ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

Postsynaptic dorsal column pathway activation during spinal cord stimulation in patients with chronic pain.

Spinal cord stimulation (SCS) treatment for chronic pain relies on the activation of primary sensory fibres ascending to the brain in the dorsal columns. While the efficacy of SCS has been demonstrated, the precise mechanism of action and nature of the fibres activated by stimulation remain largely unexplored. Our investigation in humans with chronic neuropathic pain undergoing SCS therapy, found that post-synaptic dorsal column (PSDC) fibres can be activated synaptically by the primary afferents recruited by stimulation, and axonically by the stimulation pulses directly. Synaptic activation occurred in 9 of the 14 patients analysed and depended on the vertebral level of stimulation. A clear difference in conduction velocities between the primary afferents and the PSDC fibres were observed. Identification of PSDC fibre activation in humans emphasises the need for further investigation into the role they play in pain relief and the sensory response sensation (paraesthesia) experienced by patients undergoing SCS.

Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial.

Importance: Chronic pain is debilitating and profoundly affects health-related quality of life. Spinal cord stimulation (SCS) is a well-established therapy for chronic pain; however, SCS has been limited by the inability to directly measure the elicited neural response, precluding confirmation of neural activation and continuous therapy. A novel SCS system measures the evoked compound action potentials (ECAPs) to produce a real-time physiological closed-loop control system. Objective: To determine whether ECAP-controlled, closed-loop SCS is associated with better outcomes compared with fixed-output, open-loop SCS at 24 months following implant. Design, Setting, and Participants: The Evoke study was a double-blind, randomized, controlled, parallel arm clinical trial with 36 months of follow-up. Participants were enrolled from February 2017 to 2018, and the study was conducted at 13 US investigation sites. SCS candidates with chronic, intractable back and leg pain refractory to conservative therapy, who consented, were screened. Key eligibility criteria included overall, back, and leg pain visual analog scale score of 60 mm or more; Oswestry Disability Index score of 41 to 80; stable pain medications; and no previous SCS. Analysis took place from October 2020 to April 2021. Interventions: ECAP-controlled, closed-loop SCS was compared with fixed-output, open-loop SCS. Main Outcomes and Measures: Reported here are the 24-month outcomes of the trial, which include all randomized patients in the primary and safety analyses. The primary outcome was a reduction of 50% or more in overall back and leg pain assessed at 3 and 12 months (previously published). Results: Of 134 randomized patients, 65 (48.5%) were female and the mean (SD) age was 55.2 (10.6) years. At 24 months, significantly more closed-loop than open-loop patients were responders (≥50% reduction) in overall pain (53 of 67 [79.1%] in the closed-loop group; 36 of 67 [53.7%] in the open-loop group; difference, 25.4% [95% CI, 10.0%-40.8%]; P = .001). There was no difference in safety profiles between groups (difference in rate of study-related adverse events: 6.0 [95% CI, -7.8 to 19.7]). Improvements were also observed in health-related quality of life, physical and emotional functioning, and sleep, in parallel with opioid reduction or elimination. Objective neurophysiological measurements substantiated the clinical outcomes and provided evidence of activation of inhibitory pain mechanisms. Conclusions and Relevance: ECAP-controlled, closed-loop SCS, which elicited a more consistent neural response, was associated with sustained superior pain relief at 24 months, consistent with the 3- and 12-month outcomes.

Electrophysiological Responses in the Human S3 Nerve During Sacral Neuromodulation for Fecal Incontinence.

Intra-operative electrode placement for sacral neuromodulation (SNM) relies on visual observation of motor contractions alone, lacking complete information on neural activation from stimulation. This study aimed to determine whether electrophysiological responses can be recorded directly from the S3 sacral nerve during therapeutic SNM in patients with fecal incontinence, and to characterize such responses in order to better understand the mechanism of action (MOA) and whether stimulation is subject to changes in posture. Eleven patients undergoing SNM were prospectively recruited. A bespoke stimulating and recording system was connected (both intraoperatively and postoperatively) to externalized SNM leads, and electrophysiological responses to monopolar current sweeps on each electrode were recorded and analyzed. The nature and thresholds of muscle contractions (intraoperatively) and patient-reported stimulation perception were recorded. We identified both neural responses (evoked compound action potentials) as well as myoelectric responses (far-field potentials from muscle activation). We identified large myelinated fibers (conduction velocity: 36-60 m/s) in 5/11 patients, correlating with patient-reported stimulation perception, and smaller myelinated fibers (conduction velocity <15 m/s) in 4/11 patients (not associated with any sensation). Myoelectric responses (observed in 7/11 patients) were attributed to pelvic floor and/or anal sphincter contraction. Responses varied with changes in posture. We present the first direct electrophysiological responses recorded from the S3 nerve during ongoing SNM in humans, showing both neural and myoelectric responses. These recordings highlight heterogeneity of neural and myoelectric responses (relevant to understanding MOA of SNM) and confirm that electrode lead position can change with posture.

ECAP-Controlled Closed-Loop Spinal Cord Stimulation Efficacy and Opioid Reduction Over 24-Months: Final Results of the Prospective, Multicenter, Open-Label Avalon Study.

INTRODUCTION: Chronic pain is a major public health concern, as is the associated use of opioid medications, highlighting the importance of alternative treatments, such as spinal cord stimulation (SCS). Here, we present the final 24-month results of the Avalon study, which investigated the use of the first closed-loop SCS system in patients with chronic pain. The system measures the evoked compound action potentials (ECAPs) elicited by each stimulus pulse and drives a feedback loop to maintain the ECAP amplitude near constant. METHODS: Fifty patients were implanted with the Evoke system (Saluda Medical) and followed over 24-months. Pain, quality of life (QOL), function, sleep, and medication use were collected at baseline and each scheduled visit. ECAP amplitudes and programming adjustments were also monitored. RESULTS: At 24 months, responder rates (≥ 50% pain reduction) and high responder rates (≥ 80% pain reduction) for overall pain were 89.5% and 68.4%, respectively, the latter up from 42.2% at 3 months. Significant improvements from baseline were observed in QOL, function, and sleep over the 24 months, including ≥ 80% experiencing a minimally important difference in QOL and > 50% experiencing a clinically significant improvement in sleep. At 24 months, 82.8% of patients with baseline opioid use eliminated or reduced their opioid intake. Over the course of the study, reprogramming need fell to an average of less than once a year. CONCLUSION: Over a 24-month period, the Evoke closed-loop SCS maintained its therapeutic efficacy despite a marked reduction in opioid use and steady decrease in the need for reprogramming.

The Effect of Spinal Cord Stimulation Frequency on the Neural Response and Perceived Sensation in Patients With Chronic Pain.

BACKGROUND: The effect of spinal cord stimulation (SCS) amplitude on the activation of dorsal column fibres has been widely studied through the recording of Evoked Compound Action Potentials (ECAPs), the sum of all action potentials elicited by an electrical stimulus applied to the fibres. ECAP amplitude grows linearly with stimulus current after a threshold, and a larger ECAP results in a stronger stimulus sensation for patients. This study investigates the effect of stimulus frequency on both the ECAP amplitude as well as the perceived stimulus sensation in patients undergoing SCS therapy for chronic back and/or leg pain. METHODS: Patients suffering with chronic neuropathic lower-back and/or lower-limb pain undergoing an epidural SCS trial were recruited. Patients were implanted according to standard practice, having two 8-contact leads (8 mm inter-electrode spacing) which overlapped 2-4 contacts around the T9/T10 interspace. Both lead together thus spanning about three vertebral levels. Neurophysiological recordings were taken during the patient's trial phase at two routine follow-ups using a custom external stimulator capable of recording ECAPs in real-time from all non-stimulating contacts. Stimulation was performed at various vertebral levels, varying the frequency (ranging from 2 to 455 Hz) while all other stimulating variables were kept constant. During the experiments subjects were asked to rate the stimulation-induced sensation (paraesthesia) on a scale from 0 to 10. RESULTS: Frequency response curves showed an inverse relationship between stimulation sensation strength and ECAP amplitude, with higher frequencies generating smaller ECAPs but stronger stimulation-induced paraesthesia (at constant stimulation amplitude). Both relationships followed logarithmic trends against stimulus frequency meaning that the effects on ECAP amplitude and sensation are larger for smaller frequencies. CONCLUSION: This work supports the hypothesis that SCS-induced paraesthesia is conveyed through both frequency coding and population coding, fitting known psychophysics of tactile sensory information processing. The inverse relationship between ECAP amplitude and sensation for increasing frequencies at fixed stimulus amplitude questions common assumptions of monotonic relationships between ECAP amplitude and sensation strength.

Sustained Long-Term Outcomes With Closed-Loop Spinal Cord Stimulation: 12-Month Results of the Prospective, Multicenter, Open-Label Avalon Study.

BACKGROUND: Spinal cord stimulation (SCS) activates the dorsal column fibers using electrical stimuli. Current SCS systems function in fixed-output mode, delivering the same stimulus regardless of spinal cord (SC) activation. OBJECTIVE: To present long-term outcomes of a novel closed-loop SCS system that aims to maintain the SC activation near a set target level and within a therapeutic window for each patient. SC activation is measured through the evoked compound action potential (ECAP) generated by each stimulus pulse. METHODS: Fifty patients with lower back and/or leg pain who were successfully trialed received a permanent system (Evoke; Saluda Medical, Sydney, Australia). Ratings of pain (visual analog scale), quality of life, function, sleep, and medication use were collected at baseline and at each visit. SC activation levels were reported in summary statistics. The therapeutic window for each individual patient was defined as the range of ECAP amplitudes between sensation threshold and uncomfortably strong stimulation. RESULTS: At 12 mo, the proportion of patients with ≥50% relief was 76.9% (back), 79.3% (leg), and 81.4% (overall), and the proportion with ≥80% pain relief was 56.4% (back), 58.6% (leg), and 53.5% (overall). Patients spent a median of 84.9% of their time with stimulation in their therapeutic window, and 68.8% (22/32) eliminated or reduced their opioid intake. Statistically significant improvements in secondary outcomes were observed. CONCLUSION: The majority of patients experienced more than 80% pain relief with stable SC activation, as measured by ECAP amplitude at 12 mo, providing evidence for the long-term effectiveness of the Evoke closed-loop SCS system.

Quantifying harms to others due to alcohol consumption in Germany: a register-based study.

BACKGROUND: The consumption of alcohol increases the risk of drinkers harming others. The extent of alcohol's morbidity and mortality harms to others in Germany in 2014 was estimated for (1) fetal alcohol syndrome (FAS) or fetal alcohol spectrum disorders (FASD) among newborns, (2) road traffic fatalities, and (3) interpersonal violence-related deaths. METHODS: The incidences of FAS and FASD were estimated by means of a meta-analytical approach, combining data on alcohol use during pregnancy and the risk relationship between alcohol consumption during pregnancy and FAS/FASD. In order to estimate alcohol-attributable road traffic fatalities and interpersonal violence due to the drinking of others, an attributable fraction methodology was applied to cause-of-death statistics for road traffic and interpersonal violence-related deaths. RESULTS: For 2014, the incidences of FAS and FASD were estimated at 41 children per 10,000 live births (95% CI 24; 63) and 177 children per 10,000 live births (95% CI 135; 320), or 2930 (95% CI 1720; 4500) and 12,650 (95% CI 9650; 23,310) children, respectively. Furthermore, alcohol was estimated to be responsible for 1214 (95% CI 1141; 1287) third-party road traffic fatalities and 55 (95% CI 46; 64) deaths from interpersonal violence, representing 45.1% of all third-party road traffic fatalities and 14.9% of all interpersonal violence deaths. CONCLUSION: These study's estimates indicate there is a substantial degree of health harm to third parties caused by alcohol in Germany. While more research on harms to others caused by alcohol is needed to provide comprehensive estimates, the results indicate a need for effective prevention.

Are the "Best Buys" for Alcohol Control Still Valid? An Update on the Comparative Cost-Effectiveness of Alcohol Control Strategies at the Global Level.

OBJECTIVE: Evidence on the comparative cost-effectiveness of alcohol control strategies is a relevant input into public policy and resource allocation. At the global level, this evidence has been used to identify so-called best buys for noncommunicable disease prevention and control. This article uses global evidence on alcohol use exposures and risk relations, as well as on intervention costs and impacts, to re-examine the comparative cost-effectiveness of a range of alcohol control strategies. METHOD: A "generalized" approach to cost-effectiveness analysis was adopted. A new modeling tool (OneHealth) was used to estimate the population-level effects of interventions. Interventions that reduce the harmful use of alcohol included brief psychosocial interventions, excise taxes, and the enactment as well as enforcement of restrictions on alcohol marketing, availability, and drink-driving laws. Costs were estimated in international dollars for the year 2010 and effects expressed in healthy life years gained. Analysis was carried out for 16 countries spanning low-, middle-, and high-income settings. RESULTS: Increasing excise taxes has a low cost (

Reduction of mortality following better detection of hypertension and alcohol problems in primary health care in Spain. / Reducción de la mortalidad mediante una mejor detección de la hipertensión y los problemas con el alcohol en atención primaria de salud en España.

Through a simulation study, we estimated the potential effects of better detection of hypertension and improved screening for alcohol problems with subsequent interventions. Results showed that if 50% of Spanish males between 40 and 64 years of age who are currently unaware of their hypertension become aware of their condition and receive the usual treatment, and 50% of these males with hypertension are screened for alcohol and are treated for hazardous drinking or alcohol use disorders, then the percentage of uncontrolled hypertension among men with hypertension decreases from 61.2% to 55.9%, i.e. by 8.6%, with about 1/3 of the effect due to the alcohol intervention. For women, likewise, these interventions would decrease the percentage of women in the same age group with uncontrolled hypertension by 7.4% (about 40% due to the alcohol intervention). The reduction of blood pressure in the population would avoid 412 premature CVD deaths (346 in men, 66 in women) within one year. Therefore, better detection of hypertension and screening for alcohol with subsequent interventions would result in marked reductions of uncontrolled hypertension and CVD mortality.

Se estudian mediante una simulación los potenciales beneficios que puede comportar una mejora en la detección y tratamiento de la hipertensión y de los problemas relacionados con el alcohol. Los resultados muestran que si el 50% de los varones españoles entre 40 y 64 años que desconocen que padecen hipertensión fuesen detectados y recibiesen tratamiento; y si en el 50% de los varones hipertensos se realizase el cribado de consumo alcohólico y recibieran consejo para la reducción de consumos o tratamiento cuando procediera, el porcentaje de hipertensión no controlada descendería del 61,2% al 55,9% (una reducción del 8,6%). Un tercio del efecto es atribuible a la intervención sobre el alcohol. De forma similar, las mismas intervenciones en mujeres de los mismos grupos etarios implicarían una reducción del 7,4% de la hipertensión no controlada (40% debido a la intervención sobre alcohol). La reducción de la presión arterial en la población permitiría evitar 412 muertes prematuras por patología cardiovascular (346 varones y 66 mujeres) anualmente. Una mejor detección de la hipertensión y el cribado de consumos alcohólicos con las consiguientes intervenciones resultarían en una marcada reducción de la hipertensión no controlada y de las muertes de origen cardiovascular.

Global prevalence of alcohol use and binge drinking during pregnancy, and fetal alcohol spectrum disorder.

Alcohol use during pregnancy is an established cause of fetal alcohol spectrum disorder (FASD), with heavy drinking during pregnancy being explicitly linked to fetal alcohol syndrome (FAS). This paper presents recent estimates of the prevalence of: (i) any amount of alcohol use during pregnancy; (ii) one or more binge drinking episode(s) (4 or more standard drinks on a single occasion) during pregnancy; (iii) FAS; and (iv) FASD among the general population globally and by World Health Organization region. It is apparent, based on the presented estimates, that alcohol use and binge drinking occur frequently among pregnant women in many countries and as a result, FASD is a prevalent alcohol-related developmental disability. Urgent action is required around the globe to eliminate prenatal alcohol exposure and prevent future children, adolescents, and adults from having FASD.

Reducción de la mortalidad mediante una mejor detección de la hipertensión y los problemas con el alcohol en atención primaria de salud en España / Reduction of mortality following better detection of hypertension and alcohol problems in primary health care in Spain

Se estudian mediante una simulación los potenciales beneficios que puede comportar una mejora en la detección y tratamiento de la hipertensión y de los problemas relacionados con el alcohol. Los resultados muestran que si el 50% de los varones españoles entre 40 y 64 años que desconocen que padecen hipertensión fuesen detectados y recibiesen tratamiento; y si en el 50% de los varones hipertensos se realizase el cribado de consumo alcohólico y recibieran consejo para la reducción de consumos o tratamiento cuando procediera, el porcentaje de hipertensión no controlada descendería del 61,2% al 55,9% (una reducción del 8,6%). Un tercio del efecto es atribuible a la intervención sobre el alcohol. De forma similar, las mismas intervenciones en mujeres de los mismos grupos etarios implicarían una reducción del 7,4% de la hipertensión no controlada (40% debido a la intervención sobre alcohol). La reducción de la presión arterial en la población permitiría evitar 412 muertes prematuras por patología cardiovascular (346 varones y 66 mujeres) anualmente. Una mejor detección de la hipertensión y el cribado de consumos alcohólicos con las consiguientes intervenciones resultarían en una marcada reducción de la hipertensión no controlada y de las muertes de origen cardiovascular

Through a simulation study, we estimated the potential effects of better detection of hypertension and improved screening for alcohol problems with subsequent interventions. Results showed that if 50% of Spanish males between 40 and 64 years of age who are currently unaware of their hypertension become aware of their condition and receive the usual treatment, and 50% of these males with hypertension are screened for alcohol and are treated for hazardous drinking or alcohol use disorders, then the percentage of uncontrolled hypertension among men with hypertension decreases from 61.2% to 55.9%, i.e. by 8.6%, with about 1/3 of the effect due to the alcohol intervention. For women, likewise, these interventions would decrease the percentage of women in the same age group with uncontrolled hypertension by 7.4% (about 40% due to the alcohol intervention). The reduction of blood pressure in the population would avoid 412 premature CVD deaths (346 in men, 66 in women) within one year. Therefore, better detection of hypertension and screening for alcohol with subsequent interventions would result in marked reductions of uncontrolled hypertension and CVD mortality

The effect of a reduction in alcohol consumption on blood pressure: a systematic review and meta-analysis.

BACKGROUND: Although it is well established that heavy alcohol consumption increases the risk of hypertension, little is known about the effect of a reduction of alcohol intake on blood pressure. We aimed to assess the effect of a reduction in alcohol consumption on change in blood pressure stratified by initial amount of alcohol consumption and sex in adults. METHODS: In this systematic review and meta-analysis, we searched MedLine, Embase, CENTRAL, and ClinicalTrials.gov from database inception up to July 13, 2016, for trials investigating the effect of a change of alcohol consumption on blood pressure in adults using keywords and MeSH terms related to alcohol consumption, blood pressure, and clinical trials, with no language restrictions. We also searched reference lists of identified articles and published meta-analyses and reviews. We included full-text articles with original human trial data for the effect of a change of alcohol consumption on blood pressure in adults, which reported a quantifiable change in average alcohol consumption that lasted at least 7 days and a corresponding change in blood pressure. We extracted data from published reports. We did random-effects meta-analyses stratified by amount of alcohol intake at baseline. All meta-analyses were done with Stata (version 14.1). For the UK, we modelled the effect of a reduction of alcohol consumption for 50% of the population drinking more than two standard drinks per day (ie, 12 g pure alcohol per drink). FINDINGS: 36 trials with 2865 participants (2464 men and 401 women) were included. In people who drank two or fewer drinks per day, a reduction in alcohol was not associated with a significant reduction in blood pressure; however, in people who drank more than two drinks per day, a reduction in alcohol intake was associated with increased blood pressure reduction. Reduction in systolic blood pressure (mean difference -5·50 mm Hg, 95% CI -6·70 to -4·30) and diastolic blood pressure (-3·97, -4·70 to -3·25) was strongest in participants who drank six or more drinks per day if they reduced their intake by about 50%. For the UK, the results would translate into more than 7000 inpatient hospitalisations and 678 cardiovascular deaths prevented every year. INTERPRETATION: Reducing alcohol intake lowers blood pressure in a dose-dependent manner with an apparent threshold effect. Implementation of effective alcohol interventions in people who drink more than two drinks per day would reduce the disease burden from both alcohol consumption and hypertension, and should be prioritised in countries with substantial alcohol-attributable risk. FUNDING: National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH).

Towards new recommendations to reduce the burden of alcohol-induced hypertension in the European Union.

BACKGROUND: Hazardous and harmful alcohol use and high blood pressure are central risk factors related to premature non-communicable disease (NCD) mortality worldwide. A reduction in the prevalence of both risk factors has been suggested as a route to reach the global NCD targets. This study aims to highlight that screening and interventions for hypertension and hazardous and harmful alcohol use in primary healthcare can contribute substantially to achieving the NCD targets. METHODS: A consensus conference based on systematic reviews, meta-analyses, clinical guidelines, experimental studies, and statistical modelling which had been presented and discussed in five preparatory meetings, was undertaken. Specifically, we modelled changes in blood pressure distributions and potential lives saved for the five largest European countries if screening and appropriate intervention rates in primary healthcare settings were increased. Recommendations to handle alcohol-induced hypertension in primary healthcare settings were derived at the conference, and their degree of evidence was graded. RESULTS: Screening and appropriate interventions for hazardous alcohol use and use disorders could lower blood pressure levels, but there is a lack in implementing these measures in European primary healthcare. Recommendations included (1) an increase in screening for hypertension (evidence grade: high), (2) an increase in screening and brief advice on hazardous and harmful drinking for people with newly detected hypertension by physicians, nurses, and other healthcare professionals (evidence grade: high), (3) the conduct of clinical management of less severe alcohol use disorders for incident people with hypertension in primary healthcare (evidence grade: moderate), and (4) screening for alcohol use in hypertension that is not well controlled (evidence grade: moderate). The first three measures were estimated to result in a decreased hypertension prevalence and hundreds of saved lives annually in the examined countries. CONCLUSIONS: The implementation of the outlined recommendations could contribute to reducing the burden associated with hypertension and hazardous and harmful alcohol use and thus to achievement of the NCD targets. Implementation should be conducted in controlled settings with evaluation, including, but not limited to, economic evaluation.

Global Prevalence of Fetal Alcohol Spectrum Disorder Among Children and Youth: A Systematic Review and Meta-analysis.

Importance: Prevalence estimates are essential to effectively prioritize, plan, and deliver health care to high-needs populations such as children and youth with fetal alcohol spectrum disorder (FASD). However, most countries do not have population-level prevalence data for FASD. Objective: To obtain prevalence estimates of FASD among children and youth in the general population by country, by World Health Organization (WHO) region, and globally. Data Sources: MEDLINE, MEDLINE in process, EMBASE, Education Resource Information Center, Cumulative Index to Nursing and Allied Health Literature, Web of Science, PsychINFO, and Scopus were systematically searched for studies published from November 1, 1973, through June 30, 2015, without geographic or language restrictions. Study Selection: Original quantitative studies that reported the prevalence of FASD among children and youth in the general population, used active case ascertainment or clinic-based methods, and specified the diagnostic guideline or case definition used were included. Data Extraction and Synthesis: Individual study characteristics and prevalence of FASD were extracted. Country-specific random-effects meta-analyses were conducted. For countries with 1 or no empirical study on the prevalence of FASD, this indicator was estimated based on the proportion of women who consumed alcohol during pregnancy per 1 case of FASD. Finally, WHO regional and global mean prevalence of FASD weighted by the number of live births in each country was estimated. Main Outcomes and Measures: Prevalence of FASD. Results: A total of 24 unique studies including 1416 unique children and youth diagnosed with FASD (age range, 0-16.4 years) were retained for data extraction. The global prevalence of FASD among children and youth in the general population was estimated to be 7.7 per 1000 population (95% CI, 4.9-11.7 per 1000 population). The WHO European Region had the highest prevalence (19.8 per 1000 population; 95% CI, 14.1-28.0 per 1000 population), and the WHO Eastern Mediterranean Region had the lowest (0.1 per 1000 population; 95% CI, 0.1-0.5 per 1000 population). Of 187 countries, South Africa was estimated to have the highest prevalence of FASD at 111.1 per 1000 population (95% CI, 71.1-158.4 per 1000 population), followed by Croatia at 53.3 per 1000 population (95% CI, 30.9-81.2 per 1000 population) and Ireland at 47.5 per 1000 population (95% CI, 28.0-73.6 per 1000 population). Conclusions and Relevance: Globally, FASD is a prevalent alcohol-related developmental disability that is largely preventable. The findings highlight the need to establish a universal public health message about the potential harm of prenatal alcohol exposure and a routine screening protocol. Brief interventions should be provided, where appropriate.

Estimating the harms and costs of cannabis-attributable collisions in the Canadian provinces.

INTRODUCTION: In 2012, 10% of Canadians used cannabis and just under half of those who use cannabis were estimated to have driven under the influence of cannabis. Substantial evidence has accumulated to indicate that driving after cannabis use increases collision risk significantly; however, little is known about the extent and costs associated with cannabis-related traffic collisions. This study quantifies the costs of cannabis-related traffic collisions in the Canadian provinces. METHODS: Province and age specific cannabis-attributable fractions (CAFs) were calculated for traffic collisions of varying severity. The CAFs were applied to traffic collision data in order to estimate the total number of persons involved in cannabis-attributable fatal, injury and property damage only collisions. Social cost values, based on willingness-to-pay and direct costs, were applied to estimate the costs associated with cannabis-related traffic collisions. The 95% confidence intervals were calculated using Monte Carlo methodology. RESULTS: Cannabis-attributable traffic collisions were estimated to have caused 75 deaths (95% CI: 0-213), 4407 injuries (95% CI: 20-11,549) and 7794 people (95% CI: 3107-13,086) were involved in property damage only collisions in Canada in 2012, totalling $1,094,972,062 (95% CI: 37,069,392-2,934,108,175) with costs being highest among younger people. DISCUSSION: The cannabis-attributable driving harms and costs are substantial. The harm and cost of cannabis-related collisions is an important factor to consider as Canada looks to legalize and regulate the sale of cannabis. This analysis provides evidence to help inform Canadian policy to reduce the human and economic costs of drug-impaired driving.

Life-time risk of mortality due to different levels of alcohol consumption in seven European countries: implications for low-risk drinking guidelines.

BACKGROUND AND AIMS: Low-risk alcohol drinking guidelines require a scientific basis that extends beyond individual or group judgements of risk. Life-time mortality risks, judged against established thresholds for acceptable risk, may provide such a basis for guidelines. Therefore, the aim of this study was to estimate alcohol mortality risks for seven European countries based on different average daily alcohol consumption amounts. METHODS: The maximum acceptable voluntary premature mortality risk was determined to be one in 1000, with sensitivity analyses of one in 100. Life-time mortality risks for different alcohol consumption levels were estimated by combining disease-specific relative risk and mortality data for seven European countries with different drinking patterns (Estonia, Finland, Germany, Hungary, Ireland, Italy and Poland). Alcohol consumption data were obtained from the Global Information System on Alcohol and Health, relative risk data from meta-analyses and mortality information from the World Health Organization. RESULTS: The variation in the life-time mortality risk at drinking levels relevant for setting guidelines was less than that observed at high drinking levels. In Europe, the percentage of adults consuming above a risk threshold of one in 1000 ranged from 20.6 to 32.9% for women and from 35.4 to 54.0% for men. Life-time risk of premature mortality under current guideline maximums ranged from 2.5 to 44.8 deaths per 1000 women in Finland and Estonia, respectively, and from 2.9 to 35.8 deaths per 1000 men in Finland and Estonia, respectively. If based upon an acceptable risk of one in 1000, guideline maximums for Europe should be 8-10 g/day for women and 15-20 g/day for men. CONCLUSIONS: If low-risk alcohol guidelines were based on an acceptable risk of one in 1000 premature deaths, then maximums for Europe should be 8-10 g/day for women and 15-20 g/day for men, and some of the current European guidelines would require downward revision.

The relationship between different dimensions of alcohol use and the burden of disease-an update.

BACKGROUND AND AIMS: Alcohol use is a major contributor to injuries, mortality and the burden of disease. This review updates knowledge on risk relations between dimensions of alcohol use and health outcomes to be used in global and national Comparative Risk Assessments (CRAs). METHODS: Systematic review of reviews and meta-analyses on alcohol consumption and health outcomes attributable to alcohol use. For dimensions of exposure: volume of alcohol use, blood alcohol concentration and patterns of drinking, in particular heavy drinking occasions were studied. For liver cirrhosis, quality of alcohol was additionally considered. For all outcomes (mortality and/or morbidity): cause of death and disease/injury categories based on International Classification of Diseases (ICD) codes used in global CRAs; harm to others. RESULTS: In total, 255 reviews and meta-analyses were identified. Alcohol use was found to be linked causally to many disease and injury categories, with more than 40 ICD-10 three-digit categories being fully attributable to alcohol. Most partially attributable disease categories showed monotonic relationships with volume of alcohol use: the more alcohol consumed, the higher the risk of disease or death. Exceptions were ischaemic diseases and diabetes, with curvilinear relationships, and with beneficial effects of light to moderate drinking in people without heavy irregular drinking occasions. Biological pathways suggest an impact of heavy drinking occasions on additional diseases; however, the lack of medical epidemiological studies measuring this dimension of alcohol use precluded an in-depth analysis. For injuries, except suicide, blood alcohol concentration was the most important dimension of alcohol use. Alcohol use caused marked harm to others, which has not yet been researched sufficiently. CONCLUSIONS: Research since 2010 confirms the importance of alcohol use as a risk factor for disease and injuries; for some health outcomes, more than one dimension of use needs to be considered. Epidemiological studies should include measurement of heavy drinking occasions in line with biological knowledge.