Search

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of SARS-CoV-2 vaccination during pregnancy, versus placebo or no vaccination during pregnancy, for preventing COVID-19 disease in mothers and infants., (Copyright © 2025 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between September 1, 2020, and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and, as the NCO, otitis externa. The SCRI used a 60-day control window and dose-specific 28-day risk windows, stratified by vaccine brand and adjusted for calendar time. The QBA included two scenarios: (1) baseline probability of the confounder was higher in the control window and (2) vice versa. The NCO was not associated with any of the COVID-19 vaccine types or doses except Moderna dose 1 (IRR = 1.09; 95% CI 1.01-1.09). The QBA suggested that even the strongest literature-reported confounder (COVID-19; RR for myocarditis = 18.3) could only explain away part of the observed effect, from IRR = 3 to IRR = 1.40. The SCRI seems robust to unmeasured confounding in the COVID-19 setting, although a strong unmeasured confounder could bias the observed effect upward. Replication of our findings for other safety signals would strengthen this conclusion. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

We aim to estimate the incidence rates (IRs) of SARS-CoV-2 infections stratified by disease severity and comorbidities in pediatric population and to describe the COVID-19 vaccination coverage in children with and without comorbidities. A population-based cohort study was conducted in 6 electronic healthcare records databases from Italy, Spain, and Norway. The study lasted from 1 January 2020 to the latest databases' available data in each site, i.e., in Italian ARS Tuscany and PEDIANET: December 2021, in Spanish BIFAP: February 2022; SIDIAP: June 2022, and VID: December 2021. Finally, in Norwegian Health Registries: December 2021. Children and adolescents were included and stratified into three age categories (< 5, 5- < 12, and 12- < 18 years old). IRs (95% confidence intervals) per 100 person-years (PY) for non-severe (positive SARS-CoV-2 test or diagnosis without hospitalization) and severe COVID-19 (hospitalization, intensive care unit admission, and death after COVID-19) are reported. The cumulative COVID-19 vaccination rollout was stratified by population with and without comorbidities. The study population comprised 5,654,040 individuals < 18 years of age (51% females) across the six European databases (median age: 6 years), with 1.4 to 8.5% of them having at least one at-risk comorbidity for severe COVID-19. Incidence rates of severe COVID-19 were low (0-1 per 100 PY) but 3 to 4 times higher among children and adolescents with comorbidities during Omicron BA.1-2 wave in December 2021-January 2022. Percentages of vaccination rollout in the general population were between 13% in PEDIANET-IT and 64% in BIFAP-ICU-ES. In ARS-IT and SIDIAP-IT, vaccination rate in children with comorbidities was slightly lower than that in the general population., Conclusion: Severe COVID-19 was rare across databases, but up to 3 to 4 times higher in children with comorbidities during the predominance of Omicron BA.1-2 variant in winter 2021-2022. COVID-19 vaccination coverage was slightly lower in children with comorbidities in ARS (Tuscany) and SIDIAP (Catalonia) data sources. Our findings will inform future public policies aimed to protect the pediatric population, both within these countries and globally., What Is Known: • Pediatric population is susceptible to SARS-CoV-2 infection. • COVID-19 severity rates in children vary across study settings and context., What Is New: • This study confirms the low severity rates of COVID-19 in the pediatric population based on a large cohort of children and adolescents residing in Spain, Italy, and Norway. • Incidence of severe COVID-19 in children and adolescents with comorbidities was up to 3 to 4 times higher than in the general pediatric population during the SARS-CoV-2 high transmission wave of Omicron BA.1-2 variant in winter 2021-2022 in Italy and Spain., Competing Interests: Declarations Ethics approval Most data partners that provided data for the herein-presented results had passed the local ethical review process for the whole COVID-19 Vaccine Monitor study (EUPAS42467); Norwegian data (NHR): Regional Committee for Research Ethics (approval number 155294/REK Nord) and the Data Protection Officer at the University of Oslo (approval number 523275); Valencian data (VID): Comité Ético de Investigación con Medicamentos del Hospital General Universitario de Elche (approval number: PI-90/2021); Catalonian data (SIDIAP): Comitè Ètic d'Investigació amb medicaments (CEIm) de l'IDIAP Jordi Gol (approval number: 21/199-PCV); and BIFAP (several Spanish regions): Comité de Ética de la Investigación con Medicamentos del Hospital Universitario de la Princesa and Comité Científico de BIFAP (approval number: CEIm 14/21). There was no need of ethical committee approval for Italian databases (ARS and PEDIANET). This research adhered to the rules and principles of the European Network of Centers of Pharmacoepidemiology and Pharmacovigilance (ENCePP) Code of Conduct. Consent to participate This research was conducted using secondary heathcare data. Informed consent to participate was not obtained. The whole COVID-19 Vaccine Monitor study (EUPAS42467) was conducted following the ENCePP Code of Conduct. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Apparent resistant hypertension (aTRH) is a significant public health issue. Once low adherence to antihypertensive treatment has been ruled out and true resistant hypertension is diagnosed, aldosterone-direct-renin-ratio (ADRR) aids in the screening of an aldosterone-producing adenoma (APA) and primary aldosteronism (PA). Once PA and other secondary causes have been ruled out, the values of aldosterone and renin allow patients to be classified into phenotypes such as low renin hypertension (LRH), Liddle's-like (LLph), and primary hyperaldosteronism (PAph). These classifications could aid in the treatment decision-making process. However, optimal cut-off points for these classifications remain uncertain. This study aims to assess the prevalence of these phenotypes and the behavior of different cut-offs of the ADRR in an Afro-Colombian population with apparent resistant hypertension, as well to describe their sodium consumption. Afro-descendant individuals 18 years of age or older, diagnosed with resistant hypertension and attending to a primary care center in Colombia were recruited as volunteers. As part of the study, their plasma renin concentration (PRC) and plasma aldosterone concentration (PAC) were measured. The phenotypes were categorized into three groups based on multiple cut-off points from different authors: low renin and low aldosterone phenotype (LLph), low renin and high aldosterone phenotype (PAph), and high renin and high aldosterone phenotype, referred to as the renal phenotype (Rph). The prevalence of ADRR values exceeding the cut-off and phenotypes were calculated. A linear regression model was derived to assess the effect of sodium consumption with PAC, PRC and ADRR. A total of 88 patients with aTRH were included. Adherence to at least 3 antihypertensive medications was 62.5%. The median age was 56 years (IQR 48-60), 44% were female, and 20% had diabetes. The study found that the prevalence of ADRR values exceeding the cut-off ranged from 4.5 to 23%, while low-renin hypertension (LRH) varied from 15 to 74%, Rph was found in approximately 30 to 34% of patients, PAph in 30 to 51%, and the LLph in 15 to 41%, respectively, depending on the specific cut-off value by different authors. Notably, sodium consumption was associated with lower aldosterone (β - 0.15, 95% CI [- 0.27, - 0.03]) and renin concentrations (β - 0.75, 95% CI [- 1.5, - 0.02]), but ADRR showed no significant association with sodium consumption. There were no significant differences in prevalences between the groups taking < 3 vs ≥ 3 antihypertensive medications. Altered aldosterone-direct-renin-ratio, low renin hypertension, Liddle's-like, and primary hyperaldosteronism are prevalent phenotypes in patients within Afro-Colombian patients with apparent treatment-Resistant hypertension., (© 2024. The Author(s).)

Purpose: Real-world evidence (RWE) is increasingly used for medical regulatory decisions, yet concerns persist regarding its reproducibility and hence validity. This study addresses reproducibility challenges associated with diversity across real-world data sources (RWDS) repurposed for secondary use in pharmacoepidemiologic studies. Our aims were to identify, describe and characterize practices, recommendations and tools for collecting and reporting diversity across RWDSs, and explore how leveraging diversity could improve the quality of evidence., Methods: In a preliminary phase, keywords for a literature search and selection tool were designed using a set of documents considered to be key by the coauthors. Next, a systematic search was conducted up to December 2021. The resulting documents were screened based on titles and abstracts, then based on full texts using the selection tool. Selected documents were reviewed to extract information on topics related to collecting and reporting RWDS diversity. A content analysis of the topics identified explicit and latent themes., Results: Across the 91 selected documents, 12 topics were identified: 9 dimensions used to describe RWDS (organization accessing the data source, data originator, prompt, inclusion of population, content, data dictionary, time span, healthcare system and culture, and data quality), tools to summarize such dimensions, challenges, and opportunities arising from diversity. Thirty-six themes were identified within the dimensions. Opportunities arising from data diversity included multiple imputation and standardization., Conclusions: The dimensions identified across a large number of publications lay the foundation for formal guidance on reporting diversity of data sources to facilitate interpretation and enhance replicability and validity of RWE., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Introduction: The aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis., Methods: We used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures., Results: We included 1,757 cases of myocarditis. For analyses of the first dose of the Pfizer vaccine, to which all databases contributed information, we found results consistent with a null effect in both of the SCRI and extended SCCS, but some indication of a harmful effect in a standard SCCS. For the second dose, we found evidence of a harmful association for all study designs, with relatively similar effect sizes (SCRI pre = 1.99, 1.40 - 2.82; SCRI post 2.13, 95 %CI - 1.43, 3.18; standard SCCS 1.79, 95 %CI 1.31 - 2.44, extended SCCS 1.52, 95 %CI = 1.08 - 2.15). Adjustment for calendar time did not change these conclusions. Findings using all designs were also consistent with a harmful effect following a second dose of the Moderna vaccine., Conclusions: In the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: University Medical Center Utrecht in collaboration with the Vaccine Monitoring Collaboration for Europe network (VAC4EU). reports financial support was provided by European Medicines Agency. Anna Schultze reports a relationship with GSK that includes: funding grants. Ian Douglas reports a relationship with GSK that includes: equity or stocks and funding grants. Fabio Riefolo reports a relationship with TEAMIT Institute, a research management organisation that participates in financially supported studies for the European Medicines Agency and related healthcare authorities, pharmaceutical companies, and the European Union that includes: employment. Felipe Villalobos, Meritxell Palleja-Millan, Carlo Alberto Bissacco and Elena Segundo reports a relationship with IDIAPJGol, which receives institutional research funding from public and private partners, pharmaceutical companies and regulatory agencies that includes: employment. Miriam Sturkenboom reports a relationship with University Medical Center Utrecht, which conducts studies for the European Medicines Agency, the European Commission and medicine manufacturers, all according to the ENCePP code of conduct that includes: employment. Carlos E. Duran reports a relationship with University Medical Center Utrecht, which receives institutional research funding from pharmaceutical companies and regulatory agencies that includes: employment. Rosa Gini and Davide Messina reports a relationship with ARS Tuscany, which reports funding from the Innovative Medicines Initiative, RTI, PHARMO, University of Southern Denmark, University of Utrecht, Eli Lilly, Pfizer, Novartis, AstraZeneca, Galapagos, and LeoPharma that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier India Pvt Ltd. All rights reserved.)

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Durán, Riera-Arnau, Abtahi, Pajouheshnia, Hoxhaj, Gamba, Alsina, Martin-Perez, Garcia-Poza, Llorente-Garcia, Gonzalez-Bermejo, Ibánez, Sabaté, Vidal, Ballarín, Sanfélix-Gimeno, Rodríguez-Bernal, Peiró, García-Sempere, Sanchez-Saez, Ientile, Ingrasciotta, Guarneri, Tanaglia, Tari, Herings, Houben, Swart-Polinder, Holthuis, Huerta, Gini, Roberto, Bartolini, Paoletti, Limoncella, Girardi, Hyeraci, Andersen, Kristiansen, Hallgreen, Klungel and Sturkenboom.)

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018., Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions., Methods: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.01.2010-31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures., Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention -7.7%), Spain (-11.3%), and UK (-5.9%) and a non-significant decline in the Netherlands (-3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07)., Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future., (© 2023. The Author(s).)

Background: Post-marketing vaccine safety surveillance aims to monitor and quantify adverse events following immunization in a population, but little is known about their implementation in low- and middle-income countries (LMICs). We aimed to synthesize methodological approaches used to assess adverse events following COVID-19 vaccination in LMICs., Methods: For this systematic review, we searched articles published from 1 December 2019 to 18 February 2022 in main databases, including MEDLINE and Embase. We included all peer-reviewed observational COVID-19 vaccine safety monitoring studies. We excluded randomized controlled trials and case reports. We extracted data using a standardized extraction form. Two authors assessed study quality using the modified Newcastle-Ottawa Quality Assessment Scale. All findings were summarized narratively using frequency tables and figures., Results: Our search found 4254 studies, of which 58 were eligible for analysis. Many of the studies included in this review were conducted in middle-income countries, with 26 studies (45%) in lower-middle-income and 28 (48%) in upper-middle-income countries. More specifically, 14 studies were conducted in the Middle East region, 16 in South Asia, 8 in Latin America, 8 in Europe and Central Asia, and 4 in Africa. Only 3% scored 7-8 points (good quality) on the Newcastle-Ottawa Scale methodological quality assessment, while 10% got 5-6 points (medium). About 15 studies (25.9%) used a cohort study design and the rest were cross-sectional. In half of them (50%), vaccination data were gathered from the participants' self-reporting methods. Seventeen studies (29.3%) used multivariable binary logistic regression and three (5.2%) used survival analyses. Only 12 studies (20.7%) performed model diagnostics and validity checks (e.g., the goodness of fit, identification of outliers, and co-linearity)., Conclusions: Published studies on COVID-19 vaccine safety surveillance in LMICs are limited in number and the methods used do not often address potential confounders. Active surveillance of vaccines in LMICs are needed to advocate vaccination programs. Implementing training programs in pharmacoepidemiology in LMICs is essential.

Background: Estimates of the association between COVID-19 vaccines and myo-/pericarditis risk vary widely across studies due to scarcity of events, especially in age- and sex-stratified analyses. Methods: Population-based cohort study with nested self-controlled risk interval (SCRI) using healthcare data from five European databases. Individuals were followed from 01/01/2020 until end of data availability (31/12/2021 latest). Outcome was first myo-/pericarditis diagnosis. Exposures were first and second dose of Pfizer, AstraZeneca, Moderna, and Janssen COVID-19 vaccines. Baseline incidence rates (IRs), and vaccine- and dose-specific IRs and rate differences were calculated from the cohort The SCRI calculated calendar time-adjusted IR ratios (IRR), using a 60-day pre-vaccination control period and dose-specific 28-day risk windows. IRRs were pooled using random effects meta-analysis. Findings: Over 35 million individuals (49·2% women, median age 39-49 years) were included, of which 57·4% received at least one COVID-19 vaccine dose. Baseline incidence of myocarditis was low. Myocarditis IRRs were elevated after vaccination in those aged < 30 years, after both Pfizer vaccine doses (IRR = 3·3, 95%CI 1·2-9.4; 7·8, 95%CI 2·6-23·5, respectively) and Moderna vaccine dose 2 (IRR = 6·1, 95%CI 1·1-33·5). An effect of AstraZeneca vaccine dose 2 could not be excluded (IRR = 2·42, 95%CI 0·96-6·07). Pericarditis was not associated with vaccination. Interpretation: mRNA-based COVID-19 vaccines and potentially AstraZeneca are associated with increased myocarditis risk in younger individuals, although absolute incidence remains low. More data on children (≤ 11 years) are needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bots, Riera-Arnau, Belitser, Messina, Aragón, Alsina, Douglas, Durán, García-Poza, Gini, Herings, Huerta, Sisay, Martín-Pérez, Martin, Overbeek, Paoletti, Pallejà-Millán, Schultze, Souverein, Swart, Villalobos, Klungel and Sturkenboom.)

Introduction: A large proportion of medicine product labels lack information on safety in pregnancy and breastfeeding. To address this gap, pharmaceutical companies are requested to develop post-approval studies regarding the use of drugs by pregnant and breastfeeding women., Objective: Our study aims to review key features of observational studies in pregnancy and breastfeeding and their impact on the respective medicine product labels., Methods: Observational studies focusing on the safety evaluation of medicines used during pregnancy and breastfeeding were selected from the European Union Register of Post-Authorization Studies (EU PAS register) and ClinicalTrials.gov. We extracted information on the variables of interest and performed an impact assessment on the respective label., Results: A total of 141 observational studies were eligible. Of these, 63 studies (45%) were based on primary data collection and 55 studies (39%) on secondary use of health data. A small number of studies (8%) aimed to evaluate drug safety during breastfeeding. Studies using secondary data collection lasted around 2.9 years as opposed to 7.5 years' duration for studies using primary data collection. Only two product labels were updated based on the study results., Conclusion: The duration is significantly longer for studies based on primary data collection, and these are also smaller in size (less power), whereas outcomes of interest are similar. For completed studies, the impact on the label was very low. Given the gap in adequate pregnancy information on product labels, the current process of generating evidence in pregnancy and breastfeeding seems neither efficient nor impactful. To support evidence-based decision making by prescribers, this current process might be redesigned., (© 2022. The Author(s).)

Over recent years, the research community has been increasingly using preprint servers to share manuscripts that are not yet peer-reviewed. Even if it enables quick dissemination of research findings, this practice raises several challenges in publication ethics and integrity. In particular, preprints have become an important source of information for stakeholders interested in COVID19 research developments, including traditional media, social media, and policy makers. Despite caveats about their nature, many users can still confuse pre-prints with peer-reviewed manuscripts. If unconfirmed but already widely shared first-draft results later prove wrong or misinterpreted, it can be very difficult to "unlearn" what we thought was true. Complexity further increases if unconfirmed findings have been used to inform guidelines. To help achieve a balance between early access to research findings and its negative consequences, we formulated five recommendations: (a) consensus should be sought on a term clearer than 'pre-print', such as 'Unrefereed manuscript', "Manuscript awaiting peer review" or ''Non-reviewed manuscript"; (b) Caveats about unrefereed manuscripts should be prominent on their first page, and each page should include a red watermark stating 'Caution-Not Peer Reviewed'; (c) pre-print authors should certify that their manuscript will be submitted to a peer-review journal, and should regularly update the manuscript status; (d) high level consultations should be convened, to formulate clear principles and policies for the publication and dissemination of non-peer reviewed research results; (e) in the longer term, an international initiative to certify servers that comply with good practices could be envisaged., (© 2021. The Author(s).)

Background: Many new cancer drugs are being approved by reputed regulatory authorities without evidence of overall survival benefit, quality of life improvement, and often based on clinical trials at high risk of bias. In recent years, most Latin American (LA) countries have reformed their marketing authorization (MA) rules to directly accept or abbreviate the approval process in case of earlier authorization by the European Medicines Agency (EMA) and the US Food and Drug Administration, mainly. This study assessed the potential impact of decisions taken by EMA regarding the approval of new cancer drugs based on no evidence of overall survival or in potentially biased clinical trials in LA countries., Design: Descriptive analysis., Setting: Publicly accessible marketing authorization databases from LA regulators, European Public Assessment Report by EMA, and previous studies accessing EMA approvals of new cancer drugs 2009-2016., Main Outcome and Measures: Number of new cancer drugs approved by LA countries without evidence of overall survival (2009-2013), and without at least one clinical trial scored at low risk of bias, or with no trial supporting the marketing authorization at all (2014-2016)., Results: Argentina, Brazil, Chile, Colombia, Ecuador, Panama and Peru have publicly accessible and trustful MA databases and were included. Of the 17 cancer drugs approved by EMA (2009-2013) without evidence of OS benefit after a postmarketing median time of 5.4 years, 6 LA regulators approved more than 70% of them. Of the 13 drugs approved by EMA (2014-2016), either without supporting trial or with no trial at low risk of bias, Brazil approved 11, Chile 10, Peru 10, Argentina 10, Colombia 9, Ecuador 9, and Panama 8., Conclusions: LA countries keep approving new cancer drugs often based on poorly performed clinical trials measuring surrogate endpoints. EMA and other reputed regulators must be aware that their regulatory decisions might directly influence decisions regarding MA, health budgets and patient's care elsewhere., Competing Interests: The authors have declared that no competing interests exist.

Objective: To describe the current status of regulatory reliance in Latin America and the Caribbean (LAC) by assessing the countries' regulatory frameworks to approve new medicines, and to ascertain, for each country, which foreign regulators are considered as trusted regulatory authorities to rely on., Methods: Websites from LAC regulators were searched to identify the official regulations to approve new drugs. Data collection was carried out in December 2019 and completed in June 2020 for the Caribbean countries. Two independent teams collected information regarding direct recognition or abbreviated processes to approve new drugs and the reference (trusted) regulators defined as such by the corresponding national legislation., Results: Regulatory documents regarding marketing authorization were found in 20 LAC regulators' websites, covering 34 countries. Seven countries do not accept reliance on foreign regulators. Thirteen regulatory authorities (Argentina, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Mexico, Panama, Paraguay, Peru, Uruguay, and the unique Caribbean Regulatory System for 15 Caribbean States) explicitly accept relying on marketing authorizations issued by the European Medicines Agency, United States Food and Drug Administration, and Health Canada. Ten countries rely also on marketing authorizations from Australia, Japan, and Switzerland. Argentina, Brazil, Chile, and Mexico are reference authorities for eight LAC regulators., Conclusions: Regulatory reliance has become a common practice in the LAC region. Thirteen out of 20 regulators directly recognize or abbreviate the marketing authorization process in case of earlier approval by a regulator from another jurisdiction. The regulators most relied upon are the European Medicines Agency, United States Food and Drug Administration, and Health Canada.

Very few studies exist of legal interventions (national laws) for essential medicines as part of universal health coverage in middle-income countries, or how the effect of these laws is measured. This study aims to critically assess whether laws related to universal health coverage use five objectives of public health law to promote medicines affordability and financing, and to understand how access to medicines achieved through these laws is measured. This comparative case study of five middle-income countries (Ecuador, Ghana, Philippines, South Africa, Ukraine) uses a public health law framework to guide the content analysis of national laws and the scoping review of empirical evidence for measuring access to medicines. Sixty laws were included. All countries write into national law: (a) health equity objectives, (b) remedies for users/patients and sanctions for some stakeholders, (c) economic policies and regulatory objectives for financing (except South Africa), pricing, and benefits selection (except South Africa), (d) information dissemination objectives (ex. for medicines prices (except Ghana)), and (e) public health infrastructure. The 17 studies included in the scoping review evaluate laws with economic policy and regulatory objectives ( n = 14 articles), health equity ( n = 10), information dissemination ( n = 3), infrastructure ( n = 2), and sanctions ( n = 1) (not mutually exclusive). Cross-sectional descriptive designs ( n = 8 articles) and time series analyses ( n = 5) were the most frequent designs. Change in patients' spending on medicines was the most frequent outcome measure ( n = 5). Although legal interventions for pharmaceuticals in middle-income countries commonly use all objectives of public health law, the intended and unintended effects of economic policies and regulation are most frequently investigated.

Introduction: New-onset diabetes after transplantation (NODAT) is associated with immunosuppression. Its complications can negatively influence patients' quality of life, which is why it is important to study the associated risk factors and expand the possible therapies in this particular group of patients. Materials and methods . Case-control study nested in a retrospective cohort. It included patients who received kidney transplantation at the high complexity University Hospital Fundación Valle del Lili in Cali, Colombia, between 1995 and 2014. Two controls were assigned for each case, depending on the type of donor and the date of the surgery. Information was collected from clinical records and the institutional TRENAL registry. We carried out a descriptive analysis of the selected variables and identified the risk factors with conditional logistic regression., Results: 122 cases were identified to which 224 controls were assigned. The median age was 44 years (IQR: 34-55), and 54% were men. Having >50 years of age at the time of transplantation (OR: 3.18, 95% CI: 1.6-6.3, p = 0.001), body mass index >30 kg/m 2 (OR: 3.6, 95% CI: 1.3-9.7, p = 0.010) and being afro-descendant (OR: 2.74, 95% CI: 1.1-6.5, p = 0.023) were identified as risk factors for the development of NODAT. Pretransplant fasting plasma glucose >100 mg/dl (OR: 2.9, 95% CI: 1.4-6.4, p = 0.005) and serum triglycerides >200 mg/dl (OR: 2.5, 95% CI: 1.4-4.4, p = 0.002) were also reported as independent risk factors., Conclusion: We ratify some risk factors for the development of this important disease, which include certain modifiable characteristics. Interventions aimed at changes in lifestyle could be established in a timely manner before transplant surgery., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 Guillermo E. Guzmán et al.)

Background: The widespread growth of higher education is increasing the heterogeneity of university students in terms of socioeconomic characteristics, academic story and cultural background. Medical schools are not an exception of this phenomenon., Aim: To compare the academic background and self-directed learning behavior of students who entered to a public medial school between 2010 and 2014., Material and Methods: A non-probabilistic sample of 527 medical students aged between 17 and 29 years (60% men), was studied. Their academic information was collected from the University data base; they answered the Self-directed learning readiness scale of Fisher., Results: Students from the 2014 cohort had higher high school grades than their counterparts. The scores in mathematics of the Scholarship Aptitude Test (SAT) were higher in the cohorts of 2010 and 2011. Those of the sciences test were superior in the 2013 cohort. The 2014 cohort had the lower general score of self-directed learning behaviors., Conclusions: The lower SAT and self-directed learning scores of the students entering medical school in 2014, indicate the progressive increase in the heterogeneity of Medical students.

Purpose: We systematically review the cross-national drug utilization studies performed in Latin America (LA) in order to analyze the methods applied and assess the validity of the data to ensure the comparability., Methods: A systematic search in Medline, Embase, and BIREME was performed. Drug utilization studies including LA countries and comparing drug exposure data on volume were included. The data validity was judged independently by two authors as having low, medium, high, or unclear risk of bias., Results: Out of 1191 articles, 25 were kept for full text reading. Finally, five studies were selected. Eight different Latin American countries were involved in the comparisons. The selected studies analyzed wholesale data from a private research company collecting information from the private healthcare sector. In three studies, a high risk of bias in the extrapolation method applied was identified. In one study, a risk of data collection bias was detected. The most frequent limitation detected by the original authors was related to the unavailability of information from the public sector in LA., Conclusion: Drug utilization studies comparing data cross-nationally are scarce in LA. In general, validity of the comparisons is hampered by a potential risk of extrapolation bias given the lack of available data on drug consumption from the public healthcare sector. Setting up systems to remediate this situation is a future challenge for researchers and (supra)national authorities in the region., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Cinacalcet is an effective treatment for hypercalcemia due to persistent hyperparathyroidism (HPT) in patients who have undergone kidney transplantation (KT). Few data are available about their long-term follow-up., Objective: We aimed to evaluate the long-term efficacy of cinacalcet in functioning stable KT subjects with hypercalcemia secondary to persistent HPT., Material and Methods: Twenty-three patients (6 men) with a stable KT showed persistent hypercalcemia (>12 months) secondary to HPT (parathyroid hormone by radioimmunoassay [iPTH] > 150 pg/mL). The mean age was 54 ± 13 years. Time after KT to beginning cinacalcet treatment was 36.5 ± 37.9 (range 12 to 172) months. Initial cinacalcet doses were 30 mg/d. Median follow-up was 53 ± 7.4 months (range 42 to 60 months). We determined serum calcium, phosphorus, alkaline phosphatase, iPTH, creatinine, and immunosuppressant concentrations at baseline as well as 3, 6, and 12 months and after every 6 months thereafter., Results: Initial serum calcium was 11 ± 0.65 mg/dL and mean calcium during treatment, 10.25 ± 0.81 mg/dL (P < .001). Initial serum phosphorus was 2.8 ± 0.58 mg/dL and mean value serum phosphorus during the treatment period, 3.13 ± 0.6 mg/dL (P = 0.015). Initial iPTH was 260 ± 132 pg/mL and during the treatment period; 237 ± 131 pg/mL (P = ns). There was no change in renal function nor in immunosuppressant blood levels. Doses of cinacalcet at the end of the follow-up were 40.4 ± 18.9 mg/d., Conclusion: Cinacalcet was effective for long-term control of hypercalcemia related to persistent HPT for patients with stable KT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Levels of fibroblast growth factor (FGF)-23, a phosphaturic hormone, increase from the early stages of CKD and are dramatically elevated in dialysis patients. Excessive FGF-23 may be involved in the hypophosphatemia and inappropriately low calcitriol levels observed after kidney transplantation (KT).This prospective observational cohort study was carried out to determine whether there are any differences in the changes in FGF-23 levels after surgery in KT recipients according to whether they were or not on dialysis before transplantation and to assess the influence of FGF-23 in the development of posttransplantation hypophosphatemia., Methods: Consecutive KT recipients at the Hospital Clinic of Barcelona were recruited. Patients developing delayed graft function were excluded. Mineral metabolism parameters, including C-terminal fragment of FGF-23, intact parathyroid hormone, and 1,25(OH)(2)D(3), were measured in 72 KT recipients (58 on dialysis before transplantation and 14 preemptive transplant recipients) at baseline, on day 15, and at 1, 3, and 6 months after transplantation. No patients received treatment with calcimimetics, bisphosphonates, vitamin D, or phosphate supplementation during the follow-up., Results: FGF-23 decreased significantly in the first month after transplantation. Baseline and FGF-23 levels within the first posttransplantation month were lower in preemptive transplant recipients than in patients on dialysis at transplantation. Serum phosphate levels were lower in dialysis patients until the third month after transplantation. Pretransplantation FGF-23 was the main predictor of posttransplantation phosphate blood levels., Conclusions: FGF-23 levels and the risk of developing posttransplantation hypophosphatemia were lower in preemptive kidney transplant recipients than in patients on dialysis before transplantation.

Background: Secondary hyperparathyroidism that persists after kidney transplantation (KT), is the main cause of hypercalcemia. Cinacalcet has been used to control hypercalcemia in KT patients., Objective: The aim of this study was to evaluate the effect of de novo cinacalcet in KT patients with hypercalcemia and the evolution after its withdrawal., Methods: This observational study included 41 KT patients (17 men) with persistent hypercalcemia (>6 months), defined as serum calcium (sCa) ≥10.5 mg/dL, and a mean age of 51.1 ± 13.3 years with a functional allograft for >12 months. The time after surgery to begin cinacalcet was 33 months (range, 12.5-81.3). The initial dose of cinacalcet was 30 mg/d. In a subgroup of 14 patients cinacalcet was stopped after 1 year. We studied the evolution of serum levels of calcium, phosphorus, intact pathyroid hormone (iPTH), and serum creatinine., Results: Calcemia normalized in all patients (sCa <10.2 mg/dL). iPTH decreased (basal 267 ± 212 pg/mL vs final: 219 ± 160 pg/mL; P = ns) Serum phosphorus increased (basal 2.85 ± 0.48 mg/dL vs final 3.16 ± 0.50 mg/dL; P = ns). Renal function remained stable (basal creatinine 1.49 ± 0.48 vs final 1.47 ± 0.32 mg/dL; P = ns). After stopping cinacalcet, in group 1 calcemia persisted at normal levels in 50% (n = 7), but the drug had to be reintroduced in the other 50% after 10 ± 7.9 months. No adverse events were documented., Conclusions: Cinacalcet is an effective alternative for the treatment of hypercalcemia in patients with persistent hyperparathyroidism after KT. Once the treatment is started, there is presently no invice to disclose to who tolerate its withdrawal or the time to do so., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Secondary hyperparathyroidism is a relevant problem in patients on dialysis. Cinacalcet in regular clinical practice increases the percentage of patients achieving treatment targets for PTH, Ca and P. We evaluated allograft calcification in serial protocol biopsies after transplantation among patients receiving Cinacalcet on dialysis but discontinued after surgery., Methods: This retrospective single-centre study included kidney allograft recipients who were receiving Cinacalcet for more than 6 months before surgery and had it withdrawn thereafter. The 46 patients including 17 women showed a mean overall age of 54 ± 30 years. Protocol graft biopsy was performed at 3 and at 12 months. Biochemical analyses at the time of biopsy included blood levels of creatinine, phosphorus, calcium, alkaline phosphatases, iPTH, and proteinuria., Results: Any biopsy showed nephrocalcinosis either intratubular calcifications, or in the parenchyma. There were no changes in calcemia (10.22 ± 0.7 to 10.27 ± 0.7 mg/dL), in alkaline phosphatase (259 ± 119.6 to 255 ± 122.3 mg/dL) nor in iPTH (317 ± 220.2 to 320 ± 168.8 pg/mL) between 3 and 12 months respectively. There was a slight but non-significant increase in serum phosphorus (2.79 ± 0.8 to 3.22 ± 0.9 mg/dL), serum creatinine (1.53 ± 0.6 to 1.84 ± 1.2 mg/dL) and proteinuria (528 ± 603 to 879 ± 1398 mg/24h) between 3 and 12 months respectively., Conclusions: Withdrawal of Cinacalcet at the time of renal transplantation was not a risk factor for allograft calcifications in the early post-transplant period., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objectives: Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition that almost exclusively affects patients with chronic kidney disease. Several therapies have been employed to treat this disease but with irregular results. We report a prospective case series of eight patients diagnosed with CUA in our unit between 2002 and 2010., Material and Method: The series consisted of eight patients with CUA (including 4 men, 5 dialysis patients and 3 with functioning allografts) who were treated with bisphosphonates. The diagnosis was by clinical suspicion and a confirmatory biopsy. Five patients had a previous history of high calcium-phosphorus product, 6 had a history of high parathyroid hormone levels (>800pg/ml), 4 had undergone parathyroidectomy, 5 had a history of high cumulative doses of steroids, and 6 patients were under dicoumarin treatment. None of the patients were obese or had diabetes mellitus., Results: In all patients, progression of skin lesions stopped between 2 to 4 weeks after starting bisphosphonate therapy, with no changes in blood levels of calcium and phosphate. Improvement in pain and lesions was faster in patients receiving intravenous ibandronate. All of these patients remained on bisphosphonate treatment for at least 6 months until the wounds healed completely. No recurrences have been observed after follow-up periods between 1 and 9 years. Renal function remained stable in transplant recipients. The treatment was well tolerated and no adverse effects were observed., Conclusions: Bisphosphonates could be a new and attractive alternative to treat CUA.

Near-peer teaching is an educational format which utilizes tutors who are more advanced in a curriculum's content to supervise students' activities and to act as instructors in laboratory settings. This format is often used in anatomy laboratory courses. The goal of the present study is to describe the design and implementation of near-peer teaching in an anatomy course and to evaluate students' perceptions of the program. A total of 700 students were registered for this anatomy course which employed near-peer instructors. Of enrolled students, 558 (79.7%) agreed to participate in this study. In general, the practical section (e.g., the clinical hour, image-based anatomy session, and gross anatomy laboratory) of the course was viewed more favorably compared to the theory section (54.8%, n = 306), with dissection and prosection in the laboratory rated as the most valued experiences (34.9%, n = 195). Near-peer teaching is a viable option that satisfies the demands of modern curricula using small groups. This format stimulates learning within courses that have large numbers of students and low faculty-to-student ratios., (Copyright © 2012 American Association of Anatomists.)

Background: Longer and more frequent dialysis sessions have demonstrated excellent survival and clinical advantages, while online haemodiafiltration (OL-HDF) provides the most efficient form of dialysis treatment. The aim of this study was to evaluate the beneficial effects of a longer (nocturnal) and more frequent (every-other-day) dialysis schedule with OL-HDF at the same or the highest convective volume., Methods: This prospective, in-centre crossover study was carried out in 26 patients, 18 males and 8 females, 49.2±14 years old, on 4-5 h thrice-weekly post-dilution OL-HDF, switched to nocturnal every-other-day OL-HDF. Patient inclusion criteria consisted of stable patients with good vascular access and with good prospects for improved occupational, psychological and social rehabilitation. Patients were randomly assigned into two groups: Group A received the same convective volume as previously for 6 months followed by a higher convective volume for a further 6 months, while Group B received the same schedule in reverse order., Results: Nocturnal every-other-day OL-HDF was well tolerated and 56% of patients who were working during the baseline period continued to work throughout the study with practically no absenteeism. The convective volume was 26.7±2 L at baseline, 27.5±2 with the unchanged volume and 42.9±4 L with the higher volume. eKt/V increased from 1.75±0.4 to 3.37±0.9. Bicarbonate, blood urea nitrogen (BUN) and creatinine values decreased, while phosphate levels fell markedly with a 90% reduction in phosphate binders. Blood pressure and left ventricular hypertrophy (LVH) improved and the use of anti-hypertensive drugs decreased. In both groups, BUN, creatinine and β2-microglobulin reduction ratios improved. Different removal patterns were observed for myoglobin, prolactin and α1-acid glycoprotein., Conclusions: Nocturnal every-other-day OL-HDF could be an excellent therapeutic alternative since good tolerance and occupational rehabilitation, marked improvement in dialysis dose, nutritional status, LVH, phosphate and hypertension control and a substantial reduction in drug requirements were observed. In this crossover study, different removal patterns of large solutes were identified.

Haemolytic-uraemic syndrome is a clinical syndrome characterized by thrombocytopaenia, non-autoimmune haemolytic anaemia and renal impairment. Pathological alterations in kidney samples show thrombotic microangiopathy. The underlying pathogenesis is endothelial cell injury with thrombotic occlusion of the arterioles and capillaries. A variety of causes have been identified, associated with infection of Escherichia coli O157:H7, environmental factors as immunosuppressive drugs and genetic deficiencies in complement regulatory factors. The latter is called atypical haemolytic-uraemic syndrome (aHUS). Here, we present a patient with severe aHUS with complement factor H deficiency triggered by cocaine use and recurrence after kidney transplantation. The patient restarted haemodialysis for severe renal insufficiency and anti-C5 antibody eculizumab was used as salvage treatment with progressive recovery of graft function and suppression of dialysis.

Introduction: The World Health Organization recommended strategy for global tuberculosis control is a short-course, clinically administered treatment, This approach has approximately 70% coverage in Colombia., Objective: The clinical, epidemiological and microbiological characteristics along with drug therapy outcomes were described in newly diagnosed, pulmonary tuberculosis patients., Materials and Methods: This was a descriptive study, conducted as part of a multicenter clinical trial of tuberculosis treatment. A cohort of 106 patients with pulmonary tuberculosis were recruited from several public health facilities in Cali between April 2005 and June 2006. Sputum smear microscopy, culture, drug susceptibility tests to first-line anti-tuberculosis drugs, chest X- ray and HIV-ELISA were performed. Clinical and epidemiological information was collected for each participant. Treatment was administered by the local tuberculosis health facility. Food and transportation incentives were provided during a 30 month follow-up period., Results: The majority of patients were young males with a diagnostic delay longer than 9 weeks and a high sputum smear grade (2+ or 3+). The initial drug resistance was 7.5% for single drug treatment and 1.9% for multidrug treatments. The incidence of adverse events associated with treatment was 8.5%. HIV co-infection was present in 5.7% of the cases. Eighty-six percent of the patients completed the treatment and were considered cured. The radiographic presentation varied within a broad range and differed from the classic progression to cavity formation., Conclusion: Delay in tuberculosis diagnosis was identified as a risk factor for treatment compliance failure. The study population had similar baseline epidemiologic characteristics to those described in other cohort studies.

Leg ulcers are a manifestation of antiphospholipid syndrome (APS), and characteristically respond poorly to treatment. Because the similar findings both clinical and pathological to pyoderma gangrenosum (PG), we treated these patients with a combination of immunosuppression (steroids, azathioprine or cyclosporine), acetylsalicylic acid and anticoagulation. We evaluated the response to the combined treatment with steroids, immunosuppression, acetylsalicylic acid, anticoagulation and local measures in patients with APS and leg ulcers resembling PG. We studied 8 women with leg ulcers of a cohort of 53 patients with APS (15%). Pathological findings of PG were observed in all patients. Seven patients (87.5%) received cyclosporine as usual for the treatment of PG, and all patients received steroids and anticoagulation with warfarin. Cicatrisation was present in all patients in 7 months. Leg ulcers in patients with APS may be resemble to PG, and their treatment with immunosuppression, acetylsalicylic acid and anticoagulation is effective for this severe and poorly responding condition.

Aim: To compare the dynamics in vivo and in vitro calcium-PTH release of uremic patients with secondary hyperparathyroidism and their hyperplasic parathyroid glands after parathyroidectomy., Materials and Methods: Seven patients with secondary HPT and their 23 hyperplasic glands obtained after surgical parathyroidectomy were evaluated. In vivo studies of the PTH secretion curve were obtained by induction of hypocalcemia and hypercalcemia with a continuous endovenous infusion of sodium EDTA and Ca gluconate, respectively. For the in vitro studies, small parathyroid pieces of 1 mm were sequentially transferred to wells with varying Ca concentrations: 0.4, 0.6, 0.8, 1, 1.25 and 1.5 mM. iPTH concentrations were determined in the medium., Results: The in vivo set point did not correlate with the basal, maximal or minimal PTH concentrations, although it correlated significantly with the basal serum Ca concentration (r = 0.62, p < 0.02). Both in vivo and in vitro PTH secretion curves were sigmoidal, although the in vivo set point was higher than the in vitro (1.57 +/- 0.05 vs. 1.27 +/- 0.07 mM, p < 0.001). The degree of maximal PTH inhibition were similar in both circumstances (30.5 +/- 8.1 vs. 33.6 +/- 5.4 %; p = NS) with a significant direct correlation (r = 0.901; p < 0.01)., Conclusions: The in vivo set point of calcium is more closely related to serum calcium concentration than to basal iPTH concentration. Although there are differences between the in vivo and in vitro calcium set point the maximal degree of PTH inhibition was similar in both circumstances.

Aim: To compare the dynamics of calcium-regulated PTH secretion in vitro from adenomatous versus hyperplastic glands and to investigate the relationship between the parathyroid cell cycle and the calcium-regulated PTH secretion in these glands., Materials and Methods: A total of 31 parathyroid glands (8 adenomatous and 23 hyperplastic) from 8 patients with primary hyperparathyroidism and 7 with secondary hyperparathyroidism respectively were studied. For the evaluation of calcium-regulated PTH secretion, small parathyroid pieces of 1 mm were sequentially transferred to wells with varying Ca concentrations: 0.4, 0.6, 0.8, 1, 1.25 and 1.35 or 1.5 mM. PTH concentrations were determined in the medium. For the parathyroid cell cycle studies, parathyroid cells were isolated without the use of enzymes and cell cycle was analyzed using the method described by Vindelov. The nuclei were acquired by flow cytometer and analyzed using the CELLFIT software., Results: In parathyroid tissues from hyperplastic glands, the increase in extracellular calcium produced a decrease in PTH secretion which was apparent with a calcium level as low as 0.8 mM and the maximal inhibition of PTH secretion was obtained with a calcium of 1.25 mM, by the contrary, adenomatous glands required a calcium of 1.2 mM to produce a minimal decrease in PTH secretion. In hyperplastic parathyroid glands but not in parathyroid adenomas there was a significant correlation between the percentage of cells in G0/G1 phase with the set point (r = 0.914; P < 0.005) and the basal serum Ca (r = 0.862; P < 0.02)., Conclusions: The control of the extracellular calcium-PTH release in vitro is less sensitive in parathyroid adenomas than hyperplasic parathyroid glands. In parathyroid hyperplasia the cell proliferation may be regulated by the extracellular calcium concentration (higher calcemia less proliferation).