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1.
J Fr Ophtalmol ; 45(8): 860-871, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35914962

ABSTRACT

Neurotrophic keratopathy (NK) is a degenerative corneal disease with a loss of corneal sensitivity and impairment of corneal healing. Low dose insulin eyedrops have been shown to be a simple and effective treatment for refractory NK when the response to the usual treatment is incomplete. At present, there are no commercially available forms, and there is no data regarding the stability of these products as prepared by compounding pharmacies. In this work, we studied the physicochemical and microbiological stability of an insulin ophthalmic formulation obtained by mixing insulin lispro in artificial tears with a polyethylene and propylene glycol base. The stability of this 1IU/mL insulin ophthalmic formulation was analysed for 12 months in low-density polyethylene (LDPE) multidose eye droppers at 4°C. The studied parameters of physicochemical stability were: visual inspection, turbidity, UV spectral absorption, osmolality and pH. In addition, insulin and m-cresol concentrations and quantification of impurities (insulin covalent aggregates and insulin fragments) were studied thanks to the development of a new Size Exclusion Chromatographic method. For unopened eye droppers, all tested physicochemical parameters remained stable for 12 months at 4°C, and excellent microbiological stability was obtained. In conditions of simulated use, these parameters also remained stable for one month at 4°C, and no impact of potential temperature rises on the insulin and m-cresol concentrations in the insulin eyedropper was observed.


Subject(s)
Corneal Dystrophies, Hereditary , Keratitis , Cresols , Humans , Insulin Lispro , Lubricant Eye Drops , Ophthalmic Solutions , Polyethylene , Propylene Glycols
2.
Infect Dis Ther ; 11(4): 1609-1629, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35716251

ABSTRACT

INTRODUCTION: 'Real-world' data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs. METHODS: Data were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose. RESULTS: Overall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole). CONCLUSIONS: In this 'real-world' study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.

3.
J Antimicrob Chemother ; 77(5): 1461-1467, 2022 04 27.
Article in English | MEDLINE | ID: mdl-35233608

ABSTRACT

OBJECTIVES: To assess the impact of gestational antibiotics on the risk of preterm birth, since a healthy maternal microbiome may be protective. METHODS: Population-based cohort study including all first pregnancies in Sweden (2006-16). The association between gestational and recent pre-conception systemic antibiotics and preterm birth was assessed by multivariable logistic regression presented as ORs and 95% CIs, adjusted for comorbidities (hypo- and hyperthyroidism, hypertension, or diabetes mellitus pre-gestation), trimester, antibiotic class and treatment duration. RESULTS: Compared with non-users, antibiotic exposure was associated with increased risks of preterm birth in mothers with comorbidities (OR = 1.32, 95% CI 1.18-1.48) and without (OR = 1.09, 95% CI 1.06-1.13). Pre-conception use showed no association, while risk was increased for first and second trimester use and decreased for third trimester use. The increased risks were seen for the following antibiotic groups in mothers without and with comorbidities, respectively: macrolides, lincosamides and streptogramins (OR = 1.63, 95% CI 1.45-1.83; OR = 2.48, 95% CI 1.72-3.56); quinolones (OR = 1.60, 95% CI 1.32-1.94; OR = 2.11, 95% CI 1.12-4.03); non-penicillin ß-lactams (OR = 1.15, 95% CI 1.07-1.24; OR = 1.39, 95% CI 1.07-1.83); other antibacterials (OR = 1.09, 95% CI 1.03-1.14; 1.38, 95% CI 1.16-1.63); and penicillins (OR = 1.04, 95% CI 1.01-1.08; 1.23, 95% CI 1.09-1.40). Antibiotic indications were not available, which could also affect preterm birth. CONCLUSIONS: Antibiotic use during pregnancy was associated with an increased risk of preterm birth, especially in mothers with chronic diseases.


Subject(s)
Premature Birth , Anti-Bacterial Agents/adverse effects , Cohort Studies , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Trimester, Second , Premature Birth/epidemiology , Sweden/epidemiology
4.
Antimicrob Agents Chemother ; 66(4): e0241421, 2022 04 19.
Article in English | MEDLINE | ID: mdl-35341315

ABSTRACT

Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) present a global clinical threat, as these ß-lactamases confer resistance to carbapenems and oxyimino-cephalosporins. Recent clinically identified KPC variants with substitutions at Ambler position D179, located in the Ω loop, are resistant to the ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam, but susceptible to meropenem-vaborbactam. To gain insights into ceftazidime-avibactam resistance conferred by D179N/Y variants of KPC-2, crystal structures of these variants were determined. The D179N KPC-2 structure revealed that the change of the carboxyl to an amide moiety at position 179 disrupted the salt bridge with R164 present in wild-type KPC-2. Additional interactions were disrupted in the Ω loop, causing a decrease in the melting temperature. Shifts originating from N179 were also transmitted toward the active site, including ∼1-Å shifts of the deacylation water and interacting residue N170. The structure of the D179Y KPC-2 ß-lactamase revealed more drastic changes, as this variant exhibited disorder of the Ω loop, with other flanking regions also being disordered. We postulate that the KPC-2 variants can accommodate ceftazidime because the Ω loop is displaced in D179Y or can be more readily displaced in D179N KPC-2. To understand why the ß-lactamase inhibitor vaborbactam is less affected by the D179 variants than avibactam, we determined the crystal structure of D179N KPC-2 in complex with vaborbactam, which revealed wild-type KPC-2-like vaborbactam-active site interactions. Overall, the structural results regarding KPC-2 D179 variants revealed various degrees of destabilization of the Ω loop that contribute to ceftazidime-avibactam resistance, possible substrate-assisted catalysis of ceftazidime, and meropenem and meropenem-vaborbactam susceptibility.


Subject(s)
Ceftazidime , beta-Lactamase Inhibitors , Anti-Bacterial Agents/pharmacology , Azabicyclo Compounds/pharmacology , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Ceftazidime/pharmacology , Drug Combinations , Klebsiella pneumoniae/genetics , Meropenem/pharmacology , Microbial Sensitivity Tests , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases/genetics
6.
J Intern Med ; 289(6): 840-850, 2021 06.
Article in English | MEDLINE | ID: mdl-33340186

ABSTRACT

BACKGROUND: Currently, weight loss remains the main management strategy for NAFLD, but the weight loss intention and methods remain poorly characterized. METHODS: We analysed data about the perception of weight status, intention and methods to lose weight amongst 3,822 persons with NAFLD (United States Fatty Liver Index ≥ 30) from the National Health and Nutrition Examination Survey, 2001-2014. RESULTS: Only 53.9% of people with NAFLD intended to lose weight, 91.8% with perception of overweight and 8.2% with normal weight perception. Persons with perception of overweight or overweight/obese status were four times more likely to try to lose weight (adjusted odds ratios 3.9 and 4.2, respectively, both P < 0.0001). Younger age, women, higher educational level, Hispanic and blacks (versus whites) were significant independent factors associated with weight loss intention. Notably, ≤10% attended weight loss programme. Metabolic equivalent of task hours per week was significantly higher in whites who exercised to lose weight (vs. no exercise, P = 0.003) but not in other racial/ethnic groups. Interestingly, calorie intake was similar between those who dieted versus not (2056 vs. 1970 kcal/day, P = 0.11). About 30% reported ≥ 10-lb weight loss, with 50% higher odds of success for men but there was no difference by race/ethnicity. CONCLUSION: Overweight or obese perception was a key driver in weight loss activities but was inconsistent with actual weight status and varied by race/ethnicity and other sociodemographic factors. Weight loss programme is under-utilized and should take in account of weight perception training and culturally appropriate approach.


Subject(s)
Body Image , Intention , Non-alcoholic Fatty Liver Disease , Weight Loss , Body Mass Index , Female , Humans , Male , Nutrition Surveys , Obesity/therapy , Overweight/therapy , Sociodemographic Factors , United States/epidemiology
7.
J Hosp Infect ; 109: 58-64, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33358930

ABSTRACT

BACKGROUND: Hospitals are sources for acquisition of carbapenem-resistant Entero-bacterales (CRE), and it is believed that the contamination of healthcare personnel (HCP) hands and clothing play a major role in patient-to-patient transmission of antibiotic-resistant bacteria. AIM: The aim of this study was to determine which HCP types, HCP-patient interactions, and patient characteristics are associated with greater transmission of CRE to HCP gloves and gowns in the hospital. METHODS: This was a prospective observational cohort study that enrolled patients with recent surveillance or clinical cultures positive for CRE at five hospitals in four states in the USA. HCP gloves and gown were cultured after patient care. Samples were also obtained from patients' stool, perianal area, and skin of the chest and arm to assess bacterial burden. FINDINGS: Among 313 CRE-colonized patients and 3070 glove and gown cultures obtained after patient care, HCP gloves and gowns were found to be contaminated with CRE 7.9% and 4.3% of the time, respectively. Contamination of either gloves or gowns occurred in 10.0% of interactions. Contamination was highest (15.3%) among respiratory therapists (odds ratio: 3.79; 95% confidence interval: 1.61-8.94) and when any HCP touched the patient (1.52; 1.10-2.12). Associations were also found between CRE transmission to HCP gloves or gown and: being in the intensive care unit, having a positive clinical culture, and increasing bacterial burden on the patient. CONCLUSION: CRE transmission to HCP gloves and gown occurred frequently. These findings may inform evidence-based policies about what situations and for which patients contact precautions are most important.


Subject(s)
Carbapenems , Drug Resistance, Bacterial , Enterobacteriaceae , Equipment Contamination , Protective Clothing , Cross Infection , Delivery of Health Care , Gloves, Protective , Humans , Prospective Studies , Risk Factors , United States
8.
Data Brief ; 32: 106216, 2020 Oct.
Article in English | MEDLINE | ID: mdl-33150197

ABSTRACT

[This corrects the article DOI: 10.1016/j.dib.2018.11.111.].

9.
J Intern Med ; 288(1): 139-151, 2020 07.
Article in English | MEDLINE | ID: mdl-32319718

ABSTRACT

BACKGROUND: Updated prevalence and outcome data for nonobese NAFLD for the multi-ethnic US population is limited. OBJECTIVES: We aimed to investigate the prevalence, clinical characteristics and mortality of obese and nonobese individuals with NAFLD in the United Sates. METHODS: A retrospective study was conducted using the 1999-2016 NHANES databases. We determined hazard ratio stratified by obesity status in NAFLD individuals using Cox regression and log-rank test. RESULTS: Overall NAFLD prevalence was 32.3%: 22.7% were obese and 9.6% were nonobese, with increasing trend over time for obese NAFLD, but not nonobese NAFLD. Amongst those with NAFLD, 29.7% (95% CI: 27.8%-31.7%) were nonobese, of which 13.6% had lean NAFLD. Nonobese NAFLD was more common in older (40.9% if ≥ 65 vs. 24.2% if < 65 years), male (34.0% vs. 24.2%) and foreign-born Asian people (39.8% vs. 11.4%) and uncommon in black (11.5% vs 30-35% in other ethnicities, P < 0.001). Metabolic comorbidities were common in nonobese NAFLD individuals who also had more advanced fibrosis. Nonobese NAFLD individuals had higher 15-year cumulative all-cause mortality (51.7%) than obese NAFLD (27.2%) and non-NAFLD (20.7%) (P < 0.001). However, DM and fibrosis, but neither obese nor nonobese NAFLD compared to non-NAFLD was independently associated with higher mortality. CONCLUSION: Nonobese NAFLD makes up about one-third of the NAFLD in the United States (even higher in older, male and foreign-born individuals) and carries higher mortality than obese NAFLD. Screening for NAFLD should be considered in high-risk groups even in the absence of obesity.


Subject(s)
Non-alcoholic Fatty Liver Disease/epidemiology , Obesity/epidemiology , Adolescent , Adult , Age Distribution , Aged , Diabetes Mellitus/epidemiology , Female , Humans , Liver Cirrhosis/epidemiology , Male , Middle Aged , Prevalence , Racial Groups/statistics & numerical data , Retrospective Studies , Sex Distribution , United States/epidemiology , Young Adult
10.
J Intern Med ; 287(6): 711-722, 2020 06.
Article in English | MEDLINE | ID: mdl-32128904

ABSTRACT

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a rising global disease associated with clinical and economic burdens. OBJECTIVES: We aimed to quantify NAFLD prevalence and awareness to provide stakeholders necessary information to combat NAFLD burden. METHODS: This study utilizes data from the National Health and Nutrition Examination Survey 2011-2016 and included 4538 adult participants who did not have heavy drinking or viral hepatitis history. The US fatty liver index defined NAFLD and NAFLD fibrosis score defined fibrosis. NAFLD awareness was captured by questionnaire. RESULTS: Amongst the study population of 4538 persons, NAFLD prevalence was 32.5%, lowest in non-Hispanic Blacks (18.0%) and Asians (18.1%), highest amongst Mexican Americans (48.4%). Within the NAFLD group, advanced fibrosis was highest in non-Hispanic Blacks (28.5%) and lowest amongst non-Hispanic Asians (2.7%). Of the 1473 (97.5%) NAFLD participants who answered NAFLD awareness question, 90% visited a healthcare centre at least once in the past year, but only 5.1% were aware of having NAFLD. On weighted population estimates, 77.33 million persons had NAFLD, 17.63 million had advanced fibrosis, and 73.39 million NAFLD participants were not aware of having NAFLD. CONCLUSIONS: Of 77.33 million people in the United States have NAFLD with 17.63 million having advanced fibrosis, with lowest prevalence in non-Hispanic Asians and highest in Mexican Americans. A conundrum exists amongst non-Hispanic Blacks who have low NAFLD prevalence but highest prevalence of advanced fibrosis. Awareness of NAFLD was low across all ethnicities. Effort is needed to improve disease awareness whilst addressing NAFLD clinical burden across ethnicities.


Subject(s)
Ethnicity/statistics & numerical data , Health Knowledge, Attitudes, Practice , Non-alcoholic Fatty Liver Disease/epidemiology , Racial Groups/statistics & numerical data , Adult , Black or African American/psychology , Black or African American/statistics & numerical data , Alcoholism/complications , Alcoholism/epidemiology , Alcoholism/psychology , Asian/psychology , Asian/statistics & numerical data , Ethnicity/psychology , Female , Hepatitis, Viral, Human/complications , Hepatitis, Viral, Human/epidemiology , Hepatitis, Viral, Human/psychology , Hispanic or Latino/psychology , Hispanic or Latino/statistics & numerical data , Humans , Male , Mexican Americans/psychology , Mexican Americans/statistics & numerical data , Middle Aged , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/psychology , Nutrition Surveys , Prevalence , Racial Groups/psychology , Surveys and Questionnaires , United States/epidemiology , White People/psychology , White People/statistics & numerical data , Young Adult
11.
Trop Biomed ; 37(2): 372-378, 2020 Jun 01.
Article in English | MEDLINE | ID: mdl-33612806

ABSTRACT

Interleukin (IL)-1 beta (IL-1ß), IL-2, Interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) in the pleural fluid are valuable biomarkers in early diagnosis of Tuberculous Pleural Effusion (TPE). This study aimed to analyze the diagnostic values of some cytokines (IFN-γ, TNF-α, IL-1ß, and IL-2) in pleural fluid for identifying TPE in Vietnam. We performed a cross-sectional study on tuberculosis (TB) patients with pleural effusion. Pleural IFN-γ, TNF-α, IL-1ß, IL-2 were measured by ELISA® Kit (Abcam, USA) on Biotek system. Receiver operating characteristic curves (ROC), an area under the curve (AUC), sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (ACC) of IFN-γ, TNF-α, IL-1ß, IL-2 in identifying TBE were assessed. Among 386 patients, 234 (60,6%) had TPE, and 152 (39,4%) did not have TPE. The median of IL-2, TNF-α, and IFN-γ levels were significantly higher in TPE compared to the non-TPE group (p<0.05). AUC for IL-1ß, IL-2, TNF-α, and IFN-γ were 0.54, 0.57, 0.62. 0.84 (p<0.05), respectively. The sensitivity of IL-1ß, IL-2, TNF-α, and IFN-γ in the diagnosis of TPE were 82.1, 53.4, 77.8, and 80.3, while the specificity was 28,4, 69.7, 47.4, and 80.9, respectively. IFN-γ and TNF-α are potential biomarkers in diagnosing TPE.


Subject(s)
Cytokines/analysis , Pleural Effusion/diagnosis , Tuberculosis, Pleural/diagnosis , Adult , Aged , Area Under Curve , Biomarkers/analysis , Cross-Sectional Studies , Female , Humans , Interferon-gamma , Interleukin-1beta , Interleukin-2 , Male , Middle Aged , Predictive Value of Tests , Sensitivity and Specificity , Tumor Necrosis Factor-alpha , Vietnam
12.
Tropical Biomedicine ; : 372-378, 2020.
Article in English | WPRIM (Western Pacific) | ID: wpr-823205

ABSTRACT

@# Interleukin (IL)-1 beta (IL-1β), IL-2, Interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) in the pleural fluid are valuable biomarkers in early diagnosis of Tuberculous Pleural Effusion (TPE). This study aimed to analyze the diagnostic values of some cytokines (IFN-γ, TNF-α, IL-1β, and IL-2) in pleural fluid for identifying TPE in Vietnam. We performed a cross-sectional study on tuberculosis (TB) patients with pleural effusion. Pleural IFN-γ, TNF-α, IL-1β, IL-2 were measured by ELISA® Kit (Abcam, USA) on Biotek system. Receiver operating characteristic curves (ROC), an area under the curve (AUC), sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (ACC) of IFN-γ, TNF-α, IL-1β, IL-2 in identifying TBE were assessed. Among 386 patients, 234 (60,6%) had TPE, and 152 (39,4%) did not have TPE. The median of IL-2, TNF-α, and IFN-γ levels were significantly higher in TPE compared to the non-TPE group (p<0.05). AUC for IL-1β, IL-2, TNF-α, and IFN-γ were 0.54, 0.57, 0.62. 0.84 (p<0.05), respectively. The sensitivity of IL-1β, IL-2, TNF-α, and IFN-γ in the diagnosis of TPE were 82.1, 53.4, 77.8, and 80.3, while the specificity was 28,4, 69.7, 47.4, and 80.9, respectively. IFN-γ and TNF-α are potential biomarkers in diagnosing TPE.

13.
Antimicrob Agents Chemother ; 63(12)2019 09 09.
Article in English | MEDLINE | ID: mdl-31527035

ABSTRACT

The pharmacokinetics (PK) and dialytic clearance of isavuconazole in vitro and in 7 solid organ transplant patients undergoing continuous renal replacement therapy (CRRT) were evaluated. In vivo, mean (± SD) plasma PK parameters of isavuconazole were: C max 4.00±1.45 mg/L, C min 1.76±0.76 mg/L, t ½ 48.36±29.78 h, Vss 288.78±182.11 L, CLss 4.85±3.79 L/h, and AUC 54.01±20.98 mg ⋅ h/L. Transmembrane clearance represented just 0.7% of the total isavuconazole clearance. These data suggest that isavuconazole is not readily removed by CRRT and no dose adjustments are necessary.

14.
BMJ Open ; 9(8): e028248, 2019 08 18.
Article in English | MEDLINE | ID: mdl-31427323

ABSTRACT

OBJECTIVE: China's national hepatitis burden is high. This study aims to provide a detailed national-level description of the reported incidence of viral hepatitis in China during 2004-2016. DESIGN: Observational study. SETTING: Data were obtained from China's National Notifiable Disease Reporting System, and changing trends were estimated by joinpoint regression analysis. PARTICIPANTS: In this system, 16 927 233 reported viral hepatitis cases occurring during 2004-2016 were identified. PRIMARY OUTCOME MEASURE: Incidence rates per 100 000 person-years and changing trends were calculated. RESULTS: There were 16 927 233 new cases of viral hepatitis reported in China from 2004 to 2016. Hepatitis B (HBV) (n=13 543 137, 80.00%) and hepatitis C (HCV) (n=1 844 882, 10.90%) accounted for >90% of the cases. The overall annual percent change (APC) in reported cases of viral hepatitis and HBV were 0.3%(95% CI -2.0 to 0.8, p=0.6) and -0.2% (95% CI -1.6 to 1.2, p=0.8), respectively, showing a stable trend. HBV rates were highest in the 20-29 year old age group and lowest in younger individuals, likely resulting from the universal HBV vaccination. The reported incidence of HCV and hepatitis E (HEV) showed increasing trends; the APCs were 14.5% (95% CI 13.1 to 15.9, p<0.05) and 4.7% (95% CI 2.8 to 6.7, p<0.05), respectively. The hepatitis A (HAV) reporting incidence decreased, and the APC was -13.1% (95% CI -15.1 to -11.0, p<0.05). There were marked differences in the reporting of hepatitis among provinces. CONCLUSIONS: HBV continues to constitute the majority of viral hepatitis cases in China. Over the entire study period, the HBV reporting incidence was stable, the HCV and HEV incidence increased and the HAV incidence decreased. There were significant interprovincial disparities in the burden of viral hepatitis, with higher rates in economically less-developed areas. Vaccination is important for viral hepatitis prevention and control.


Subject(s)
Hepatitis A/epidemiology , Hepatitis B/epidemiology , Hepatitis C/epidemiology , Hepatitis E/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , China/epidemiology , Databases, Factual , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Middle Aged , Young Adult
15.
J Antimicrob Chemother ; 74(3): 633-638, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30534964

ABSTRACT

OBJECTIVES: To ensure the accuracy of susceptibility testing methods for ceftazidime/avibactam. METHODS: The performances of the Etest (bioMérieux), 30/20 µg disc (Hardy diagnostics) and 10/4 µg disc (Mast Group) were evaluated against the reference broth microdilution (BMD) method for 102 clinically relevant Gram-negative organisms: 69 ceftazidime- and meropenem-resistant Klebsiella pneumoniae and 33 MDR non-K. pneumoniae. Essential and categorical agreement along with major and very major error rates were determined according to CLSI guidelines. RESULTS: A total of 78% of isolates were susceptible to ceftazidime/avibactam. None of the three methods met the defined equivalency threshold against all 102 organisms. The Etest performed the best, with categorical agreement of 95% and major errors of 6.3%. Against the 69 ceftazidime- and meropenem-resistant K. pneumoniae, only the Etest and the 10/4 µg disc met the equivalency threshold. None of the three methods met equivalency for the 33 MDR isolates. There were no very major errors observed in any analysis. These results were pooled with those from a previous study of 74 carbapenem-resistant Enterobacteriaceae and data from the ceftazidime/avibactam new drug application to define optimal 30/20 µg disc thresholds using the error-rate bound model-based approaches of the diffusion breakpoint estimation testing software. This analysis identified a susceptibility threshold of ≤19 mm as optimal. CONCLUSIONS: Our data indicate that the Etest is a suitable alternative to BMD for testing ceftazidime/avibactam against ceftazidime- and meropenem-resistant K. pneumoniae. The 30/20 µg discs overestimate resistance and may lead to the use of treatment regimens that are more toxic and less effective.


Subject(s)
Anti-Bacterial Agents/pharmacology , Azabicyclo Compounds/pharmacology , Ceftazidime/pharmacology , Gram-Negative Bacteria/drug effects , Microbial Sensitivity Tests/methods , beta-Lactamase Inhibitors/pharmacology , Drug Combinations , Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacterial Infections/microbiology , Humans , beta-Lactam Resistance
16.
Lupus ; 27(13): 2003-2011, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30157716

ABSTRACT

Fatigue is a common, disabling problem that is highly prevalent in patients with systemic lupus erythematous (SLE). More recently, vitamin D status has been established as a potential contributor to SLE pathogenesis and manifestations, in particular fatigue. This review summarizes the literature regarding the role of vitamin D in SLE, and provides an overview of the recent literature examining the association between vitamin D and fatigue in patients with SLE. Finally, the role of vitamin D supplementation in the treatment of SLE-related fatigue is considered.


Subject(s)
Fatigue/etiology , Lupus Erythematosus, Systemic/complications , Vitamin D Deficiency/complications , Vitamin D/physiology , Dietary Supplements , Fatigue/drug therapy , Humans , Randomized Controlled Trials as Topic , Risk Assessment , Risk Factors , Treatment Outcome , Vitamin D/therapeutic use , Vitamin D Deficiency/drug therapy
17.
J Viral Hepat ; 25(11): 1331-1340, 2018 11.
Article in English | MEDLINE | ID: mdl-29851204

ABSTRACT

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.


Subject(s)
Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Pteridines/administration & dosage , Pteridines/pharmacology , Adult , Aged , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Cytokines/blood , Cytokines/immunology , DNA, Viral/blood , Double-Blind Method , Drug Therapy, Combination , Female , Hepatitis B Surface Antigens/blood , Hepatitis B e Antigens/blood , Hepatitis B virus/genetics , Hepatitis B virus/immunology , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/immunology , Hepatitis B, Chronic/virology , Humans , Interferon-alpha/blood , Interferon-alpha/immunology , Male , Middle Aged , Pteridines/adverse effects , Seroconversion , Tenofovir/administration & dosage , Tenofovir/adverse effects , Tenofovir/pharmacology , Treatment Outcome , Viral Load/drug effects , Young Adult
19.
PLoS One ; 13(6): e0198969, 2018.
Article in English | MEDLINE | ID: mdl-29949600

ABSTRACT

Leptin is an adipo-myokine that regulates appetite and energy expenditure by a neuroendocrine feedback loop. Leptin levels are positively correlated with BMI in the spinal cord injury population and leptin levels are greater in individuals with spinal cord injury compared to uninjured controls. Leptin is produced in multiple tissues, including fat, bone, and skeletal muscle and is a putative biomarker of sedentary behavior in older adults. We assessed body composition leptin, adiponectin, and IL-6 levels in 205 men with chronic spinal cord injury. We found no association between age, injury duration, injury level, injury completeness, or walking status and leptin. There was a significant positive association between lean mass and leptin in men with SCI that was independent of fat. Adjusting for body composition, leptin levels were positively associated with IL-6 and negatively associated with adiponectin levels. When considering men with SCI and sarcopenic obesity, only fat mass remained positively associated with leptin. We found no association between IL-6, adiponectin, or lean mass and leptin in the sarcopenic obesity group. Our findings suggest that lean mass is an under recognized, but substantial, source of circulating leptin. Furthermore, SCI-related sarcopenic obesity may result in dysregulated adipo-myokine metabolism with local and systemic physiologic effects.


Subject(s)
Body Composition , Leptin/blood , Spinal Cord Injuries/blood , Spinal Cord Injuries/metabolism , Adult , Aged , Aged, 80 and over , Chronic Disease , Humans , Male , Middle Aged , Young Adult
20.
Aliment Pharmacol Ther ; 48(1): 44-54, 2018 07.
Article in English | MEDLINE | ID: mdl-29797518

ABSTRACT

BACKGROUND: Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis. METHODS: This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death. RESULTS: Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P < 0.001) while patients receiving anti-viral therapy had increased 5-year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti-viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001). CONCLUSIONS: Anti-viral therapy improved overall survival in patients with HBV-related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti-viral therapy in HBV-related HCC and better linkage-to-care for HBV patients are needed.


Subject(s)
Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Hepatitis B/drug therapy , Hepatitis B/mortality , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Practice Patterns, Physicians'/statistics & numerical data , Aged , Asia/epidemiology , Carcinoma, Hepatocellular/virology , Cohort Studies , Drug Misuse/statistics & numerical data , Female , Health Services Misuse/statistics & numerical data , Hepatitis B/complications , Hepatitis B virus/physiology , Humans , Inappropriate Prescribing/statistics & numerical data , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Liver Cirrhosis/mortality , Liver Cirrhosis/virology , Liver Neoplasms/virology , Male , Middle Aged , Neoplasm Staging , Survival Analysis , United States/epidemiology
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