Verifying Temporal Heap Properties Specified via Evolution Logic

This paper addresses the problem of establishing temporal properties of programs written in languages, such as Java, that make extensive use of the heap to allocate--- and deallocate---new objects and threads. Establishing liveness properties is a particularly hard challenge. One of the crucial obstacles is that heap locations have no static names and the number of heap locations is unbounded. The paper presents a framework for the verification of Java-like programs. Unlike classical model checking, which uses propositional temporal logic, we use first-order temporal logic to specify temporal properties of heap evolutions; this logic allows domain changes to be expressed, which permits allocation and deallocation to be modelled naturally. The paper also presents an abstract-interpretation algorithm that automatically verifies temporal properties expressed using the logic

Typestate verification: Abstraction techniques and complexity results

AbstractWe consider the problem of typestate verification for shallow programs; i.e., programs where pointers from program variables to heap-allocated objects are allowed, but where heap-allocated objects may not themselves contain pointers. We prove a number of results relating the complexity of verification to the nature of the finite state machine used to specify the property. Some properties are shown to be intractable, but others which appear to be quite similar admit polynomial-time verification algorithms. Our results serve to provide insight into the inherent complexity of important classes of verification problems. In addition, the program abstractions used for the polynomial-time verification algorithms may be of independent interest

Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution

Abstract Background: People with cancer with febrile neutropenia are at risk of severe infections and mortality and are thus treated empirically with broad-spectrum antibiotic therapy. However, the recommended duration of antibiotic therapy differs across guidelines. Objectives: To assess the safety of protocol-guided discontinuation of antibiotics regardless of neutrophil count, compared to continuation of antibiotics until neutropenia resolution in people with cancer with fever and neutropenia, in terms of mortality and morbidity. To assess the emergence of resistant bacteria in people with cancer treated with short courses of antibiotic therapy compared with people with cancer treated until resolution of neutropenia. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10) in the Cochrane Library, MEDLINE, Embase, and LILACS up to 1 October 2018. We searched the metaRegister of Controlled Trials and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov for ongoing and unpublished trials. We reviewed the references of all identified studies for additional trials and handsearched conference proceedings of international infectious diseases and oncology and haematology conferences. Selection criteria: We included randomised controlled trials (RCTs) that compared a short antibiotic therapy course in which discontinuation of antibiotics was guided by protocols regardless of the neutrophil count to a long course in which antibiotics were continued until neutropenia resolution in people with cancer with febrile neutropenia. The primary outcome was 30-day or end of follow-up all-cause mortality. Data collection and analysis: Two review authors independently reviewed all studies for eligibility, extracted data, and assessed risk of bias for all included trials. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) whenever possible. For dichotomous outcomes with zero events in both arms of the trials, we conducted meta-analysis of risk differences (RDs) as well. For continuous outcomes, we extracted means with standard deviations (SD) from the studies and computed mean difference (MD) and 95% CI. If no substantial clinical heterogeneity was found, trials were pooled using the Mantel-Haenszel fixed-effect model. Main results: We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections.We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. Authors' conclusions: We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance

Association of vancomycin serum concentrations with efficacy in patients with MRSA infections: a systematic review and meta-analysis

AbstractRecent Infectious Diseases Society of America guidelines for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend maintaining vancomycin trough concentrations of 15–20 mg/L for serious infections. We conducted a systematic review and meta-analysis of all studies assessing the impact of low (<15 mg/L) vs. high (≥15 mg/L) vancomycin trough level on the efficacy of MRSA infections treatment. Four prospective and 12 retrospective studies were included (2003 participants). No significant difference was demonstrated between low and high vancomycin trough level for the outcome of all-cause mortality (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.78–1.46, I2 = 28%). In studies evaluating mainly MRSA pneumonia, there was significantly higher mortality with low vancomycin level (OR 1.78, 95% CI 1.11–2.84). No significant difference was demonstrated in treatment failure rates (OR 1.25, 95% CI 0.88–1.78, I2 = 51%). However, excluding one outlier study from the analysis, treatment failure became significantly higher in patients with low vancomycin trough level (OR 1.46, 95% CI 1.12–1.91, I2 = 16%). Microbiologic failure rates were significantly higher in patients with low vancomycin levels (OR 1.56, 95% CI 1.08–2.26, I2 = 0%). Nephrotoxicity was significantly higher with vancomycin levels of ≥15 mg/L. However, no cases of irreversible renal damage were reported. Current data on the effectiveness of higher vancomycin trough levels in the treatment of MRSA infections are limited to few prospective and mainly retrospective studies. Our findings support the current recommendations for maintaining vancomycin trough levels of ≥15 mg/L in the treatment of severe MRSA infections, although no difference in all-cause mortality was observed

Considerations for the optimal management of antibiotic therapy in elderly patients

Objectives: To maximise efficacy and minimise toxicity, special considerations are required for antibiotic prescription in elderly patients. This review aims to provide practical suggestions for the optimal management of antibiotic therapy in elderly patients. Methods: This was a narrative review. A literature search of published articles in the last 15 years on antibiotics and elderly patients was performed using the Cochrane Library and PubMed electronic databases. The three priority areas were identified: (i) pharmacokinetics/pharmacodynamics (PK/PD) for optimising dosage regimens and route of administration; (ii) antibiotic dosages in some special subpopulations; and (iii) treatment considerations relating to different antibiotic classes and their adverse events. Results: Clinicians should understand the altered PK/PD of drugs in this population owing to co-morbid conditions and normal physiological changes associated with ageing. The body of evidence justifies the need for individualised dose selection, especially in patients with impaired renal and liver function. Clinicians should be aware of the major drug–drug interactions commonly observed in the elderly as well as potential side effects. Conclusion: Antibiotic therapy in the elderly requires a comprehensive approach, including strategies to improve appropriate antibiotic prescribing, limit their use for uncomplicated infections and ensure the attainment of an optimal PK/PD target. To this purpose, further studies involving the elderly are needed to better understand the PK of antibiotics. Moreover, it is necessary to assess the role therapeutic drug monitoring in guiding antibiotic therapy in elderly patients in order to evaluate its impact on clinical outcome

Interprocedural shape analysis for effectively cutpoint-free programs

Abstract. We present a framework for local interprocedural shape analysis that computes procedure summaries as transformers of procedure-local heaps (the parts of the heap that the procedure may reach). A main challenge in procedurelocal shape analysis is the handling of cutpoints, objects that separate the input heap of an invoked procedure from the rest of the heap, which-from the viewpoint of that invocation-is non-accessible and immutable. In this paper, we limit our attention to effectively cutpoint-free programsprograms in which the only objects that separate the callee&apos;s heap from the rest of the heap, when considering live reference fields, are the ones pointed to by the actual parameters of the invocation. This limitation (and certain variations of it, which we also describe) simplifies the local-reasoning about procedure calls because the analysis needs not track cutpoints. Furthermore, our analysis (conservatively) verifies that a program is effectively cutpoint-free

Considerations for the optimal management of antibiotic therapy in elderly patients

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Wearable biosensors have the potential to monitor physiological changes associated with opioid overdose among people who use drugs: A proof-of-concept study in a real-world setting

INTRODUCTION: Wearable biosensors have the potential to monitor physiological change associated with opioid overdose among people who use drugs. METHODS: We enrolled 16 individuals who reported ≥ 4 daily opioid use events within the previous 30 day. Each was assigned a wearable biosensor that measured respiratory rate (RR) and actigraphy every 15 s for 5 days and also completed a daily interview assessing drug use. We describe the volume of RR data collected, how it varied by participant characteristics and drug use over time using repeated measures one-way ANOVA, episodes of acute respiratory depression (≤5 breaths/minute), and self-reported overdose experiences. RESULTS: We captured 1626.4 h of RR data, an average of 21.7 daily hours/participant over follow-up. Individuals with longer injection careers and those engaging in polydrug use captured significantly fewer total hours of respiratory data over follow-up compared to those with shorter injections careers (94.7 vs. 119.9 h, p = 0.04) and injecting fentanyl exclusively (98.7 vs. 119.5 h, p = 0.008), respectively. There were 385 drug use events reported over follow-up. There were no episodes of acute respiratory depression which corresponded with participant reports of overdose experiences. DISCUSSION: Our preliminary findings suggest that using a wearable biosensor to monitor physiological changes associated with opioid use was feasible. However, more sensitive biosensors that facilitate triangulation of multiple physiological data points and larger studies of longer duration are needed

Validation of the INCREMENT-SOT-CPE score in a large cohort of liver transplant recipients with carbapenem-resistant Enterobacterales infection

Background: Management of infections due to carbapenemase-resistant Enterobacterales (CRE) in solid organ transplant (SOT) recipients remains a difficult challenge. The INCREMENT-SOT-CPE score has been specifically developed from SOT recipients to stratify mortality risk, but an external validation is lacking.Methods: Multicenter retrospective cohort study of liver transplant (LT) recipients colonized with CRE infection who developed infection after transplant over 7-year period. Primary endpoint was all-cause 30-day mortality from infection onset. A comparison between INCREMENT-SOT-CPE and other selected scores was performed. A two-level mixed effects logistic regression model with random effects for the center was fitted. Performance characteristics at optimal cut-point were calculated. Multivariable Cox regression analysis of risk factors for all-cause 30-day mortality was carried out.Results: Overall, 250 CRE carriers developed infection after LT and were analyzed. The median age was 55 years (interquartile range [IQR]: 46-62) and 157 were males (62.8%). All-cause 30-day mortality was 35.6%. A sequential organ failure assessment (SOFA) score &gt;= 11 showed a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 69.7%, 76.4%, 62.0%, 82.0%, and 74.0%, respectively. An INCREMENT-SOT-CPE &gt;= 11 reported a sensitivity, specificity, PPV, NPV, and accuracy of 73.0%, 62.1%, 51.6%, 80.6% and 66.0%, respectively. At multivariable analysis acute renal failure, prolonged mechanical ventilation, INCREMENT-SOT-CPE score &gt;= 11 and SOFA score &gt;= 11 were independently associated with all-cause 30-day mortality, while a tigecycline-based targeted regimen was found to be protective.Conclusions: Both INCREMENT-SOT-CPE &gt;= 11 and SOFA &gt;= 11 were identified as strong predictors of all-cause 30-day mortality in a large cohort of CRE carriers developing infection after LT