The most fundamental law of economics links the price of a product to the demand for that product. Accordingly, increases in the monetary price of alcohol  would be expected to lower alcohol consumption and its adverse consequences. Studies investigating such a relationship found that alcohol prices were one factor influencing alcohol consumption among youth and young adults. Other studies determined that increases in the total price of alcohol can reduce drinking and driving and its consequences among all age groups; lower the frequency of diseases, injuries, and deaths related to alcohol use and abuse; and reduce alcohol-related violence and other crime. Since the early 1980s, a growing number of economists have examined the impact of the price of alcoholic beverages on alcohol consumption. Other studies have evaluated the effects of price on various outcomes related to alcohol consumption, including nonfatal and fatal motor vehicle crashes and other injuries, liver cirrhosis and other alcohol-related mortality, and violence and other crime. This research, which has used a wide variety of data, generally has concluded that increases in the prices of alcoholic beverages lead to reductions in drinking and heavy drinking as well as in the consequences of alcohol use and abuse. This conclusion concurs with a fundamental law of economics called the downward sloping demand curve, which states that as the price of a product rises, the quantity demanded of that product falls. Since the price of alcohol can be manipulated through excise tax policies, the findings regarding the relationship between alcohol price and alcohol consumption clearly are relevant for policy-makers interested in reducing alcohol consumption and its adverse consequences. Indeed, Federal, State, and local governments have implemented many policies to combat alcohol abuse in the past two decades see .per se illegal to drive either with blood alcohol concentrations (BACs) well below those considered the legal limit of intoxication in adults  or, in some States, with any measurable BACs. These measures have made it more difficult for youths to obtain alcohol and have increased the expected legal costs of drinking by imposing fines for the possession of alcohol and for drinking and driving by underage people.The major policy element of U.S. programs to deter teenage and young adult drinking has been to increase State minimum legal drinking ages (MLDAs). This trend began in 1976 with the increase in the MLDA in Minnesota from 18 to 19 years of age. An additional 27 States had increased their MLDAs by the time Congress passed the Federal Uniform Drinking Age Act of 1984. This Act pressured all States into raising the MLDA to 21 years by withholding part of their Federal highway funding if they failed to comply. After an unsuccessful challenge to the law’s constitutionality, all States raised their MLDAs to 21 years by July 1988.Other policies in the campaign to discourage alcohol abuse have targeted all drinkers, and some measures have targeted abusive drinkers. For example, Public Law 100–690 mandated that, beginning in November 1989, a label warning of the dangers of drinking and driving, alcohol consumption during pregnancy, and other (unspecified) health consequences of drinking appear on all alcoholic beverage containers. By raising awareness of potential health consequences of drinking, such warning labels can increase consumers’ perceptions of the costs associated with drinking alcoholic beverages.Similarly, the Alcohol Traffic Safety Act of 1983 encouraged States to enact hundreds of new and stronger laws related to driving under the influence of alcohol (DUI). For example, these measures eased the standards required for arresting and convicting drunk drivers, imposed more severe and certain penalties upon conviction for drunk driving, and increased the allocation of resources for apprehending drunk drivers. Again, such increases in the probabilities of arrest and conviction for drunk driving as well as in the penalties upon conviction raised the expected legal costs of drinking and driving.Many States and localities also have adopted policies that raise the time costs associated with obtaining alcoholic beverages or otherwise reduce alcohol availability for all drinkers. For example, these policies include regulations that limit the places and/or times where alcohol can be sold, restrict or ban “happy hours,” require server training and/or licensing, and hold servers liable for the harmful actions related to the excessive drinking of those they are serving.One policy that has only rarely been used, however, is an increase in the monetary price of alcohol, which could be achieved by raising taxes on alcoholic beverages. During the past 50 years, Federal, State, and local taxes on alcohol have been raised only modestly and infrequently and almost always with the intent of increasing revenues rather than discouraging alcohol use and abuse. For example, Title XI of the Omnibus Budget Reconciliation Act of 1990 increased Federal excise tax rates on beer and wine for the first time since November 1951 and the tax on distilled spirits for only the second time during this period.Although some evidence suggests that Congress may have been motivated by the health promotion aspects of higher alcoholic-beverage taxes , these i3The potential effects of greater increases in the monetary price of alcohol are explored in the feature article.— Frank J. Chaloupka, Michael Grossman, Henry Saffer1So-called grandfather clauses in some States kept the effective age below 21 until mid-1989.2Excise taxes differ from sales taxes in that they are a flat tax amount based on the quantity purchased rather than a certain percentage of the purchase price. Generally, excise taxes are not paid directly by consumers but are passed on to consumers in the form of higher retail prices. In contrast, consumers pay a sales tax directly when they make a purchase.3These computations are based on Bureau of Labor Statistics data from various years.CookPJMooreMJTaxation of alcoholic beveragesHiltonMEBlossGEconomics and the Prevention of Alcohol-Related ProblemsNIAAA Research Monograph No. 25NIH Pub. No. 93–3513Bethesda, MDNational Institute on Alcohol Abuse and Alcoholism19933358GodfreyJAlcohol taxes: From the whiskey rebellion to the 1990 budget summitTax Notes4821371990One policy that has largely been ignored, however, is an increase in the monetary price of alcohol, which could be achieved by raising taxes on alcoholic beverages. At least in part as a result of this stability of Federal, State, and local alcoholic beverage taxes, the real prices of alcoholic beverages  have declined significantly over time. For example, between 1975 and 1990, the real price of distilled spirits fell by 32 percent, the real price of wine fell by 28 percent, and the real price of beer fell by 20 percent.This article reviews studies that have analyzed the effects of price increases on alcohol consumption and its adverse consequences. After discussing some analytical considerations, the article focuses on the effects of alcohol prices and taxes on consumption by youths and young adults. It then considers the impacts of prices and taxes on indicators of alcohol abuse, such as motor vehicle crashes, health effects, and violence and other crime, among drinkers of all ages, including youths and young adults. The studies discussed in this article capitalize on the substantial variation in alcohol prices across the United States that exists primarily as a result of the vastly differing State excise tax rates on alcoholic beverages. Most of the studies employ the price of beer or the State excise tax on beer as a measure of the cost of alcohol because beer is the beverage of choice among Americans, particularly among youths.Economic studies of alcohol demand focus mainly on the effects of price on alcohol consumption. To describe the sensitivity of consumption to changes in monetary price, economists frequently refer to the price elasticity of demandAnalyses using individual-level data  suggest that alcohol demand may be even more responsive to price than these estimates indicate, possibly because this approach can obtain differential price responses among respondents of different age groups . More reOne consideration that must be kept in mind when interpreting price effects such as those discussed throughout this article is that these effects are not based on natural experiments. For example, no data are available comparing the amounts of alcohol consumed by individuals or groups at different prices, with all other variables held constant. Instead, researchers use cross-sectional data, which measure consumption for individuals or groups at a given moment in time, or time series of such cross-sectional analyses from more than 1 year. And although investigators in these studies attempt to control for as many confounding variables  as possible, these efforts can never be complete. These caveats place limits on the ability to infer cause-and-effect relationships from the study findings.Another consideration when analyzing price effects on alcohol consumption is the potentially addictive nature of alcohol. Next to cigarette smoking, excessive drinking is the most common example of legally consuming an addictive substance. However, alcohol and tobacco are linked to adverse health outcomes and to addiction in different ways. For example, overwhelming evidence indicates that any level of smoking has detrimental health effects. Furthermore, a large proportion of smokers become addicted to nicotine and therefore smoke a substantial quantity of cigarettes each day. Accordingly, researchers can usually focus their analyses on whether and how much a person smokes because these measures are highly correlated with the smoking-related costs of interest.With alcohol, however, the situation is more complex. Many people regularly consume small quantities of alcohol without becoming addicted. Furthermore, most people who drink alcohol do not harm themselves or others; indeed, moderate alcohol consumption has been shown to lower the risk of coronary heart disease in men . The advMuch of the alcohol-related economic research considers alcohol consumption by all segments of the population. Nevertheless, it is crucial to focus on the price sensitivity of youth and young-adult drinking and heavy drinking because the incidence of alcohol-related problems, particularly drinking and driving, is disproportionately high among these age groups. Fatal motor vehicle crashes are the leading cause of death of people under the age of 35, and alcohol is involved in more than one-half of these fatal crashes. In 1995, fatalities per car miles of travel of people between the ages of 16 and 24 were more than twice as large as those of people ages 25 and over . MoreoveTwo studies estimated the effects of price on alcohol use by youths ages 16 to 21 using data from the National Health and Nutrition Examination Surveys . The datDrinking frequency in the past year, which classified youths as frequent drinkers (more than 30 drinking occasions in the past year), fairly frequent drinkers (10 to 30 drinking occasions), infrequent drinkers (1 to 9 drinking occasions), or abstainers (no drinking in the past year)Drinking frequency in the past month, which was structured similarlyThe presence of at least one binge-drinking occasion  in the 2 weeks prior to the survey. These binge-drinking occasions, which serve as an indicator of heavy drinking, are most likely to have negative consequences and, therefore, are of most concern to policymakers.The researchers analyzed the 1982 and 1989 samples separately to examine potential changes in the price sensitivity of youth alcohol use resulting from the introduction of a uniform MLDA of 21 years in all States. For both years, higher beer excise taxes significantly reduced both the frequency of youth drinking and the probability of heavy drinking. As with the studies by The investigators estimated the potential results of a policy that would have equated the tax on the alcohol in beer to the tax on the alcohol in distilled spirits in 1951 and adjusted the tax for the rate of inflation since 1951. Such an increase would have resulted in a more than tenfold increase in the tax. The results implied that such a policy would have reduced the number of underage college women who drank in the past year by about 15 percent and the number of underage and older college women engaging in any binge drinking by roughly 20 percent. In contrast to these statistically significant negative effects of price on underage drinking and binge drinking by female students, no such effect was found for male students.The insignificant effects of price on drinking among male college students and the relatively small effects for female college students likely result, at least in part, from errors in the measure of price used . ResearcAt least for some consumers, the demand for alcoholic beverages may differ from the demands for most other consumer products because of the addictive nature of alcohol. Prior to the work by The Becker-Murphy model also predicts that the short-term price elasticity, which holds past consumption constant, must be smaller in absolute value than the long-term price elasticity, which allows past consumption to vary.The study found consistent evidence that increases in the price of alcohol resulting from higher monetary prices significantly reduced the number of alcoholic drinks consumed by young adults in the past year. Moreover, the analyses provided strong evidence that drinking in this age group is addictive in the sense that a strong interdependency existed among past, current, and future alcohol consumption. That is, current drinking decisions depended on past alcohol consumption and influenced future consumption. These findings are generally consistent with studies employing data from the National Longitudinal Survey of Youth to estimate alcohol demand using a model that also accounts for the addictive nature of alcohol consumption.The finding that drinking by young adults can be considered an addictive behavior has important implications for the effects of price on alcohol consumption. For example, when Using the estimates derived from models accounting for addiction, Taken together, these findings on the relationship between price and demand for alcohol have important implications for policies aimed at curbing alcohol use and abuse among youths and young adults. First, this research demonstrates that increases in the price of alcoholic beverages, which could be achieved by raising alcohol taxes, effectively can reduce drinking and heavy drinking. Second, the results demonstrate that the long-run price elasticity of demand when accounting for the addictive aspects of drinking is well above both the short-run elasticity and the elasticity obtained when ignoring addictive aspects. This finding implies that previous estimates of the effects of tax increases on alcohol use among youths and young adults and its consequences significantly understate the benefits of higher taxes. Third, the finding that young adults are farsighted in terms of future alcohol consumption implies that policies that raise the perceived future costs of alcohol use and abuse can significantly reduce current drinking.As is the case with much social science research, these findings and implications must be qualified because they are not derived from controlled experiments that can definitively establish that a certain factor causes a specific outcome. One can argue that the effects of taxes or prices in the studies just summarized are biased because they do not account for unmeasured determinants of consumption that are correlated with the cost of alcohol. For example, States in which antidrinking sentiment is widespread and alcohol consumption is low may enact high alcohol excise taxes as part of the political process. In this case, the price elasticities that emerge from analyses that only consider price but omit overall drinking sentiment overstate the true influence of price. Conversely, States in which pro-drinking sentiment is widespread  and alcohol consumption is high may enact high alcohol taxes because the taxation of alcohol is an attractive source of revenue. In these cases, price elasticities are understated if they are obtained from analyses that omit drinking sentiment.Using data from the Monitoring the Future surveys of high school seniors conducted between 1977 and 1992, These conclusions are not definitive, however. For example, This discrepancy in findings may stem from the fact that the relative stability of the beer tax makes it highly correlated with other State indicators . Accordingly, it is difficult to distinguish the effects of the beer tax and other State fixed effects. Furthermore, as mentioned earlier, State excise taxes are an imperfect measure of the price of alcohol, and biases resulting from measurement errors are exacerbated in fixed-effects models. Thus, although most of the empirical literature supports the conclusion that excise tax increases tend to curtail alcohol consumption and heavy drinking by underage youths and young adults, more research on this important issue is necessary.In addition to examining the effects of the price of alcohol on consumption, numerous economists have studied the impact of price on consequences of alcohol use and abuse. These consequences include fatal and nonfatal motor vehicle crashes and other injuries, liver cirrhosis mortality and other health consequences, and violence and other crime. This section summarizes findings from recent research conducted by the authors of this article as well as from other key studies —can reduce drinking and driving and its consequences among all age groups. As is the case with the effects of beer taxes on consumption, however, the estimated magnitude of the beer tax effects on motor vehicle mortality depends somewhat on whether State-fixed effects are included in the statistical models used. For example, Excessive alcohol consumption can have numerous adverse health effects; accordingly, reductions in alcohol consumption related to price increases might also reduce adverse health effects. Several studies have examined the impact of alcohol prices on liver cirrhosis mortality rates, a key adverse outcome associated with long-term heavy alcohol consumption that accounts for more than 20,000 deaths annually. For example, This finding was confirmed by In contrast to the two studies just discussed, Again, the general conclusion that can be drawn from this research is that increases in the full price of alcoholic beverages would reduce various diseases, injuries, and deaths related to alcohol use and abuse. Moreover, given the results of most studies analyzing liver cirrhosis rates, these reductions of adverse health effects would not be limited to injuries and deaths among light and moderate drinkers but would also affect heavy drinkers.Because a variety of crimes are related to alcohol use and abuse , numerouSeveral studies examined the effects of alcohol regulation on violence and crime using individual-level data. The results of these analyses indicated that increases in the beer tax may decrease the incidence of child abuse committed by women but not by men. Thus, a 10-percent increase in the excise tax on beer was estimated to reduce the number of mothers who commit violent acts against their children by approximately 2 percent. This estimate was not influenced by State-level fixed effects, suggesting that it was indeed a policy effect.Another study focused on the relationship between alcohol prices and spouse abuse  . This anGetting in trouble with the police or with residence hall or other college authoritiesDamaging property or pulling a fire alarmGetting into an argument or a fightTaking advantage of another person sexually or having been taken advantage of sexually.The study found that the incidence of each of these four acts of violence is inversely related to the beer price in the State in which the student attends college. For example, a 10-percent price increase would result in the following reductions in violent acts:The proportion of students who get into trouble with the police and college authorities would decline from 12.3 percent to 11.7 percent.The proportion of students involved in property damage would be reduced from 7.5 percent to 7.1 percent.The percentage of students who get into verbal or physical fights would fall from 31.2 percent to 30.2 percent.The proportion of students involved in sexual misconduct would decline from 14.3 percent to 13.8 percent.The number of students involved in violence each year would be reduced by approximately 200,000, or by 4 percent.In summary, the findings discussed in this section clearly indicate that, as with alcohol consumption and other outcomes related to alcohol abuse, increases in the full price of alcoholic beverages are an effective means of reducing alcohol-related violence and other crime.This article has summarized the economic research examining the impact of the full price of alcoholic beverages on drinking and heavy drinking by teenagers and young adults. It also has reviewed similar research that explores the relationship between price and outcomes related to the abuse of alcohol by youths and adults, including drinking and driving and motor vehicle crashes, health consequences of alcohol consumption, and violence and other crime. The majority of this research clearly supports the view that increases in the monetary prices of alcoholic beverages, which can be achieved by raising Federal, State and local alcohol taxes, significantly reduce alcohol consumption.Of course, one must keep in mind the caveat mentioned previously concerning the need to exercise caution in interpreting cause-and-effect relationships from the types of analyses discussed in this article. Nevertheless, the weight of the evidence is impressive. Moreover, several studies have concluded that these reductions in consumption are not limited to the infrequent, light, or moderate drinkers but also pertain to frequent and heavy drinkers. Furthermore, increases in price also lead to reductions in many of the consequences of heavy drinking. Two studies, however, have suggested that a subset of heavy drinkers—the upper 5 percent—may be unresponsive to price . BecauseGiven this evidence, increases in the prices of alcoholic beverages appear to be an effective policy for reducing alcohol consumption and its consequences. In reality, however, alcoholic beverage prices have declined relative to the prices of other goods and services for most of the past 50 years. This price decline is the result in large part of the infrequent and relatively small changes in Federal and State taxes. Based on the evidence presented here, it appears likely that this decline in real prices has kept alcohol consumption and many of the problems associated with alcohol use and abuse at levels higher than they would otherwise be.In formulating the appropriate alcohol tax policies, it would be useful to have information on the differential price responsiveness of the outcomes considered here by gender, race, and ethnicity. For example, evidence suggests that certain drinking patterns are more sensitive to price among female college students than among male college students. It also appears as if child abuse committed by women is more responsive to price than child abuse committed by men, although that finding is based on fairly old data. To date, however, no large-scale studies have considered gender differences in price effects for a variety of outcomes in a systematic fashion. Similarly, little is known about racial or ethnic differences in price effects. Thus, researchers do not know whether the beneficial effects of tax increases on alcohol abuse will be shared equally by all population subgroups, or whether policies in addition to tax increases must be pursued to curtail abuse in certain groups.Another area in which knowledge is lacking pertains to how the beneficial effects of moderate alcohol consumption would be altered by tax increases. For example, would coronary heart disease rise, and if so, by how much? And what is the trade-off between reductions in alcohol abuse and deteriorations in coronary health that may accompany tax hikes? Answers to these questions and the identification of population subgroups that are most or least sensitive to alcohol prices and taxes deserve high priority on an agenda for future research.


Swedish National Quality Registries (NQRs) are observational clinical registries that have long been seen as an underused resource for research and quality improvement (QI) in health care. In recent years, NQRs have also been recognised as an area where patients can be involved, contributing with self-reported experiences and estimations of health effects. This study aimed to investigate what the registry management perceived as barriers and facilitators for the use of NQRs in QI, research, and interaction with patients, and main activities undertaken to enhance their use for these purposes. The aim was further to identify potential differences between various types of NQRs for their use in these areas.n = 18) were conducted and analysed iteratively using conventional and directed content analysis.In this multiple case study, nine NQRs were purposively selected. Interviews (A recent national investment initiative enabled more intensive work with development areas previously identified by the NQR management teams. The recent focus on value-based health care and other contemporary national healthcare investments aiming at QI and public benchmarking were perceived as facilitating factors. Having to perform double registrations due to shortcomings in digital systems was perceived as a barrier, as was the lack of authority on behalf of the registry management to request participation in NQRs and QI activities based on registry outcomes. The registry management teams used three strategies to enhance the use of NQRs: ensuring registering of correct and complete data, ensuring updated and understandable information available for patients, clinicians, researchers and others stakeholders, and intensifying cooperation with them. Varied characteristics of the NQRs influenced their use, and the possibility to reach various end-users was connected to the focus area and context of the NQRs.The recent national investment initiative contributed to already ongoing work to strengthen the use of NQRs. To further increase the use, the demands of stakeholders and end-users must be in focus, but also an understanding of the NQRs’ various characteristics and challenges. The end-users may have in common a need for training in the methodology of registry based research and benchmarking, and how to be more patient-centred. There has been an increasing international interest in developing, improving and evaluating healthcare systems not only in terms of service, e.g. availability, but also in terms of other outcomes relevant to creating value for the different stakeholders, above all for the patients –3. One sThe Swedish NQRs have also long been seen as a “largely untapped resource” , especiaTo fulfil the identified potential of the NQRs more knowledge on how their use can be enhanced is needed. An opportunity for such studies arose when a five-year national investment initiative was launched in 2012 in order to promote the use of the Swedish NQRs for clinical development and QI, patient interaction, and research. The Swedish Government and the authorities responsible for healthcare jointly invested more than SEK 1.5 billion on the development of the NQRs. Accordingly, the aim of this study was to investigate what the registry management perceived as barriers and facilitators for the use of NQRs in QI, research, and interaction with patients, and the main activities undertaken to enhance their use for these purposes. The aim was further to identify potential differences between various types of NQRs for their use in these three areas.A multiple case study design  based onIn Sweden, the responsibility for financing and organising health services lies upon the 21 counties and regions. Services are tax-funded and provided mainly by public providers, but the share of private services with public funding has increased, especially in primary health care. In the Swedish setting a care commissioner is “a state authority, county council and municipality in the case of such health and medical care that an authority, county council or municipality is responsible for, and other legal entity or individual entrepreneur who carries out health and medical care” . In thisIn Sweden, quality registries collect information from registry users to calculate and report on quality of care indicators. In contrast to internal quality development systems, NRQs collect information from numerous care providers. The first national quality registry, initiated in 1975 by orthopedic surgeons, was the Swedish Knee Arthroplasty Register. It has since then been followed by an increasing number of registries, today more than 100, focusing on specific disorders or healthcare processes . Three cA quality registry is a structured and automated collection of information about patients, initiated in order to develop and secure care quality and to make comparisons on regional and national level  and can Since the 1990s, registries have been able to apply for funding from national agencies such as the National Board of Health and Welfare and SALAR. In 2012, a national initiative was launched to enhance the use of NQRs for clinical development and QI, patient interaction, and research. During 5 years (2012–2016), the Swedish Government and the authorities responsible for healthcare jointly invested just over SEK 1.5 billion (in excess of the regular funding) to further develop the NQRs. Six regional Quality Registry Centres (QRCs) were also financed within this initiative to support NQRs to reach the goals of the initiative .The original purpose of the NQRs was to agree on and spread best practice. Today, the purpose has expanded to encompass research and benchmarking, which has put an emphasis on the need to guarantee the quality of the NQRs. On a national, regional or hospital level, aggregated data is compiled to compare different care providers’ results or outcomes. To support the improvement of local clinical practices, data are or need to be real-time and fed back to practitioners . FurtherThe selection was done iteratively in several steps in order to obtain a purposive sample. The following steps and criteria were applied. Firstly, having a certification level of 1 or 2 served as an inclusion criteria. At the time of the selection Feb, 2015), 41 registries were certified at level 1 or 2. Secondly, NQRs were selected to show wide variation based on type of registry , 20 ensu15, 41 reData collection consisted of 18 individual interviews with two persons representing each NQR. Prior to the interviews one researcher (EG) approached registry holders to inform about the study, obtain informed consent to participate and book a time for a telephone interview. The registry holders were also asked to provide a second name from the registry management team who was approached in the same way. All persons approached accepted to be interviewed. Interviews were conducted in Swedish from March to June 2015 by three researchers . A semi-structured interview guide was developed with open-ended questions concerning how the registry had been working in order to meet the three main areas for the use of NQRs. The questions were formulated in line with the aim and focused on the following themes: action strategies, targets, activities, interaction with others, and facilitating and hindering factors. Interviews lasted from 45 min to 1 h, were recorded and transcribed verbatim.Documents and websites were used to familiarise ourselves with the NQRs, i.e., by providing descriptions of missions, goals and activities and the scope of the NQR. The NQR organisation and financial reporting was analysed to objectify statements about staffing and financial resources.The transcribed interviews were analysed iteratively using both conventional and directed content analysis . Two resInnovation, Individual professional, Patient, Social context, Organisational context, and Economic and political context. A bottom-up approach was used for identifying and naming subcategories. Illustrative quotes were selected to exemplify each category. The translation of the quotes were made when finalising the manuscript and verified by all authors.As for addressing change barriers and facilitators in healthcare, a directed content analysis approach was applied using Grol and Wensing’s model  for the The NQRs in this study generally had a governance structure that included a steering committee and a registry operations office. The size of the steering committees varied from 8 to 29 people and were mostly comprised of clinicians, administrators, and patient representatives. Registry office full time staff accounted for between 17 and 83% of the budget. The two registries with the highest percentage (74% and 83%) offered consultation services for their users. The NQRs studied are described in more detail below  or for long-term follow-up of patients with chronic disorders. The technical development of the registries, e.g. online reporting and the possibility for providers, patients and the general public to access data from registries, were perceived as facilitating improvement and stimulating patient involvement. Moreover, informants described how the use of online reports could enhance meetings with head of units, as well as meetings with patients.A major barrier mentioned by all informants was “double registration”, where healthcare professionals register  data in electronic health records and in several registries, as systems are not integrated due to technical and/or legal issues. Informants further described a close relation between national evidence-based guidelines and what is entered into the registry, e.g. quality indicators for follow-up and benchmarking of results.Informants expressed the importance of having the health and social care professionals “on board” and motivated when it came to registration and use of data. They had experienced a change in attitude over time and an increasing awareness and interest from the units, which was considered as enabling factors. They also mentioned the importance of having unit managers that value continuous QI and national guidelines. However, as registry holders, they can only provide data from the registries, but do not have the mandate to make the units register data or use data in, for example, their clinical practice.All registries had an organised process for when researchers and others wanted to extract data. In most cases the steering committee was involved in the decision process, and in many cases they were also involved in the research. Moreover, informants called for the possibility to create a mutual research platform by linking the registry platform with other population-based databases about healthcare consumption, diagnostics, etc.Informants mentioned the stimulating effect of active patients and patient organisations, and an increased sensitivity on behalf of the registries as to what kind of information patients may need.One barrier from the patients’ perspective was to understand the registries’ output data, especially for patients with reduced cognitive skills. Making registry data more accessible for lay people was regarded as necessary. Lack of computer skills, survey saturation and the complicated process related to assuring confidentiality were also mentioned.The registry holders arranged regular meetings either on a national or regional level where clinicians could meet to discuss results, QI efforts, and research projects. Visits to individual units were also seen as a facilitator in promoting QI efforts and research activities. Other facilitating means mentioned was access to statisticians, enthusiasts and solid routines on the web for data extraction for research. Additionally, recent trends and a parallel focus on for example value-based health care and co-creation of care, were mentioned as drivers for developing patient-reported outcome and experience measures (PROMs and PREMs) and research projects with this focus.A major barrier was the competition and conflicts regarding how to allocate time, both when it came to time for clinical work and for QI activities. Time allocation between the different NQRs, as some clinics had to register in several NQRs, and the problem with incompatible IT systems were also described as barriers. Some registry holders expressed the need for employers and responsible authorities  to actually request that the units spend time on registering in and using data from NQRs. Such an instruction was perceived to greatly benefit the use of NQRs in all areas.Financial arrangements, regulations, guidelines, IT-systems, and policies, was seen as both enabling and hindering the use of the NQRs. Other contemporary national healthcare investments have helped to change attitudes and increased interest for QI projects. The large national investments recently put into the registries have mainly been used for allocating time or improving IT-platforms. When asked about the national initiative, informants expressed that the increased funding had made it possible to develop areas that had previously been thought of but not prioritised due to lack of financial resources. However, it was also mentioned that the initiative had used a top-down perspective when setting the goal and follow-up indicators, instead of asking the NQRs what they wanted to focus on within the frame of the initiative’s three focus areas.Three subcategories emerged from the interviews to enhance the use of NQRs for QI, research and interaction with stakeholders: a) activities to ensure that correct and complete data is registered, b) activities to ensure accessible, updated and understandable information available for all stakeholders, and c) activities to promote cooperation with target groups Table . StakehoThe NQRs’ management team routinely performed time consuming quality controls by comparing patient records with data entered into the registries. However, the informants expressed that the ideal way would be to electronically document directly into the registry. Only one of the nine registries was constructed in this way and the informants from the other registries described various unsuccessful actions to achieve such a solution.Another activity expressed was online access to registered data. All registries had been involved in such development for several years and were now able to provide online access. One NQR had also developed a much appreciated risk evaluation tool for more valid comparisons between different providers. Verifying and evaluating the evidence base of the data in the registry was said to be in the hands of the researchers assigned to develop new or revise already existing national guidelines. This characterised the work of NQRs, which had either started to check adherence to established guidelines or to construct a knowledge base for development of clinical practice guidelines.Informants described different action strategies for communicating the information generated by NQRs to stakeholders. Registry based research results are presented at national and international scientific meetings, and registry reports at national, regional and/or local meetings with involved professions. The regional/local meetings are designed either for managers responsible for the care produced by the units, or for specialists engaged in the care of patients with registry specific diagnoses. The registry-focused meetings concentrate on learning from results and improvements over the past year, and identifying aspects in need of improvement or more research.All informants underlined the importance of openness when presenting registry based information. Data were presented on unit levels with two exceptions: units with a very low number of patients, and units where the integrity of the patients being treated was at risk. No data referring to individual physicians were openly presented. Informants described plans and activities to improve accessibility of registry based information, for example several language options or pedagogical illustrations. Some described arranging information meetings with and for patients.Another important service was to provide online, updated and processed reports for clinical users. There is a possibility for the units to follow their quality performance, at any given moment, in relation to set goals. Aggregated data is also provided in the annual reports where the units can compare their results nationally and, in some cases, internationally.Cooperation with healthcare providers, including managers and policymakers, was described in terms of providing updated results of the most important quality measures. Based on key measures, one registry provided support for clinical improvement work through regional representatives who regularly visited all units participating in the registry in the particular region. Another registry sent questionnaires to the participating units asking how the results were used, revealing that some did not make use of the registry data reported to them.The most common way to offer collaboration was to invite healthcare units to participate in an improvement project set up by the registry management, often with support from a QRC. A few informants described more targeted strategies where units in need of improving their performance were identified and offered support in setting up and pursuing improvement projects. Some registries offered consultation services directed at physicians in need of discussing a clinical problem with a colleague.Informants described various strategies for cooperation with patients. For registries with existing patient associations a common feature was to have one or two representatives in the steering committee from that association. When no relevant patient associations were established there were alternative ways to ensure patient representation. Registry representatives were also regularly invited to patient associations’ meetings to present current registry information. Patient cooperation and participation in the design of questionnaires, information materials and guidelines was described as an important feature in the use of NQRs for clinical development.The use of NQR data in patient consultations was described as a very important measure to support patient engagement (e.g. support self-care) and thus promote patient cooperation in the development of registries. Informants described how patient-specific data, including questionnaires filled in by the patient, were used in patient meetings to discuss treatment results and disease control.All informants underlined the importance of cooperating with researchers and using registry data for scientific purposes. Research questions were often raised within the registry itself and handled by one or two researchers in the steering committee or were advertised and presented at various user meetings as suggestion for scientific studies. In recent years, the informants confirmed an explosive interest concerning data access for research purposes. This was said to be due to the stimulating effects on both established and potential researchers by well-developed routines for accessing registry data.When informants were asked if the type of registry  or type of care process (acute/short or chronic/life-long) impacted their ability to reach the goals of the national initiative many reported they had not reflected on this.Long-term and chronic condition registries were said to create greater interest among patients (and care providers). Depending on what kind of care the registry covers, different prerequisites were described in terms of communication and adjustment to target groups. For example, a registry that only covered a few specialist clinics versus registries with many contacts in hospitals, social care and home care would require different strategies.Patient interaction was more likely to be captured by long-term care registries since they generally communicate with patient organisations and active patients living with the condition. Some informants thought that patient interaction might be more difficult in registries covering for example elderly and/or dementia care, intensive care (sometimes unconscious patients), psychiatry or defined interventions (diagnostic or therapeutic). Informants pointed out that accessible online data was more difficult to provide for registries where results are not immediate or intuitive, or when it takes time for results to appear.This study, based on information from nine well-developed Swedish NQRs, has shown that they are perceived as an innovation with high potential for QI, research and knowledge development, and for patient involvement, but that the use for these purposes is still in its infancy.One major facilitator for enhancing the use of the NQRs was having sufficient funding. The recent national investment initiative enabled the development of areas previously identified by the NQR management teams. The relatively recent focus on value-based health care was pointed out as an especially positive facilitator, as well as other contemporary national healthcare investments aiming at QI and public benchmarking. The current focus on value-based health care has also stimulated patient involvement and the increased use of PROMs and PREMs in registries. However, real patient involvement will require more direct interaction with both individual patients and groups of patients. For example, patient and patient representatives can add important perspectives of the care process, choice of variables, and data presentation if involved in the NQR steering group or in focus groups. This is something that has been encouraged by the national initiative, but a lot remains to be done. During patient consultation, clinical measures are complemented with patient dependent measures providing opportunities for a shared and more holistic overview of the patient’s health status, which can facilitate patient interaction and co-production of care , 29. It A major barrier was users having to perform double registration due to shortcomings in design of the digital systems which has also been pointed out in other studies , 13. LesIn fact, one could say that this whole initiative lacks a multilevel approach in accordance with Ferlie & Shortell’s Framework for change, which is characterised by four essential core properties needed in order to really achieve change and thereby improved quality of care. These core properties are: “1) leadership at all levels; 2) a pervasive culture that supports learning throughout the care process; 3) an emphasis on the development of effective teams; and 4) greater use of information technologies for both continuous improvement work and external accountability” . The natIndeed, the great variety of strategies among quality registries to achieve the three goals of the national initiative, i.e., to increase their use for QI, research, and patient engagement, may reflect that more emphasis was put, on the national level, on policy formulation than policy implementation. We find the model for evidence-informed policy formulation and implementation, presented by Strehlenert et al.  enlighteThe registry management teams used three different strategies to enhance the use of NQRs within the three focus areas: ensuring registering of correct and complete data, ensuring updated and understandable information available for all stakeholders, and intensifying cooperation with relevant stakeholders. However, the need of improving methodological competence among registry researchers, especially concerning use of epidemiologic methods, did not surface as a chosen strategy to enhance the use of NQRs. This has been emphasized by Adami and Hernan  as a cruFurthermore, there were no examples in our study, that the registry management teams offered support for benchmarking processes. Such processes differ from standard quality improvement processes by “the dynamic of comparing and learning from each other”  and the The characteristics of the NQRs have an influence on their use. This study showed that the type of registry and its potential use may be connected to what kind of data is registered, the specific condition or type of care process followed, whether it is acute/short or chronic/life-long intervention, and if the registry focuses on diagnosis or on risk assessments and prevention. This has also been observed by Fredriksson et al.  studyingMost of the previous studies involving NQRs have focused on one registry or addressed the NQRs as a phenomenon e.g. , 11, 13), 1311, 1This study has shown that the potential use of NQRs for QI, research and interaction with stakeholders is related to the funding of the registries and that a recent national investment initiative contributed to already ongoing purposeful work to strengthen what was seen as facilitating factors  and likewise counteract perceived barriers (such as lack of authority). Whether this in fact led to the intended goal of the initiative: increased use of NQRs for QI, research and interaction with stakeholders, has not been examined in this study.The way the registries in fact are used for these purposes is a question for the end-users, i.e. the clinicians, the researchers and the patients. For future national investment initiatives, where an increased use of the registries is desirable, the needs of these end-users must be in focus. Since there is a great variation between different types of registries it is reasonable to believe that there is variation in prerequisites when it comes to enhancing their use for QI, research and interaction with stakeholders. However, the end-users of the different registries may all have in common a need for information on and training in the methodology of registry based research as well as benchmarking methodology, i.e. how to learn from best practices, and how to involve patients and families in patient centred care.


The registry is free of charge and is designed for exploratory and confirmatory studies within applied science as well as basic and preclinical research. The registration form helps scientists plan their study thoroughly by asking detailed questions concerning study design, methods, and statistics. With registration, the study automatically receives a digital object identifier (DOI) that marks it as intellectual property of the researcher. To accommodate the researchers concerns about theft of ideas, users can restrict the visibility of their registered studies for up to 5 years. The full content of the study becomes publicly accessible at the end of the embargo period. Because the platform is embedded in the infrastructure of the German Federal Government, continuity and data security are provided. By registering a study in the ASR, researchers can show their commitment to transparency and data quality to reviewers and editors, to third-party donors, and to the general public.The Animal Study Registry , which was launched in January 2019 for pre-registration of animal studies in order to increase transparency and reproducibility of bioscience research and to promote animal welfare.This Community Page article presents the Animal Study Registry ( The scientific community is striving for greater transparency in animal research as a measure to enhance the reproducibility of results and to gain more knowledge from animal studies.Missing efficacy was found to be the main reason for clinical failure of drug candidates –4, and ip-hacking, and poor statistical design [Numerous factors contribute to the irreproducibility of research studies. Biological heterogeneity and complexity as well as the use of nonstandard methods or technologies certainly are the most common reasons for lack of reproducibility . Other kl design –9. Misidl design .Dissecting the fundamental structure of a research project can help solve the problems mentioned above. Research projects can be divided into 5 stages: planning, execution, documentation, analysis, and publication. Adjusting each of these steps can significantly refine the whole scientific process. Improving the statistical planning of studies by increasing the statistical power can raise the reproducibility of results by preventing the overestimation of effect sizes and reducing false positive outcomes ,12. LoweThe Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines were developed to support scientists already at the stage of planning an animal experiment . It is ap-hacking). Thereby the credibility in research findings can be regained as the data of a publication become traceable and can be directly related to the original study plan [We believe that preregistration of research studies can be more effective, because it tackles the problem at its earliest stage and brings researchers to consider all relevant details for a future project in an interactive and self-obliged manner. Preregistration means that researchers describe and register a study design, including statistical planning and method description prior to the first experiment. Being asked distinctive questions, researchers are supported in thoroughly planning their animal experiments. They become aware of important measures to increase data quality, such as randomization and blinding, before they conduct the experiments. In addition, researchers will be stimulated to consider whether the planned study aims to generate or to test a hypothesis. Distinguishing between the exploratory (hypothesis generating) or confirmatory (hypothesis testing) nature of a study can raise awareness on HARKing, i.e., the habit of presenting results based on a post hoc hypothesis as if they were confirming a hypothesis . The traudy plan . In the udy plan . In factudy plan .There are two ways of preregistration; i.e., study protocols can be registered in a public registry or can be submitted to a journal as a registered report. Advantages of registered reports are the peer-review of the study protocol providing feedback to the author and, with acceptance, the guaranteed publication of the results independently from the outcome . The benwww.animalstudyregistry.org; 10.17590/asr.0000091), have been registered. It will therefore be a crucial challenge for the future to create incentives for the preregistration of animal studies.In January 2019, the German Centre for the Protection of Laboratory Animals (Bf3R) has launched the ASR (The ASR registration process consists of four main steps: (1) entering the data, (2) submitting the study, (3) registration of the study, and (4) publication of the study . To regiGeneral informationThis section gives a short overview of the study:Study titleShort summary of the studyAuthor’s name and affiliationStudy designA detailed description of the study design is crucial for preregistration. We encourage researchers to make the description of the study design as transparent as possible, e.g., using timelines, providing a clear definition of the experimental and the control groups, parallel groups or cross-over design, and indicating if animals have been used in previous procedures. The following aspects can be considered essential for a transparent preregistration of a study design:Confirmatory studies: A clear hypothesis must be provided.Exploratory studies: Because of the nature of the study, it is often not possible to state a clear hypothesis, thus, the research question should be specified as much as possible.Free text fields are available to describe legitimate modifications of these classical approaches, e.g., when one study serves both exploratory and confirmatory purposes.Method of blindingMethod of randomization.If no blinding and/or randomization will be applied, the reasons should be briefly stated.MethodsMultiple methods can be entered in the preregistration form.All details of the used methods necessary for the interpretation and replication of the results shall be provided; this may include the following:Details of the apparatusDescription of the consumables including the supplierSoftware used for analysisTime of the day when the experiments will be conductedMeasured parameters and their respective unitPrevious handling or training of animalsMethod of euthanasia in case of ex vivo studiesDetails of the narcotic and/or analgesic treatment Details of the drugs and substances being used including, e.g., name of the supplier, route of administration, dosing, treatment intervals, duration and time point of the treatmentProvision of the suppliers’ name and catalog number if antibodies will be usedA list of all cell lines, viruses, DNA or RNA constructs, and bacteria that will be used. For all cell lines, provision of the source of the cell line, authentication, and tests for mycoplasma contamination. If possible, use the respective standard nomenclature.StatisticsMultiple statistical analyses can be indicated in one preregistration entry and connected to the respective experimental method.At least the following aspects in should be included:The main experimental endpoints the sample size calculation relies onA sample size calculationAny additional outcomes measures that will be assessedWhat kind of primary statistical analysis will be usedExclusion criteria for certain data points if applicableAnimalsBeing able to identify which animal strain is used in an experiment is a crucial aspect of reproducibility in animal research. The exact nomenclature of the strain or breed, including the name of the breeder or supplier, should be specified. For genetically altered animals, international nomenclature standards should be used, and the type of the genetic manipulation should be briefly described.Please also provide further information about the animals:Sex, age or age range (in days/month),Body weight (in g or kg) or where applicable, size, length, or height of the animals (in mm or cm) at the beginning of your experiments.This list can be complemented with any other information concerning animal characteristics relevant for the reproducibility of the study.As living or housing conditions also may have a big impact on the study outcome, the ASR preregistration form asks you to provide information on the following aspects of animal living or housing conditions:Husbandry type Dark/light cycle Humidity and temperature Single housing/group housing Cage/tank type and size Bedding material Environmental enrichment Cage changing practices Feeding practices Water quality/supply Information on any refinement measures implemented in the research project should be provided.Any additional information you consider important for the reproducibility and transparency of your study can be added. Furthermore, every section offers the possibility to upload additional data.The intellectual property and the associated theft of ideas are major concerns brought forward by scientists . To addrEvery researcher worldwide can use the ASR to register any kind of study involving any animal species, whether it is a vertebrate or invertebrate or an in vivo or ex vivo experiment. The ASR asks researchers to classify their study as either a confirmatory or an exploratory research project. Confirmatory studies that test a priori hypotheses usually derived from a theory based on previous information are particularly suitable for preregistration ,30. In tTo adequately represent the exploratory research process in the ASR, it might be appropriate to submit multiple preregistrations, each of them covering a part of the research project. The ASR allows the duplication of a registration entry with a new title. Text fields remaining the same for all parts of the study do not have to be filled in again , and researchers can simply modify only the necessary parts. If several studies are linked or form a major project, it should be reflected in the study titles, e.g., as part 1, 2, 3, or as pilot and follow-up study.Furthermore, in each section, free text fields are available to describe legitimate modifications of these classical approaches, e.g., when one study serves both exploratory and confirmatory purposes. It is expected that a description of an adequate statistical analysis in such cases will be provided.Research studies, especially exploratory studies, can be performed over a long period and often the course of the experiments cannot be predicted in detail. Thus, the ASR offers the possibility to add comments to a registered study to state or to explain any kind of changes to the original study plan. The comment feature helps reflect the full experimental process and include information potentially beneficial for other researchers, such as methodological dead-ends.Because most scientific publications only report successful experiments and do not contain any information about what went wrong in the research process, registries like the ASR become an important tool to save this information for the scientific community. This can prevent the repetition of mistakes as well as unnecessary animal experiments that will not deliver the envisaged outcome.With the completion of the study, the comment feature can also be used to refer to the final or preprint publication(s), to other registered studies, or to data sets stored in open access repositories.Each submitted comment will be published with a date together with the contents of the original entry.One major concern brought up when preregistration is mentioned is the possible theft of ideas if full contents of a study become visible long before the publication of the data. To address this issue, the ASR offers the possibility to restrict the visibility of an entry for up to 5 years. During this time, only the title and a short summary of the study as well as the name of the institution and, optionally, the name of the researcher are publicly visible. However, for the entire embargo period, the researcher can download a PDFcopy of the registered study containing all study details and metadata that can be attached to a manuscript submitted for publication. Thereby peer reviewers are able to compare the original research protocol with the submitted manuscript. The timespan of 5 years was chosen on the internal experience concerning the average period of research funding as well as duration of research projects. In addition, every study registered in the ASR automatically receives a DOI by DataCite, which marks the study as the intellectual property of the researcher. The platform is embedded in the infrastructure of the German Federal Government; thus, continued operation of the platform and data security are provided.Improving the quality of scientific studies might have been the initial idea behind the development of study registries for preclinical research. However, the resulting benefits for animal welfare are in no way inferior. In fact, preregistration responds to an increasing public concern about animal welfare and the limited usefulness of results gained from animal experiments . Poor reWith a separate section referring to animals asking detailed questions concerning husbandry and animal characteristics, such as strain or breed, genetic manipulations, age, sex or body weight, researchers have to consider all factors influencing animal welfare and the experimental outcome already when planning their experiments. Sharing experience about housing, handling, and refinement measures can accelerate the progress in improving laboratory animal welfare.p-hacking, and poor statistical design.Reliable and transparent data are essential to make the scientific and public discourse on animal experiments more transparent. As an early measure within the scientific process, preregistration of studies can raise researchers’ awareness of reporting bias, HARKing, Although the primary goal of the ASR is to improve the quality of bioscience research involving animals, it also promotes animal welfare. Preregistration may increase the chance of publishing “negative” results and thereby reducing the publication bias. Nondisclosure of negative results hampers the progress of the entire biomedical research, though its consequences are particularly serious in research using animals. Here, leaving out information may lead to unnecessary duplication of experiments and to wasting animal lives.The creation of new incentives could help preregistration to prevail in the future. However, the number of preregistrations already sharply increased in the last years, especially in disciplines like psychology . By prer


Numerous studies evaluated thecharacteristics of this important cell that led to tremendous discoveries. Since its first observation and description in1677, many important characteristics have been described regarding this highly fascinating gamete. In this review,we intend to provide a historical account of the numerous milestones and breakthroughs achieved related to sperma-tozoa. We conducted a review of the literature by selecting the most important subjects with regards to spermatozoa.Since their discovery by van Leeuwenhoek, spermatozoa have been studied by scientists to better understand theirphysiology and process of interaction with their female counterpart, the oocyte, in order to treat and resolve infertilityproblems. Three centuries after van Leeuwenhoek’s discovery, the 100,000th article about these cells was published. Itis encouraging that sperm research reached this landmark, but at the same time it is clear that further research on malereproductive physiology and spermatozoa is required to shed more light on their function and pathology in order toreduce the number of unexplained infertility cases. The 100,000 Few cells have attracted the world’s attention and intriguedscientists throughout history as much as the malegamete or spermatozoon. It is one of the most fascinatingand important cells. A crucial part is involved in thefecundation process due to its role in the delivery of malegenetic material and proteins to the oocyte at the time offertilization. Despite the vital dependence of human lifeon the interaction between gametes, research on humanand male reproduction is less than infectious diseases.This is perhaps due to the emergent and expansive natureof infections. Only 0.4% of all scientific papers publishedover the last 50 years have pertained to spermatozoa despitetheir discovery in 1677 by van Leeuwenhoek ] literatureusing the term “sperm” without any limitation on the dateof publication. In addition, we determined the numbersof publications on another topic of major interest to thescientific community-viral infection caused by the humanimmunodeficiency virus (HIV). Furthermore, we evaluatedthe relationship between HIV and sperm articles inthe last 30 years, and conducted a review of the literatureabout the most important findings. We selected and discussedmilestones that pertained to spermatozoa.In 2016, the 100,000th article on HIV was published in the year2000 . In the database used for this analysis (PubMed), thenumber of results retrieved with the term “sperm” wasmuch greater than when we used the term “spermatozoa”.The 100,000During June 1843, according to PubMed, there werethree manuscripts published. Two papers, one originaland one editorial , 3, dealIt is important to note that since 1990 the relationship between articles published about HIV and sperm were similar . In addition, there were significantly more (P<0.0001) numbers of papers published during the last three decades (1990-2016) in PubMed about HIV  compared to spermatozoa , among others. However, the story of the discovery of sperm has originated more than three centuries ago, in 1677. Without any scientific purpose and purely driven by human curiosity, van Leeuwenhoek and his assistant described animalculae , which constitutes the basis for supporting the key functions of the spermatozoa, is formed through the glycolysis and oxidative phosphorylation pathways. To date, a discrepancy has been reported as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization . McCarthIn 1929, Macomber and Sanders  were theIn 1932, Baskin  describe Another important milestone was reached in 1942, when Lasley et al.  .Oxidative stress is one of the major causes of defective sperm function and male infertility because it causes lipid peroxidation and disrupts the integrity of sperm DNA. This, in turn, can affect sperm motility and limit fertilizing potential as a result of collateral damage to proteins and lipids in the sperm plasma membrane. In addition, reactive oxygen species increase as a consequence of leukocyte infiltration. A variety of primary factors can initiate oxidative stress such as infection, age, obesity, and exposure to a variety of adverse environmental influences. Despite the resultant oxidative damage to the sperm’s chromatin, once fertilization occurs, the oocyte can repair most of the damaged sperm DNA .In 1947, Dan  exploredAfter the initial discovery of sperm and identifying the relationship of sperm with fertility, investigations started to focus more intensively on the process of sperm transfer to the oocyte. During the first in vivo fertilization trials in rabbits, it was observed that the sperm must remain in the fallopian tubes for six hours prior to ovulation, thereby pointing to a possible physiological change that the spermatozoa have to undergo in the female tract .Spermatogenesis occurs in the testis, after which the sperm move to the epididymis for final maturation. Once ejaculated, sperm can undergo two phenomena, capacitation and the acrosome reaction, which thereby renders them able to fertilize oocytes . The metth century, researchers analyzed sperm structure to deduce phylogenetic relationships between taxa. Variations in the size, shape, and physiology of spermatozoa in the animal kingdom and their relation to the method of reproduction captivated the biologists of the time. Between 1940 and 1950, with the development of the electron microscope, ultra-thin dissection, and new staining techniques, researchers could observe the structure of spermatozoa from various species. One of the most interesting findings was made by Franzén   published its first manual on the examination of human semen . Since then, the manual has been regularly updated with new versions published in 1987, 1992, and 1999; each edition has contained new proposals, the latest changes, and revised cut-off values for the semen variables. After rigorous scrutiny, the latest edition was published in 2010. This edition is believed to be one of the most comprehensive manuals to date because the authors have based updated semen variables on real life data which included men of proven fertility and secondly presented results as lower reference limits (5centile) .in vitro by the addition of albumin, which mediated cholesterol efflux and hyperactivation. This unique movement pattern is considered to give spermatozoa the strong thrusting power that allows them to penetrate the zona pellucida, and occurs on completion of the capacitation process  was developed in 1984 to evaluate the functional integrity of the human sperm membrane. The principle of this technique is based on the fact that human spermatozoa “swell” under hypo-osmotic conditions due to the influx of water and subsequent membrane expansion. This technique is extremely important because membrane integrity is vital for sperm metabolism and the correct change in membrane properties required for a successful union with the female gamete. HOS can thus be used in the diagnosis of male infertility. Investigators have stated that any compounds that change osmolality and significantly enhance sperm swelling should be removed from IVF media .Later, Kruger et al.  describein vitro. However, this binding step is believed to provide unique information that predicts the sperm’s ultimate fertilizing potential  was transformed with the first reports of intracytoplasmic sperm injection (ICSI). This technique allows the direct injection of a single spermatozoon into the ooplasm of metaphase-II oocytes, after which the embryos are placed in utero.6/ml in 1940 to 66×106/ml in 1990, and in seminal volume from 3.40 ml to 2.75 ml among men without a history of infertility. This finding could be related to a concomitant increase in the incidence of genitourinary abnormalities, such as testicular cancer, and possibly cryptorchidism and hypospadias, which impact male gonadal function. The analysis was based on a total of 61 papers published between 1938 and 1990 that included data on 14947 men. Some researchers criticized the ‘Carlsen study’ based on the study design, the heterogeneity of the groups investigated, statistical evaluation, non-standardized methodology used for semen analysis, and variation in abstinence times. The authors of one specific manuscript who opposed this spermatic crisis article concluded with a sentence to motivate future research: “it must be acknowledged that the research group that led us down the wrong path also demonstrated how we can get back on the proper research track”  that mediates sperm adhesion to the zona pellucida, was described . Such kein vivo  and obtained 12 offspring. These animals were proven fertile as examined by brother-sister mating. The researchers therefore demonstrated that the organ culture conditions, without a circulatory system as in vivo, could support complete spermatogenesis of mice. This finding will definitely contribute to the development of new diagnostic and therapeutic techniques for male infertility (Spermatogenesis is one of the most complex and longest processes of sequential cell proliferation and differentiation known to man. Therefore, the ertility .In this journey through the history of sperm, we have observed how human curiosity prompted the description of natural phenomena and the attempts made to try to explain these phenomena. Strictly speaking, it is impossible to discover facts of nature that have been in existence for thousands of years. We therefore clarify and define the use of the word ‘discover’ as "looking with new eyes", which encompasses acute observation, critical thinking, relating ideas, and questioning those events that we encounter on a daily basis as part of the miracle of life. Advances in modern technology allow us to find answers to rephrased Pleaquestions and analyse them from a new perspective in our attempt to explore and understand complex functional and molecular processes.Physiological knowledge of each human organ system and cell allows us to understand not only how the human body works, but also where and how alterations, specifically in the male reproductive tract, may affect the continuation of life. Understanding sperm biology allows for a significant impact on infertility. For example, by increasing the chance of fertilizing the oocyte with enhancing the male gamete’s presence at the site of fertilization. New technologies allow us to investigate unexplained male infertility and possibly lead to the discovery of new and novel treatment solutions, thereby reducing the prevalence of cases of idiopathic infertility.Finally, this review reminds us that the greatest advantage of recollecting history is that it can solve old problems with new methodologies that understand their nature. We can conclude that despite numerous advances and new insights published in these 100,000 articles, more research on human reproduction, especially on spermatozoon, are needed to help reduce the overall numbers of patients who suffer from infertility.As authors of this review and seeing the historical development of this magnificent cell, we thank the researchers who are part of this journey in knowledge for their incredible contributions and invite new researchers to remember that curiosity is the best human attribute. We apologize to authors whose important contributions we could not cite due to limitations in reference number.


Well-designed health warnings on tobacco packaging enhance cost-effectively public awareness of the risks of using tobacco products. However, many countries have experienced difficulties in implementing pictorial warnings. The purpose of this study is to present the topics that arose during the legislative process that preceded implementation of graphic health warning labels (GHWLs) on tobacco products in South Korea, and discuss the outcomes.We used qualitative content analysis to analyze lawmakers’ statements, and those of committee members in meetings that preceded the drafting of the legislative document pertaining to GHWLs in South Korea.In discussions surrounding the adoption of the GHWLs, the main point of contention was the level of disgust induced by pictorial warnings. When discussing how warnings should be inscribed on packaging after adoption of GHWLs, lawmakers disagreed regarding the physical position of the warnings. Because of continuous objections raised by some lawmakers, implementation of GHWLs was delayed, and, when actually introduced, the warnings were toned down. Some lawmakers communicated with tobacco companies; thus the companies participated in the legislative process in South Korea.To prevent tobacco companies from negatively influencing tobacco control efforts, it is essential that all communications with such companies be publicly disclosed and that the tobacco industry be prohibited from contacting lawmakers involved in the legislative process of tobacco control. In particular, Article 11 states that tobacco packaging should include warning text and pictures or pictograms that cover 50% or more of the principal display area, and that relevant parties are obliged to comply within 3 years of the convention’s ratification1. To date, however, only 64% of the relevant parties have adopted pictorial warnings3.Article 11 of the Framework Convention on Tobacco Control (FCTC), and the guidelines thereof, emphasize that well-designed health warnings on tobacco packaging enhance cost-effectively public awareness of the risks of using tobacco products4, although South Korea ratified the FCTC in 20055. Since 2002, bills proposing revisions to the National Health Promotion Act (NHPA) (thus requiring the implementation of GHWLs) were routinely abandoned without any deliberation in the National Assembly of Korea (‘the Assembly’)5; for a period exceeding 10 years, the bills died in committees without ever being debated.In South Korea, graphic health warning labels (GHWLs) were implemented 23 December 20166. Worldwide, the methods by which the tobacco industry opposes tobacco control are similar; an analysis thereof will facilitate the establishment of tobacco control policies7.It is important to analyze the legislative process when seeking to implement policies; and it is necessary to anticipate and deal with barriers and challengesHere, we describe the topics raised in the legislative debates that preceded the implementation of GHWLs in South Korea, and their outcomes. We explore whether the tobacco industry had interfered in the legislative process, and suggest strategies that could lower barriers to the strengthening of tobacco control policies in South Korea and elsewhere.8. The NHPA is concerned with the details of tobacco control, including health warnings on tobacco products8; the Tobacco Business Act was designed to improve the contributions of the tobacco industry to the national economy by formalizing tobacco production and distribution9. We explored only the process of NHPA revision, as achieved via the Enforcement Decree of the National Health Promotion Act (EDNHPA), which contains the technical details of GHWL enforcement by the NHPA10.Current South Korean laws concerning tobacco control include the Tobacco Business Act and the NHPA12 describe how the legislative process in South Korea involves multiple steps, including the drafting of a bill, consulting with relevant organizations, pre-publication of the bill, examination of the bill by the Legislation and Judiciary Committee (LJC) 11, deliberation and resolution of the bill by the National Assembly, and, finally, promulgation of the bill (https://elaw.klri.re.kr/eng_service/step.do)13. On the other hand, an Enforcement Decree does not require deliberation by the Assembly. Instead, the regulations are examined by the Regulatory Reform Committee (RRC), which is composed of both members of the government and civilians13. We focused on the revision of two laws concerning GHWLs: the NHPA and ENDHPA. We qualitatively analyzed the content of legislative documents produced by the lawmakers.The National Assembly Act and Regulations on Management of Legislative Affairshttp://likms.assembly.go.kr/bill/main.do) using the keywords ‘National Health Promotion Act’14. For each bill, the system includes the reports and minutes of every committee and plenary meeting. We identified 192 amendment bills and selected 13 related to GHWLs, excluding those increasing tax on tobacco products and expanding smoke-free areas, among others. We then collected 15 meeting minutes related to the selected bills: 10 from the Health and Welfare Committee, 3 from the LJC, and 2 from the Assembly plenary session.The study is divided into two parts, by data source . When anText related to GHWLs was extracted from the minutes and classified as either negative or positive in terms of GHWL implementation. Positive text included arguments in favor of GHWL implementation, such as support for the original plan of the Ministry of Health and Welfare (MOHW). Text opposing tobacco control or requesting weakening of the original draft was considered negative. Using an inductive approach, the first author selected relevant sentences, grouped them, and developed preliminary themes. After repeating this process, all authors discussed and agreed on the final overall themes and translated relevant text from Korean to English.In terms of the EDNHPA, we analyzed documents associated with the RRC, including meeting agendas and minutes; these recorded the major discussion points and final committee decisions. During the legislative process dealing with the technical details of GHWLs, the RRC twice (on 22 April and 13 May 2016) examined revised EDNHPA bills prepared by the MOHW. The minutes of both meetings were obtained from the MOHW and the Korea Health Promotion Institute. The first author identified key issues, and all authors reviewed and discussed the texts.A bill requesting legal incorporation of GHWLs was submitted 12 times  during the period between the 16th Assembly (from 30 May 2000 to 29 May 2004) and the 19th Assembly (from 30 May 2012 to 29 May 2016) (Supplementary file). After three rounds of examination by a committee of the LJC, the final bill was adopted at an Assembly Plenary session on 29 May 2015 and the law came into effect on 23 December 2016 .LJC member comments opposing implementation of GHWLs were coded into four themes: 1) Insult to smokers and violation of smokers’ rights to pursue happiness; 2) Violation of the rights of the tobacco industry; 3) Protection of tobacco farmers; and 4) Strengthening of mass media campaigns rather than use of GHWLs . One LJCSome lawmakers argued that tobacco products are legally manufactured and sold under the Tobacco Business Act, so the rights of businesses and tobacco farmers should also be protected. There was also an opinion that tobacco consumption should be reduced in a healthy manner, such as through mass media campaigns and education.Others claimed that this proviso clause, i.e. that the warning picture should be based on facts without being overly obnoxious, should not be included in the law because it is against the purpose of the Act. Moreover, as it is difficult to measure feelings objectively, it was asserted that ‘overly obnoxious’ is not an appropriate legal term.Although the warning size reduction was not accepted, the final version of the NHPA included the proviso clause limiting the expression of pictorial warnings to reflect the proposal of the LJC members.During the LJC meeting of 1 May 2015, a member of the LJC (Lawmaker Lim) stated: ‘Today, I received data from KT&G. After I read it, I thought that, if the bill passed, the circumstances for tobacco growers would become more difficult’. As interactions between lawmakers and tobacco companies  lack transparency, it is difficult to determine how the tobacco company contacted the lawmaker or what information was conveyed. However, it is possible that the company contacted a lawmaker to present the company view, or that of tobacco farmers. The member in question continued to consistently oppose implementation of GHWLs.‘Because GHWLs limit the design, which is governed by the authority of tobacco manufacturers, the top positioning of pictorial warnings on tobacco products violates the principle of proportionality. And consumers may therefore find it difficult to select the tobacco products’. At the first RRC meeting, some members also recommended that the requirement of positioning pictures at the top of packaging should be removed and the GHWLs be positioned at the bottom of cigarette packs.The original plan by the MOHW was to locate the pictorial warnings at the top of cigarette packs . However15. The results showed that participants focused more on the upper than the lower position15. Finally, the RRC accepted that the GHWLs would be positioned at the top.However, the MOHW requested a re-examination of this issue and submitted additional documents in support of positioning the GHWLs at the top. As part of this re-examination, the Korea Health Promotion Institute, on behalf of the MOHW, conducted an experimental study to evaluate differences in eye fixation according to the position of the warning images using an eye-tracker deviceThe RRC proposed two additional recommendations. First, the time until changes had to be made to the GHWLs was extended from 18 to 24 months. Second, the RRC recommended that the paragraph prohibiting the retailer from covering the pictures at the point-of-sale be removed. These were eventually reflected in the final EDNHPA, while the plan to position at the top remained unchanged .The minutes of the first RRC meeting at which the EDNHPA was discussed show that the committee included two members, Suh and Son, representing the tobacco industry: one had served as a non-executive director of KT&G and the other had worked as an advisor to the law office of Philip Morris, which is currently in litigation with the National Health Insurance Corporation. These members stated that the scientific evidence supporting the effectiveness of positioning a pictorial warning at the top was insufficient. Additionally, they argued that placing a pictorial warning at the top of cigarette packets would force store owners to re-install shelves that hid the pictures, a process associated with replacement costs. The RRC thus recommended that the GHWLs be positioned at the bottom of the cigarette packs. However, these two members did not attend the RRC re-examination.16. Despite their proven efficacy, and the efforts of the MOHW and some members of the Assembly to implement GHWLs, it took 14 years before they were finally implemented after first being proposed at the National Assembly in South Korea. Because of continued objections by certain lawmakers, the policy was delayed and subsequently weakened.Use of GHWLs represents a scientifically proven, cost-effective tobacco control policy that does not involve pricing; GHWLs are a means of direct regulation of the tobacco industry itself rather than smokers, and can increase the efficacy of anti-smoking policies without the need for public sector spending17: Graphic warnings ‘demonize’ smokers; Large graphic health warnings violate tobacco manufacturers’ rights to property, including trade mark protection; If the government wants to disseminate health-warning messages, it should use billboards or TV commercials. These situations may indicate that tobacco companies had made direct or indirect contact with some lawmakers, where such contact may have influenced lawmakers’ decisions in the legislative process.Although rare, connections between the tobacco industry and certain lawmakers were identified in South Korea. In particular, persons directly or indirectly involved with tobacco companies served as ‘civilians’ examining the law concerning GHWLs. Furthermore, some lawmakers’ statements were almost identical to the arguments that the tobacco industry had previously used in its attempts to block the implementation of GHWLs7. This may indicate that the tobacco industry’s influence on the legislative process reduced the efficacy of the GHWLs in South Korea.Given these opinions, the original plan was modified to weaken the effect of GHWLs during the legislative process. These outcomes also aligned with the tobacco industry’s strategy to obstruct the legislation related to tobacco control, by substituting the industry’s proposal in place of the original plan18, it is difficult to identify tactics that clearly attest to the inappropriate influence that it is believed to exert on lawmakers19. According to Article 5.3 of the FCTC, tobacco industry workers and representatives should not be involved in any organization or committee involved in policy formulation and the implementation process, in the interest of protecting tobacco control policies from commercial and other vested interests in the tobacco industry1. However, not only supporting groups, which include a tobacco growers’ association, a smokers’ rights group, and tobacco retailing, advertising, law firms20 and some compromised lawmakers, were able to participate in the legislative process in South Korea, despite the fact that they had strong interests in the tobacco industry.However, there is insufficient evidence regarding the means by which the tobacco industry exerted an inappropriate influence on lawmakers. Although the tobacco industry undertakes lobbying to increase its profits by influencing the legislative process20. The international tobacco industry has sought to reduce the size of warning labels21, to limit the number of colors used22, and to render the pictorial warnings ineffective23. The industry has also asserted that the images violate freedom of expression, trademark property rights24 and even freedom of religion23. All of these tactics have delayed implementation of tobacco control policies and undermined their effectiveness26. In India, GHWL implementation was delayed by both international and domestic tobacco companies27; GHWLs have yet to be implemented in the United States because of lawsuits filed by the tobacco industry28.Other countries have experienced delays and difficulties in GHWL implementation, caused principally by tobacco industry interference 29, any tobacco control regulations may be nationally implemented under the FCTC, as well as by state and local governments, which have implemented such regulations to improve the health of their citizens. In the 2003 Hun-Ma457 case30, the Constitutional Court of Korea acknowledged that both the right to smoke cigarettes freely and the right to avoid smoking are constitutional rights. The right to smoke freely is recognized on the basis of human dignity, the right to pursue happiness under Article 10 of the Constitution, and the right to privacy under Article 17 of the Constitution31. The Court stressed that the right to avoid cigarette smoking, which is the right of the non-smokers not to smoke and to be free from cigarette smoking, is also based upon Articles 10 and 17 of the Constitution, and the constitutionally guaranteed right to health and right to life, in the sense that the health and life of non-smokers who are exposed to passive cigarette smoking are endangered.In South Korea, the industry has sought to weaken GHWLs by limiting the images used and reducing their size; the suggestion is that the images and warnings violate smokers’ fundamental rights. As the right to smoke is a limitable constitutional rightBecause both rights are constitutional rights, when they are in conflict—when a policy promotes one right while restricting the other—the Constitutional Court should decide whether such a restriction is constitutional. The Court noted that the right to avoid cigarette smoking is based not only upon the right to privacy but also upon the right to life, which is the premise of all basic rights and occupies the highest position. Therefore, the Court stated, the right to avoid cigarette smoking is a basic right that is prioritized over the right to smoke cigarettes.32. Furthermore, any information provided by the tobacco industry, and any interactions between lawmakers/committee members and the industry, should be disclosed33. Individual lawmakers should be obligated to disclose any relationship with a tobacco company34.To combat this, a system by which the media and community can monitor all lawmakers and members of committees and organizations involved in the legislative process of tobacco control should be established and made accessible by the public35. When plain packaging was implemented in Australia, the tobacco industry argued that this would lead to longer transaction times and customer frustration36. However, no increases in pack transaction times were observed . Additionally, tobacco companies argued that cigarette advertising and display at the point-of-sale target only adult smokers39. In fact, frequent exposure to tobacco advertising is associated with higher levels of cigarette brand awareness, and increased rates of smoking initiation41 and susceptibility among youth43. Therefore, public health advocates should consistently provide scientific evidence that may be brought to bear upon the regulatory process, and should pressure policymakers to swiftly adopt regulations45.We found that timely research on implementation of tobacco control policies was useful. As indicated by the data showing the effectiveness of positioning health warnings on the upper part of the cigarette pack, scientific investigation plays a key role in overturning unsubstantiated opinions47. In this study, however, only the minutes and meeting documents were analyzed. During the qualitative content analysis of the minutes, we found no evidence of monetary donations, or donations of any other type, to lawmakers from the tobacco industry. To supplement the study’s main findings, we recommend further analysis of tobacco industry documents in a follow-up investigation. Second, the materials subjected to analysis were not sufficient. To overcome the limitations of such data, several studies have analyzed the contents of media reports49, since data not considered previously can be extracted from media reports. Third, this study dealt only with the implementation of GHWLs. If future studies were performed examining other tobacco control issues, including tobacco taxation and the designation of non-smoking areas, more of the tobacco companies’ activities, and the political impact thereof, could be identified. Consequently, an expansion in the scope of research in this area is required.This study has several limitations. First, insufficient evidence of a direct connection between the tobacco industry and lawmakers was uncovered. Numerous previous studies have proven the tobacco industry’s use of tactics aimed at delaying and weakening tobacco control policies, by analyzing documents originating from the tobacco industryThe implementation of GHWLs was delayed and weakened due to continued objections by certain lawmakers during the legislative process. These lawmakers had direct or indirect relationships with tobacco companies but nonetheless participated in the GHWL legislative process. However, the commitment of the government (e.g. the MOHW) and a range of research studies, played an important role in refuting oppositional arguments. To promote policies aimed at strengthening tobacco control regulation in the future, it will be necessary not only to prevent any direct or indirect participation on the part of tobacco companies in the legislative process but also to provide a method of monitoring these activities.Click here for additional data file.