Controversias en Dermatología
Vitamin D: Evidence and Controversies: Comment on the Article by Gilaberte et al.
Vitamina D: Evidencia y Controversias: comentarios sobre el artículo de Gilaberte et al.
William B. Grant
Sunlight, Nutrition, and Health Research Center, San Francisco, USA
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Muchos melanomas poseen una activación constitutiva de receptores de factores de crecimiento con actividad tirosin-cinasa (RTK) (pe, c-Kit, PDGFR-α y/o EGFR), ya sea por amplificaciones o mutaciones de los genes que los codifican. Asímismo, presentan activación de la vía de señalización de las MAP-cinasas (proteín cinasas activadas por mitógenos) (RAS/RAF/MEK/ERK), debida fundamentalmente a mutaciones de NRAS o de BRAF. Con frecuencia, poseen además activada la vía de las fosfatidil-inositol 3 cinasas (PI3K) (PI3K/AKT), de forma secundaria a las mutaciones de NRAS, por amplificación de AKT y, especialmente favorecida por la pérdida del papel inhibidor de PTEN, resultado de mutaciones, deleciones o silenciamientos del gen supresor tumoral PTEN. Por otro lado, en la activación del ciclo celular, contribuyen las deleciones, silenciamientos y mutaciones de CDKN2A, que repercuten en defectos de las 2 proteinas codificadas por este gen (p16 y p14), así como las amplificaciones de CDK4 y CCND1 (ciclina D1). Todo ello influye en el deterioro de la actividad de la proteína propapoptótica p53 (que también puede estar mutada en algunos casos) y la sobreexpresión de proteínas antiapoptóticas de la familia de Bcl-2.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R.M. Martí, A. Sorolla, A. Yeramian" "autores" => array:3 [ 0 => array:2 [ "nombre" => "R.M." "apellidos" => "Martí" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Sorolla" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Yeramian" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1578219012002168" "doi" => "10.1016/j.adengl.2012.08.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219012002168?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S000173101100514X?idApp=UINPBA000044" "url" => "/00017310/0000010300000007/v1_201304241417/S000173101100514X/v1_201304241417/es/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Controversias en Dermatología</span>" "titulo" => "Vitamin D: Evidence and Controversies: Comment on the Article by Gilaberte et al." "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "591" "paginaFinal" => "594" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "William B. Grant" "autores" => array:1 [ 0 => array:3 [ "nombre" => "William B." "apellidos" => "Grant" "email" => array:2 [ 0 => "wbgrant@infionline.net" 1 => "http://www.sunarc.org" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Sunlight, Nutrition, and Health Research Center, San Francisco, USA" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Vitamina D: Evidencia y Controversias: comentarios sobre el artículo de Gilaberte et al." ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The recent review in this journal serves as a good introduction to the controversies surrounding scientific findings and policy recommendations regarding vitamin D, its health benefits, requirements for optimal health, and how to obtain adequate vitamin D<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. The literature is full of contradictory findings, opinions, and recommendations, so unless one has studied it carefully for an extended period making sense of it at face value is difficult. The crux of the problem is that, because of inherent or practical limitations, different types of studies can arrive at different conclusions. This commentary on the work of Gilaberte and colleagues offers more insight into how to assess and interpret the literature on vitamin D and UV irradiance.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Studies of vitamin D deficiency and disease outcomes</span><p id="par0010" class="elsevierStylePara elsevierViewall">There are several ways of determining the role of vitamin D deficiency in the risk of disease. Ecological studies—which investigate the relationship between geographical variation in disease outcomes and the risk-modifying factors for each geographical unit of population or seasonal variation—can be useful in identifying and quantifying relationships between solar UV-B doses and disease outcome. The ecological approach has linked low solar UV-B doses to about 20 types of cancer.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The time-varying ecological study approach has linked solar UV-B to reduced risk of influenza.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Observational studies can be either case–control studies, which measure serum 25-hydroxyvitamin D [25(OH)D] concentrations at time of diagnosis, or nested case–control studies derived from cohort studies. Cohort studies compare patients who have the disease with similar healthy controls, grouping the disease by quantiles of 25(OH)D concentration. Case–control studies find stronger inverse correlations between 25(OH)D concentration and disease incidence because nested case–control studies measure vitamin D status with a single serum 25(OH)D concentration at time of enrollment; over time, this sole measure becomes less reliable.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Cross-sectional studies are snapshots of health conditions and biometric values made by random sampling of the population.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In randomized controlled trials (RCTs), some participants receive the agent and others a placebo. Participants are followed up for weeks to years, and health outcomes, both positive and negative, are noted. Using RCTs to study the effects of vitamin D on disease outcome poses many problems: the dose is often inadequate, compliance may be poor, other sources of vitamin D exist, and serum 25(OH)D response to oral vitamin D intake varies considerably from person to person.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Vitamin D requirements</span><p id="par0030" class="elsevierStylePara elsevierViewall">With this background, we can now address how vitamin D requirements can and should be determined. Relationships between serum 25(OH)D concentration and disease outcome are essential. Ecological studies provide indirect information because they use indices of solar UV-B dose. RCTs generally use a single dose and so have difficulty representing the entire relationship unless several such studies are included in a meta-analysis or in a pooled analysis. That leaves observational studies, which use serum 25(OH)D concentrations and generally provide 4–5 values for serum 25(OH)D concentration to use in determining relative risk (RR), hazard ratio or odds ratio (OR). Because single observational studies have large uncertainties, several observational studies should be combined in either a pooled analysis or a meta-analysis.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In an earlier work, I recently combined observational studies of breast and colorectal cancer incidence with respect to serum 25(OH)D concentration in meta-analyses.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Values from various studies were combined by overlaying the values such that the center of the regression fit to each study overlapped. Then the values were combined into a single data set and fit with a power law function. For breast cancer, the OR decreased from unity at 22<span class="elsevierStyleHsp" style=""></span>nmol/L to about 0.43 near 100<span class="elsevierStyleHsp" style=""></span>nmol/L, with little apparent change at higher values. For colorectal cancer, the OR dropped from unity near 12<span class="elsevierStyleHsp" style=""></span>nmol/L to 0.32 at 100<span class="elsevierStyleHsp" style=""></span>nmol/L. In both cases, the OR decreased rapidly at first and then more slowly at higher 25(OH)D concentrations.</p><p id="par0040" class="elsevierStylePara elsevierViewall">I previously reported a similar analysis for cardiovascular disease. The third-order fit to the data found the hazard ratio decreasing from unity near 18<span class="elsevierStyleHsp" style=""></span>nmol/L to 0.51 at 100<span class="elsevierStyleHsp" style=""></span>nmol/L, with little change at higher values.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In an observational study, those with serum 25(OH)D concentrations below 95<span class="elsevierStyleHsp" style=""></span>nmol/L had an increased risk of acute respiratory infections, whereas those with higher levels did not.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">More recently, a rigorous meta-analysis examined all-cause mortality rate as a function of serum 25(OH)D concentration at time of enrollment in 11 studies.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The second-order fit to the RR decreased from unity at an assumed value of 27.5<span class="elsevierStyleHsp" style=""></span>nmol/L to 0.68 at 80<span class="elsevierStyleHsp" style=""></span>nmol/L and then started to increase. However, the 95% confidence interval at 80<span class="elsevierStyleHsp" style=""></span>nmol/L extended from 0.60 to 0.78 and increased in deviation from the RR at values up to 115<span class="elsevierStyleHsp" style=""></span>nmol/L, so it is not clear whether the upturn is real.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Thus, from the observational and cross-sectional studies, the optimal serum 25(OH)D concentration—defined as the point at which the data currently available no longer show improved health outcome—is between 75<span class="elsevierStyleHsp" style=""></span>nmol/L and 100<span class="elsevierStyleHsp" style=""></span>nmol/L. This is the same as the range determined by vitamin D experts at a meeting in Paris in September 2009.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Recommendations</span><p id="par0060" class="elsevierStylePara elsevierViewall">Ideally, vitamin D recommendations would be made based on the best scientific evidence available, with review by vitamin D experts and subject to peer review. The Intergovernmental Panel on Climate Change used that approach to assess the evidence regarding climate change. At least 1000 climate change researchers prepared the <span class="elsevierStyleItalic">IPCC Fourth Assessment Report: Climate Change 2007</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and another thousand reviewed it. Unfortunately, the Institute of Medicine's Committee to Review Dietary Reference Intakes for Vitamin D and Calcium was composed of 14 scientists with expertise in nutrition, but varied expertise regarding vitamin D. The committee prepared a report,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> limiting its review to selected RCTs, and solicited—but ignored and refused to make public—peer reviews of the final document. Thus, this document lacks the kind of scientific authority that would be expected for such an important topic.</p><p id="par0065" class="elsevierStylePara elsevierViewall">After the Institute of Medicine released this report, the US Endocrine Society recommended a vitamin D level of at least 75<span class="elsevierStyleHsp" style=""></span>nmol/L.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Vitamin D confers important benefits during pregnancy. Serum 25(OH)D concentrations above 75–100<span class="elsevierStyleHsp" style=""></span>nmol/L greatly reduce the risk of bacterial vaginosis, preeclampsia, primary Cesarean delivery, premature birth, low birth weight, birth defects, and rickets.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> A recent RCT involving pregnant and nursing women in South Carolina found that 4000<span class="elsevierStyleHsp" style=""></span>IU of vitamin D<span class="elsevierStyleInf">3</span> per day was generally required to reach optimal serum 25(OH)D and 1,25-dihydroxyvitamin D concentrations and have enough unconverted vitamin D<span class="elsevierStyleInf">3</span> available in breast milk for the infant.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> No adverse effects, such as changes in serum or urine calcium concentrations, occurred.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Benefits of optimal 25(OH)D concentrations</span><p id="par0075" class="elsevierStylePara elsevierViewall">The health benefits of vitamin D extend from better pregnancy and birth outcomes<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> to reduced risk of many types of cancer,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> cardiovascular disease,<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,16,17</span></a> diabetes,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> respiratory infections,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,8</span></a> and many other conditions and diseases (for more information see <a href="http://www.vitamindcouncil.org/health-conditions/">http://www.vitamindcouncil.org/health-conditions/</a>). The 25(OH)D concentration–disease outcome relations have been used to estimate how raising population mean serum 25(OH)D concentrations from 50–55<span class="elsevierStyleHsp" style=""></span>nmol/L to 100–110<span class="elsevierStyleHsp" style=""></span>nmol/L would reduce mortality rates for countries and continents. The study for the United States found that doing so could avoid approximately 400<span class="elsevierStyleHsp" style=""></span>000 premature deaths per year,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> representing 17% of all deaths. A worldwide study found mortality rate reductions of 8%–17%, increasing worldwide life expectancy by 2 years.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">UV irradiance</span><p id="par0080" class="elsevierStylePara elsevierViewall">Solar UV-B irradiance is the primary source of vitamin D for most people on Earth. Skin pigmentation has adapted to the prevailing solar UV doses in places where humans have lived for thousands of years. As descendants of a long line of Spaniards, modern Spaniards’ skin is well adapted to solar radiation in Spain: dark enough to protect against the adverse effects without sunscreen yet light enough to permit adequate production of vitamin D.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> One adaptation to life in mid-latitudes is the ability to tan, which increases protection against UV irradiance by a factor of 2–4.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Several studies offer evidence that Spaniards can and should experience solar UV-B with strong benefits and limited risks. In an ecological study of cancer mortality rates in Spain during 1978–1992, nonmelanoma skin cancer mortality rates were inversely correlated with 15 types of cancer, including melanoma for females.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Mortality rates for nonmelanoma skin cancer were much lower than the all-cancer mortality rate.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Many people are concerned about the risk of melanoma from solar UV irradiance. However, those exposed to the sun occupationally have no greater risk of developing melanoma than those who are not so exposed.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Risk of melanoma is associated with intermittent UV irradiance<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and sunburn.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Another risk factor associated with solar UV irradiance is development of basal cell carcinoma or squamous cell carcinoma. A study in Denmark found that those who developed basal cell carcinoma had a lower mortality rate than those who did not (10-year RR<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.91 [95% confidence interval, 0.89–0.92]).<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Producing vitamin D from solar U-VB irradiance in the summer is easy. The important considerations are solar zenith angle (for optimal production, the sun should be within 45 degrees of being overhead), the amount of surface area exposed, time in the sun, and age. With whole-body exposure, one can make at least 10,000<span class="elsevierStyleHsp" style=""></span>IU of vitamin D<span class="elsevierStyleInf">3</span> in less time than it would take to develop erythema (redness).</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0105" class="elsevierStylePara elsevierViewall">This review offers considerable evidence that higher serum 25(OH)D concentrations would greatly reduce the risk of disease and increase life expectancy in Spain. It would be worthwhile for health policy makers in Spain to review the evidence, with input from UV irradiance and vitamin D researchers in Spain and elsewhere, and then make recommendations for public policy.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0110" class="elsevierStylePara elsevierViewall">Dr. William Grant has received funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres96855" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec84014" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres96854" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec84013" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Studies of vitamin D deficiency and disease outcomes" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Vitamin D requirements" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Recommendations" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Benefits of optimal 25(OH)D concentrations" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "UV irradiance" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-01-04" "fechaAceptado" => "2012-01-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec84014" "palabras" => array:5 [ 0 => "Vitamin D" 1 => "Cancer" 2 => "Immunology" 3 => "UV rays" 4 => "Melanoma" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec84013" "palabras" => array:4 [ 0 => "Vitamina D" 1 => "Cáncer" 2 => "Inmunología" 3 => "Rayos UV, Melanoma" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Vitamin D deficiency is associated with increased risk of approximately 100 conditions and diseases. Ecological, observational, and cross-sectional studies as well as randomized controlled trials support these associations. Observational studies, with support from the other types, provide the data needed to determine how serum 25-hydroxyvitamin D [25(OH)D] concentration affects disease incidence and mortality rates. The findings for breast and colorectal cancer, respiratory infections, and all-cause mortality rates indicate that benefits increase as serum 25(OH)D concentrations increase to between 75 and 100<span class="elsevierStyleHsp" style=""></span>nmol/L. Reaching those levels takes up to 5000<span class="elsevierStyleHsp" style=""></span>IU of vitamin D per day, with considerable individual variation. The main sources of vitamin D that can help people reach those levels are UV-B irradiance and vitamin D<span class="elsevierStyleInf">3</span> supplements. The skin characteristics—both in terms of pigmentation and ability to tan—of most inhabitants of Spain are ideally suited for regular moderate solar UV irradiance. In general, melanoma risk is low in southern Europe. Risk of nonmelanoma skin cancer is higher, but such cancers are seldom fatal, and a study in Denmark found a 9% reduction in 10-year all-cause mortality rate for patients diagnosed with basal cell carcinoma.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La deficiencia de Vitamina D se asocia con un riesgo aumentado de unas 100 condiciones y enfermedades. Estudios ecológicos, observacionales y trasversales así como ensayos controlados y randomizados apoyan estas asociaciones. Estudios observacionales, con el apoyo de otros tipos, proporcionan los datos necesarios para determinar como la concentración en suero de 25-hidroxivitamina D (25[OH]D) afecta la incidencia de enfermedad y las tasas de mortalidad. Los datos sobre carcinoma colorrectal y mama así como la tasa de mortalidad por todas las causas indican que los beneficios aumentan con niveles de 25(OH)D entre 75 y 100<span class="elsevierStyleHsp" style=""></span>nmol/L. Para alcanzar estos niveles, hacen falta unas 5.000<span class="elsevierStyleHsp" style=""></span>UI de vitamina D por día, con bastante variación individual. Las fuentes principales de la vitamina D que puede ayudar a las personas a alcanzar estos niveles son la radiación UV-B y los suplementos de vitamina D<span class="elsevierStyleInf">3</span>. Las características de la piel- tanto en términos de pigmentación como de capacidad para broncearse - de la mayoría de los habitantes de España son muy adecuadas para una moderada exposición al sol. En general, el riesgo de melanoma es bajo en el sur de Europa. El riesgo de cáncer de piel no melanoma es más alto, aunque tales cánceres no suelen conllevar mortalidad. Un estudio de Dinamarca encontró una reducción del 9% en la tasa de mortalidad por todas las causas en 10 años para pacientes diagnosticados de carcinoma basocelular.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:22 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin D: evidence and controversies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Y. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 2 | 2 | 4 |
| 2024 Octubre | 48 | 60 | 108 |
| 2024 Septiembre | 38 | 28 | 66 |
| 2024 Agosto | 49 | 57 | 106 |
| 2024 Julio | 44 | 30 | 74 |
| 2024 Junio | 53 | 22 | 75 |
| 2024 Mayo | 41 | 24 | 65 |
| 2024 Abril | 47 | 24 | 71 |
| 2024 Marzo | 52 | 30 | 82 |
| 2024 Febrero | 36 | 36 | 72 |
| 2024 Enero | 48 | 26 | 74 |
| 2023 Diciembre | 38 | 14 | 52 |
| 2023 Noviembre | 40 | 29 | 69 |
| 2023 Octubre | 42 | 22 | 64 |
| 2023 Septiembre | 49 | 28 | 77 |
| 2023 Agosto | 27 | 15 | 42 |
| 2023 Julio | 44 | 44 | 88 |
| 2023 Junio | 27 | 18 | 45 |
| 2023 Mayo | 22 | 11 | 33 |
| 2023 Abril | 21 | 19 | 40 |
| 2023 Marzo | 42 | 18 | 60 |
| 2023 Febrero | 38 | 20 | 58 |
| 2023 Enero | 31 | 34 | 65 |
| 2022 Diciembre | 45 | 55 | 100 |
| 2022 Noviembre | 34 | 44 | 78 |
| 2022 Octubre | 56 | 49 | 105 |
| 2022 Septiembre | 39 | 65 | 104 |
| 2022 Agosto | 45 | 55 | 100 |
| 2022 Julio | 34 | 55 | 89 |
| 2022 Junio | 22 | 37 | 59 |
| 2022 Mayo | 42 | 45 | 87 |
| 2022 Abril | 30 | 40 | 70 |
| 2022 Marzo | 32 | 52 | 84 |
| 2022 Febrero | 27 | 27 | 54 |
| 2022 Enero | 40 | 46 | 86 |
| 2021 Diciembre | 35 | 49 | 84 |
| 2021 Noviembre | 28 | 36 | 64 |
| 2021 Octubre | 33 | 44 | 77 |
| 2021 Septiembre | 24 | 39 | 63 |
| 2021 Agosto | 26 | 38 | 64 |
| 2021 Julio | 21 | 34 | 55 |
| 2021 Junio | 25 | 29 | 54 |
| 2021 Mayo | 31 | 57 | 88 |
| 2021 Abril | 90 | 104 | 194 |
| 2021 Marzo | 35 | 35 | 70 |
| 2021 Febrero | 22 | 34 | 56 |
| 2021 Enero | 27 | 31 | 58 |
| 2020 Diciembre | 34 | 29 | 63 |
| 2020 Noviembre | 24 | 19 | 43 |
| 2020 Octubre | 20 | 14 | 34 |
| 2020 Septiembre | 39 | 27 | 66 |
| 2020 Agosto | 37 | 19 | 56 |
| 2020 Julio | 20 | 6 | 26 |
| 2020 Junio | 26 | 26 | 52 |
| 2020 Mayo | 31 | 25 | 56 |
| 2020 Abril | 34 | 30 | 64 |
| 2020 Marzo | 28 | 16 | 44 |
| 2020 Febrero | 2 | 7 | 9 |
| 2020 Enero | 0 | 11 | 11 |
| 2019 Diciembre | 4 | 2 | 6 |
| 2019 Noviembre | 0 | 1 | 1 |
| 2019 Septiembre | 4 | 0 | 4 |
| 2019 Julio | 0 | 1 | 1 |
| 2019 Junio | 2 | 29 | 31 |
| 2019 Mayo | 1 | 26 | 27 |
| 2019 Abril | 3 | 8 | 11 |
| 2019 Marzo | 3 | 14 | 17 |
| 2019 Febrero | 0 | 3 | 3 |
| 2019 Enero | 2 | 4 | 6 |
| 2018 Diciembre | 3 | 1 | 4 |
| 2018 Noviembre | 2 | 1 | 3 |
| 2018 Octubre | 1 | 1 | 2 |
| 2018 Septiembre | 4 | 0 | 4 |
| 2018 Julio | 1 | 0 | 1 |
| 2018 Abril | 1 | 0 | 1 |
| 2018 Febrero | 19 | 3 | 22 |
| 2018 Enero | 24 | 6 | 30 |
| 2017 Diciembre | 30 | 11 | 41 |
| 2017 Noviembre | 21 | 4 | 25 |
| 2017 Octubre | 29 | 3 | 32 |
| 2017 Septiembre | 22 | 13 | 35 |
| 2017 Agosto | 25 | 9 | 34 |
| 2017 Julio | 24 | 4 | 28 |
| 2017 Junio | 32 | 13 | 45 |
| 2017 Mayo | 32 | 8 | 40 |
| 2017 Abril | 33 | 25 | 58 |
| 2017 Marzo | 23 | 27 | 50 |
| 2017 Febrero | 22 | 13 | 35 |
| 2017 Enero | 18 | 7 | 25 |
| 2016 Diciembre | 38 | 6 | 44 |
| 2016 Noviembre | 27 | 10 | 37 |
| 2016 Octubre | 42 | 20 | 62 |
| 2016 Septiembre | 37 | 10 | 47 |
| 2016 Agosto | 33 | 8 | 41 |
| 2016 Julio | 33 | 3 | 36 |
| 2016 Junio | 4 | 0 | 4 |
| 2016 Mayo | 7 | 0 | 7 |
| 2016 Abril | 15 | 3 | 18 |
| 2016 Marzo | 10 | 4 | 14 |
| 2016 Febrero | 9 | 2 | 11 |
| 2016 Enero | 12 | 16 | 28 |
| 2015 Diciembre | 11 | 13 | 24 |
| 2015 Noviembre | 14 | 16 | 30 |
| 2015 Octubre | 18 | 16 | 34 |
| 2015 Septiembre | 4 | 5 | 9 |
| 2015 Agosto | 17 | 6 | 23 |
| 2015 Julio | 72 | 2 | 74 |
| 2015 Junio | 56 | 6 | 62 |
| 2015 Mayo | 115 | 26 | 141 |
| 2015 Abril | 98 | 22 | 120 |
| 2015 Marzo | 71 | 6 | 77 |
| 2015 Febrero | 53 | 2 | 55 |
| 2015 Enero | 52 | 1 | 53 |
| 2014 Diciembre | 51 | 0 | 51 |
| 2014 Noviembre | 40 | 0 | 40 |
| 2014 Octubre | 54 | 0 | 54 |
| 2014 Septiembre | 51 | 0 | 51 |
| 2014 Agosto | 15 | 0 | 15 |
| 2014 Julio | 14 | 0 | 14 |
| 2014 Junio | 28 | 0 | 28 |
| 2014 Mayo | 23 | 0 | 23 |
| 2014 Abril | 10 | 1 | 11 |
| 2014 Marzo | 28 | 15 | 43 |
| 2014 Febrero | 28 | 13 | 41 |
| 2014 Enero | 31 | 13 | 44 |
| 2013 Diciembre | 38 | 16 | 54 |
| 2013 Noviembre | 29 | 15 | 44 |
| 2013 Octubre | 27 | 29 | 56 |
| 2013 Septiembre | 34 | 26 | 60 |
| 2013 Agosto | 17 | 21 | 38 |
| 2013 Julio | 17 | 19 | 36 |
| 2013 Junio | 20 | 20 | 40 |
| 2013 Mayo | 26 | 15 | 41 |
| 2013 Abril | 27 | 16 | 43 |
| 2013 Marzo | 31 | 12 | 43 |
| 2013 Febrero | 36 | 12 | 48 |
| 2013 Enero | 24 | 9 | 33 |
| 2012 Diciembre | 30 | 12 | 42 |
| 2012 Noviembre | 7 | 8 | 15 |
| 2012 Octubre | 12 | 10 | 22 |
| 2012 Septiembre | 18 | 23 | 41 |
| 2012 Agosto | 7 | 4 | 11 |
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