A Multicenter, International Cohort Analysis of 1435 Cases to Support Clinical Trial Design in Acute Pancreatitis

Background: C-reactive protein level (CRP) and white blood cell count (WBC) have been variably used in clinical trials on acute pancreatitis (AP). We assessed their potential role. Methods: First, we investigated studies which have used CRP or WBC, to describe their current role in trials on AP. Second, we extracted the data of 1435 episodes of AP from our registry. CRP and WBC on admission, within 24 h from the onset of pain and their highest values were analyzed. Descriptive statistical tools as Kruskal-Wallis, Mann-Whitney U, Levene's F tests, Receiver Operating Characteristic (ROC) curve analysis and AUC (Area Under the Curve) with 95% confidence interval (CI) were performed. Results: Our literature review showed extreme variability of CRP used as an inclusion criterion or as a primary outcome or both in past and current trials on AP. In our cohort, CRP levels on admission poorly predicted mortality and severe cases of AP; AUC: 0.669 (CI:0.569-0.770); AUC:0.681 (CI: 0.601-0.761), respectively. CRP levels measured within 24 h from the onset of pain failed to predict mortality or severity; AUC: 0.741 (CI:0.627-0.854); AUC:0.690 (CI:0.586-0.793), respectively. The highest CRP during hospitalization had equally poor predictive accuracy for mortality and severity AUC:0.656 (CI:0.544-0.768); AUC:0.705 (CI:0.640-0.769) respectively. CRP within 24 h from the onset of pain used as an inclusion criterion markedly increased the combined event rate of mortality and severe AP (13% for CRP > 25 mg/l and 28% for CRP > 200 mg/l). Conclusion: CRP within 24 h from the onset of pain as an inclusion criterion elevates event rates and reduces the number of patients required in trials on AP.Peer reviewe

Bidirectional Relationship Between Reduced Blood pH and Acute Pancreatitis: A Translational Study of Their Noxious Combination

Acute pancreatitis (AP) is often accompanied by alterations in the acid-base balance, but how blood pH influences the outcome of AP is largely unknown. We studied the association between blood pH and the outcome of AP with meta-analysis of clinical trials, and aimed to discover the causative relationship between blood pH and AP in animal models. PubMed, EMBASE, and Cochrane Controlled Trials Registry databases were searched from inception to January 2017. Human studies reporting systemic pH status and outcomes (mortality rate, severity scores, and length of hospital stay) of patient groups with AP were included in the analyses. We developed a new mouse model of chronic metabolic acidosis (MA) and induced mild or severe AP in the mice. Besides laboratory blood testing, the extent of pancreatic edema, necrosis, and leukocyte infiltration were assessed in tissue sections of the mice. Thirteen studies reported sufficient data in patient groups with AP (n = 2,311). Meta-analysis revealed markedly higher mortality, elevated severity scores, and longer hospital stay in AP patients with lower blood pH or base excess (P < 0.001 for all studied outcomes). Meta-regression analysis showed significant negative correlation between blood pH and mortality in severe AP. In our mouse model, pre-existing MA deteriorated the pancreatic damage in mild and severe AP and, vice versa, severe AP further decreased the blood pH of mice with MA. In conclusion, MA worsens the outcome of AP, while severe AP augments the decrease of blood pH. The discovery of this vicious metabolic cycle opens up new therapeutic possibilities in AP

Evidence for diagnosis of early chronic pancreatitis after three episodes of acute pancreatitis : a cross-sectional multicentre international study with experimental animal model

Chronic pancreatitis (CP) is an end-stage disease with no specific therapy; therefore, an early diagnosis is of crucial importance. In this study, data from 1315 and 318 patients were analysed from acute pancreatitis (AP) and CP registries, respectively. The population from the AP registry was divided into AP (n=983), recurrent AP (RAP, n=270) and CP (n=62) groups. The prevalence of CP in combination with AP, RAP2, RAP3, RAP4 and RAP5+was 0%, 1%, 16%, 50% and 47%, respectively, suggesting that three or more episodes of AP is a strong risk factor for CP. Laboratory, imaging and clinical biomarkers highlighted that patients with RAP3+do not show a significant difference between RAPs and CP. Data from CP registries showed 98% of patients had at least one AP and the average number of episodes was four. We mimicked the human RAPs in a mouse model and found that three or more episodes of AP cause early chronic-like morphological changes in the pancreas. We concluded that three or more attacks of AP with no morphological changes to the pancreas could be considered as early CP (ECP).The new diagnostic criteria for ECP allow the majority of CP patients to be diagnosed earlier. They can be used in hospitals with no additional costs in healthcare.Peer reviewe

Clinical Utilization of the FilmArray Meningitis/Encephalitis (ME) Multiplex Polymerase Chain Reaction (PCR) Assay

Objective: To assess the clinical utilization and performance of the FilmArray® Meningitis/Encephalitis (ME) multiplex polymerase chain reaction (PCR) panel in a hospital setting.Background: Rapid diagnosis and treatment of central nervous system (CNS) infections are critical to reduce morbidity and mortality. The ME panel is a Food and Drug Administration (FDA) approved rapid multiplex PCR assay that targets 14 bacteria, viruses, and fungi. Previous studies show an overall agreement of 93–99% between the ME panel and conventional diagnostic testing. However, few studies have evaluated the clinical implementation of the ME assay, which is available for routine use at our institution.Methods: We performed a single center retrospective chart review of inpatients who underwent ME panel testing from August 2016 to May 2017. Clinical, radiologic, and laboratory data were reviewed to determine the clinical significance of results. Indication for lumbar puncture (LP), time to results of the ME panel, and duration of antimicrobial therapy were evaluated.Results: Seven hundred and five inpatients underwent ME testing, of whom 480 (68.1%) had clinical suspicion for CNS infection with 416 (59.0%) receiving empiric antimicrobial treatment for CNS infection. The median time-to-result of the ME panel was 1.5 h (IQR, 1.4–1.7). Overall agreement between the ME panel results and clinico-laboratory assessment was 98.2%. Forty-five patients tested positive by ME, of which 12 (26.6%) were determined likely to be clinically insignificant.Conclusions: Routine availability of the ME panel led to overutilization of diagnostic test ordering, as demonstrated by the fact that over one-third of ME panel tests performed were ordered for patients with little or no suspicion for CNS infection. The median time from LP to ME panel result was 1.5 h (IQR, 1.4–1.7). The ME panel's rapid turn-around time contributed to the overuse of the test. Approximately one-quarter of positive ME results were deemed clinically insignificant, though the impact of these positive results requires additional evaluation. Twenty-four and forty-eight hours after the ME panel resulted, 68 and 25% of patients started on empiric therapy remained on antibiotics, respectively. The median time from diagnosis to discontinuation and/or narrowing of antibiotic coverage was 25.6 h (IQR, 3.6–42.5). Further consideration of the appropriate indications for use of the ME panel in clinical settings is required

A 2500-yr late holocenemulti-proxy record of vegetation and hydrologic changes from a cave guano-clay sequence in SW Romania

We provide sedimentological, geochemical, mineral magnetic, stable carbon isotope, charcoal, and pollen-based evidence froma guano/clay sequence in Gaura cuMuscă Cave (SWRomania), fromwhichwe deduced that from ~1230 BC to ~AD 1240 climate oscillated betweenwet and dry. From ~1230 BC to AD 1000 the climate was wetter than the present, prompting flooding of the cave, preventing bats fromroosting, and resulting in a slowrate of clay accumulation. The second half of the MedievalWarm Period (MWP) was generally drier; the cave experienced occasional flash flooding in between which maternity bat roosts established in the cave. One extremely wet event occurred around AD 1170, when Fe/Mn and Ti/Zr ratios show the highest values coincident with a substantial increase of sediment load in the underground stream. The mineral magnetic characteristics for the second part of the MWP indicate the partial input of surface-sourced sediments reflecting agricultural development and forest clearance in the area. Pollen and microcharcoal studies confirm that the overall vegetation cover and human land use have not changed much in this region since the medieval times

Multilocus Sequence Typing as a Replacement for Serotyping in Salmonella enterica

Salmonella enterica subspecies enterica is traditionally subdivided into serovars by serological and nutritional characteristics. We used Multilocus Sequence Typing (MLST) to assign 4,257 isolates from 554 serovars to 1092 sequence types (STs). The majority of the isolates and many STs were grouped into 138 genetically closely related clusters called eBurstGroups (eBGs). Many eBGs correspond to a serovar, for example most Typhimurium are in eBG1 and most Enteritidis are in eBG4, but many eBGs contained more than one serovar. Furthermore, most serovars were polyphyletic and are distributed across multiple unrelated eBGs. Thus, serovar designations confounded genetically unrelated isolates and failed to recognize natural evolutionary groupings. An inability of serotyping to correctly group isolates was most apparent for Paratyphi B and its variant Java. Most Paratyphi B were included within a sub-cluster of STs belonging to eBG5, which also encompasses a separate sub-cluster of Java STs. However, diphasic Java variants were also found in two other eBGs and monophasic Java variants were in four other eBGs or STs, one of which is in subspecies salamae and a second of which includes isolates assigned to Enteritidis, Dublin and monophasic Paratyphi B. Similarly, Choleraesuis was found in eBG6 and is closely related to Paratyphi C, which is in eBG20. However, Choleraesuis var. Decatur consists of isolates from seven other, unrelated eBGs or STs. The serological assignment of these Decatur isolates to Choleraesuis likely reflects lateral gene transfer of flagellar genes between unrelated bacteria plus purifying selection. By confounding multiple evolutionary groups, serotyping can be misleading about the disease potential of S. enterica. Unlike serotyping, MLST recognizes evolutionary groupings and we recommend that Salmonella classification by serotyping should be replaced by MLST or its equivalents

Forest plot analysis of mortality rate using random-effects model in septic patients with hypothermia (body temperature up to 36.0°C; <i>n</i> = 890).

<p>Forest plot analysis of mortality rate using random-effects model in septic patients with hypothermia (body temperature up to 36.0°C; <i>n</i> = 890).</p

Forest plot analysis of mortality rate using random-effects model in septic patients with normothermia (body temperature between 36.1 and 38.0°C; <i>n</i> = 3,904).

<p>Forest plot analysis of mortality rate using random-effects model in septic patients with normothermia (body temperature between 36.1 and 38.0°C; <i>n</i> = 3,904).</p