had much higher survival rates than patients in the end stage of disease.Conclusion ALSS is a reliable therapy for advanced liver diseases and treatment at early or middle stages is appropriate.

Fenofibrate for patients with asymptomatic primary biliary cirrhosis

AIM:Primary biliary cirrhosis (PBC) is a chronic, cholestatic disease of autoimmune etiology,the histology of which shows a destruction of the intrahepatic bile duct and portal inflammation. Ursodeoxycholic acid (UDCA) is now used as a first-line drug for asymptomatic PBC (aPBC) because it is reported that UDCA decreases mortality and prolongs the time of liver transplantation.However, only 20-30% of patients respond fully to UDCA.Recently,lipoprotein-lowering agents have been found to be effective for PBC.The aim of this study was to examine the safety and efficacy of fenofibrate, a member of the fibrate class of hypolipidemic and anti-inflammatory agent via peroxysome proliferatory-activated receptor α,in patients with aPBC.METHODS:Fenofibrate was administered for twelve weeks in nine patients with aPBC who failed to respond to UDCA.UDCA was used along with fenofibrate during the study.The data from aPBC patients were analyzed to assess the biochemical effect of fenofibrate during the study.RESULTS: The serum levels of alkaline phosphatase (ALP)(285±114.8IU/L) and immunoglobulin M (IgM) (255.8±85.9mg/dl) significantly decreased to 186.9±76.2IU/L and 192.9±67.5mg/dL respectively, after fenofibrate treatment in patients with aPBC (P<0.05). Moreover,the titer of antimitochondrial antibody (AMA) also decreased in 4 of 9 patients with aPBC. No adverse reactions were observed in any patients.CONCLUSION:Fenofibrate appears to be significantly effective in treating patients with aPBC who respond incompletely to UDCA alone.Although the mechanism of fenofibrate on aPBC has not yet been fully clarified,combination therapy using fenofibrate and UDCA might be related to the anti-immunological effects, such as the suppression of AMA production as well as its antiinflammatory effect.

Infliximab to treat severe ulcerative colitis

A 48-year-old female with severe ulcerative colitis refractory to conventional therapy was referred to our facility for management. The patient showed extensive ulcerative colitis since the age of 20 years and had failed therapy with 5-aminosalicylic acid agents and azathioprine. The disease remained active despite treatment with steroids and cyclosporine. The clinical and endoscopic parameters were consistent with severe disease. Infectious precipitants were ruled out. Given the severity of the disease and in order to avoid a colectomy, we started the patient on infliximab therapy. A dramatic clinical and endoscopic response was observed and she remained in remission at the end of a 1-year follow-up period. We discuss findings in the literature regarding the use ofinfliximab therapy in patients with ulcerative colitis who have failed steroids and cyclosporine.

Second-line bismuth-containing quadruple therapy for Helicobacter pylori eradication and impact of diabetes

To investigate Helicobacter pylori (H. pylori) eradication rates using second-line bismuth-containing quadruple therapy and to identify predictors of eradication failure.METHODSThis study included 636 patients who failed first-line triple therapy and received 7 d of bismuth-containing quadruple therapy between January 2005 and December 2015. We retrospectively demonstrated H. pylori eradication rates with respect to the year of therapy as well as demographic and clinical factors. H. pylori eradication was confirmed by a 13C-urea breath test or a rapid urease test at least 4 wk after the completion of bismuth-based quadruple therapy: proton pump inhibitor, metronidazole, bismuth, and tetracycline.RESULTSThe overall eradication rates by intention-to-treat analysis and per-protocol analysis were 73.9% (95%CI: 70.1%-77.4%) and 94.5% (95%CI: 92.4%-96.5%), respectively. Annual eradication rates from 2005 to 2015 were 100.0%, 92.9%, 100.0%, 100.0%, 100.0%, 97.4%, 100.0%, 93.8%, 84.4%, 98.9%, and 92.5%, respectively, by per-protocol analysis. A multivariate analysis showed that diabetes mellitus (OR = 3.99, 95%CI: 1.56-10.20, P = 0.004) was associated with H. pylori eradication therapy failure.CONCLUSIONThe second-line bismuth-containing quadruple therapy for H. pylori infection is still effective in Korea, and diabetes mellitus is suggested to be a risk factor for eradication failure.

Failure treatment strategy and fault-tolerant path planning of a space manipulator with free-swinging joint failure

Aiming at a space manipulator with free-swinging joint failure, a failure treatment strategy and fault-tolerant path planning method is proposed in this paper. This method can realize failure treatment of a space manipulator with free-swinging joint failure through determination of the optimal locked joint angle and dynamics model reconfiguration. Fault-tolerant path planning is realized by the establishment of the degraded workspace with integrated kinematics performance(DWWIKP) and an improved A-Star(A*) algorithm. This paper has the following contributions.The determination of the optimal locked joint angle can ensure that the manipulator is able to continue follow-up tasks while maximizing the workspace of the manipulator after locking the fault joint. Underactuated control of a high degree-of-freedom(DOF) manipulator can be effectively solved through dynamics model reconfiguration. The analysis process of the dynamics coupling relationship can be applied to cases where the active joint and the passive joint are parallel or perpendicular to each other. The establishment of the DWWIKP can demonstrate the kinematics performance of the manipulator in both joint space and operation space comprehensively. The improved A*algorithm based on the integrated kinematics performance index(IKPI) can search a fault-tolerant task trajectory that satisfies the requirements of reachability and the overall kinematics performance simultaneously. The method proposed in this paper is verified by a 7-DOF manipulator, and it is available to any DOF manipulator with free-swinging joint failure.