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.

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.

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.

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.

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.

Modelling the impact of alcohol consumption on cardiovascular disease mortality for comparative risk assessments: an overview.

BACKGROUND: Although alcohol consumption has long been considered as a risk factor for chronic disease, the relationship to cardiovascular disease (CVD) is complex and involves at least two dimensions: average volume of alcohol consumption and patterns of drinking. The objective of this contribution was to estimate the burden of CVD mortality caused by alcohol consumption. METHODS: Risk assessment modelling with alcohol-attributable CVD mortality as primary outcome. The mortality burden of ischaemic heart disease (IHD) and ischaemic stroke (IS) attributable to alcohol consumption was estimated using attributable-fraction methodology. Relative Risk (RR) data for IHD and IS were obtained from the most comprehensive meta-analyses (except for Russia and surrounding countries where alcohol RR data were obtained from a large cohort study). Age-group specific RRs were calculated, based on large studies. Data on mortality were obtained from the World Health Organization's Global Health Estimates and alcohol consumption data were obtained from the Global Information System on Alcohol and Health. Risk of former drinkers was modelled taking into account global differences in the prevalence of sick quitters among former drinkers. Alcohol-attributable mortality estimates for all other CVD causes except IHD and IS were obtained from the 2014 Global Status Report on Alcohol and Health. RESULTS: An estimated 780,381 CVD deaths (441,893 and 338,490 CVD deaths among men and women respectively) were attributable to alcohol consumption globally in 2012, accounting for 1.4 % of all deaths and 26.6 % of all alcohol-attributable deaths. This is in contrast to the previously estimated 1,128,273 CVD deaths attributable to alcohol consumption globally, and represents a decrease of 30.8 % in alcohol-attributable CVD mortality and of 10.6 % in the global burden of all alcohol-attributable deaths. CONCLUSIONS: When the most comprehensive and recent systematic reviews and meta-analyses are taken as bases, the net impact of alcohol consumption on CVD is lower than previously estimated.

Temporal Changes in Alcohol-Related Morbidity and Mortality in Germany.

AIMS: Trends in morbidity and mortality, fully or partially attributable to alcohol, for adults aged 18-64 were assessed for Germany. METHODS: The underestimation of population exposure was corrected by triangulating survey data with per capita consumption. Alcohol-attributable fractions by sex and two age groups were estimated for major disease categories causally linked to alcohol. Absolute numbers, population rates and proportions relative to all hospitalizations and deaths were calculated. RESULTS: Trends of 100% alcohol-attributable morbidity and mortality over thirteen and eighteen years, respectively, show an increase in rates of hospitalizations and a decrease in mortality rates. Comparisons of alcohol-attributable morbidity including diseases partially caused by alcohol revealed an increase in hospitalization rates between 2006 and 2012. The proportion of alcohol-attributable hospitalizations remained constant. Rates of alcohol-attributable mortality and the proportion among all deaths decreased. CONCLUSIONS: The increasing trend in mortality due to alcohol until the mid-1990s has reversed. The constant proportion of all hospitalizations that were attributable to alcohol indicates that factors such as improved treatment and easier health care access may have influenced the general increase in all-cause morbidity. To further reduce alcohol-related mortality, efforts in reducing consumption and increasing treatment utilization are needed.

Prevalence of and potential influencing factors for alcohol dependence in Europe.

Alcohol use disorders (AUDs), and alcohol dependence (AD) in particular, are prevalent and associated with a large burden of disability and mortality. The aim of this study was to estimate prevalence of AD in the European Union (EU), Iceland, Norway, and Switzerland for the year 2010, and to investigate potential influencing factors. The 1-year prevalence of AD in the EU was estimated at 3.4% among people 18-64 years of age in Europe (women 1.7%, men 5.2%), resulting in close to 11 million affected people. Taking into account all people of all ages, AD, abuse and harmful use resulted in an estimate of 23 million affected people. Prevalence of AD varied widely between European countries, and was significantly impacted by drinking cultures and social norms. Correlations with level of drinking and other drinking variables and with major known outcomes of heavy drinking, such as liver cirrhosis or injury, were moderate. These results suggest a need to rethink the definition of AUDs.

Burden of disease associated with alcohol use disorders in the United States.

BACKGROUND: Alcohol use disorders (AUD) have long been considered to be some of the most disabling mental disorders; however, empirical data on the burden of disease associated with AUD have been sparse. The objective of this article is to quantify the burden of disease (in disability-adjusted life years [DALYs] lost), deaths, years of life lost due to premature mortality (YLL), and years of life lost due to disability (YLD) associated with AUD for the United States in 2005. METHODS: Statistical modeling was based on epidemiological indicators derived from the National Epidemiologic Survey on Alcohol and Related Conditions. Formal consistency analyses were applied. Risk relations were taken from recent meta-analyses and the disability weights from the burden of disease study of the National Institutes of Health. Monte Carlo simulations were used to derive confidence intervals. All analyses were performed by sex and age. Sensitivity analyses were undertaken on key indicators. RESULTS: In the United States in 2005, 65,000 deaths, 1,152,000 YLL, 2,443,000 YLD, and 3,595,000 DALYs were associated with AUD. For individuals 18 years of age and older, AUD were associated with 3% of all deaths (5% for men and 1% for women), and 5% of all YLL (7% for men and 2% for women). The majority of the burden of disease associated with AUD stemmed from YLD, which accounted for 68% of DALYs associated with AUD (66% for men and 74% for women). The youngest age group had the largest proportion of DALYs associated with AUD stemming from YLD. CONCLUSIONS: Using data from a large representative survey (checked for consistency) and by combining these data with the best available evidence, we found that AUD were associated with a larger burden of disease than previously estimated. To reduce this disease burden, implementation of prevention interventions and expansion of treatment are necessary.

The potential impact of increased treatment rates for alcohol dependence in the United Kingdom in 2004.

BACKGROUND: Alcohol consumption has been linked to a considerable burden of disease in the United Kingdom (UK), with most of this burden due to heavy drinking and Alcohol Dependence (AD). However, AD is undertreated in the UK, with only 8% of those individuals with AD being treated in England and only 6% of those individuals with AD being treated in Scotland. Thus, the objective of this paper is to quantify the deaths that would have been avoided in the UK in 2004 if the treatment rate for AD had been increased. METHODS: Data on the prevalence of AD, alcohol consumption, and mortality were obtained from the Adult Psychiatric Morbidity Survey, the Global Information System on Alcohol and Health, and the 2004 Global Burden of Disease study respectively. Data on the effectiveness of pharmacological treatment and Motivational Interviewing/Cognitive Behavioural Therapy were obtained from Cochrane reviews and meta-analyses. Simulations were used to model the number of deaths under different treatment scenarios. Sensitivity analyses were performed to model the effects of Brief Interventions and to examine the effect of using AD prevalence data obtained from the National Institute for Health and Clinical Excellence. RESULTS: In the UK, 320 female and 1,385 male deaths would have been avoided if treatment coverage of pharmacological treatment had been increased to 20%. This decrease in the number of deaths represents 7.9% of all alcohol-attributable deaths (7.0% of all alcohol-attributable deaths for women and 8.1% of all alcohol-attributable deaths for men). If we used lower AD prevalence rates obtained from the National Institute for Health and Clinical Excellence, then treatment coverage of pharmacological treatment in hospitals for 20% of the population with AD would have resulted in the avoidance of 529 deaths in 2004 (99 deaths avoided for women and 430 deaths avoided for men). CONCLUSIONS: Increasing AD treatment in the UK would have led to a large number of deaths being avoided in 2004. Increased AD treatment rates not only impact mortality but also impact upon the large burden of disability and morbidity attributable to AD, as well as the associated social and economic burdens.

The effects of capping the alcohol consumption distribution and relative risk functions on the estimated number of deaths attributable to alcohol consumption in the European Union in 2004.

BACKGROUND: When calculating the number of deaths attributable to alcohol consumption (i.e., the number of deaths that would not have occurred if everyone was a lifetime abstainer), alcohol consumption is most often modelled using a capped exposure distribution so that the maximum average daily consumption is 150 grams of pure alcohol. However, the effect of capping the exposure distribution on the estimated number of alcohol-attributable deaths has yet to be systematically evaluated. Thus, the aim of this article is to estimate the number of alcohol-attributable deaths by means of a capped and an uncapped gamma distribution and capped and uncapped relative risk functions using data from the European Union (EU) for 2004. METHODS: Sex- and disease-specific alcohol relative risks were obtained from the ongoing Global Burden of Disease, Comparative Risk Assessment Study. Adult per capita consumption estimates were obtained from the Global Information System on Alcohol and Health. Data on the prevalence of current drinkers, former drinkers, and lifetime abstainers by sex and age were obtained from various population surveys. Alcohol-attributable deaths were calculated using Alcohol-Attributable Fractions that were calculated using capped (at 150 grams of alcohol) and uncapped alcohol consumption distributions and capped and uncapped relative risk functions. RESULTS: Alcohol-attributable mortality in the EU may have been underestimated by 25.5% for men and 8.0% for women when using the capped alcohol consumption distribution and relative risk functions, amounting to the potential underestimation of over 23,000 and 1,100 deaths in 2004 in men and women respectively. Capping of the relative risk functions leads to an estimated 9,994 and 468 fewer deaths for men and for women respectively when using an uncapped gamma distribution to model alcohol consumption, accounting for slightly less than half of the potential underestimation. CONCLUSIONS: Although the distribution of drinkers in the population and the exact shape of the relative risk functions at large average daily alcohol consumption levels are not known, the findings of our study stress the importance of conducting further research to focus on exposure and risk in very heavy drinkers.

Alcohol consumption, alcohol dependence and related harms in Spain, and the effect of treatment-based interventions on alcohol dependence.

Alcohol consumption in Spain has traditionally followed the Mediterranean drinking pattern, featuring daily drinking with meals, beer as the preferred beverage, and comparatively little drinking to intoxication. Alcohol dependence (AD), one of the most detrimental disorders caused by alcohol, was prevalent in 0.2% of women and 1.2% of men, corresponding to 31,200 women and 186,000 men in Spain with AD in 2005 in the age group of 15 to 64 year. These prevalence estimates of alcohol dependence are likely underestimated due to limitations in the World Mental Health Survey which cannot be fully corrected for; however, the estimates of AD for Spain represent the most accurate and up to date estimates available. Alcohol creates a significant health burden in Spain with 11.3 premature deaths in women per 100,000 aged 15 to 64 years, and 40.9 premature deaths in men per 100,000 in the same age group were due to alcohol consumption (data for 2004). This amounts to 8.4% of all female deaths and 12.3% of all the male deaths in this age group being attributable to alcohol consumption. A large percentage of these harms were due to heavy alcohol consumption and AD. AD is undertreated in Spain, with less than 10% of all people with AD treated. For those who are treated, psychotherapy is the most utilized form of treatment to avoid relapse. If 40% of AD patients in Spain were treated with pharmacological treatment (the most effective treatment method), 2.2% of female and 6.2% of male deaths due to AD would be prevented within one year. Thus by increasing treatment rates is an important means of reducing the alcohol-attributable mortality and health burden in Spain.

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.

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.

Global burden of injuries attributable to alcohol consumption in 2004: a novel way of calculating the burden of injuries attributable to alcohol consumption.

BACKGROUND: Alcohol consumption is a major risk factor for injuries; however, international data on this burden are limited. This article presents new methods to quantify the burden of injuries attributable to alcohol consumption and quantifies the number of deaths, potential years of life lost (PYLL), and disability-adjusted life years (DALYs) lost from injuries attributable to alcohol consumption for 2004. METHODS: Data on drinking indicators were obtained from the Comparative Risk Assessment study. Data on mortality, PYLL, and DALYs for injuries were obtained from the World Health Organization. Alcohol-attributable fractions were calculated based on a new risk modeling methodology, which accounts for average and heavy drinking occasions. 95% confidence intervals (CIs) were calculated using a Monte Carlo simulation method. RESULTS: In 2004, 851,900 (95% CI: 419,400 to 1,282,500) deaths, 19,051,000 (95% CI: 9,767,000 to 28,243,000) PYLL, and 21,688,000 (95% CI: 11,097,000 to 32,385,000) DALYs for people 15 years and older were due to injuries attributable to alcohol consumption. With respect to the total number of deaths, harms to others were responsible for 15.1% of alcohol-attributable injury deaths, 14.5% of alcohol-attributable injury PYLL, and 11.35% of alcohol-attributable injury DALYs. The overall burden of injuries attributable to alcohol consumption corresponds to 17.3% of all injury deaths, 16.7% of all PYLL, and 13.6% of all DALYs caused by injuries, or 1.4% of all deaths, 2.0% of all PYLL, and 1.4% of all DALYs in 2004. CONCLUSIONS: The novel methodology described in this article to calculate the burden of injuries attributable to alcohol consumption improves on previous methodology by more accurately calculating the burden of injuries attributable to one's own drinking, and for the first time, calculates the burden of injuries attributable to the alcohol consumption of others. The burden of injuries attributable to alcohol consumption is large and is entirely avoidable, and policies and strategies to reduce it are recommended.

Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms.

BACKGROUND: The goals of our study are to determine the most appropriate model for alcohol consumption as an exposure for burden of disease, to analyze the effect of the chosen alcohol consumption distribution on the estimation of the alcohol Population- Attributable Fractions (PAFs), and to characterize the chosen alcohol consumption distribution by exploring if there is a global relationship within the distribution. METHODS: To identify the best model, the Log-Normal, Gamma, and Weibull prevalence distributions were examined using data from 41 surveys from Gender, Alcohol and Culture: An International Study (GENACIS) and from the European Comparative Alcohol Study. To assess the effect of these distributions on the estimated alcohol PAFs, we calculated the alcohol PAF for diabetes, breast cancer, and pancreatitis using the three above-named distributions and using the more traditional approach based on categories. The relationship between the mean and the standard deviation from the Gamma distribution was estimated using data from 851 datasets for 66 countries from GENACIS and from the STEPwise approach to Surveillance from the World Health Organization. RESULTS: The Log-Normal distribution provided a poor fit for the survey data, with Gamma and Weibull distributions providing better fits. Additionally, our analyses showed that there were no marked differences for the alcohol PAF estimates based on the Gamma or Weibull distributions compared to PAFs based on categorical alcohol consumption estimates. The standard deviation of the alcohol distribution was highly dependent on the mean, with a unit increase in alcohol consumption associated with a unit increase in the mean of 1.258 (95% CI: 1.223 to 1.293) (R2 = 0.9207) for women and 1.171 (95% CI: 1.144 to 1.197) (R2 = 0. 9474) for men. CONCLUSIONS: Although the Gamma distribution and the Weibull distribution provided similar results, the Gamma distribution is recommended to model alcohol consumption from population surveys due to its fit, flexibility, and the ease with which it can be modified. The results showed that a large degree of variance of the standard deviation of the alcohol consumption Gamma distribution was explained by the mean alcohol consumption, allowing for alcohol consumption to be modeled through a Gamma distribution using only average consumption.

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.

Estimating uncertainty of alcohol-attributable fractions for infectious and chronic diseases.

BACKGROUND: Alcohol is a major risk factor for burden of disease and injuries globally. This paper presents a systematic method to compute the 95% confidence intervals of alcohol-attributable fractions (AAFs) with exposure and risk relations stemming from different sources. METHODS: The computation was based on previous work done on modelling drinking prevalence using the gamma distribution and the inherent properties of this distribution. The Monte Carlo approach was applied to derive the variance for each AAF by generating random sets of all the parameters. A large number of random samples were thus created for each AAF to estimate variances. The derivation of the distributions of the different parameters is presented as well as sensitivity analyses which give an estimation of the number of samples required to determine the variance with predetermined precision, and to determine which parameter had the most impact on the variance of the AAFs. RESULTS: The analysis of the five Asian regions showed that 150 000 samples gave a sufficiently accurate estimation of the 95% confidence intervals for each disease. The relative risk functions accounted for most of the variance in the majority of cases. CONCLUSIONS: Within reasonable computation time, the method yielded very accurate values for variances of AAFs.

Developing a method to derive alcohol-attributable fractions for HIV/AIDS mortality based on alcohol's impact on adherence to antiretroviral medication.

BACKGROUND: Alcohol consumption is causally linked to nonadherence to antiretroviral treatment that in turn causes an increase in HIV/AIDS mortality. This article presents a method to calculate the percentage of HIV/AIDS deaths attributable to alcohol consumption and the associated uncertainty. METHODS: By combining information on risk relations from a number of published sources, we estimated alcohol-attributable fractions (AAFs) of HIV/AIDS in a stepwise procedure. First, we estimated the effect of alcohol consumption on adherence to antiretroviral treatment, and then we combined this estimate with the impact of nonadherence on death. The 95% uncertainty intervals were computed by estimating the variance of the AAFs using Taylor series expansions of one and multiple variables. AAFs were determined for each of the five Global Burden of Disease regions of Africa, based on country-specific treatment and alcohol consumption data from 2005. RESULTS: The effects of alcohol on HIV/AIDS in the African Global Burden of Disease regions range from 0.03% to 0.34% for men and from 0% to 0.17% for women, depending on region and age category. The detrimental effect of alcohol consumption was statistically significant in every region and age category except for the North Africa/Middle East region. CONCLUSIONS: Although the method has its limitations, it was shown to be feasible and provided estimates of the impact of alcohol use on the mortality outcome of HIV/AIDS.

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.