How to Prescribe Drugs With an Identified Proarrhythmic Liability.

This is an article in the Journal of Clinical Pharmacology's Core Entrustable Professional Activities in Clinical Pharmacology series that discusses drug-induced proarrhythmia and is offered as a teaching aid for medical students and residents. Drugs from diverse pharmacological classes can lead to multiple types of arrhythmias including the polymorphic ventricular tachycardia torsades de pointes (TdP). Although typically occurring in self-limiting bursts with or without associated symptoms, which can range from mild lightheadedness and palpitations to syncope and seizures, TdP can also occasionally progress to ventricular fibrillation and sudden cardiac death. To provide patients with the optimal therapeutic benefits of potentially proarrhythmic drugs, prescribers are responsible for obtaining a good understanding of the compound's benefit-risk properties and perform a judicious assessment of the patient's clinical characteristics and individual risk factors. Dose adjustments and/or additional monitoring of electrocardiograms and electrolyte balances may be appropriate in some cases. This article explains the pharmacological mechanism of action of drug-induced proarrhythmia associated with compounds that prolong the repolarization period, illustrates how this liability is conveyed in a drug's prescribing information (label), details the clinical characteristics of patients most susceptible to this type of proarrhythmia, and describes interventions that can be made if TdP occurs. Three clinical vignettes are provided at the end of the article to highlight the relevance of the preceding discussions.

Effect of a national urgent care telephone triage service on population perceptions of urgent care provision: controlled before and after study.

OBJECTIVE: To measure the effect of an urgent care telephone service NHS 111 on population perceptions of urgent care. DESIGN: Controlled before and after population survey, using quota sampling to identify 2000 respondents reflective of the age/sex profile of the general population. SETTING: England. 4 areas where NHS 111 was introduced, and 3 control areas where NHS 111 had yet to be introduced. PARTICIPANTS: 28 071 members of the general population, including 2237 recent users of urgent care. INTERVENTION: NHS 111 offers advice to members of the general population seeking urgent care, recommending the best service to use or self-management. Policymakers introduced NHS 111 to improve access to urgent care. OUTCOMES MEASURES: The primary outcome was change in satisfaction with recent urgent care use 9 months after the launch of NHS 111. Secondary outcomes were change in satisfaction with urgent care generally and with the national health service. RESULTS: The overall response rate was 28% (28 071/100 408). 8% (2237/28 071) had used urgent care in the previous 3 months. Of the 652 recent users of urgent care in the NHS 111 intervention areas, 9% (60/652) reported calling NHS 111 in the 'after' period. There was no evidence that the introduction of NHS 111 was associated with a changed perception of recent urgent care. For example, the percentage rating their experience as excellent remained at 43% (OR 0.97, 95% CI 0.69 to 1.37). Similarly, there was no change in population perceptions of urgent care generally (1.06, 95% CI 0.95 to 1.17) or the NHS (0.94, 95% CI 0.85 to 1.05) following the introduction of NHS 111. CONCLUSIONS: A new telephone triage service did not improve perceptions of urgent care or the health service. This could be explained by the small amount of NHS 111 activity in a large emergency and urgent care system.

Investigating the effects of caffeine on executive functions using traditional Stroop and a new ecologically-valid virtual reality task, the Jansari assessment of Executive Functions (JEF(©)).

OBJECTIVE: Caffeine has been shown to have effects on certain areas of cognition, but in executive functioning the research is limited and also inconsistent. One reason could be the need for a more sensitive measure to detect the effects of caffeine on executive function. This study used a new non-immersive virtual reality assessment of executive functions known as JEF(©) (the Jansari Assessment of Executive Function) alongside the 'classic' Stroop Colour-Word task to assess the effects of a normal dose of caffeinated coffee on executive function. METHOD: Using a double-blind, counterbalanced within participants procedure 43 participants were administered either a caffeinated or decaffeinated coffee and completed the 'JEF(©)' and Stroop tasks, as well as a subjective mood scale and blood pressure pre- and post condition on two separate occasions a week apart. JEF(©) yields measures for eight separate aspects of executive functions, in addition to a total average score. RESULTS: Findings indicate that performance was significantly improved on the planning, creative thinking, event-, time- and action-based prospective memory, as well as total JEF(©) score following caffeinated coffee relative to the decaffeinated coffee. The caffeinated beverage significantly decreased reaction times on the Stroop task, but there was no effect on Stroop interference. CONCLUSION: The results provide further support for the effects of a caffeinated beverage on cognitive functioning. In particular, it has demonstrated the ability of JEF(©) to detect the effects of caffeine across a number of executive functioning constructs, which weren't shown in the Stroop task, suggesting executive functioning improvements as a result of a 'typical' dose of caffeine may only be detected by the use of more real-world, ecologically valid tasks.

Assessment of elevated compartment pressures by pressure-related ultrasound: a cadaveric model.

PURPOSE: There is a risk of misinterpreting the clinical signs of acute compartment syndrome of the lower limb resulting in delayed fasciotomy. Up to date, the diagnosis of compartment syndrome is based on clinical assessment and of invasive needle pressure measurement in uncertain cases. Close monitoring is necessary for early recognition of raising compartment pressures. Clinical assessment of muscle firmness by the physician's palpation alone is unreliable. Thus, a device objectifying this assessment would be beneficial. The purpose of this study was to determine the feasibility of muscle compartment elasticity measurements by a novel and non-invasive device using pressure-related ultrasound. METHODS: In a cadaveric model, the anterior tibial compartment was prepared to simulate raising intra-compartmental pressures (0-80 mmHg) by saline infusion. Standard invasive pressure monitoring was compared with a novel method to determine tissue elasticity. Changing cross-sectional view in B-mode ultrasound was exerted to measure the compartment depth before and after physician's probe compression of 100 mmHg. Compartment displacement (∆d) was measured and related to the corresponding compartmental pressure (Spearman correlation coefficient). Delta (mm) of the control group at 10 mmHg compartment pressure was compared with measured data at rising compartmental pressures of 30, 50, and 70 mmHg using the Wilcoxon rank-sum test. The intra-observer reliability (κ) was additionally calculated. RESULTS: Fresh and never frozen lower human limbs (n = 6) were used. The average displacement measured in the anterior tibial compartment was 2.7 mm (0.3-6.7 mm). A concordant consistent correlation between the compartmental displacement and the intra-compartmental pressure occurred. The Spearman coefficient (r s = 0.979) showed a significant correlation between the rising pressure and the decreasing tissue displacement visualized by ultrasound. The intra-observer value kappa showed reliable values (κ 10 = 0.73, κ 30 = 0.80, and κ 70 = 0.79). CONCLUSIONS: We introduce a new method of ultrasound imaging enhanced with probe pressure measurement to determine changes of the visco-elastic behavior of isolated muscle compartments. Pressure-related ultrasound could be a reliable tool to determine the correlation between the measured compartmental displacement and the increasing intra-compartmental pressure. Its accuracy revealed promising results. This technique may help the physician to objectify the clinical assessment of compartment elasticity, mainly indicated in cases of unconscious patients and imminent pathology. Further clinical studies and improvements of this technique are required to prove its accuracy and reliability in cases of compartment syndrome.

Estimating the burden of psychiatric disorders in adolescence: the impact of subthreshold disorders.

PURPOSE: We examine the impact of including subthreshold disorders on estimating psychiatric morbidity burden in adolescents. To more fully understand this burden it is important to focus on both full syndrome and subthreshold disorders and the impairment associated with each, since evidence suggests prevalence of subthreshold disorders is substantial as is impairment. METHODS: Data were analyzed from a probability sample of 4,175 youths 11-17 years of age. We examine the prevalence of DSM-IV disorders (FS) and subthreshold (SUB) disorders, with and without impairment. Diagnostic categories examined were anxiety, mood, attention deficit hyperactivity disorder, disruptive, and substance use disorders in the past year. RESULTS: The prevalence of any FS disorders was 16.1 and 42.3 % for SUB. The combined prevalence was 58.4 %. By requiring impairment, the prevalence of any FS in the past year dropped to 8 % and for SUB to 15.7 %, with a combined overall rate of 23.7 %. For FS disorders, 49.6 % met criteria for moderate to severe impairment, compared to 37.8 % for SUB. One in four adolescents had either an FS or SUB disorder with impairment. CONCLUSION: The results indicate that SUB disorders constitute a major public health burden in terms of psychiatric morbidity among adolescents. Given their substantial impairment and their high prevalence, consideration should be given to including SUB disorders in estimates of the public health burden psychiatric morbidity. Doing so would provide a more accurate estimate of psychiatric morbidity.

Assessment of drug-induced increases in blood pressure during drug development: report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.

An antibiotic formulary for a tertiary care foot clinic: admission avoidance using intramuscular antibiotics for borderline foot infections in people with diabetes.

AIMS: To develop an antibiotic foot formulary for the empirical treatment of diabetes-related foot infections presenting to our service. Subsequently, to asses costs associated with the introduction of our protocol, in particular to assess the effect on admissions avoidance and any cost savings achieved. METHODS: We reviewed several existing antibiotic protocols. We analysed data on costs related to treatment and admission rates prior to and after the introduction of the protocol. RESULTS: We rationalized our antibiotic protocol and adapted the Infectious Disease Society of America guideline by introducing a category of 'moderate infection-borderline admission' to our classification. This enabled the administration of outpatient intramuscular antibiotics. After introducing the rationalized protocol, our average antibiotic prescribing costs for a 3-week course of treatment fell from £17.12 to £16.42. Over 22 months of follow-up, 26 episodes were eligible for treatment with intramuscular antibiotics. Over the same time period, 121 people were admitted directly from the foot clinic. The costs saved as a result of avoided or delayed admission for those 26 episodes was over £76 000. For 12 people who required subsequent admission, their length of hospital stay was significantly shorter than those admitted directly [9.25 days (range 2-25) vs. 16.11 (2-64), P = 0.045]. CONCLUSIONS: By modifying the Infectious Disease Society of America classification and adopting a protocol to administer outpatient oral and intramuscular antibiotics, we have led to substantial cost savings, shorter hospital admissions and also have developed a successful admissions avoidance strategy.

Psychological distress and unmet supportive care needs in cancer patients and carers who contact cancer helplines.

Cancer information services are a highly accessible source of support for people affected by cancer. To date the nature and extent of distress experienced by such callers and their unmet support needs have not been well described. A cross-sectional survey of 354 cancer patients and 336 carers who reported elevated distress on contact with a cancer information service assessed socio-demographic variables; anxiety, depression and somatization; unmet supportive care needs; cancer-specific distress; presenting problems; post-traumatic growth. Adjustment to cancer was most commonly reported; followed by anxiety. In all, 53.4% of patients and 45.2% of carers reached caseness in anxiety, depression or somatization. Carers had higher distress ratings and intrusive thinking compared to patients; whereas patients had higher somatization. For patients, most unmet supportive care needs were psychological; for carers unmet needs were related to health care services and information related to the person diagnosed with cancer. Being single, unemployed, in treatment, having higher initial distress scores, higher intrusion and avoidance predicted poorer outcomes. Information service frameworks should include distress screening and clear triage and referral processes for psychological care.

Pharmaceutical interventions for obesity: a public health perspective.

The prevalence of obesity, a major risk factor for many chronic diseases, has risen in most developed countries over the past several decades. The economic burden for both public and private health care systems is substantial. Although certain non-pharmaceutical interventions have been proven efficacious in specific populations, the lack of scalability has caused many of these programmes to fail in sustainably decreasing the percent of patients who are overweight or obese. The benefits of other interventions, such as pharmaceutical agents, medical devices and surgery, should therefore be carefully considered: this article focuses on the first of these strategies. Various pharmaceutical products have been plagued with safety concerns or patient non-adherence because of unpleasant side effects. Therefore, the need for additional antiobesity drugs that are both safe and effective is considerable. This article discusses the regulatory landscape for the development of new antiobesity compounds in the United States and Europe and considers the ramifications of greater or lesser regulatory burdens.

School-based screening for suicide risk: balancing costs and benefits.

OBJECTIVES: We examined the effects of a scoring algorithm change on the burden and sensitivity of a screen for adolescent suicide risk. METHODS: The Columbia Suicide Screen was used to screen 641 high school students for high suicide risk (recent ideation or lifetime attempt and depression, or anxiety, or substance use), determined by subsequent blind assessment with the Diagnostic Interview Schedule for Children. We compared the accuracy of different screen algorithms in identifying high-risk cases. RESULTS: A screen algorithm comprising recent ideation or lifetime attempt or depression, anxiety, or substance-use problems set at moderate-severity level classed 35% of students as positive and identified 96% of high-risk students. Increasing the algorithm's threshold reduced the proportion identified to 24% and identified 92% of high-risk cases. Asking only about recent suicidal ideation or lifetime suicide attempt identified 17% of the students and 89% of high-risk cases. The proportion of nonsuicidal diagnosis-bearing students found with the 3 algorithms was 62%, 34%, and 12%, respectively. CONCLUSIONS: The Columbia Suicide Screen threshold can be altered to reduce the screen-positive population, saving costs and time while identifying almost all students at high risk for suicide.

Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development.

This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question.

School age outcome of hospitalisation with respiratory syncytial virus infection of prematurely born infants.

BACKGROUND: Hospitalisation due to respiratory syncytial virus (RSV) infection in the first 2 years after birth has been associated with increased healthcare utilisation and associated costs up to 5 years of age in children born prematurely at less than 32 weeks of gestation who developed bronchopulmonary dysplasia (BPD). A study was undertaken to determine whether hospitalisation due to RSV infection in the first 2 years was associated with increased morbidity and lung function abnormalities in such children at school age, and if any effects were influenced by age. METHODS: Healthcare utilisation and cost of care in years 5-7 were reviewed in 147 children and changes in healthcare utilisation between 0 and 8 years were assessed also using results from two previous studies. At age 8-10 years, 77 children had their lung function assessed and bronchial hyper-responsiveness determined. RESULTS: Children hospitalised with RSV infection (n = 25) in the first 2 years had a greater cost of care related to outpatient attendance than those with a non-respiratory or no admission (n = 72) when aged 5-7 years (p = 0.008). At 8-10 years of age, children hospitalised with RSV infection (n = 14) had lower forced expiratory volume in 0.75 s (FEV(0.75)) (p = 0.015), FEV(0.75)/forced vital capacity (p = 0.027) and flows at 50% (p = 0.034) and 75% (p = 0.006) of vital capacity than children hospitalised for non-RSV causes (n = 63). Healthcare utilisation decreased with increasing age regardless of RSV hospitalisation status. CONCLUSIONS: In prematurely born children who had BPD, hospitalisation due to RSV infection in the first 2 years is associated with reduced airway calibre at school age.