Surge of Midazolam Use in the Midst of Lorazepam Shortage.

BACKGROUND: Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings. PROCEDURES: This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies. RESULTS: The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly. CONCLUSIONS: Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.

Urinary detection of early responses to checkpoint blockade and of resistance to it via protease-cleaved antibody-conjugated sensors.

Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered protease activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. The sensors consist of a library of mass-barcoded protease substrates that, when cleaved by tumour proteases and immune proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random forest classifiers trained on mass spectrometry signatures from a library of αPD1-conjugated mass-barcoded activity sensors for differentially expressed tumour proteases and immune proteases can be used to detect early antitumour responses and discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Biomarkers of protease activity may facilitate the assessment of early responses to ICB therapy and the classification of refractory tumours based on resistance mechanisms.

Engrailed 2 deficiency and chronic stress alter avoidance and motivation behaviors.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by impairments in social interaction, cognition, and communication, as well as the presence of repetitive or stereotyped behaviors and interests. ASD is most often studied as a neurodevelopmental disease, but it is a lifelong disorder. Adults with ASD experience more stressful life events and greater perceived stress, and frequently have comorbid mood disorders such as anxiety and depression. It remains unclear whether adult exposure to chronic stress can exacerbate the behavioral and neurodevelopmental phenotypes associated with ASD. To address this issue, we first investigated whether adult male and female Engrailed-2 deficient (En2-KO, En2-/-) mice, which display behavioral disturbances in avoidance tasks and dysregulated monoaminergic neurotransmitter levels, also display impairments in instrumental behaviors associated with motivation, such as the progressive ratio task. We then exposed adult En2-KO mice to chronic environmental stress (CSDS, chronic social defeat stress), to determine if stress exacerbated the behavioral and neuroanatomical effects of En2 deletion. En2-/- mice showed impaired instrumental acquisition and significantly lower breakpoints in a progressive ratio test, demonstrating En2 deficiency decreases motivation to exert effort for reward. Furthermore, adult CSDS exposure increased avoidance behaviors in En2-KO mice. Interestingly, adult CSDS exposure also exacerbated the deleterious effects of En2 deficiency on forebrain-projecting monoaminergic fibers. Our findings thus suggest that adult exposure to stress may exacerbate behavioral and neuroanatomical phenotypes associated with developmental effects of genetic En2 deficiency.

EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke.

BACKGROUND: Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality. AIM: Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology to critically evaluate the evidence regarding potential links and the impact of therapy. MATERIALS AND METHODS: Thirteen research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta-analyses; second, primary studies post-dating the systematic reviews/meta-analyses. A total of 445 studies were evaluated and 88 were included. Statements were generated regarding current evidence and clinical practice. RESULTS: Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle-aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment-compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, whilst CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, whilst the pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post-stroke insomnia and RLS and their association with a less favourable stroke outcome, whilst treatment data are scarce. DISCUSSION/CONCLUSION: Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.

European Respiratory Society guidelines on long-term home non-invasive ventilation for management of COPD

While the role of acute non-invasive ventilation (NIV) has been shown to improve outcome in acute life-threatening hypercapnic respiratory failure in COPD, the evidence of clinical efficacy of long-term home NIV (LTH-NIV) for management of COPD is less. This document provides evidence-based recommendations for the clinical application of LTH-NIV in chronic hypercapnic COPD patients. The European Respiratory Society task force committee was composed of clinicians, methodologists and experts in the field of LTH-NIV. The committee developed recommendations based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology. The GRADE Evidence to Decision framework was used to formulate recommendations. A number of topics were addressed under a narrative format which provides a useful context for clinicians and patients. The task force committee delivered conditional recommendations for four actionable PICO (target population-intervention-comparator-outcome) questions, 1) suggesting for the use of LTH-NIV in stable hypercapnic COPD; 2) suggesting for the use of LTH-NIV in COPD patients following a COPD exacerbation requiring acute NIV 3) suggesting for the use of NIV settings targeting a reduction in carbon dioxide and 4) suggesting for using fixed pressure support as first choice ventilator mode. Managing hypercapnia may be an important intervention for improving the health outcome of COPD patients with chronic respiratory failure. The task force conditionally supports the application of LTH-NIV to improve health outcome by targeting a reduction in carbon dioxide in COPD patients with persistent hypercapnic respiratory failure. These recommendations should be applied in clinical practice by practitioners that routinely care for chronic hypercapnic COPD patients.

Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline

This document provides clinical recommendations for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations. It represents a collaborative effort between the European Respiratory Society and the American Thoracic Society.Comprehensive evidence syntheses were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts.After considering the balance of desirable (benefits) and undesirable consequences (burden in the form of adverse effects and cost), quality of evidence, feasibility, and acceptability of various interventions, the Task Force made recommendations for mucolytic, long-acting muscarinic antagonist, phosphodiesterase-4 inhibitor (roflumilast) and macrolide therapy, as well as a conditional recommendation against fluoroquinolone therapy. All of the recommendations were conditional, except for a strong recommendation for the use of a long-acting antimuscarinic agent versus a long-acting ß2-adrenergic, indicating that there was uncertainty about the balance of desirable and undesirable consequences of the intervention, and that well-informed patients may make different choices regarding whether to have or not have the specific intervention.The guideline summarises the evidence and provides recommendations for pharmacological therapy for the prevention of COPD exacerbations

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia

Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce the need for red blood cell transfusions; however, they increase the risk of thromboembolic events and mortality. The impact of ESAs on quality of life (QoL) is controversial and led to different recommendations of medical societies and authorities in the USA and Europe. We aimed to critically evaluate and quantify the effects of ESAs on QoL in cancer patients. METHODS: We included data from randomised controlled trials (RCTs) on the effects of ESAs on QoL in cancer patients. Randomised controlled trials were identified by searching electronic data bases and other sources up to January 2011. To reduce publication and outcome reporting biases, we included unreported results from clinical study reports. We conducted meta-analyses on fatigue- and anaemia-related symptoms measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and FACT-Anaemia (FACT-An) subscales (primary outcomes) or other validated instruments. RESULTS: We identified 58 eligible RCTs. Clinical study reports were available for 27% (4 out of 15) of the investigator-initiated trials and 95% (41 out of 43) of the industry-initiated trials. We excluded 21 RTCs as we could not use their QoL data for meta-analyses, either because of incomplete reporting (17 RCTs) or because of premature closure of the trial (4 RCTs). We included 37 RCTs with 10581 patients; 21 RCTs were placebo controlled. Chemotherapy was given in 27 of the 37 RCTs. The median baseline haemoglobin (Hb) level was 10.1 g dl(-1); in 8 studies ESAs were stopped at Hb levels below 13 g dl(-1) and in 27 above 13 g dl(-1). For FACT-F, the mean difference (MD) was 2.41 (95% confidence interval (95% CI) 1.39-3.43; P<0.0001; 23 studies, n=6108) in all cancer patients and 2.81 (95% CI 1.73-3.90; P<0.0001; 19 RCTs, n=4697) in patients receiving chemotherapy, which was below the threshold (≥ 3) for a clinically important difference (CID). Erythropoiesis-stimulating agents had a positive effect on anaemia-related symptoms (MD 4.09; 95% CI 2.37-5.80; P=0.001; 14 studies, n=2765) in all cancer patients and 4.50 (95% CI 2.55-6.45; P<0.0001; 11 RCTs, n=2436) in patients receiving chemotherapy, which was above the threshold (≥ 4) for a CID. Of note, this effect persisted when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. There was some evidence that the MDs for FACT-F were above the threshold for a CID in RCTs including cancer patients receiving chemotherapy with Hb levels below 12 g dl(-1) at baseline and in RCTs stopping ESAs at Hb levels above 13 g dl(-1). However, these findings for FACT-F were not confirmed when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. CONCLUSIONS: In cancer patients, particularly those receiving chemotherapy, we found that ESAs provide a small but clinically important improvement in anaemia-related symptoms (FACT-An). For fatigue-related symptoms (FACT-F), the overall effect did not reach the threshold for a CID.

The current prevalence of child sexual abuse worldwide: a systematic review and meta-analysis.

OBJECTIVES: Systematic reviews on prevalence estimates of child sexual abuse (CSA) worldwide included studies with adult participants referring on a period of abuse of about 50 years. Therefore we aimed to describe the current prevalence of CSA, taking into account geographical region, type of abuse, level of country development and research methods. METHODS: We included studies published between 2002 and 2009 that reported CSA in children below 18 years. We performed a random effects meta-analysis and analyzed moderator variables by meta-regression. RESULTS: Fifty-five studies from 24 countries were included. According to four predefined types of sexual abuse, prevalence estimates ranged from 8 to 31 % for girls and 3 to 17 % for boys. Nine girls and 3 boys out of 100 are victims of forced intercourse. Heterogeneity between primary studies was high in all analyses. CONCLUSIONS: Our results based on most recent data confirm results from previous reviews with adults. Surveys in children offer most recent estimates of CSA. Reducing heterogeneity between studies might be possible by standardized measures to make data more meaningful in international comparisons.

Expression of a conditioned place preference or spatial navigation task following muscimol-induced inactivations of the amygdala or dorsal hippocampus: A double dissociation in the retrograde direction.

Previous work indicates an essential role of the basolateral amygdala in stimulus-reward learning and the dorsal hippocampus in spatial learning and memory. The goal of the present, experiments was to examine the involvement of the amygdala and hippocampus in performance of tasks requiring stimulus-reward and spatial/relational learning and memory processes in the retrograde direction. Accordingly, this series of experiments tested the effects of temporary, inactivations directed at the basolateral nucleus of the amygdala or dorsal hippocampus on the, expression of a conditioned place preference (CPP) task or a spatial navigation water task. The results, of Experiments 1a and b showed that inactivations of the amygdala impaired the expression of a, previously acquired CPP but did not impair the expression of a learned spatial response required for, accurate performance of a spatial navigation task. The results of Experiments 2a and b showed that, inactivations of the dorsal hippocampus impaired expression of a learned response required for the, accurate performance of a spatial navigation task but did not impair the learned response required for, the expression of a CPP. Taken together, the results showed a functional dissociation between the, effects of amygdala or hippocampal dysfunction on the expression of these different classes of tasks.

Changing incidence, type, and natural history of conduction defects after coronary artery bypass grafting.

BACKGROUND: Cardiac conduction defects occur after cardiac surgery. We hypothesized that population aging and increased use of beta-blockers would increase the incidence of new conduction defects after coronary surgery. METHODS: We examined the medical records of 800 coronary artery bypass grafting (CABG) patients (400 from 1991 and 400 from 2001). Exclusion criteria included the following: preexisting conduction defect, permanent pacemaker, and perioperative atrial fibrillation, leaving 303 and 269 patients, respectively, included in the two study years. The incidence, type, and persistence of new conduction defects were determined from the preoperative, postoperative, and the predischarge electrocardiogram. Multivariate analysis identified predictors of new defects. RESULTS: Study populations were well-matched. There was a marked decrease in the incidence of new postoperative conduction defects from 1991 (19%) to 2001 (6%). There was also a change in the most frequently occurring block, from a right-bundle-branch-block in 1991 (10%) to first-degree atrioventricular block (3%) in 2001. Finally, conduction defects in 1991 were more transient. While 19% of 1991 patients showed a conduction defect early postoperatively, only 9% were persistent. In 2001, the incidence of conduction defects at discharge (7%), was equivalent to that early postoperatively (6%). Predictors of new conduction defects included year of operation, age, intraaortic balloon counterpulsation, number of vessels bypassed, and crystalloid cardioplegia. CONCLUSIONS: Our results were the opposite of those predicted. Our report identifies a changing incidence, type, and natural history of conduction defects after CABG. Our comparison demonstrated a decrease in the incidence of new conduction defects, as well as a qualitative change in the defects identified. Multivariate analysis provided predictors of new conduction defects after CABG.

Electrical stimulation of the hippocampus disrupts prepulse inhibition in rats: frequency- and site-dependent effects.

Prepulse inhibition (PPI) is a normal reduction in the startle response produced when a brief, low intensity stimulus is presented prior to a startle-evoking stimulus. PPI is often disrupted in humans diagnosed with schizophrenia. As similar stimuli elicit PPI in rodents and humans, interventions in rodents that disrupt PPI may reveal aspects of neuronal dysfunction relevant to schizophrenia. Stimulation of the ventral hippocampus (vHip) with NMDA significantly increases dopamine (DA) efflux in the nucleus accumbens (NAc) and disrupts PPI, whereas NMDA infusion into the dorsal hippocampus (dHip) fails to alter PPI. Our previous research shows that brief periods of 20 Hz electrical vHip stimulation also significantly increase NAc DA efflux. The present experiments assessed the effects of stimulating the vHip or dHip on PPI and NAc DA efflux. As predicted, 20 Hz stimulation (10 s, 300 microA) of the vHip, but not the dHip, reversibly disrupted PPI. In contrast, 2 Hz stimulation (100 s, 300 microA) of the vHip failed to affect PPI. Microdialysis experiments revealed that 20 Hz stimulation of the vHip increased NAc DA efflux only in the hemisphere ipsilateral to the stimulating electrode, whereas 20 Hz stimulation of the dHip failed to affect NAc DA efflux. These data demonstrate the regional specificity and frequency-dependent effects of hippocampal activity on PPI. Additionally, it is intriguing that both chemical and electrical stimulation of the vHip disrupt PPI and increase NAc DA efflux, however, the relevance of these changes in NAc DA efflux to the disruption of PPI remains to be determined.