The enzyme toilet rim block ‘pCure’ does not efficiently remove drug residues in a hospital setting - exemplifying the importance of on-site implementation testing

Introduction: Negative environmental effects of active pharmaceutical ingredients (APIs) are increasingly recognized, especially concerning antibiotics, and hospitals are important point sources. “pCure” is a toilet rim block containing API-degrading enzymes; the producing company claims positive in vitro results but no implementation studies have been performed. Materials and methods: In a university hospital setting, 16 weeks were randomized to installation or no installation of pCure in all 261 toilets connected to the same cesspit where sewage water was sampled daily. Ninety-six samples were analyzed for 102 APIs using liquid chromatography/tandem mass spectrometry. Results and Discussion: Fifty-one APIs were detected with a large variation in levels but no significant differences in the initial statistical analysis. More statistical testing of API level ratios (pCure installed/not installed) yielded some cases of significant decrease. Differences were small and not consistent when comparing means and medians. We cannot exclude a small pCure effect but clearly pCure has no effect of biological importance. Conclusion: pCure is not useful to reduce drug residue discharge in a hospital setting. In a bigger perspective, our study exemplifies that products claiming to reduce an environmental problem need to be tested in on-site implementation studies by independent researchers before reaching the market

Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation : Study protocol for a registry-based randomised controlled trial

Background: Oral anticoagulation therapy is recommended for the prevention of recurrent ischemic stroke in patients with atrial fibrillation (AF). Current guidelines do not provide evidence-based recommendations on optimal time-point to start anticoagulation therapy after an acute ischemic stroke. Non-vitamin K antagonist oral anticoagulants (NOACs) may offer advantages compared to warfarin because of faster and more predictable onset of action and potentially a lower risk of intracerebral haemorrhage also in the acute phase after an ischemic stroke. The TIMING study aims to establish the efficacy and safety of early vs delayed initiation of NOACs in patients with acute ischemic stroke and AF. Methods/Design: The TIMING study is a national, investigator-led, registry-based, multicentre, open-label, randomised controlled study. The Swedish Stroke Register is used for enrolment, randomisation and follow-up of 3000 patients, who are randomised (1:1) within 72 h from ischemic stroke onset to either early (≤ 4 days) or delayed (≥ 5-10 days) start of NOAC therapy. The primary outcome is the composite of recurrent ischemic stroke, symptomatic intracerebral haemorrhage, or all-cause mortality within 90 days after randomisation. Secondary outcomes include: individual components of the primary outcome at 90 and 365 days; major haemorrhagic events; functional outcome by the modified Rankin Scale at 90 days; and health economics. In an optional biomarker sub-study, blood samples will be collected after randomisation from approximately half of the patients for central analysis of cardiovascular biomarkers after study completion. The study is funded by the Swedish Medical Research Council. Enrolment of patients started in April 2017. Conclusion: The TIMING study addresses the ongoing clinical dilemma of when to start NOAC after an acute ischemic stroke in patients with AF. By the inclusion of a randomisation module within the Swedish Stroke Register, the advantages of a prospective randomised study design are combined with the strengths of a national clinical quality register in allowing simplified enrolment and follow-up of study patients. In addition, the register adds the possibility of directly assessing the external validity of the study findings. Trial registration: ClinicalTrials.gov, NCT02961348. Registered on 8 November 2016

The Clinical Course of Alcohol Use Disorder Depicted by Digital Biomarkers

Aims: This study introduces new digital biomarkers to be used as precise, objective tools to measure and describe the clinical course of patients with alcohol use disorder (AUD). Methods: An algorithm is outlined for the calculation of a new digital biomarker, the recovery and exacerbation index (REI), which describes the current trend in a patient's clinical course of AUD. A threshold applied to the REI identifies the starting point and the length of an exacerbation event (EE). The disease patterns and periodicity are described by the number, length, and distance between EEs. The algorithms were tested on data from patients from previous clinical trials (n = 51) and clinical practice (n = 1,717). Results: Our study indicates that the digital biomarker-based description of the clinical course of AUD might be superior to the traditional self-reported relapse/remission concept and conventional biomarkers due to higher data quality (alcohol measured) and time resolution. We found that EEs and the REI introduce distinct tools to identify qualitative and quantitative differences in drinking patterns (drinks per drinking day, phosphatidyl ethanol levels, weekday and holiday patterns) and effect of treatment time. Conclusions: This study indicates that the disease state-level, trend and periodicity-can be mathematically described and visualized with digital biomarkers, thereby improving knowledge about the clinical course of AUD and enabling clinical decision-making and adaptive care. The algorithms provide a basis for machine-learning-driven research that might also be applied for other disorders where daily data are available from digital health systems

Decompression alone or decompression with fusion for lumbar spinal stenosis : a randomized clinical trial with two-year MRI follow-up

Aims: The aims of this study were first, to determine if adding fusion to a decompression of the lumbar spine for spinal stenosis decreases the rate of radiological restenosis and/or proximal adjacent level stenosis two years after surgery, and second, to evaluate the change in vertebral slip two years after surgery with and without fusion. Methods: The Swedish Spinal Stenosis Study (SSSS) was conducted between 2006 and 2012 at five public and two private hospitals. Six centres participated in this two--year MRI follow--up. We randomized 222 patients with central lumbar spinal stenosis at one or two adjacent levels into two groups, decompression alone and decompression with fusion. The presence or absence of a preoperative spondylolisthesis was noted. A new stenosis on two--year MRI was used as the primary outcome, defined as a dural sac cross--sectional area = 75 mm2 at the operated level (restenosis) and/or at the level above (proximal adjacent level stenosis). Results: A total of 211 patients underwent surgery at a mean age of 66 years (69% female): 103 were treated by decompression with fusion and 108 by decompression alone. A two--year MRI was available for 176 (90%) of the eligible patients. A new stenosis at the operated and/or adjacent level occurred more frequently after decompression and fusion than after decompression alone (47% vs 29%; p = 0.020). The difference remained in the subgroup with a preoperative spondylolisthesis, (48% vs 24%; p = 0.020), but did not reach significance for those without (45% vs 35%; p = 0.488). Proximal adjacent level stenosis was more common after fusion than after decompression alone (44% vs 17%; p < 0.001). Restenosis at the operated level was less frequent after fusion than decompression alone (4% vs 14%; p = 0.036). Vertebral slip increased by 1.1 mm after decompression alone, regardless of whether a preoperative spondylolisthesis was present or not. Conclusion: Adding fusion to a decompression increased the rate of new stenosis on two--year MRI, even when a spondylolisthesis was present preoperatively. This supports decompression alone as the preferred method of surgery for spinal stenosis, whether or not a degenerative spondylolisthesis is present preoperatively

The Precision HYpertenSIon Care (PHYSIC) study : a double-blind, randomized, repeated cross-over study

High blood pressure is the leading risk factor for premature deaths and a major cost to societies worldwide. Effective blood pressure-lowering drugs are available, but patient adherence to them is low, likely partly due to side effects. To identify patient-specific differences in treatment effects, a repeated cross-over design, where the same treatment contrasts are repeated within each patient, is needed. Such designs have been surprisingly rarely used, given the current focus on precision medicine. The Precision HYpertenSIon Care (PHYSIC) study aims to investigate if there is a consistent between-person variation in blood pressure response to the common blood pressure-lowering drug classes of a clinically relevant magnitude, given the within-person variation in blood pressure. The study will also investigate the between-person variation in side effects of the drugs. In a double-blind, randomized, repeated cross-over trial, 300 patients with mild hypertension will be treated with four blood pressure-lowering drugs (candesartan, lisinopril, amlodipine, and hydrochlorothiazide) in monotherapy, with two of the drugs repeated for each patient. If the study indicates that there is a potential for precision hypertension care, the most promising predictors of blood pressure and side effect response to the drugs will be explored, as will the potential for development of a biomarker panel to rank the suitability of blood pressure-lowering drug classes for individual patients in terms of anticipated blood pressure effects and side effects, with the ultimate goal to maximize adherence. The study follows a protocol pre-registered at ClinicalTrials.gov with the identifier NCT02774460

On-site pilot testing of hospital wastewater ozonation to reduce pharmaceutical residues and antibiotic-resistant bacteria

Hospital sewage constitutes an important point source for antibiotics and antibiotic-resistant bacteria due to the high antibiotic use. Antibiotic resistance can develop and cause problems in sewage systems within hospitals and municipal wastewater treatment plants, thus, interventions to treat hospital sewage on-site are important. Ozonation has proven effective in treating relatively clean wastewater, but the effect on untreated wastewater is unclear. Therefore, we piloted implementation of ozonation to treat wastewater in a tertiary hospital in Uppsala, Sweden. We measured active pharmaceutical ingredients (APIs) using liquid chromatography-mass spectrometry and antibiotic-resistant Enterobacteriaceae using selective culturing pre-and post-ozonation. Comparing low (1 m3 /h) and high (2 m3 /h) flow, we obtained a 'dose-dependent' effect of API reduction (significant reduction of 12/29 APIs using low and 2/29 APIs using high flow, and a mean reduction of antibiotics of 41% using low vs. 6% using high flow, 25% vs. 6% for all APIs). There was no significant difference in the amount of antibiotic-resistant Enterobacteiaceae pre-and post-ozonation. Our results demonstrate that ozonation of untreated wastewater can reduce API content. However, due to the moderate API decrease and numerous practical challenges in the on-site setting, this specific ozonation system is not suitable to implement at full scale in our hospital

Additional file 1: of Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation: study protocol for a registry-based randomised controlled trial

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents. (PDF 244 kb