Predictors of Treatment Outcomes in ANCA-Associated Vasculitis with Severe Kidney Failure

Background and objectives

In ANCA-associated GN, severe renal dysfunction portends a poor prognosis for renal recovery and patient survival. This study evaluated the prognostic factors affecting renal and patient outcomes in patients presenting with severe kidney failure to guide immunosuppressive therapy.

Design, setting, participants, & measurements

This study retrospectively evaluated clinical and histopathologic characteristics of 155 patients who underwent biopsy between October 1985 and February 2011 (median eGFR at presentation, 7.1 ml/min per 1.73 m²; 87% required hemodialysis), all treated with immunosuppressive medications. Three outcomes of interest were measured: patient survival, renal survival, and treatment response (defined as dialysis-free survival without active vasculitis by 4 months after biopsy). Competing risk, Cox, and logistic regression analyses were conducted for each outcome measure.

Results

Within 4 months after biopsy, treatment response was attained in 51% of patients, 35% remained on dialysis, and 14% died. In a competing risk analysis, estimated cumulative incidence rates of ESRD and disease-related mortality were 26% and 17% at 1 year and 32% and 28% at 5 years, respectively. Cyclophosphamide therapy and treatment response by 4 months were independently associated with patient and renal survival, adjusting for the percentage of normal glomeruli, histopathologic chronicity index score, and baseline clinical characteristics. Only 5% of patients still dialysis dependent at 4 months subsequently recovered renal function. Low chronicity index score (odds ratio [OR], 1.16; 95% confidence interval [95% CI], 1.04 to 1.30, per unit decrease) and baseline eGFR>10 ml/min per 1.73 m² (OR, 2.77; 95% CI, 1.09 to 7.01) were significantly associated with treatment response by 4 months. Among cyclophosphamide-treated patients, the likelihood of treatment response was >14% even with highest chronicity index score and eGFR<10 ml/min per 1.73 m².

Conclusions

Although low baseline renal function and severe renal scarring are associated with lower treatment response rate, no “futility” threshold could be identified. Conversely, continued immunosuppressive therapy beyond 4 months is unlikely to benefit patients who remain dialysis dependent.     

Risk indicators for the presence and extent of root caries among caries-active adults enrolled in the Xylitol for Adult Caries Trial (X-ACT)

Objective

This paper uses baseline data from a randomized clinical trial to evaluate cross-sectional indicators of root caries in caries-active adults.

Materials and methods

Adults (21–80?years) having at least 12 erupted teeth and between one and ten caries lesions were enrolled. Participants (n?=?437) received caries exams by trained, calibrated examiners and responded to baseline demographic and medical–dental questionnaires. We examined associations between baseline characteristics and (1) the presence of any root caries using Mantel–Haenszel hypothesis tests and odds ratio (OR) estimators and (2) the number of root surfaces with caries among study participants with exposed root surfaces (n?=?349) using Mantel–Haenszel mean score tests and Mann–Whitney estimators.

Results/conclusions

Adjusting for study site and age, male gender [OR, 1.72; 95% confidence interval (CI), 1.08, 2.78], white race (OR, 2.39; 95% CI, 1.43, 3.98), recent dental visit (OR, 1.98; 95% CI, 1.07, 3.66), poor self-described oral health (OR, 2.65; 95% CI, 1.10, 6.39), and recent professional fluoride treatment (OR, 1.85; 95% CI, 1.06, 3.25) were significantly associated with increased odds to have any root caries, and study participants with exposed root surfaces characterized by male gender [Mann–Whitney probability estimate (MW)?=?0.57; 95% CI, 0.51, 0.63), white race (MW, 0.61; 0.55, 0.68), recent dental visit (MW, 0.58; 0.50, 0.67), poor self-described oral health (MW, 0.61; 0.53, 0.69), and flossing at least once per day (MW, 0.57; 95% CI, 0.51, 0.62) were significantly more likely to have a greater number of root surfaces with caries than a randomly selected study participant from their respective complementary subgroups (female gender, non-white, etc.).

Clinical relevance

Our findings may help identify individuals at higher root caries risk.     

Identification of anti-Epstein-Barr virus (EBV) antibody signature in EBV-associated gastric carcinoma

Gastric Cancer - Around 10% of gastric carcinomas (GC) contain Epstein–Barr virus (EBV) DNA. We characterized the GC-specific antibody response to this common infection, which may provide a...     

Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUC_pred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUC_target). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUC_first). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P?=?.12, .004, and <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUC_pred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUC_first from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUC_first being within the ±10% target range (P?=?.04 for both associations). There was no significant association between AUC_first and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.     

Two-year bond strengths of "all-in-one" adhesives to dentine

Objectives

To test the long-term in vitro bonding performance of “all-in-one” self-etch adhesives to dentine.

Methods

Adper Prompt (3M ESPE), Bond Force (Tokuyama), Brush &; Bond (Parkell), iBond Self Etch (Heraeus Kulzer), OptiBond All-In-One (Kerr), and Xeno IV (Dentsply Caulk) were tested. The two-step self-etch adhesive Clearfil SE Bond (Kuraray) served as the control. Extracted human teeth were assigned to groups after creation of smear layer on occlusal dentine. Adhesives were applied according to manufacturers’ instructions, and resin composite (Filtek Z250, 3M ESPE) build-ups were placed. The bonded specimens were sectioned into beams after 24 h of storage in water. Microtensile bond strengths (μTBS) was determined at baseline, and following one and two years of water storage using an EZ-Test device (Shimadzu). Representative specimens were examined under field emission scanning electron microscope. Fracture mode was recorded. The data were analyzed using linear mixed effects and least square means analyses. The significance level was set at 0.01 for the pairwise comparisons and at 0.05 for the overall model effects.

Results

The mean μTBS decreased significantly over time for Adper Prompt, iBond Self Etch, and OptiBond All-In-One. After two years of water ageing, Bond Force, Brush &; Bond, OptiBond All-In-One, and Xeno IV had mean μTBS values not statistically different from Clearfil SE Bond.

Conclusions

After two years of water ageing, Clearfil SE Bond outperformed two of six all-in-one adhesives. That indicates that the composition of the adhesives rather than their application approach is accountable for their performance.

Clinical significance

Despite the data available suggesting that most all-in-one adhesives are severely affected by hydrolytic degradation, results of the present in vitro study suggest that some may perform as well as the clinically proven Clearfil SE Bond in the longer term.     

Serological profiling of Crohn’s disease and ulcerative colitis patients reveals anti-microbial antibody signatures

BACKGROUNDThe healthcare burden of inflammatory bowel disease (IBD) is rising globally and there are limited non-invasive biomarkers for accurate and early diagnosis. AIMTo understand the important role that intestinal microbiota play in IBD pathogenesis and identify anti-microbial antibody signatures that benefit clinical management of IBD patients.METHODSWe performed serological profiling of 100 Crohn’s disease (CD) patients, 100 ulcerative colitis (UC) patients and 100 healthy controls against 1173 bacterial and 397 viral proteins from 50 bacteria and 33 viruses on protein microarrays. The study subjects were randomly divided into discovery (n = 150) and validation (n = 150) sets. Statistical analysis was performed using R packages. RESULTSAnti-bacterial antibody responses showed greater differential prevalence among the three subject groups than anti-viral antibody responses. We identified novel antibodies against the antigens of Bacteroidetes vulgatus (BVU_0562) and Streptococcus pneumoniae (SP_1992) showing higher prevalence in CD patients relative to healthy controls. We also identified antibodies against the antigen of Streptococcus pyogenes (SPy_2009) showing higher prevalence in healthy controls relative to UC patients. Using these novel antibodies, we built biomarker panels with area under the curve (AUC) of 0.81, 0.87, and 0.82 distinguishing CD vs control, UC vs control, and CD vs UC, respectively. Subgroup analysis revealed that penetrating CD behavior, colonic CD location, CD patients with a history of surgery, and extensive UC exhibited highest antibody prevalence among all patients. We demonstrated that autoantibodies and anti-microbial antibodies in CD patients had minimal correlation.CONCLUSIONWe have identified antibody signatures for CD and UC using a comprehensive analysis of anti-microbial antibody response in IBD. These antibodies and the source microorganisms of their target antigens improve our understanding of the role of specific microorganisms in IBD pathogenesis and, after future validation, should aid early and accurate diagnosis of IBD.