Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin.

BACKGROUND: Inflammation contributes to the pathophysiology of major depressive disorder (MDD), and anti-inflammatory strategies might therefore have therapeutic potential. This trial aimed to determine whether adjunctive aspirin or rosuvastatin, compared with placebo, reduced depressive symptoms in young people (15-25 years). METHODS: YoDA-A, Youth Depression Alleviation with Anti-inflammatory Agents, was a 12-week triple-blind, randomised, controlled trial. Participants were young people (aged 15-25 years) with moderate to severe MDD (MADRS mean at baseline 32.5 ± 6.0; N = 130; age 20.2 ± 2.6; 60% female), recruited between June 2013 and June 2017 across six sites in Victoria, Australia. In addition to treatment as usual, participants were randomised to receive aspirin (n = 40), rosuvastatin (n = 48), or placebo (n = 42), with assessments at baseline and weeks 4, 8, 12, and 26. The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: At the a priori primary endpoint of MADRS differential change from baseline at week 12, there was no significant difference between aspirin and placebo (1.9, 95% CI (- 2.8, 6.6), p = 0.433), or rosuvastatin and placebo (- 4.2, 95% CI (- 9.1, 0.6), p = 0.089). For rosuvastatin, secondary outcomes on self-rated depression and global impression, quality of life, functioning, and mania were not significantly different from placebo. Aspirin was inferior to placebo on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) at week 12. Statins were superior to aspirin on the MADRS, the Clinical Global Impressions Severity Scale (CGI-S), and the Negative Problem Orientation Questionnaire scale (NPOQ) at week 12. CONCLUSIONS: The addition of either aspirin or rosuvastatin did not to confer any beneficial effect over and above routine treatment for depression in young people. Exploratory comparisons of secondary outcomes provide limited support for a potential therapeutic role for adjunctive rosuvastatin, but not for aspirin, in youth depression. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12613000112763. Registered on 30/01/2013.

Changing predictors of statin initiation in US women over two decades.

PURPOSE: To describe changing roles of predictors of statin initiation before and after incident coronary heart disease, and before and after publication of National Cholesterol Education Program Adult Treatment Panel-III (ATP-III) guidelines in a cohort of US women. METHODS: We identified 34 382 women enrolled into the Women's Health Study from 1993 to 1995 and followed up until 2012. Proportions of previous nonusers initiating statins were described over time. We used multivariable linear regression models to estimate adjusted initiation proportion differences (IPDs) for initiation overall, separately before and after incident coronary heart disease, and separately for ATP-II and ATP-III time periods. RESULTS: Key predictors of initiation overall were self-reported total cholesterol, and previous incident coronary heart disease, cerebrovascular disease, and diabetes. Adjusted IPDs (percentage) for total cholesterol > 240 vs <200 mg/dL were 7.5 (95% confidence interval [CI], 7.0-8.0) and 9.3 (95% CI, 8.7-9.9) during ATP-II and ATP-III time periods, respectively. Adjusted IPDs in women with diabetes were 7.0 (95% CI, 6.3-7.8) and 11.9 (95% CI, 6.7-17.0) for primary and secondary prevention, respectively, and 3.1 (95% CI, 2.1-4.0) and 9.2 (95% CI 8.2-10.2) for before and after ATP-III, respectively. CONCLUSIONS: Secular trends reflected evolution toward risk factor-based treatment indications for statin initiation with increased initiation among diabetics and women with normal and borderline cholesterol. The role of serum cholesterol changed over time, though the character was scale (multiplicative vs additive) dependent. In pharmacoepidemiologic studies of statins, strength of confounding by important variables sometimes unmeasured in claims data, such as cholesterol level, may be calendar time dependent.

Comparison of application of 2013 ACC/AHA guideline and 2011 European Society of Cardiology guideline for the management of dyslipidemias for primary prevention in a Turkish cohort.

OBJECTIVE: Atherosclerotic cardiovascular disease is a major global cause of death. The common approach in primary prevention of cardiovascular disease is to identify patients at high risk for cardiovascular disease. This article analyzes and compares the application of 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline and the 2011 European Society of Cardiology (ESC) guideline for the management of dyslipidemias for primary prevention in Turkish population. METHODS: The study included 833 patients (482 women and 351 men). Risk scores were calculated according to both guidelines and indications for statin treatment were determined according to sex and age group. Variables are presented as mean±SD or median with interquartile range for continuous data and as proportions for categorical data. Variables were analyzed by unpaired t-test, Mann-Whitney U test, chi-square or Fischer's exact test as appropriate. RESULTS: The ACC/AHA would suggest statin treatment in 415 patients out of 833 (49.5%), while ESC would recommend statin for 193 patients out of 833 (23.1%)(p<0.001). Statins would be recommended for 40.4% of women and 62.6% of men for primary prevention by the ACC/AHA, while this figure was 12% for women and 38.4% for men according to the ESC guideline (p<0.001 for both). CONCLUSION: When compared to the ESC guideline, the ACC/AHA guideline suggests augmented statin treatment for primary prevention in Turkish population.

Trends in Statin Use in Seniors 1999 to 2013: Time Series Analysis.

PURPOSE: To examine HMG-CoA reductase inhibitor (statin) drug dispensing patterns to Nova Scotia Seniors' Pharmacare program (NSSPP) beneficiaries over a 14-year period in response to: 1) rosuvastatin market entry in 2003, 2) JUPITER trial publication in 2008, and 3) generic atorvastatin availability in 2010. METHODS: All NSSPP beneficiaries who redeemed at least one prescription for a statin from April 1, 1999 to March 31, 2013 were included. Aggregated, anonymous monthly prescription counts were extracted by the Nova Scotia Department of Health and Wellness (Nova Scotia, Canada) and changes in dispensing patterns of statins were measured. Data were analyzed using descriptive analyses and interrupted time series methods. RESULTS: The percentage of NSSPP beneficiaries dispensed any statin increased from 5.3% in April 1999 to 20.7% in March 2013. In 1999, most NSSPP beneficiaries were dispensed either simvastatin (29.5%) or atorvastatin (28.7%). When rosuvastatin was added to the NSSPP Formulary in August 2003, prescriptions dispensed for simvastatin, lovastatin, pravastatin, and fluvastatin declined significantly (slope change, -0.0027; 95% confidence interval (CI), (-0.0046, -0.0009)). This significant decline continued following the publication of JUPITER (level change, -0.1974; 95% CI, (-0.2991, -0.0957)) and the availability of generic atorvastatin (level change, -0.2436; 95% CI, (-0.3314, -0.1558)). Atorvastatin was not significantly affected by any of the three interventions, although it maintained an overall decreasing trend. Only upon the availability of generic atorvastatin did the upward trend in rosuvastatin use decrease significantly (slope change, -0.0010, 95% CI, (-0.0015, -0.0005)). CONCLUSIONS: The type and rate of statins dispensed to NSSPP beneficiaries changed from 1999 to 2013 in response to the availability of new agents and publication of the JUPITER trial. The overall proportion of NSSPP beneficiaries dispensed a statin increased approximately 4-fold during the study period. In 2013, rosuvastatin was the most commonly dispensed statin (44.1%) followed by atorvastatin (39.1%).

Prescribing patterns, adherence and LDL-cholesterol response of type 2 diabetes patients initiating statin on low-dose versus standard-dose treatment: a descriptive study.

AIMS: The aim of this study was to describe and compare treatment modifications and discontinuation, adherence levels and response to treatment in patients with type 2 diabetes initiating on low-dose vs. standard-dose statin treatment. METHODS: A 2-year follow-up cohort study was performed using data from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database in patients with type 2 diabetes initiating statin treatment between January 2007 and December 2012. First, we determined whether there were differences in treatment modifications and discontinuation after statin initiation between patients starting on a low-dose vs. standard-dose. Second, we looked at differences in adherence and LDL-cholesterol response after 2 years follow-up between these groups. RESULTS: Around 22% of patients initiated statin treatment on a dose lower than recommended. More than half of them remained on a low dose during a 2-year follow-up period, whereas less than 15% received a dose increase. Of the patients initiating on standard-dose, also more than half remained on the same treatment during this period, whereas 8% received a dose decrease without subsequent increase. Over 25% of patients starting on low-dose or standard-dose treatment discontinued treatment, often within the first 180 days after initiation or after a first treatment change. Patients on low-dose treatment had lower adherence levels and were less likely to have adequate LDL-cholesterol response compared with patients on standard-dose after 2 years follow-up. CONCLUSIONS: Current patterns of statin treatment in patients with type 2 diabetes are suboptimal, with discontinuation, inadequate adherence levels and lack of treatment intensification seen in those who had inadequate LDL-cholesterol response after 2 years of follow-up. Patients starting on low-dose had more treatment modifications, discontinuation and adherence problems as compared with those starting on standard-dose treatment, which calls for a closer look at the rationale of starting patients on low-dose statin treatment.

Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and low-income countries: an analysis of the PURE study data.

BACKGROUND: WHO has targeted that medicines to prevent recurrent cardiovascular disease be available in 80% of communities and used by 50% of eligible individuals by 2025. We have previously reported that use of these medicines is very low, but now aim to assess how such low use relates to their lack of availability or poor affordability. METHODS: We analysed information about availability and costs of cardiovascular disease medicines (aspirin, ß blockers, angiotensin-converting enzyme inhibitors, and statins) in pharmacies gathered from 596 communities in 18 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. Medicines were considered available if present at the pharmacy when surveyed, and affordable if their combined cost was less than 20% of household capacity-to-pay. We compared results from high-income, upper middle-income, lower middle-income, and low-income countries. Data from India were presented separately given its large, generic pharmaceutical industry. FINDINGS: Communities were recruited between Jan 1, 2003, and Dec 31, 2013. All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low-income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0·14% of households in high-income countries (14 of 9934 households), 25% of upper middle-income countries (6299 of 24,776), 33% of lower middle-income countries (13,253 of 40,023), 60% of low-income countries (excluding India; 1976 of 3312), and 59% households in India (9939 of 16,874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio [OR] 0·16, 95% CI 0·04-0·57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0·16, 0·04-0·55). INTERPRETATION: Secondary prevention medicines are unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle-income, and low-income countries, which have very low use of these medicines. Improvements to the availability and affordability of key medicines is likely to enhance their use and help towards achieving WHO's targets of 50% use of key medicines by 2025. FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

Algoritmo de actuación en la farmacia comunitaria para optimizar la utilización de estatinas / Algorithm of proceedings in the community pharmacy to optimize the use of statins

Introdución: Pacientes en tratamiento con estatinas suelen presentar numerosos problemas relacionados con la medicación, no solo de seguridad sino también de necesidad y de efectividad. Objetivo: Proponer un algoritmo de actuación del farmacéutico comunitario en la dispensación de estatinas para optimizar la utilización de este grupo de medicamentos. Material y métodos: Recogida de datos (cuestionario) en farmacia comunitaria (3 meses) en pacientes con prescripción de estatinas. Determinación de presión arterial, IMC, perímetro abdominal y cálculo del riesgo cardiovascular (RCV) (tablas SCORE y REGICOR). Resultados: Se incluyen 48 pacientes. Se evidencia falta de control del colesterol (25%) y de la presión arterial (48%). Se deriva al médico el 21% que tiene la presión arterial >140/90 mm Hg y no están diagnosticados. También se derivan al médico cuando la falta de adherencia no es la causa de la inefectividad (29%) o cuando no tienen RCV alto (38%) que justifique la necesidad de estatina. En los restantes se detecta necesidad de información/educación y se interviene. Se han realizado un total de 145 intervenciones en el 90% de pacientes incluidos. En base a estos resultados se propone un algoritmo simplificado de actuación en la dispensación de estatinas. Conclusiones: El grupo de pacientes tratados con estatinas es susceptible de actuación por parte del farmacéutico comunitario, que, mediante un algoritmo de actuación sencillo, puede detectar durante la dispensación numerosos problemas relacionados con la medicación e intervenir para mejorar el uso y la efectividad de estos fármacos

Introduction: Patients taking statins often have many problems related to the medication, not only with reference to safety but also to necessity and effectiveness. Objective: To propose an algorithm of proceedings for the community pharmacist when dispensing statins so as to optimize the use of this group of drugs. Material and methods: Data collection (questionnaire) in a community pharmacy (3 months) with patients who receive statins. Determination of blood pressure (BP), body mass index (BMI) and waist circumference, and calculation of cardiovascular risk (CVR) by SCORE and REGICOR tables was done. Results: 48 patients were included. It was shown a lack of control of cholesterol (25%) and blood pressure (48%). 21% of the patients were derived to the physician having blood pressure >140/90 mm Hg and were undiagnosed. When lack of adherence was not the cause of ineffectiveness (29%) or had low CVR (38%) they also were derived to the physician. In the remaining patients, lack of health information/education was detected and provided. Altogether, there have been a total of 145 interventions in 90% of patients included in the study. Based on these results, a simplified algorithm for dispensing statins is proposed. Conclusions:The community pharmacist, through the use of a simple algorithm during the dispensation of statins, can detect many problems associated with medication and intervene to improve the use and effectiveness of these drugs

Behind-the-counter statins: a silver bullet for reducing costs and increasing access?

OBJECTIVE: To examine how the 2004 introduction of behind-the-counter (BTC) simvastatin in the United Kingdom affected utilization, prices, and expenditures. DATA SOURCES/STUDY SETTING: Secondary data on simvastatin utilization, prices, and expenditures between 1997 and 2007 in the United Kingdom and four other countries. STUDY DESIGN: We used a difference-in-differences approach to estimate how the introduction of BTC simvastatin affected utilization, prices, and expenditures. This approach compares outcomes in the United Kingdom before and after the introduction of BTC simvastatin, using outcomes in countries where the drug remained prescription only to control for possible confounders. DATA COLLECTION/EXTRACTION METHODS: Data on simvastain utilization, prices, and expenditures between 1997 and 2007 in the United Kingdom and four other countries were obtained from an outside vendor. PRINCIPAL FINDINGS: The introduction of BTC simvastatin in the United Kingdom led to a significant increase in utilization of simvastatin and a significant decline in expenditures for simvastatin purchases. Our results are robust to alternate model specifications. CONCLUSIONS: Behind-the-counter statins have the potential to simultaneously increase use of statins and lower expenditures.

Ongoing measures to enhance the efficiency of prescribing of proton pump inhibitors and statins in The Netherlands: influence and future implications.

BACKGROUND: Multiple reforms have recently been introduced in The Netherlands to improve prescribing efficiency. These include preference pricing policies for multiple sourced products, guidelines, and quality and efficiency targets, as well as regular pharmacotherapy meetings. OBJECTIVES: Assess the influence of these multiple measures on prescribing efficiency. METHODS: Retrospective observational study of all reimbursed prescriptions for proton pump inhibitors and statins between 2000 and 2010 using the Genees-en hulpmiddelen Informatie Project (Health Insurance) database. Utilization measured in defined daily doses. Narrative review of reforms. RESULTS: Reimbursed expenditure for the proton pump inhibitors fell by 58% in 2010 versus 2000 despite a threefold increase in utilization, helped by increasing utilization of generic omeprazole at only 2% of the prepatent loss price in 2010. Similarly, reimbursed expenditure for the statins fell by 14% in 2010 versus 2000 despite a 3.8-fold increase in utilization. Again, this was helped by increasing utilization of generic simvastatin at only 2% of the prepatent loss originator price. CONCLUSION: Multiple supply and demand measures, including the preference pricing policy, appear to have appreciably enhanced proton pump inhibitor and statin prescribing efficiency, providing examples to other countries.

Pattern of statins' utilization at Ramathobodi Hospital, 2005 to 2007.

BACKGROUND: The use of statins at Ramathibodi, a teaching hospital, has been rising rapidly OBJECTIVE: Determine how price, volume, and drug mix (use of five brands and one generic) affect expenditure. MATERIAL AND METHOD: Dispensing records of the six statins were retrieved from database and analyzed for factors contributing to increased drug expense. RESULTS: Overall, statins' expenditure rose 35.6% and 6.4% in 2006 and 2007 respectively, mainly from civil servant outpatients who are more likely to be prescribed with brand drugs, even among new patients. In all schemes, volume effect was positive, more people use statins, and each one used a larger quantity of drug in 2007 than in 2005. The price effect was negative. Drug mix effect indicated that there was a shift from higher to lower priced drugs in capitation scheme and from lower to higher priced original drugs in a fee-for-service scheme. CONCLUSION: There is a trend of more statins utilization but with a different pattern of drug prescribed between health schemes and possible drug over-prescribed in some patients. However indication for statin use was not studied, which needs to be considered. With high use of original drugs, effective policy initiative to promote generic drug use should be implemented in order to efficiently use the limited health care resources.

Targeted versus global approaches to the management of hypercholesterolaemia.

AIMS: The role of statins in secondary prevention of cardiovascular disease is well established. However, there is debate about the most effective approach to primary prevention. This study simulated the effects of directed versus global approaches for intervention on coronary heart disease (CHD) event rates. METHODS: A primary prevention population was generated by computer simulation derived from data from the National Health Survey for England. The efficacy of reductions in cholesterol, treatment to cardiovascular risk targets and effects of phytosterols or statins were assessed. RESULTS: A 0.5 mmol/L reduction in population total cholesterol would result in a 10.4% reduction in CHD events, while 1.0 mmol/L, 1.5 mmol/L and 2.0 mmol/L reductions would achieve 21.0%, 30.6% and 41.9% reductions respectively. In statin-based cardiovascular risk targeted strategies, use of simvastatin 40 mg would result in 1.8% reduction by UK National Service Framework targets of 30%/decade CHD risk and 7.2% reduction in events for a 20%/decade target assuming perfect adherence. Similarly, aggressive primary prevention with 40 mg atorvastatin would result in a 2.5% or 10% reduction in events. Universal use of 10 mg simvastatin following an over-the-counter approach would result in a 25% reduction in CHD events. In contrast, whole population consumption of sitostanol/sitosterol products would result in 11.8% reduction. CONCLUSION: Targeting and treating high-risk individuals may be beneficial for them and rewarding for medical practitioners. However, this approach has minimal effects on the population burden of atherosclerotic disease. This study suggests that universal therapy with phytosterols and/or wider availability of statins has the potential to dramatically decrease rates of CHD.

Drug licenses: a new model for pharmaceutical pricing.

High drug prices are a major barrier to patients' access to drugs and compliance with treatment. Yet low drug prices are often argued to provide inadequate incentives for innovation. We propose a drug-licensing model for health care, which has the promise of increasing drug use without altering patients' out-of-pocket spending, health plans' costs, or drug companies' profits. In such a model, people would purchase annual drug licenses that would guarantee unfettered access to a clinically optimal number of prescriptions over the course of a year. Using the example of statins, we illustrate how such a model could be implemented.

Impact of prescription size on statin adherence and cholesterol levels.

BACKGROUND: Therapy with 3-Hydroxy-3-methylglutaryl Co-enzyme A reductase inhibitors (statins) improve outcomes in a broad spectrum of patients with hyperlipidemia. However, effective therapy requires ongoing medication adherence; restrictive pharmacy policies may represent a barrier to successful adherence, particularly among vulnerable patients. In this study we sought to assess the relationship between the quantity of statin dispensed by the pharmacy with patient adherence and total cholesterol. METHODS: We analyzed a cohort of 3,386 patients receiving more than one fill of statin medications through an integrated, inner-city health care system between January 1, 2000 and December 31, 2002. Our measure of adherence was days of drug acquisition divided by days in the study for each patient, with adequate adherence defined as > or = 80%. Log-binomial regression was used to determine the relative risk of various factors, including prescription size, on adherence. We also assessed the relationship between adherence and total cholesterol using multiple linear regression. RESULTS: After controlling for age, gender, race, co-payment, comorbidities, and insurance status, patients who obtained a majority of fills as 60-day supply compared with 30-day supply were more likely to be adherent to their statin medications (RR 1.41, 95% CI 1.28-1.55, P < 0.01). We found that statin non-adherence less than 80% was predictive of higher total serum cholesterol by 17.23 +/- 1.64 mg/dL (0.45 +/- 0.04 mmol/L). CONCLUSION: In a healthcare system serving predominantly indigent patients, the provision of a greater quantity of statin medication at each prescription fill contributes to improved adherence and greater drug effectiveness.

Efecto de la atorvastatina en la expresión de Fas (CD95/Apo-1) en tejido cerebral normal e isquémico / Effect of atorvastatin on Fas (CD95/Apo-1) expression in normal or ischemic brain

Introducción: La fisiopatología de la isquemia cerebral involucramúltiples eventos, entre ellos, importantes mecanismos apoptóticos dondela proteína Fas es expresada. Las estatinas poseen efectos neuroprotectoresindependientes de sus acciones hipolipemiantes.Objetivo: Estudiar el efecto de la atorvastatina sobre la expresión deFas en tejido cerebral isquémico.Material y métodos: Quince ratas Sprague Dawley, machos, fuerondistribuidas en tres grupos (n = 5): un grupo control sin isquemia cerebral ydos experimentales (1 y 2) sometidos a isquemia cerebral global inducidapor paro respiratorio con D-tubocurarina. El grupo experimental 2 recibióatorvastatina durante las dos semanas previas a la inducción de isquemia(10 mg/kg/día, v.o.). Se realizó inmunohistoquímica por el sistema Avidina-Biotina-Peroxidasa a muestras de la corteza cerebral frontal.Resultados: Fas se expresó en el 38% de las células del tejido noisquémico. Esta expresión aumentó en el tejido cerebral isquémico a63% (P = 0,0003). La atorvastatina inhibió significativamente la expresiónde Fas en tejido cerebral isquémico en un 23% (P = 0,0007).Conclusiones: La atorvastatina disminuyó la expresión de Fas enisquemia cerebral, contribuyendo posiblemente a una inhibición de laapoptosis. Este mecanismo de acción pudiera explicar parte de su efectoneuroprotector. Estos hallazgos sugieren que la atorvastatina pudieraresultar beneficiosa en la prevención primaria de los ataques isquémicos

Background: The physiopathology of the brain ischemia includes many events such as important apoptotic mechanisms were Fas protein is expressed. Statins have neuroprotector effects that are independent of their blood lipid reducing actions. Objective: Study of the atorvastatin effect on Fas expression in brain ischemia. Material and methods: Fifteen male Sprague Dawley rats were distributed in three groups (n=5), the control group without cerebral ischemia, in the other two experimental groups (1 and 2) a global cerebral ischemia were induced by respiratory arrest (D-tubocurarin). Experimental group 2 was treated with atorvastatin (10 mg/Kg/d, p.o.) during two weeks before the induction of the ischemia. Inmunohistochemical study of brain frontal specimens was done by the Avidin- Biotin-Peroxidase method. Results: Fas was expressed in 38% of cells in non ischemic brain, this expression increased to 63% of cells in inchemic brain samples (P = 0.0003) Fas expression in ischemia was significantly inhibited by atorvastatin in 23% (P = 0.0007) Conclusions: Atorvastatin decreased Fas expression in ischemic brain. This fact must be taken into account to explain the atorvastatin neuroprotection and suggests the potential use such as primary prevention for ischemic attacks