Urban scaling relations characterizing how diverse properties of cities vary on average with their population size have recently been shown to be a general quantitative property of many urban systems around the world. However, in previous studies the statistics of urban indicators were not analyzed in detail, raising important questions about the full characterization of urban properties and how scaling relations may emerge in these larger contexts. Here, we build a self-consistent statistical framework that characterizes the joint probability distributions of urban indicators and city population sizes across an urban system. To develop this framework empirically we use one of the most granular and stochastic urban indicators available, specifically measuring homicides in cities of Brazil, Colombia and Mexico, three nations with high and fast changing rates of violent crime. We use these data to derive the conditional probability of the number of homicides per year given the population size of a city. To do this we use Bayes’ rule together with the estimated conditional probability of city size given their number of homicides and the distribution of total homicides. We then show that scaling laws emerge as expectation values of these conditional statistics. Knowledge of these distributions implies, in turn, a relationship between scaling and population size distribution exponents that can be used to predict Zipf’s exponent from urban indicator statistics. Our results also suggest how a general statistical theory of urban indicators may be constructed from the stochastic dynamics of social interaction processes in cities. The search for a general multidisciplinary science of cities is a fundamental scientific problem with strong roots in economics Cities should be regarded primarily as dynamical social networks, constantly changing in terms of their composition and interactions. Consequently, urban indicators, denoted by In order to probe urban indicators that show granularity and a large level of temporal and geographic variation we analyze here data on annual homicides in cities of three Latin American countries over a several year period during which national homicide rates have varied substantially. We analyze data from three of the largest nations in Latin America, presently showing some of the highest homicide rates in the world: Brazil, Colombia and Mexico, for which data are available at the municipal level. The number of homicides is a quantity that is widely available at the local level in developed and developing nations. It is thought generally to be reliably reported, notwithstanding some important caveats Homicides, as the ultimate expression of violence in human societies, are a widely investigated quantity In the next section we discuss some of the characteristics of the data and our main formal objective, the estimation of the conditional probability density We have recently shown We have also observed that for US metropolitan areas many urban quantities vary only slowly, with most change being due to the temporal variation of To address these points, we introduce here new extensive data sets for homicides in three fast evolving (and developing) nations: Brazil, Colombia and Mexico. These nations are presently among the most violent in the world with registered homicide rates greater than 15 per 100,000 inhabitants, see municipio). Municipios are defined as the smallest administrative units with a local government. Because municipalities partition the entire national territory, their interpretation as urban units is flawed, just as it would be to assume that each county in the US, for example, is a city. Most municipalities consist, in fact, of several human settlements over extensive rural areas. This introduces a limitation in the resolution at the smallest population scales. At the larger population scales we can address this issue because large functional cities (metropolitan areas) are made up of a set of municipalities. Thus, bearing in mind these caveats, we adopt a definition of urban units in terms of metropolitan areas for which an official definition exists, plus the remaining non-metropolitan municipalities. Data sources, definitions and more details are provided in the Methods section.In Brazil, Colombia and Mexico the smallest spatial unit for which data are available is the municipality  is an average statement that cannot be obeyed exactly in every instance. This is not only because all cities have specific local characteristics and urban indicators fluctuate over time but, more fundamentally, because a continuous scaling relation must break down in the limit of small discrete numbers. The correct statement must then be formulated in probabilistic terms. To do this we think of both This problem is specified in terms of the conditional probability distribution function of The reason to estimate The distribution of total homicides in cities In practice, we adopt a common procedure of plotting the complementary cumulative distribution function rather than the probability density function, which avoids the noisy character of the tail for large cities.The empirical cumulative distributions of homicides for the year 2007 in Colombia, Mexico and Brazil are shown in To calculate The shape of this distribution, which we had more implicitly noted in One drawback of the log-normal distribution is that both The mean and variance are given by:The maximum likelihood estimators of the log-normal parameters are:If the normal distribution holds in terms the logarithmic variables of population given different values of We can now estimate the parameters of Eq.(5) using Eqs.(8) and (9), and plot  see  and  wFinally, using Eq.(2), we derive the conditional probability function Using Eq.(10) to replace We can expand the squared terms, the logarithms, group some of the terms, so this equation transforms into:Now, recall that both These expressions connect the log-normal statistics of the conditional distribution Determining these conditional distributions enables us to calculate their moments, such as the mean and variance. We take Eq.(10) and Eq.(16) to derive Similarly, the standard deviations From the preceding sections it should already begin to be clear how the log-normal distribution relates to Zipf’s law. We can show how a power-law distribution emerges by deriving the probability distribution of If superlinear scaling  and municipality populations at the National Administrative Department of Statistics (http://www.dane.gov.co). Brazil’s population and homicide numbers are available from the Sangari Institute and Brazilian Ministry of Justice (http://www.sangari.com/mapadaviolencia/). The data spans the years 2003–2007 for Brazil, 2004–2009 for Colombia, and 2005–2009 for Mexico. Data for Mexican municipalities was compiled by Diego Valle Homicides are defined as deaths caused by other persons, intentionally or not. Data for Colombia is available online at the National Institute of Legal Medicine and Forensic Sciences . We adopted such unofficial definitions in our analysis. For Mexico definitions are available at the National Institute of Statistics and Geography (http://www.inegi.gob.mx/est/contenidos/espanol/metodologias/otras/zonas_met.pdf), and for Brazil at the Observatory of the Metropolis (http://www.observatoriodasmetropoles.ufrj.br/metrodata/ibrm/index.html).We adopted standard definitions of metropolitan areas available at Reference Because we are interested in the regime of small numbers where the number of homicides If we let A numerical estimation of A rigorous procedure to estimate these parameters from the data, estimate the error and determine its scaling properties is part of future work.We test the log-normal distribution as a description of Maximum likelihood estimations of Error bars represent plus and minus one standard deviation about the average.The fits were performed using a Levenberg-Marquardt algorithm, which minimizes the sum of least squares of a set of non-linear equations, weighting every point by its error. The function to minimize with respect to vector parameter Here we give additional details of the calculations leading to Eq.(22). First, we write For simplicity of notation, we drop the subscript in We can now complete the square and re-arrange terms to obtain.Now, we see that the term inside the integral is a log-normal distribution, integrated over its entire domain. Consequently, the integral is a constant, regardless of the form of exactly. Then, using the fact that This relationship can also be derived in a more straightforward way under the assumptions that i) a power-law distribution for


The human signal-molecule-profiling database (HSMPD) is designed as a prospective medical database for translational bioinformatics (TBI). To explore the feasibility of low-cost database construction, we studied the roadmap of HSMPD. A HSMPD-oriented tool, called “signal-molecule-profiling (SMP) chip” was developed for data acquisition, which can be employed in the routine blood tests in hospitals; the results will be stored in the HSMPD system automatically. HSMPD system can provide data services for the TBI community, which generates a stable income to support the data acquisition. The small-scale experimental test was performed in the hospital to verify SMP chips and the demo HSMPD software. One hundred and eighty nine complete SMP records were collected, and the demo HSMPD system was also evaluated in the survey study on patients and doctors. The function of SMP chip was verified, whereas the demo HSMPD software needed to be improved. The survey study showed that patients would only accept free tests of SMP chips when they originally needed blood examinations. The study indicated that the construction of HSMPD relies on the self-motivated cooperation of the TBI community and the traditional healthcare system. The proposed roadmap potentially provides an executable solution to build the HSMPD without high costs. Research on biobanks and medical databases provide opportunities for a broad spectrum of interests and applications in translational bioinformatics (TBI). Many countries plan to invest in health IT research by constructing biobanks and health information databases . These pdatabase .Health information technology (HIT), one of the pillars in future medical systems, is based on high capacity and qualified biomedical databases . NowadayVarious biomedical databases have already been constructed worldwide, such as Human Genome Database (HGD), Recon 2, DrugBank, Human Metabolome Database, and ClinicalTrials ,13,14,15These biomedical databases can be roughly classified into three categories, according to the origin and properties of data. The first category, represented by ClinicalTrials  and Virui.e., traditional medical records will be converted into EHRs without changing the equipment and working habits of the existing system. The primal challenge of this strategy is the cost and efficiency of EHR conversion. The second strategy aims to redesign medical tools to generate automatically standard EHRs during the manipulation of doctors and nurses. It will change the machines, instead of the doctors and nurses, to avoid the conversion of medical records. According to the second strategy, the project of human signal-molecule-profiling database (HSMPD) was proposed to take advantage of the current healthcare system to build a standard prospective database as HGD. HSMPD is different from the first category of biomedical databases, because it will not be limited by any scientific experiment and will not select the donors of clinical data. HSMPD is also different from the third category of bio-databases, or a data warehouse of common EHR. The data in HSMPD are designed and standardized on the purpose of TBI, which contains large quantity of redundant information to doctors,  chip” was developed as a specific tool for the data acquisition of HSMPD. It can standardize the detection of multiple signal molecules in one blood sample. Signal molecules, e.g., hormones and cytokines, are biochemical molecules released in one part of the body and deliver messages to affected cells in other parts. Although the concentrations of signal molecules are usually extremely low, signal molecules are important to maintain and regulate the functions of the human body. SMP can be regarded a composite order set of the human body that can provide holographic data of the entire human body. Moreover, SMP is related not only to human gene mapping, but also to the interactions between the human body and the environment . The conThe SMP test can be regarded as an extended blood examination that aims to measure hundreds of cytokines and hormones by using a high-throughput tool. Given that the results of SMP tests can cover the information of regular blood tests in the hospitals, the SMP test can be accepted by doctors theoretically. Simultaneously, SMP records are good resources for multivariate analysis in TBI because SMP records embody large amounts of clinical information. Compared with other EHR systems, HSMPD is both an excellent gold mine for TBI and a compatible tool for traditional diagnosis systems.Mass data stored in the medical system are considered the foundation of TBI. However, many preliminary attempts of TBI were unsuccessful because of misinformation. High-capacity databases with standardized health information are required. In fact, research on TBI has achieved considerable development on gene-related bioinformatics because of HGD. However, TBI, at the proteome level, is lagging behind because of the unavailability of corresponding databases. The HSMPD could be a good TBI resource; however, the high cost of data acquisition is a problem. In this study, we attempted to develop another possible solution to construct a low-cost HSMPD, by which the maturity of HSMPD is accompanied by the spontaneity in economics.The SMP chip was developed for the construction of the HSMPD. This pilot study was a simulated validation in a real hospital to test the procedure of data acquisition in the HSMPD project. On the basis of the present conditions, we conducted a small-scale practical investigation on the data acquisition, storage and retrieval of SMP records in the demo HSMPD system. The feasibility and methodology of creating HSMPD was investigated and evaluated in a common hospital.To accelerate the development of public health systems, a low-cost solution is proposed to install the HSMPD without involving an enormous scientific project such as HGP. The key of the solution lies in the cooperation of IT and instrumentation engineering and the support of traditional health care systems and the TBI community .The cost of data acquisition can be partially supported by the medical system because patients are supposed to pay for their original physical examinations. However, SMP chips are more expensive than traditional diagnostic reagents under the current circumstances. The deficit should be covered by public funding or be shifted to the database users in the TBI community. In this way, the high cost of data acquisition in HSMPD could be lowered to an acceptable amount for TBI researchers.The initial step in the HSMPD project is to develop a HSMPD-oriented tool that should be standardized and high throughput to quantify hundreds of cytokines and hormones. To reduce the difficulty of data collection, SMP chips will be coupled automatically with the IT system. Furthermore, this tool should be as cheap as possible to be widely accepted by medical systems. When patients go to hospitals or health centres, SMP chips could perform the routine blood tests for hormones or cytokines because of the high efficiency and competitive price of the chips. SMP information will be decoded through a web-based program before relevant analysis reports are sent back. The SMP data will be stored in the web-based HSMPD at the same time. TBI researchers can obtain commercial information of the HSMPD at an acceptable cost, thus generating a stable income to cover the deficit during data acquisition. Once the HSMPD system is thoroughly developed, the serological criterion of SMP might become a popular multipurpose diagnostic tool. Chronic disease management, even the diagnosis of some mental diseases such as anxiety or depression, could benefit from SMP . WithoutHSMPD adopts the framework of a relational database. Each SMP data set is divided into three interrelated sections with different information sources . The folThe first section includes four fields: Record ID (RID), Patient’s Name (PN), Doctor’s Name (DN) and Nurse’s Name (NN). When patients go to the blood-collection room, nurses will check the information of the patients and input the patient records into the HSMPD system. Nurses are required to submit a one-time identity registration and login to the system before opening the Nurses worksheet. The NN field can be registered automatically when the worksheet is opened. However, the PN, DN and RID fields need to be filled-in manually. The RID is acquired from the serial numbers printed on the chip, which is the same as the exclusive record number of the corresponding SMP data.The second section includes an SMP table and the following fields: RID, Machine ID (MID) and “Time”. This section will be filled by chip readers and related programs. However, we manually completed the entries in this study because the related machines were still under development. The SMP chip was designed to be readable in microplate readers, which are widely used in biomedical laboratories. The nurses took the blood samples of patients, and we operated SMP chips to load serum samples and diagnostic reagents. The SMP chip was read in a microplate reader to generate primary data. These manual operations of SMP chips could be automatically performed by future chip readers, which can also automatically read and record the RID of the chip and the time that the test was taken. The primary SMP data were decoded, and then stored in a SMP table. RID will also be registered in the SMP table. The chip reader submits the information to a web server, and the machine ID of the chip reader is reported. The exclusive RID will be the primary key that matches the information of the first section.The third section, which will be mainly entered by doctors, includes three fields, namely, DN, medical comments (MC), and Personal Code of Patient (PCP). Doctors are also required to register before logging in. The DN field will be filled automatically when doctors open their worksheets. Besides, doctors are responsible for the private information of their patients. However, this information is not temporarily stored in HSMPD. The HSMPD system will generate PCP, the special code according to the private information of individual patients. The PCP, which is meaningless to doctors, is essential to the HSMPD because this code is the only information that TBI researchers can use to distinguish records of individual patients in the HSMPD. The merged data set from the first and second sections are presented in the corresponding doctor’s worksheet according to DN. Doctors need to check and recognize the patient information input by nurses. Three sections of that record will be related. The doctors need to add some medical comments in the SMP data of the patients. The MC section in the doctor’s worksheet is divided into two parts: the first part includes the symptom and complaints of the patient, which should be completed before conducting blood tests; the second part includes the diagnosis opinions. Both parts will be consolidated into the MC field, thus forming a complete SMP record.The initial plan was to enable patients to register and login to the HSMPD system, in which the patients can visit their own SMP record. However, some doctors had a different opinion. The doctors were worried that their patients will experience unnecessary psychological stress if the patients misunderstood the SMP information. Therefore, the IT service for patients was not tested in this trial and was left for further studies.® 2010 and shared on the intranet of the cooperating hospital to collect comments from invited doctors and nurses. Given that the utilized HSMPD is a general demonstration database, the structure and function of the demo system were limited. Based on the comments of users, the updated version of HSMPD system was developed by using Microsoft® SQL Server® 2005 while the user interfaces were written in C#(C Sharp) on Microsoft® NET Framework® 2.0.This first system of HSMPD was realized by using Microsoft AccessThe 1,536-chamber immuno-nucleic acid sequence-based amplification (immuno-NASBA) chip, named the “SMP chip”, was specifically designed for HSMPD data acquisition . The SMPIn the SMP chip, 12.5% of total chambers are preserved for calibration tests. Therefore, only 1,344 chambers were left for monitoring targeted molecules. The sensing capability of the chip depends on an isothermal amplification assay, which is regarded as a combination of sandwich immunoassay and quantitative NASBA assay . The seni.e., the participators were randomly involved in.This simulation tests were supported by a hospital, which procedures were shown in We orally interviewed the patients, doctors and nurses regarding their attitude towards the SMP test. The investigators for survey studies were divided into two groups: one group interviewed the people who will get their blood tested in the blood-collection room of hospitals, whereas the other group randomly interviewed the pedestrians in city streets far away from hospitals . The subjects for this investigation were randomly selected and unfiltered. The time period of each group was consistent and was evenly distributed in two weeks. We made further inquiries 189 amicable interviewees who were willing to take the SMP tests about their background, as well as the privacy protection in SMP data. The patients were fully informed before the voluntary agreements for SMP tests were signed. The researchers obtained the respective remaining samples from nurses after the ordinary blood tests were performed. No extra sampling of blood was performed in this study.The SMP tests were handled by our researchers, and the decoded results were imported into the demo database system within the intranet of the hospital b,c. The We simulated a TBI researcher assigned to retrieve information from the HSMPD for optimization of the HSMPD system. Both fields of SMP values and medical comments were employed for the retrieval tests, which results were simply grouped into initial subsets. Moreover, we read the entire description in MC to manually find out the missing records of the above subsets. The causes of retrieval failures were analyzed.The survey results about the patients’ attitude towards HSMPD were presented in Before this survey, the roadmap of HSMPD had two different versions. In version A, it was presumed that the patients would pay for the costs of their SMP tests, as long as SMP chips were cheap enough. Consequently, it is not necessary to commercialize any medical data, and many ethical problems can be avoided. However, plan B disagreed with the previous assumption. In version B of the roadmap, commercialization of the medical database is essential to balance income and expenses during the construction of HSMPD. The survey results clearly demonstrated that only version B is practical. The paid services of medical data in HSMPD have to be included in the roadmap of HSMPD, although more ethical issues will be caused by this action.Since the mode of data collection in the HSMPD project is passive, it does not allow the selection of test objects. The passive mode is unable to meet the needs of medical research, particularly experimental research in pharmacy. Generally, medical experiments include making assumptions, designing animal experiments between the control group and the experimental group, and conducting clinical trials to verify the hypotheses. For the short term, the HSMPD cannot fulfill the need of designing experiments. However, the HSMPD may help medical experimental research in the long run. When sufficient data accumulated in HSMPD, the medical assumptions will be easier to check by the rapid statistical analysis on the clinical cases in HSMPD.The SMP value for each patient was a multivariate set of real numbers, thus making this value suitable for storage in a multi-field table. The SMP measurement was imported into the database artificially. In the future, these data will be directly uploaded into the database by computers, thus simplifying the storage and retrieval of SMP values.MC filed is a character string inputted by doctors, which is easy to store but difficult to retrieve correctly. We also met some challenges when retrieving the MC Field. Searching for keywords in MC is easy, and the retrieval results can be simply grouped into initial subsets. However, we found some missing records upon reading the entire description in MC. Some doctors input many synonyms and some abbreviations in the MC Field, thereby causing possible retrieval failures. The majority of doctors in this study choose Chinese as their working language, but few doctors partly used English or Latin abbreviations in their comments. In addition, comments with positive or negative tones should roughly divide the previous subset into three subclasses: positive, suspected, or negative. The method to identify the positive or negative tone in the MC is another challenge in the creation of the HSMPD. Much energy and time was spent on segregating the comments here. The HSMPD might employ an intelligent user-interface of other databases to bypass this challenge.Normalized measurement of on-chip immuno-NASBA assay could provide comparative data as the traditional ELISA methods. In this study, only 189 volunteers participated in the SMP tests. Then, 189 SMP records were collected for the database. As mentioned above, the clinical samples were measured by ordinary blood tests before the testing on SMP chips. Some ordinary blood tests included some quantification ELISA tests for hormones. The comparison plots of five common targets from both SMP chip testing and ELISA methods were shown in FSH, LH, TSH, HCG and cortisol in about 40 patient specimens were measured by the two methods. From the comparison plots in The HSMPD data structure was optimized according to the comments about private information of patients. User information was divided into two sections. The privacy section cannot be accessed without the mediation of a trusted intermediary, whereas the public part is allowed to contain SMP values and medical comments from doctors. The identity information of patients is replaced by a string of numbers, PCP, which could make each clinical record anonymous to scientists. In addition, the PCP is also a pseudonym of each patient. PCP can help the TBI researchers to distinguish individual records in HSMPD and retain a clue for in-depth studies when it is necessary. To some important patients or doctors, TBI researchers could indirectly contact them through the trusted intermediary according to the PCPs. If the patients or doctors are willing to participate in the in-depth study, the researchers can access detailed clinical data. The role of PCP may then be acceptable for both parties.The input of MC in HSMPD seemed to be a challenge. From the interviews with doctors, the feedback shows their disfavour of electronic recording for the HSMPD. They prefer to use the traditional way of inputting their comments in the database system installed in the hospital. Moreover, doctors were unwilling to spend any time on filling unnecessary forms. To avoid the typing of medical comments, as some doctors suggested, the HSMPD interfaces could be merged into the local hospital information system (HIS), hence the medical records of the patients could be exported into the HSMPD automatically. Many HIS software applications have been commercialized. One of them was used inside the cooperating hospital, which has a well-designed database system to organize the daily work in the hospital. Most fields in the HSMPD, such as PN, DN, NN, MC and Time, have been built into the HIS. The HSMPD software of the next version might become an add-in program of current HIS system, which interfaces should strictly fit the current work habits of doctors and nurses.Actually, HSMPD was proposed on the basis of fundamental physiological theories. In the past decades, biologists always tried to find a simplex biomarker to represent the status of a specific disease, but such a one-variable function maybe never exist in the case of many complex diseases. However, the biologists have no alternative because few qualified serological database is available for data mining. Being a perspective database, HSMPD is an open data warehouse of serological data with medical comments. It is designed and standardized for TBI research, rather than the common healthcare processes. The outbreak of TBI applications in the serological diagnosis might appear after the completion of HSMPD. However, reducing the cost of data acquisition is crucial. The SMP chip can be considered a low-throughput protein microarray with a 3D structure, which might enhance the efficiency of the immunoassay. Given that low-cost materials and fabrication methods were employed, the cost of the SMP chip did not increase significantly compared with that of traditional microarrays. Shrinking the chips might save expensive antibodies, but the cost of detection modules will increase consequently. The compatibility of SMP chips provides multiple choices of detection modules. The current detection module was a microplate reader, whereas a more professional SMP-chip reading platform is still being developed potentially on the basis of our previous research achievements ,36,37. UThe establishment of a public HSMPD database will greatly facilitate TBI research on the association between diseases and serological patterns of patients, because scientists could study millions or billions of standard clinical SMP records in the HSMPD through biostatistics programs on a national network platform, instead of investigating hundreds of patients individually. From the viewpoint of scientists, the creation of HSMPD will significantly assist in medical research, particularly in disease diagnosis and chronic disease management.Although HSMPD has built in protection design for the privacy of participants, tremendous ethical and social controversy may be generated between scientists and participants of the HSMPD. Anonymous records have to be employed the infrastructure of the HSMPD, which means that the database will not release the fields of non-essential personal information, such as name, home address and birthday. Only physiological and medical information will be shared in the public database. Traditional consent norms and policies require participants to be fully informed of the nature and risks of the research . HoweverMoreover, the construction of the HSMPD depends on a huge investment, even if it is far less than the cost of HGP. We suggested a construction mode with minimum investment. This project needs to have relatively small investments at the early stage. However, given that the HSMPD relies on the information resource of the database, the HSMPD needs to acquire income to maintain its growth. This stage has entered a cycle of positive feedback. The larger the capability of HSMPD is, the more abundant the funding from the IT service becomes. When the HSMPD matures, commercialized HIT services will continue to bring a virtuous cycle for the entire system, whereas TBI researchers might obtain more resources for further study.The construction of high-quality clinical database might be the main bottleneck at present for the development of TBI. The HSMPD, an ideal clinical database, is designed for TBI research and supported by its standardized tool for data acquisition. The clinical records in HSMPD could be a promising resource to significantly influence the TBI research. However, nontechnical challenges mainly hinder the construction of HSMPD, including the high cost of data acquisition and some ethical issues. By comparison, the technical aspect of HSMPD project is not very challenging. A feasible solution was proposed to build the HSMPD with minimum investment, which relies on the cooperation of IT, instrumentation engineering, health care systems and the TBI community. The SMP chip and the demo HSMPD system were developed and preliminarily evaluated in the hospital. The positive results in this study demonstrated a rational and acceptable mode for the construction of HSMPD, which will play a role as the prospective bridge between traditional health care systems and the TBI community.


Health care providers are often unfamiliar with the needs of women with disability. Moreover maternity and postnatal services may not be specifically tailored to the needs of women with disability and their families. We conducted a systematic review to determine the effectiveness of healthcare interventions to improve outcomes for pregnant and postnatal women with disability and for their families.Studies on pregnant and postnatal women with disability and their families which evaluated the effectiveness of an intervention using a design that met the criteria used by the Cochrane Effective Practice and Organization of Care group were eligible for inclusion in this review. A comprehensive search strategy was carried using eleven electronic databases. No restriction on date or language was applied. Included studies were assessed for quality and their results summarized and tabulated.Only three studies fully met the inclusion criteria. All were published after 1990, and conducted as small single-centre randomized controlled trials. The studies were heterogeneous and not comparable. Therefore the main finding of this review was the lack of published research on the effectiveness of healthcare interventions to improve outcomes for pregnant women with disability and their families.More research is required to evaluate healthcare interventions to improve outcomes for pregnant women with disability and their families. More than 1 billion people, 15% of the global population, are disabled and a worldwide disability prevalence of 10% has been estimated among women of childbearing age  and, in Disability is not a straightforward term to define and many definitions are in place. Therefore, the International Classification of Functioning Disability and Health (ICF) definition was adopted for conducting this review. The ICF states that: “Disability is a decrement in functioning at the body, individual or societal level that arises when an individual with a health condition encounters barriers in the environment” and “Disability is a complex phenomenon, reflecting an interaction between features of a person’s body and features of the society in which he or she lives” . This duThe United Nations Convention enshrines human rights to education, employment, housing and transport, and in Article 23 promotes respect for home and family, specifically reproductive rights . Yet womIncreasing numbers of women with disabilities wish to become mothers . In one Although there is information about the reproductive experience of women with disability, and potential barriers to access as well as suggestions on how to improve services , there hThe environments and policies within maternity services could either contribute to, or alleviate, disability. Therefore, we decided to undertake a systematic review with the objective of determining the effectiveness of healthcare interventions in improving outcomes for pregnant and postnatal women with disability and for their families. Any strategy aiming to change health care performance in this population was considered in this review. For example assistive technology interventions such as videos, telephone helplines, resource networks, parent-to-parent links. This is a broad aim and antenatal interventions were considered separately from postnatal interventions.A preliminary protocol was designed and then independently peer-reviewed. This outlined the literature search strategy, the selection process for identifying relevant studies, the method of extracting data from eligible studies, assessing the methodological quality of individual studies, and methods of data synthesis. A project advisory group, consisting of methodologists, clinicians and representatives of relevant users and voluntary groups working in the field of maternity care and disability were invited to comment on the protocol.We only considered studies that met the criteria used by the Cochrane Effective Practice and Organization of Care group (EPOC)  for inclWe included studies carried out on the following groups: women with disability during the antenatal, intrapartum periods or in the postnatal period (up to 12 months following birth); families, partners and children of women with disability during the antenatal, intrapartum or postnatal periods; health care professionals at any time-point but aimed at improving quality and/or accessibility of maternity services for women with disability.Any intervention aiming to change health care outcomes for disabled pregnant and postnatal women and their families where the intervention took place in the antenatal period, during childbirth and in the first postnatal year was considered for inclusion. We only considered studies of interventions which were intended to tackle disabling barriers rather than the health conditions associated with disability. Studies focusing on treatment of underlying health conditions (where the focus was not primarily on the limiting or disabling aspects of these conditions) were excluded. So, for example, studies concerned with the clinical management of pre-eclampsia, anaemia, gestational diabetes, perinatal depression, and pelvic pain  were not included in this review. For most of these conditions, the Cochrane Pregnancy and Child Birth Group  has alreAs we were not clear how many studies we would find or what outcomes would be used we considered all outcomes relevant to the health and social care of our population of interest with no specific exclusions. These outcomes could include preterm birth, birth weight, stillbirth, and mode of delivery; accessing health care services; and children-parent separation rate.A comprehensive search strategy was developed  Issue 2, 2012); Medline, Ovid (1967 to March 2012); EMBASE, Ovid (1946 to March 2012); CINAHL, EBSCO (1980 to March 2012); PsychINFO, Ovid (1945 to March 2012); Latin American Caribbean Health Sciences Literature (LILACS); Index to Theses (1974 to March 2012); British Nursing Index (BNI) (1994 to March 2012); Social Science Citation Index (1952 to March 2012); and Sociological Abstract, CSA (1952 to March 2012). , The United Nations (UN), the Department of Health England (DH) and National Institute for Health and Clinical Excellence (NICE) websites. The reference lists of all included papers were searched. No language or date restrictions were applied to the searches. Attempts were made to obtain translations of included non-English articles.Articles were only rejected on initial screen if the reviewer could determine from the title and abstract that the article was not a report of an intervention, that the intervention did not address disability, or if the intervention was not conducted in relation to the antenatal or intrapartum period or in the first postnatal year. When a title/abstract could not be rejected with certainty, the full text of the article was obtained for further evaluation.Following an initial screen to exclude non-relevant studies, potentially relevant studies were assessed independently for inclusion by two assessors (RM and RG) and differences between reviewers' results resolved by discussion and, when necessary, in consultation with a third reviewer. Studies were categorised as “included” or “excluded”.A data extraction form was developed and included the following sections: study design, characteristics of the study participants such as age, disability, gestation at birth, intervention types, frequency and duration of the intervention, outcomes, and reported results. The data extraction form is available from the authors on request.Data were extracted from published reports. When missing data were identified, investigators were approached. The data were then added to the data extraction form which contained data reported in the original paper and data ultimately collected by the reviewers. One reviewer extracted the relevant data (RM) and another reviewer (RG) checked this independently. Contradictions were resolved through discussion.Risk of bias was assessed independently by two reviewers (RM and RG). The eight EPOC-described criteria have been followed: sequence generation, allocation concealments, blinding, incomplete outcome data, selective reporting, baseline characteristics, baseline outcomes, protection against contamination and other bias. Each criterion was given one of the following ratings: “yes”, “no” or “unclear”. Any discrepancies in quality rating were resolved by discussion.As we expected, the studies we identified were of an extremely heterogeneous nature. For this reason we predominantly used tabulation and narrative synthesis in summarizing the data.The electronic search strategy yielded 28,918 citations and a hundred references from other sources  -22. Two One study was rated as good quality (Scafidi & Field) , one of Blinding of participants was possible in Scafidi & Field , as the Two of the studies were free of risk of incomplete outcome data (attrition bias), this was not clear in Barbosa Regia . BaselinImbalance in the marital status of the participants was mentioned in Keltner et al. , where 5The studies were free from selective outcome reporting and other risk of bias.It was not possible to perform a meta-analysis as the included studies were not sufficiently homogeneous. Studies varied in the categories of participants, the types of intervention and the outcomes measures applied.Interventions to improve quality and accessibility of prenatal care for women with disability and their families: One study was included in this review which tested the effects of an intervention in the prenatal period. Barbosa Regia  investigInterventions to improve quality and accessibility of postnatal care for women with disability and their families: In two randomized controlled studies  ,22 the iThe family configurations in Keltner et al.  includedThe effects of a family intervention programme on the maternal-child interaction measures were assessed by Nursing Child Assessment Teaching Scale (NCATS)  based onScafidi & Field  enrolledThe Brazelton Neonatal Behaviour Assessment Scale-Kanas Supplement  was applThe literature on interventions targeting disability in pregnancy and postnatally is minimal, with only scarce evidence to inform and promote good practice. Only three studies, all with small sample sizes, were included in this review. All of the interventions reviewed were aimed at women with disability and their families. One study involved delivering training to healthcare professionals, as well as enrolling women with disability. Each of the studies reported that the interventions had a significant positive effect. Two studies were conducted in a hospital setting, giving tighter control over the intervention environment. However, the studies evaluated the effect of the intervention on a relatively small number of participants. The methodological quality of the included studies was moderate to low, with limited information available to assess other biases. We adopted a broad research focus, in terms of types of disability, health care interventions and their timing , and research participants . The considerable heterogeneity across the studies was predictable and no meta-analysis could be conducted.The review was comprehensive in its scope: over 20,000 published papers were identified. However, only a small number of studies fulfilled all of our inclusion criteria. We found that most published papers on disability and pregnancy focused on the underlying medical condition causing the impairment, which was not within the scope of this review. Those which did focus on women with disability were usually case reports, qualitative studies of patient experiences of care or small descriptive studies which were not within scope. Very few were intervention studies and of those that were, most were uncontrolled. Thus, although we identified a large body of literature dealing with the clinical management of specific conditions which are often associated with disability in pregnancy and the postnatal period the published literature on controlled evaluations of interventions to improve maternity care for disabled women in general is extremely sparse.However, we did find three useful studies which we now consider in context. The one year family home intervention programme demonstrated significant success in improving maternal-child interaction for mothers with developmental disability in Keltner et al. . This stTwo studies  ,22 in thEach of the three randomised trials -22 had vOur findings are consistent with a recently published review  of barriWe are unable to draw firm conclusions on which interventions are most effective in improving healthcare outcomes, as sufficient data on outcomes for pregnant women with disability are not yet available. The paucity of evidence is due to a lack of studies on pregnant women with disability in general. Well designed, sufficiently powered intervention studies are required.The studies currently being reviewed provide very little practical evidence of the efficacy of any interventions. The three RCTs were of a small sample size and were also prone to methodological bias. However, we are able to make some recommendations. It is quite clear that comprehensive support should be routinely provided to the families of women with developmental disabilities. Elsewhere, massage therapy could improve the behaviours and weight of newborn babies to HIV-positive mothers. Overall, HIV-positive women and their babies could benefit from an educational video to promote their attachment. The effectiveness of these interventions and other potential interventions could be established with further research. Another issue that needs to be addressed is the general lack of involvement of women with disabilities in population based research. It may reflect the more general issue that people with disabilities are often excluded from such research.The findings of this review indicate substantial gaps in the evidence on evaluated interventions designed to improve outcomes for pregnant women with disability and their families. There is an urgent need to test and evaluate the efficacy of feasible interventions, in addition to further developing study designs for the evaluation of health care interventions targeting women with disability, their families, and healthcare professionals. There is a need for large prospective controlled studies of interventions in this population. We would also suggest that any intervention should be developed in collaboration with women with disability. A recent population-based maternity survey in the UK  focusingThe authors declare that they have no competing interest.RM and RG wrote the protocol, assessed potentially relevant articles for inclusion/exclusion, conducted the methodological quality reviews, tabulated the extracted data and wrote the first draft of the paper. All authors commented on the protocol, were involved in the interpretation of the findings and edited the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/14/58/prepubMedline search.Click here for fileSearch report.Click here for fileExcluded studies.Click here for file


There have been considerable recent advancements in animal breeding and genetics relevant to disease control in cattle, which can now be utilised as part of an overall programme for improved cattle health. This review summarises the contribution of genetic makeup to differences in resistance to many diseases affecting cattle. Significant genetic variation in susceptibility to disease does exist among cattle suggesting that genetic selection for improved resistance to disease will be fruitful. Deficiencies in accurately recorded data on individual animal susceptibility to disease are, however, currently hindering the inclusion of health and disease resistance traits in national breeding goals. Developments in 'omics' technologies, such as genomic selection, may help overcome some of the limitations of traditional breeding programmes and will be especially beneficial in breeding for lowly heritable disease traits that only manifest themselves following exposure to pathogens or environmental stressors in adulthood. However, access to large databases of phenotypes on health and disease will still be necessary. This review clearly shows that genetics make a significant contribution to the overall health and resistance to disease in cattle. Therefore, breeding programmes for improved animal health and disease resistance should be seen as an integral part of any overall national disease control strategy. There continues to be very significant advances in efforts to control disease in cattle, with the potential for significant improvements to both performance and welfare. These advances have included improved understanding of disease pathophysiology and epidemiology, as well as the development of products such as antibiotics and anthelmintics for improved disease control.Concurrently, there have been considerable advances in animal breeding and genetics, relevant to animal disease control. These advances are of considerable veterinary interest, noting that observed animal performance is the outcome of the interaction between the animal's genetic makeup and the specific environment it was exposed to. Logically, therefore, improved genetics has the potential to complement current approaches to animal disease control. Improvement in animal health through genetic selection is advantageous, because genetic gain is cumulative and permanent, as the genes introduced into a population can persist for many generations. Unravelling the genetic architecture of health and disease resistance not only facilitates knowledge development on potential for breeding for improved health status but also generates knowledge for biomedical research in animals and humans including applications such as vaccine development.The objective of this review is to summarise research studies on the genetics of animal health and disease resistance in cattle, with particular reference to studies undertaken in Irish cattle. The implications of these results in breeding for improved animal health and disease resistance are discussed.Prior to discussing the genetics of animal health and disease resistance, the terms commonly used by animal breeders to describe the characteristics of a population need to be explained:The phenotype is simply the observed performance of an animal "in the field" . A phenotype, or trait, may be continuous  or discrete .The definition of genotype varies. Animal breeders commonly use genotype to describe a particular strain of animal . Molecular geneticists, however, commonly use genotype to describe the genetic variants  an individual possesses at a particular position in its DNA, also known as a locus."snips") and copy number variants (CNVs).A genetic marker is a measurable variation in the DNA sequence of a population. Common types of genetic markers, generally termed polymorphisms, include microsatellites, indels , single nucleotide polymorphisms . In the calculation of broad-sense heritability, the numerator also includes non-additive genetic variation. In this review we will only consider narrow-sense heritability estimates. Heritability varies from 0 (not heritable) to 1 (fully heritable). If the heritability is high, we can expect a large proportion of the phenotypic differences of the parents to be passed on to the progeny. Also, the larger the heritability, the greater the expressed phenotype resembles the genetic merit of the animal.Heritability summarises the proportion of phenotypic variation, or differences among a cohort of animals, attributable to genetic variation between individuals. Animal breeders commonly cite the narrow-sense heritability, denoted as Maternal heritability is the proportion of phenotypic variation among offspring that is due to the genes expressed by the dam. A maternal heritability of calving difficulty is often quoted which encompasses for example, the size of the pelvis of the dam. The direct heritability for calving difficulty is the effect of the genes of the dam (and sire) on, for example, the size of the calf. A maternal heritability has also been reported for weaning weight  which inA measure of the variation or differences within a population that is due to the differences in genetic merit of the animals. More commonly, genetic variation is expressed as the genetic standard deviation  within a population.A genetic correlation describes the strength of the linear relationship between two traits due to the genetic influences on each trait. It varies from -1 (strong negative relationship) to 0 (no relationship) to +1 (strong positive relationship between two variables). Genetic correlations can be due to the same mutation affecting both traits (termed pleiotropic effect) or different mutations affecting both traits but tending to, on average, be inherited together .Estimated breeding value is an estimate of the genetic merit for an animal for a given trait or series of traits based on an evaluation of all available data on the performance of an animal, and close relatives, for a trait. Using traditional methods of genetic evaluation, the true breeding value (or true genetic merit) is not known. The estimates of genetic merit are generally presented as the predicted transmitting ability (PTA) in dairy cattle or expected progeny difference (EPD) in beef cattle which are the EBV divided by two .Annual genetic gain for a given trait may be described by the following equation :where ΔG is annual genetic gain; i is the intensity of selection; r is the accuracy with which the genetic merit of each animal is known, σ is the genetic standard deviation ; and L is the generation interval.The greater the selection intensity the greater will be the genetic gain for that trait. The accuracy of selection is affected by both the heritability of the trait and the information available on the animal itself and its relatives. Figure There are many bovine viral diseases in Ireland, including bovine viral diarrhoea (BVD) and several viral infections associated with the respiratory system . As yet, there has been no Irish research to quantify the genetic variation present in susceptibility to bovine viral diseases.Breed differences in susceptibility to respiratory disease, however, have been demonstrated elsewhere . FurtherAs part of a larger scale study with 12 different breed types in the USA, Snowder et al.  reportedMastitis is one of the most costly diseases in dairy cattle production systems and is also likely to impact significantly on profitability in suckler beef production systems. A plethora of international scientific studies have been undertaken on the genetics of udder health, including genetic analysis of Irish Holstein-Friesian dairy cows . HeritabIn their review, Mrode and Swanson  reportedAfter mastitis, lameness is probably the next most costly disease in dairy and beef production systems. Heritability of lameness varies from 0.03 to 0.096 when scored by farmers ,11,12 orMycobacterium bovis) is perhaps the most problematic. There have been intensive national efforts in Ireland towards M. bovis eradication for many years [A broad range of other diseases in Irish cattle can be attributed to bacterial infection. Of these, bovine tuberculosis , the causative organism for Johne's disease, and these have generally been confined to analysis of antibody response to MAP. Heritability estimates vary from 0.05 to 0.15 [Few genetic parameters are available on the susceptibility to  to 0.15 -22, with to 0.15 . The gen to 0.15  as 5.4 pSalmonella typhimurium infection than Jersey calves, which suggests that genetic differences do exist. Furthermore, heritability estimates for mortality, survival time and quantitative caecal salmonella carrier state at the end of the rearing period for experimentally infected chickens was 0.12, 0.06 and 0.09, respectively [As yet, no attempt has been made to estimate the heritability for susceptibility to salmonellosis in cattle. However, Wray and Sojka  reportedectively , which sLike salmonellosis, no estimate of the heritability of brucellosis is available, although Templeton et al.  increaseSome research has been undertaken to investigate the heritability of metabolic diseases of cattle, including ketosis, hypocalcaemia , hypomagnesaemia  and displaced abomasum. In general, heritability estimates for these metabolic diseases vary from 0.009 to 0.31. Heritability estimates for hypocalcaemia vary from 0.01 to 0.13 ,27-30; tThe larger heritability for displaced abomasum relative to the other diseases may be surprising given the known influences of nutrition and management on each of these metabolic disorders. However, the larger heritability may not in fact be due to a truly greater influence of additive genetics on the trait but due to a more accurate recording of the trait since most will be diagnosed by a veterinarian. Furthermore, displaced abomasum is a binary trait, with no ambiguity with respect to the severity of disease.Most diseases impact in some way on reproductive performance. For the purpose of this review, fertility-related diseases are confined to RFM, metritis and cystic ovaries. In a study with over half a million Norwegian Red first lactation cows , the herHeringstad  documentNeospora caninum in Canadian Holstein cattle. Heritability estimates for gastrointestinal nematode burden, measured as eggs per gram of faeces or larvae per gram of faeces, ranged from 0.00 to 0.25 (SE = 0.02 to 0.05) in Dutch Holstein-Friesian cattle [Although much of the research on the genetics of susceptibility to both endo- and ecto-parasites has been undertaken in sheep , there in cattle ; the aven cattle  in a revIt is not possible to accurately quantify genetic trends for most health traits in most countries because accurate records and data on animal health are not available, certainly not routinely. Nonetheless, past genetic trends may be predicted based on estimated genetic correlations with production traits, and the impact of these correlations quantified using knowledge on past breeding goals.With several notable exceptions, particularly from the Nordic countries, breeding programmes of the past selected aggressively for increased milk production . CurrentFew estimates are currently available on the genetic correlation between milk production and several infectious diseases. Only one study has reported a genetic correlation between 305-day milk yield and serological response to MAP . DependeTable Traditional genetic evaluations use sophisticated statistical methodology to estimate the genetic merit of an animal, and require large datasets containing information on animals, their pedigree, sibs and progeny. These methods of genetic evaluation are not without their limitations, particularly when seeking to breed for improved resistance to disease. Examples of the limitations include:• the phenotype measured contains error ,• the phenotype may not be measurable in both genders ,• performance in adult cattle cannot be measured in calves, thereby delaying the time lag to identification of genetically different animals for adult performance,• antagonistic or unfavourable genetic correlations between traits of interest cannot be easily resolved , and• genotype by environment interactions may exist , which may complicate the statistical analyses.Furthermore, accurate estimates of genetic merit require large and expensive progeny testing schemes. This is particularly true for low heritability traits where large progeny group sizes with recorded health phenotypes are necessary to obtain accurate estimates of genetic merit. New technologies provide an opportunity to reduce or alleviate some of these limitations.Advancements in 'omics' technologies and how the emerging data are interpreted and combined have the potential to overcome, or at least minimise, some of the aforementioned disadvantages of the traditional methods of genetic evaluation. The recent advancements in 'omics' technologies and their applications to animal breeding have been discussed in detail by Berry et al. . Marker-Genomic selection  is now rSeveral concerns may be raised about the possible repercussions or limitations of breeding for improved animal health and resistance to disease, some of which have already been discussed in depth by Stear et al. . Concern• sustainability of breeding for resistance in the face of continuous evolution of pathogens,• the feasibility of selection for traits where little genetic variation may exist,• impact of selection for resistance to a given disease on the genetic resistance to other diseases,• the impact of selecting on a phenotype thought to reflect resistance to a disease, on the actual genetic predisposition to the disease ,• impact of selection for disease resistance on genetic gain in other traits affecting profitability, and• the cost-benefit of developing a breeding programme to select for improved resistance to disease.There is some concern that the rates of evolution of pathogen genomes are significantly more rapid that those of their vertebrate hosts . In otheAn argument is sometimes used that progression from infection to disease is purely environmental or that the heritability of disease resistance is too low for breeding to be fruitful. However, this review clearly shows genetic variation in resistance to the majority of diseases in cattle. Therefore, if sufficient phenotypic data is available, then the impact of low heritability on genetic response is minimised. Furthermore, new technologies such as genomic selection, if exploited, will further reduce the impact of low heritability on genetic gain.Interactions between diseases are expected ,15 and, Due primarily to a lack of routinely available data for a given phenotype of interest, biological predictors are sometimes used as proxies. Such proxies include reaction to the tuberculin test as a predictor of susceptibility to tuberculosis, serological response to MAP as a predictor of susceptibility to MAP, and more commonly somatic cell count as a predictor of clinical mastitis. Although the correlations amongst most predictors and the traits being predicted are strong ,17, theyResponse to selection for a given trait within a breeding goal is a function of, amongst others, the relative weight placed on that trait, the quantity of information available on that trait (which affects the accuracy of selection) and the phenotypic and genetic relationships with other traits within the breeding goal. The inclusion of a trait antagonistically correlated with performance within a breeding goal will reduce the genetic gain in the performance trait. Most studies, already discussed, have documented an antagonistic correlation between both animal health and resistance to disease and milk production Table , implyinRoutine access to accurate phenotypes is vital to achieving sustainable genetic gain in animal health and disease resistance. However, for rare diseases in particular, a cost-benefit analysis of generating sufficient data to estimate breeding values and then incorporate these values into a breeding programme should be evaluated relative to embarking on a project to control the disease through other means . This is particularly true since expected responses to genetic selection will take a long time to develop although they are cumulative and permanent. Nonetheless, the development of 'omics' technology and associated analysis of the data may ameliorate the necessity for continuous routine access to such data. Furthermore, when evaluating the economic benefit of breeding for disease resistance, some account must be taken of the impact of selection on its effects on the transmission of disease through the population and, therefore, the challenge faced by all animals including those not selected for resistance .One of the biggest constraints of breeding for improved animal health or resistance to disease is routine access to accurate phenotypes  of health traits. Therefore, research must be undertaken on the development of inexpensive and humane methods of either challenging animals for disease resistance to generate phenotypes  or the development of accurate bio-markers that can be readily measured in large numbers of animals at a relatively low cost. Furthermore, increased collaboration between veterinarians and animal breeders on the definition and collection of the relevant phenotypes, as well as the most appropriate statistical model, based on biological soundness, is vital to achieving genetic gain.Not alone do developments in animal breeding and the relevant 'omics' disciplines aid in breeding for increased resistance to infection, but elucidation of the genome of the host, coupled with the availability of the whole genome of the pathogen and how that interacts with the genome of the host, will help in determining the mode of infection and thus the development of effective vaccines or prophylactic treatments.There is overwhelming evidence that genetics make a significant contribution to the health and resistance to disease in cattle, and that the tools for simultaneous selection on these traits and other performance traits are available. Furthermore, because of differences in exposure rates as well as the lack of complete sensitivity and specificity of tests, heritability estimates for health and disease resistance traits discussed in this review are likely to be underestimates of the true heritability . AdditioThe authors declare that they have no competing interests.All authors contributed to the literature review and writing of the manuscript. All authors read and approved the final manuscript.


Background. To estimate the exposure to medicines with unknown fetal risk during pregnancy and to analyze the maternal characteristics associated with it. Methods. A questionnaire was administered to 4,189 mothers of children belonging to the 2004 Pelotas (Brazil) birth cohort study about use of any medicine during gestation. We evaluated the associations between use of medicines with unknown fetal risk and the independent variables through logistic regression models. Unknown fetal risk was defined as medicines in which studies in animals have revealed adverse effects on the fetus, and no controlled studies in women, or studies in women and animals, are available. Results. Out of the 4,189 women, 52.5% used at least one medicine from unknown fetal risk. Use of these medicines was associated with white skin color, high schooling, high income, six or more antenatal care consultations, hospital admission during pregnancy, and morbidity during gestation. Conclusion. The use of unknown fetal risk medicines is high, suggesting that their use must be addressed with caution with the aim of restricting their use to cases in which the benefits are greater than the potential risks. Studies have demonstrated high prevalence of medicine use during pregnancy. The exposure to at least one medicineduring pregnancy is most often exceeding 70% –10. A reIn many situations the use may be unnecessary and even dangerous for the fetus, although one should consider that in most cases the use of medicines to treat chronic conditions and problems associated with pregnancy can be vital to the health and well-being of the woman and the offspring , 13. Prescription of medicines during pregnancy is challenging for doctors because they need to balance the benefits of the treatment against possible damages to the fetus . Most stThe most challenging category of medicines in this case, however, is the one in which the risk to the fetus is unknown, classified by the FDA in Category C. This group represents an important fraction when considering the quantity of prescribed drugs and the number of exposed women. Studies indicate that the use of unknown fetal risk medicines during pregnancy ranges from 19% to 40% , 6, 23. In 2004, the third birth cohort in the city of Pelotas, southern Brazil was initiated. In this study, all mothers of babies born in the city's five maternities  were interviewed within the first 24 hours that succeeded childbirth. A standardized precoded questionnaire was applied, including questions about the use of any medicine during pregnancy and the initiation month and termination of this usage. The question about medicine use was: “Please, let us know the name of all medicines that you have used during pregnancy. Please remember to consider those used for nausea, heartburn, anemia, treatment of urinary tract infection, vaginal infection, high blood pressure, or diabetes.” Further details on the methodology of the cohort can be found elsewhere ,The prevalence of women exposed to the medicines with unknown fetal risk 52.5%) was higher than that observed in most studies 14.7 to 19%) [2.5% was  to 19%  but loweμg), vitamin C (70 mg), vitamin E (10 mg), and nicotinamide (17 mg). The following vitamins show positive evidence of fetal risk in concentrations higher than 400 IU and 8,000 IU/day, respectively, for Vitamin D (and D3) and vitamin A. Formulations with multiple vitamins stood out in the analyses of the medicines with unknown fetal risk during pregnancy. The risk of some vitamins during gestation is dose-dependent. The multivitamin's components were analyzed individually and classified according to their dosage in the formulation. According to Briggs et al. , the folThe use of multivitamins during pregnancy is often suggested as an intervention aimed at improving maternal and fetal health. However, substantive evidence regarding the effectiveness of multiple-micronutrient supplements during pregnancy is not available. Its use during the prenatal period is associated with controversial results in the literature which points to positive results  and lackThe analysis of the variables potentially related to a greater use of medicines with unknown fetal risk was also performed for the use of all medicines during pregnancy. White women with higher education and greater income used more medicines with unknown fetal risk. In general, higher education alone was associated with greater use of medicines, which is in agreement with a study conducted in France and others in several Brazilian cities , 36, 40.Generally speaking, the presence of morbidity was associated to an increased risk of the use of medicines in general and also medicines with unknown fetal risk. This was verified among mothers who were hospitalized during the pregnancy and those who presented depression, anemia, threat of premature birth and urinary tract infection. A greater risk of the use of medicines with unknown fetal risk was not observed specifically by the mothers suffering from high blood pressure since, methyldopa was among one of the most used antihypertensive medications by pregnant women. Methyldopa has not been confirmed to present a risk to the embryo or fetus. The increased use of medicines among mothers with chronic diseases was also verified in studies by Costa da Fonseca et al. and Guerra et al. , 36.In order to have some information about use of medicines to treat chronic diseases in pregnancy, we analyzed pregnant women with diabetes and hypertension due to the high burden of disease caused by these two illnesses in Brazil. It was observed that all antidiabetics and most antihypertensive products are of known risk, with only a small percentage of antihypertensive medicines classified as unknown fetal risk. This might be explained by more rigorous prescription patterns for treating these two diseases due to their high burden. It was possible to identify that vitamins and iron supplements play a key role at increasing the prevalence of use of medicines with unknown fetal risk in pregnancy. Another issue to be considered is that due to the low cost of iron supplements, these products are widely used by all socioeconomic groups, and therefore, exclusion of them from the analyses maximizes the differences between low and high income women. The association of number of antenatal consultations and use of medicines was also no longer significant when vitamin and iron supplements were excluded from the analysis. The use of such products is more common among low risk pregnant women and those with higher number of antenatal care consultations, because the prescription of antianemic products is highly prevalent in Brazil despite some controversies in the literature .We opted for the use of logistic regression in order to maintain comparability with most of the previous published studies in the subject. However, it should be noted that, because the outcome “use of medicines” has high prevalence, the odds ratios estimated by logistic regression are well above their respective prevalence ratios. The absence of a risk assessment in accordance with the medicine doses used by mothers is a common problem in most studies including this one. It is known that teratogenic and fetotoxic effects are usually dependent on dosage and the length of usage time . The facThe risk evaluation by the FDA and other similar classifications has been widely criticized, especially as they lead to an incorrect impression that the risk increases from A to X and that drugs from the same category present the same potential risk. Further, the system does not address potential developmental adverse events on the basis of expected incidence, severity, or reversibility, nor whether there are degrees of risk based on the dose, duration, frequency, route, or gestational timing of exposure to a given product. The FDA was led to propose, in 2008, a review to present information about medicine use during pregnancy included in the package insert of the medicines. This proposal about the new regulation has been discussed, but until now the new labeling requirements have not yet been initiated , 42, 43.The FDA initiative to revise this classification contributes to an important and necessary reflection about the safety of medicines used during gestation, considering that the classification adopted for many years confounded the prescribers in the moment to decide about the use or not of some medicines. The majority of the medicines do not clearly state the risk or safety associated with the use of the product. This fact lead the category C to an uncertain category, where data available do not state whether the medicines are safe or not. Cohort studies aimed at the measurement of the consequences of the use of medicines during pregnancy are needed. For the advancement of knowledge in this subject, the evaluation of dosages and duration of the use of each medicine by the mothers during pregnancy should be correlated to the health outcomes of the mother and newborn in different phases of development. Health professionals should be frequently educated on relationships between teratogenic agents and maternal and fetal health in order to make appropriate recommendations regarding the use of some medicines based on the best information available and not solely based on classifications that are subject to significant errors, especially for taking into account a short term follow-up of the offspring. Little is known about long term consequences for the offspring and for that reason these classification systems have limitations.In addition, regulatory changes obligating pharmaceutical companies to include more detailed information about the risks associated with the use of medicines and health professionals' training are needed, particularly during pregnancy, therefore empowering health professionals to prescribe effective and safe medicines to patients.


This paper attempts to highlight research gaps and what should be done concerning population ageing in the Ghanaian context. The proportion of the elderly increased from 4.9 percent in 1960 to 7.2 percent in 2000, while the number rose from 0.3 million to 1.4 million over the same period (an increase of 367 percent). Projection results indicate that by 2050, the aged population will account for 14.1 percent of the total population. Very little is known about the living arrangements and health profile of Ghana's older population. With increasing urbanization and modernization, it is important to know something about intergenerational transfers from adult children to their elderly parents, and characterize the elderly persons' food security strategies. Training of researchers will be important in terms of strengthening Ghana's capacity to monitor trends, as well as to conduct research and explore new directions in population ageing research. The population aged 60 years or over tripled from its number in 1950 to 600 million in 2000, and by 2006, the number of older persons had surpassed 700 million, while current projections suggest that by 2050, 2 billion older persons will be alive, implying that their number will once again triple over a span of 50 years [The numerical growth of elderly persons (population aged 60+ years) around the world is an eloquent testimony not only of reductions in fertility but also of reductions in infant and maternal mortality, improved nutrition, reduction in infectious and parasitic diseases, as well as improvement in health care, education, and income. Global total fertility rate has declined from 5.0 live births per woman in 1950–1955 to 2.7 live births per woman in 2000–2005, and is expected to further reduce to replacement level, that is 2.2 live births per woman by 2045–2050 period . Also liEmpirical evidence indicates that most nations will face population ageing to some degree over the next decades ; Myers, 1990); ). As cou990; ). A002; MyerAlthough Ghana can still be classified as a youthful population , 2;  shifted in favour of females in subsequent censuses. It is interesting to note that although Ghana's age-sex structure has not changed much during the period under review, both the number and proportion of persons aged 60 years and over have been increasing.ceteris paribus the force of mortality is felt much more in the older than younger ages. This pattern is maintained for both sexes and each sex. What is striking about the table is that the proportion of the aged population in each age group has generally risen over the years. Additionally, both the number and proportion of the elderly to the total population have consistently for both sexes and for each sex. The proportion of the elderly to the total population increased from 4.9 percent in 1960 to 7.2 percent in 2000, while the number rose from 0.3 million to 1.4 million over the same period (an increase of 367 percent). The increase in the number and proportion of the elderly persons lends itself to a number of factors. Paramount among these are improvements in life expectancy (resulting in more people surviving to old age) precipitated by improved public health measures, better nutrition and personal hygiene, and declining fertility, which reduces the share of the young children to the total population.Evidence from many countries suggests that women live longer than men Although the percentage of the elderly persons has risen significantly in rural Ghana, there is no evidence to suggest a corresponding social care for the aged. In spite of the demographic shift, older persons' concerns have remained marginal to the major social and economic debates in the country. As a result, many older people, who cannot engage in large-scale agricultural activities, are faced with inadequate and insecure income in the absence of extended family support. intermediate population, and to 31.7 years by 2050, representing an old population. It is projected that the overall dependency ratio will decline to 57.2 percent by 2050, while the aged dependency ratio will rise to 22.2 percent by 2050. Thus the coming decades will witness remarkable shifts in Ghana's population age structure toward older ages as a result of decline in the proportion of children under 15 years. The last two rows of The results of indicators of population ageing are presented in From the preceding discussion, several critical issues relating to population aging research in Ghana have emerged. Research which will inform policy and planning for an aging population is a priority area in the country. As a result of the anticipated shifts in Ghana's population age structure toward older age groups precipitated by its demographic transition process, the government should utilize available time to prepare for a future aging society by formulating effective policies and programs before population ageing becomes a substantial public and private burden. The preceding analysis has shown that the elderly will be concentrated more in the young age groups, that is, 60–69 age range. Thus, most of Ghana's older population will consist of individuals in the younger part of that age group, probably not yet in need of extensive health services and able to continue working in some capacity. Ghana's older population instead could become a resource for economic development . It is conceded that the foregoing population projection hypotheses may be imprecise because population projections are as good as the assumptions underlying them so that different assumptions will result in different population figures. Given the unpredictability of both human and reproductive behaviour, these estimates should be accepted with caution. However, the results are suggestive of what might happen in future. In particular, the population projections are needful in order to provide a veritable platform for raising awareness on aging as a policy and research issue in Ghana. The results of the study have shown the preponderance of older women relative to their male counterparts. Beside taking care of their grandchildren, meals, housework, and taking part in community affairs, elderly women in Ghana engage in much agricultural work that includes planting, weeding, watering, harvesting, processing, and storage of the food their families eat. In fact, it has been found that in most activities in the rural areas, the roles of older wives are not statistically different from their younger counterparts . ElderlyThe ageing process exposes individuals to increasing risk of illness and disability. As Ghana is a poor country, lifetime exposure to health problems means that many Ghanaians may enter old age already in chronic ill-health. Personal health consistently ranks alongside material security as a priority concern for the aged. Indeed, physical health is for many rural elderly persons their single most important asset, bound up with their ability to work in the farms, to function independently, and to maintain a reasonable standard of living. But very little is known about the health profile of Ghana's older population.Due to pervasive poverty, it is hypothesized that there is an inverse relationship between modernization and family support for the elderly, resulting in a growing incidence of low levels of well-being among the elderly persons. Yet, very little is known in Ghana and other parts of Africa about intergenerational transfers. In the traditional African society, children are expected to support their parents in old age because there is no universal social security system. With increasing urbanization and modernization, it is vitally important to know something about intergenerational transfers from adult children  to their elderly parents, and characterize the elderly persons' food security strategies in a fast-changing social and economic environment.Unfortunately, Ghana and many countries in Africa have accorded relatively low priority in their national policies to the ageing of their populations. As a result of lack of full knowledge of the implications of the changes taking place in the traditional family, it is still assumed in most of these settings that the family will continue to provide the context within which the needs of the older population could be met.Training of researchers will be important in terms of strengthening Ghana's capacity to monitor trends, as well as to conduct research and explore new directions in population ageing research. Also, subregional networks that could facilitate exchange of information, resource sharing, training opportunities, and, more importantly, effective dissemination of research findings are increasingly needful. Such networks may be developed by the relevant international agencies in conjunction with appropriate persons at the national level to ensure optimal cooperation and success of research endeavors.Although old people have existed throughout recorded history, few studies have been done to systematically investigate attitudes toward old age and the elderly persons' actual conditions in Ghana and many African countries. Such research is absolutely essential because we need to have reliable baseline information by which to assess the current conditions of the aged and on which to premise our projections and expectations about old people's situation in the future. The pace of population ageing is faster in developing countries than in developed countries. Consequently, developing countries will have less time to adjust to the consequences of population ageing. Moreover, population ageing in developing countries is taking place at lower levels of socioeconomic development than has been the case for developed countries.Furthermore, population ageing is profound, having major consequences and implications for all facets of human life. In the economic area, population ageing will have an impact on economic growth, savings, investment, consumption, labour markets, pensions, taxation, and intergenerational transfers. In the social sphere, population ageing influences family composition and living arrangements, housing demand, migration trends, epidemiology, and the need for healthcare services. In the political arena, population ageing may shape voting patterns and political representation.The foregoing presentation points to the fact that ageing should be one of the most important issues that need to be addressed in the country. In the developed countries, the demographic transition process leading to an ageing population has taken place over the span of more than a century –32. ThisBecause of these foregoing reasons, it is important that our developing country governments are sufficiently sensitized. In particular, the government of Ghana should know about the consequences and implications of the phenomenon of population ageing in order to plan for the “rainy day.” One way of doing this is to always highlight the challenges precipitated by population ageing in the country, detailing research gaps and proffering plausible solutions.