Reply to the editor

We appreciate the comments and concerns expressed by Arakawa and colleagues regarding our article, titled “Pulsatile control of rotary blood pumps: Does the modulation waveform matter?”1 Unfortunately, we have to disagree with Arakawa and colleagues. As is obvious from the title of our article, it investigates the effect of different waveforms on the heart–device interaction. In contrast to the authors' claim, this is the first article in the literature that uses basic waveforms (sine, triangle, saw tooth, and rectangular) with different phase shifts to examines their impact on left ventricular unloading. The previous publications2, 3 and 4 just varied the pump speed during systole and diastole, which was first reported by Bearnson and associates5 in 1996, and studied its effect on aortic pressure, coronary flow, and end-diastolic volume. We should mention that dp/dtmax is a load-sensitive parameter of contractility and not representative for the degree of unloading. Moreover, none of the aforementioned reports has studied mechanical unloading and in particular the stroke work of the left ventricle. Our method is unique because we do not just alternate between high and low speed but have accurate control of the waveform because of the direct drive system of Levitronix Technologies LLC (Waltham, Mass) and a custom-developed pump controller. Without referring, Arakawa and associates state “several previous studies have already reported the coronary flow diminishes as the left ventricular assist device support increases.” It should be noted that all the waveforms used in our study have 2000 rpm average value with 1000 rpm amplitude, which is not an excessive speed for the CentriMag rotary pump (Levitronix) to collapse the ventricle and diminish the coronary flow. We agree with Arakawa and coworkers that there is a need for a heart failure model to come to more relevant results with respect to clinical expectations. However, we have explored many existing models, including species and breeds that have a native proneness to cardiomyopathy, but all of them differ from the genetic presentation in humans. We certainly do not believe that the use of microembolization, in which the coronary circulation is impaired by the injection of microspheres, would form a good model from which to draw conclusions about coronary flow change under different loading conditions. A model would be needed in which either an infarct is created to mimic ischemic heart failure or the coronary circulation remains untouched to simulate, for instance, dilated cardiomyopathy. Furthermore, in discussion we clearly mention that “lack of heart failure is a major limitation of our study.” We also believe that unloading is not the only factor of the cardiac functional recovery, and an excessive unloading of the left ventricle might lead to cardiac tissue atrophy. Therefore, in our article we mention that control of the level of cardiac unloading by assist devices has been suggested as a mechanical tool to promote recovery, and more studies are required to find better strategies for the speed modulation of rotary pumps and to achieve an optimal heart load control to enhance myocardial recovery. Finally, there are many publications about pulsing rotary blood pumps and it was impossible to include them all. We preferred to reference some of the earlier basic works such as an original research by Bearnson and coworkers5 and another article published by our group,6 which is more relevant.

A systematic review and meta-analysis of factors associated with anthelmintic resistance in sheep.

BACKGROUND Anthelmintic drugs have been widely used in sheep as a cost-effective means for gastro-intestinal nematode (GIN) control. However, growing anthelmintic resistance (AHR) has created a compelling need to identify evidence-based management recommendations that reduce the risk of further development and impact of AHR. OBJECTIVE To identify, critically assess, and synthesize available data from primary research on factors associated with AHR in sheep. METHODS Publications reporting original observational or experimental research on selected factors associated with AHR in sheep GINs and published after 1974, were identified through two processes. Three electronic databases (PubMed, Agricola, CAB) and Web of Science (a collection of databases) were searched for potentially relevant publications. Additional publications were identified through consultation with experts, manual search of references of included publications and conference proceedings, and information solicited from small ruminant practitioner list-serves. Two independent investigators screened abstracts for relevance. Relevant publications were assessed for risk of systematic bias. Where sufficient data were available, random-effects Meta-Analyses (MAs) were performed to estimate the pooled Odds Ratio (OR) and 95% Confidence Intervals (CIs) of AHR for factors reported in ≥2 publications. RESULTS Of the 1712 abstracts screened for eligibility, 131 were deemed relevant for full publication review. Thirty publications describing 25 individual studies (15 observational studies, 7 challenge trials, and 3 controlled trials) were included in the qualitative synthesis and assessed for systematic bias. Unclear (i.e. not reported, or unable to assess) or high risk of selection bias and confounding bias was found in 93% (14/15) and 60% (9/15) of the observational studies, respectively, while unclear risk of selection bias was identified in all of the trials. Ten independent studies were included in the quantitative synthesis, and MAs were performed for five factors. Only high frequency of treatment was a significant risk factor (OR=4.39; 95% CI=1.59, 12.14), while the remaining 4 variables were marginally significant: mixed-species grazing (OR=1.63; 95% CI=0.66, 4.07); flock size (OR=1.02; 95% CI=0.97, 1.07); use of long-acting drug formulations (OR=2.85; 95% CI=0.79, 10.24); and drench-and-shift pasture management (OR=4.08; 95% CI=0.75, 22.16). CONCLUSIONS While there is abundant literature on the topic of AHR in sheep GINs, few studies have explicitly investigated the association between putative risk or protective factors and AHR. Consequently, several of the current recommendations on parasite management are not evidence-based. Moreover, many of the studies included in this review had a high or unclear risk of systematic bias, highlighting the need to improve study design and/or reporting of future research carried out in this field.

Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis

Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days. CONCLUSIONS Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility.