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n&#227;o h&#225; dados de comorbidades em rela&#231;&#227;o a &#243;rg&#227;os internos&#44; embora a estreita rela&#231;&#227;o entre psor&#237;ase e doen&#231;as concomitantes seja comumente aceita&#44; e o risco de uma &#250;nica doen&#231;a espec&#237;fica na psor&#237;ase tenha sido amplamente estudado&#46;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">21&#44;23&#44;24</span></a> No entanto&#44; uma an&#225;lise abrangente das comorbidades em rela&#231;&#227;o a &#243;rg&#227;os internos na psor&#237;ase ainda est&#225; faltando&#46; O objetivo do presente estudo foi investigar as diferen&#231;as entre a popula&#231;&#227;o com psor&#237;ase e a popula&#231;&#227;o geral em termos de diferentes comorbidades em &#243;rg&#227;os internos&#46; A an&#225;lise n&#227;o se limitou a valores puramente de fus&#227;o e procurou encontrar padr&#245;es de associa&#231;&#227;o entre eles&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Material e m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Revis&#227;o de literatura e estrat&#233;gia de busca</span><p id="par0010" class="elsevierStylePara elsevierViewall">Essa metan&#225;lise foi registrada no registro PROSPERO &#40;CRD 42020211821&#41;&#44; de acordo com as recomenda&#231;&#245;es do PRISMA 2020&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">25</span></a> Os bancos de dados Pubmed&#44; EMBASE e Cochrane Library foram utilizados na busca&#44; incluindo todos os estudos desde o in&#237;cio desses bancos de dados at&#233; 14 de outubro de 2020&#46; Os pesquisadores realizaram a obten&#231;&#227;o da literatura&#44; a sele&#231;&#227;o dos artigos&#44; a extra&#231;&#227;o de dados e a avalia&#231;&#227;o da qualidade do estudo&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">A estrat&#233;gia de busca incluiu uma variedade de termos relacionados &#224; psor&#237;ase e comorbidades em &#243;rg&#227;os internos&#46; Os detalhes da estrat&#233;gia de busca nos bancos de dados Pubmed&#44; Embase e Cochrane Library s&#227;o mostradas no material suplementar&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Sele&#231;&#227;o de estudos</span><p id="par0020" class="elsevierStylePara elsevierViewall">De acordo com a estrat&#233;gia PECO&#44; foram inclu&#237;dos artigos que atenderam aos seguintes crit&#233;rios&#46; Popula&#231;&#227;o&#58; inclu&#237;mos estudos que continham tanto a popula&#231;&#227;o com psor&#237;ase quanto a popula&#231;&#227;o geral&#46; Exposi&#231;&#227;o&#58; psor&#237;ase com diagn&#243;stico regular &#40;sem limite de idade&#41;&#46; Compara&#231;&#227;o&#58; pessoas sem psor&#237;ase e do mesmo ambiente de pesquisa que aquelas com psor&#237;ase&#46; Desfecho&#58; os resultados do registro foram comorbidades em &#243;rg&#227;os internos &#40;doen&#231;as cardiovasculares&#44; doen&#231;as renais&#44; doen&#231;as hep&#225;ticas&#44; doen&#231;as respirat&#243;rias&#44; doen&#231;as do ba&#231;o e doen&#231;as relacionadas ao sistema cerebrovascular&#41;&#46; Foram exclu&#237;das as publica&#231;&#245;es com dados insuficientes e reduplicados&#46; Restri&#231;&#245;es de tipo de estudo e idioma n&#227;o foram consideradas na busca inicial&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Extra&#231;&#227;o de dados e avalia&#231;&#227;o da qualidade do estudo</span><p id="par0025" class="elsevierStylePara elsevierViewall">O texto completo dos artigos que atenderam aos crit&#233;rios de elegibilidade foi selecionado para extra&#231;&#227;o de dados&#46; Os dados extra&#237;dos inclu&#237;ram primeiro autor&#44; ano de publica&#231;&#227;o&#44; pa&#237;s&#44; dados demogr&#225;ficos&#44; n&#250;mero de pacientes e tempo de seguimento&#46; Por exemplo&#44; a inten&#231;&#227;o era incluir estudos em que os pacientes claramente apresentavam doen&#231;as renais&#44; como doen&#231;a renal cr&#244;nica etc&#46; Al&#233;m disso&#44; estudos que n&#227;o tinham nada al&#233;m de dados laboratoriais anormais foram exclu&#237;dos&#46; Se um estudo fornecesse dados com diferentes tipos de psor&#237;ase &#40;leve&#44; moderada e grave&#41;&#44; os mesmos eram combinados para obter uma estimativa de todos os pacientes com psor&#237;ase&#46; Para garantir a precis&#227;o da extra&#231;&#227;o de dados&#44; qualquer diferen&#231;a encontrada nos dados poderia ser abordada consultando o artigo original&#46; A escala <span class="elsevierStyleItalic">Newcastle&#8208;Ottawa Quality Assessment Scale</span> foi utilizada para avaliar a qualidade dos estudos inclu&#237;dos&#44; com escore m&#225;ximo de 9 pontos&#44; representando a mais alta qualidade&#46; A escala avaliou a qualidade de cada estudo em tr&#234;s &#225;reas&#44; incluindo &#40;1&#41; recrutamento de sujeitos de caso e controle&#59; &#40;2&#41; comparabilidade entre os dois grupos&#59; e &#40;3&#41; identifica&#231;&#227;o dos resultados de interesse&#46; As caracter&#237;sticas dos estudos e os resultados da avalia&#231;&#227;o s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">An&#225;lise estat&#237;stica</span><p id="par0030" class="elsevierStylePara elsevierViewall">As an&#225;lises estat&#237;sticas foram realizadas por RevMan 5&#46;4 &#40;colabora&#231;&#227;o Cochrane&#41; e Stata vers&#227;o 12&#46;0 &#40;StataCorp LP&#44; College Station&#44; TX77845&#41;&#46; Os resultados foram refletidos em risco relativo agrupado &#40;RRa&#41; e IC de 95&#37;&#46; Todos os testes estat&#237;sticos foram bilaterais&#46; Os valores de p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 foram considerados significativos&#46; O teste de inconsist&#234;ncia estat&#237;stica &#40;I<span class="elsevierStyleSup">2</span>&#41; foi utilizado para avaliar a heterogeneidade&#46; O valor de I<span class="elsevierStyleSup">2</span> igual a 0&#37;&#44; 25&#37;&#44; 50&#37; e 75&#37; indicou nenhuma&#44; baixa&#44; m&#233;dia e alta heterogeneidade&#44; respectivamente&#46; As an&#225;lises de sensibilidade&#44; an&#225;lises de subgrupos e metarregress&#227;o foram realizadas para identificar fontes potenciais de heterogeneidade&#46; Al&#233;m disso&#44; os gr&#225;ficos de funil e a regress&#227;o ponderada de Egger foram usados para avaliar o potencial vi&#233;s de publica&#231;&#227;o&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Os RRa e os ICs de 95&#37; correspondentes foram estimados por meio de uma metan&#225;lise de efeito aleat&#243;rio&#46; Uma transforma&#231;&#227;o logar&#237;tmica foi realizada para os RRa estimados de tamanho de efeito m&#225;ximo ajustado e os ICs&#46; Os RRa foram submetidos ao teste Z e &#224; an&#225;lise de sensibilidade e utilizados para avaliar o efeito de estabilidade combinado&#46; O vi&#233;s de publica&#231;&#227;o foi avaliado por meio de gr&#225;ficos de funil&#46; Um funil invertido sim&#233;trico indicou que n&#227;o havia uma alta probabilidade de vi&#233;s de publica&#231;&#227;o&#46; Por fim&#44; um estudo foi retirado para avaliar seu impacto na s&#237;ntese&#46; A semelhan&#231;a dos RRa combinados antes e ap&#243;s a remo&#231;&#227;o do estudo indicou que havia um alto grau de confian&#231;a nos resultados&#46; Quando havia heterogeneidade entre os estudos&#44; foi aplicado o modelo de efeito aleat&#243;rio e o m&#233;todo de an&#225;lise de Mantel&#8208;Haenszel foi utilizado&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Resultados</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Sele&#231;&#227;o dos estudos</span><p id="par0035" class="elsevierStylePara elsevierViewall">A estrat&#233;gia de busca &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41; produziu 7&#46;412 refer&#234;ncias potencialmente relevantes &#40;3&#46;862 no Pubmed&#44; 2&#46;984 no EMBASE e 566 na Cochrane Library&#41;&#46; Ao final&#44; restaram 15 estudos retrospectivos de coorte&#44; contendo 216&#46;348 pacientes com psor&#237;ase e 9&#46;896&#46;962 popula&#231;&#227;o em geral&#46; Todos os estudos foram baseados em um banco de dados gerenciado&#44; com base em c&#243;digos de diagn&#243;stico para identificar e verificar o diagn&#243;stico de psor&#237;ase e comorbidades em &#243;rg&#227;os internos&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Caracter&#237;sticas dos estudos</span><p id="par0040" class="elsevierStylePara elsevierViewall">As principais caracter&#237;sticas cl&#237;nicas e avalia&#231;&#227;o da qualidade dos estudos inclu&#237;dos est&#227;o resumidas na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46; Esses estudos foram realizados em sete pa&#237;ses&#58; EUA&#44; Reino Unido&#44; Alemanha&#44; Dinamarca&#44; It&#225;lia&#44; Taiwan e Coreia do Sul&#46; A m&#233;dia de idade dos pacientes com psor&#237;ase variou de 12&#44;0 a 69&#44;5 anos&#44; com o sexo feminino variando de 32&#44;58 a 59&#44;19&#37;&#46; Para a popula&#231;&#227;o geral&#44; a m&#233;dia de idade variou de 12&#44;0 a 70&#44;6 anos e o sexo feminino variou de 22&#44;14 a 67&#44;42&#37;&#46; Apenas dois estudos n&#227;o relataram a m&#233;dia de idade&#44;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">26&#44;27</span></a> e um estudo investigou principalmente crian&#231;as com psor&#237;ase&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">28</span></a> Assim&#44; a amplitude das caracter&#237;sticas et&#225;rias foi grande ap&#243;s a s&#237;ntese dos dados&#46; Havia poucos dados espec&#237;ficos de comorbidades em &#243;rg&#227;os internos por ra&#231;a&#47;etnia&#46; Portanto&#44; nenhuma an&#225;lise de subgrupo foi realizada em rela&#231;&#227;o a essa vari&#225;vel&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">28&#44;29</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Psor&#237;ase e comorbidades em todos os &#243;rg&#227;os internos</span><p id="par0050" class="elsevierStylePara elsevierViewall">Os riscos de comorbidades em todos os &#243;rg&#227;os internos em pacientes com psor&#237;ase e na popula&#231;&#227;o geral s&#227;o descritos na <a class="elsevierStyleCrossRef" href="#fig0010">figura 2</a>&#46; Foram estudados principalmente o envolvimento card&#237;aco&#44; renal&#44; pulmonar&#44; cerebral e hep&#225;tico&#46; Em 15 estudos<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">26&#8211;40</span></a> havia um total de 216&#46;348 pacientes com psor&#237;ase e 9&#46;896&#46;962 controles&#46; Isso demonstrou que os pacientes com psor&#237;ase tinham um risco significativamente aumentado dessas comorbidades em &#243;rg&#227;os internos&#44; e o RRa foi de 1&#44;20 &#40;IC 95&#37; 1&#44;11&#8208;1&#44;31&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Ap&#243;s a remo&#231;&#227;o do estudo envolvendo principalmente crian&#231;as&#44;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">28</span></a> o RRa foi de 1&#44;17 &#40;IC 95&#37; 1&#44;08&#8208;1&#44;27&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Psor&#237;ase e comorbidades espec&#237;ficas de &#243;rg&#227;os</span><p id="par0055" class="elsevierStylePara elsevierViewall">Em 14 estudos&#44;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">26&#8211;34&#44;36&#8211;40</span></a> somando 210&#46;856 pacientes com psor&#237;ase e 9&#46;891&#46;470 controles&#44; o RRa para eventos cardiovasculares foi de 1&#44;20 &#40;IC 95&#37; 1&#44;11&#8208;1&#44;30&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>97&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; mostrando aumento significante na compara&#231;&#227;o com a popula&#231;&#227;o geral&#46; Em nove estudos<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">27&#44;29&#8211;31&#44;34&#8211;36&#44;38&#44;40</span></a> envolvendo 135&#46;345 pacientes com psor&#237;ase e 9&#46;699&#46;285 indiv&#237;duos controle&#44; o RRa para doen&#231;as renais foi de 1&#44;08 &#40;IC 95&#37; 0&#44;87&#8208;1&#44;33&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Em oito estudos<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">26&#44;27&#44;31&#8211;33&#44;35&#44;37&#44;40</span></a> com 103&#46;300 pacientes com psor&#237;ase e 4&#46;729&#46;963 indiv&#237;duos controle&#44; o RRa de eventos de doen&#231;a cerebrovascular foi de 1&#44;56 &#40;IC 95&#37; 1&#44;20&#8208;2&#44;04&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Em nove estudos<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">27&#44;30&#8211;32&#44;35&#44;36&#44;38&#44;40</span></a> com 132&#46;791 pacientes com psor&#237;ase e 9&#46;689&#46;831 indiv&#237;duos controle&#44; o RRa para a ocorr&#234;ncia de doen&#231;a pulmonar foi de 1&#44;05 &#40;IC 95&#37; 0&#44;89&#8208;1&#44;23&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; Em cinco estudos<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">27&#44;28&#44;35&#44;38&#44;40</span></a> envolvendo 46&#46;469 pacientes com psor&#237;ase e 131&#46;154 controles&#44; o RRa para a ocorr&#234;ncia de doen&#231;as hep&#225;ticas foi de 1&#44;75 &#40;IC95&#37; 1&#44;33&#8208;2&#44;29&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>88&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; e foi notavelmente maior do que na popula&#231;&#227;o geral &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Psor&#237;ase e comorbidades em m&#250;ltiplos &#243;rg&#227;os internos</span><p id="par0060" class="elsevierStylePara elsevierViewall">Pacientes com psor&#237;ase relataram sofrer de duas ou mais comorbidades simultaneamente&#46;<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">41&#8211;46</span></a> Portanto&#44; foram extra&#237;dos dados de dois &#243;rg&#227;os dos estudos inclu&#237;dos e os RRa foram calculados &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46; O RRa para doen&#231;as renais mais eventos cardiovasculares foi de 1&#44;09 &#40;IC 95&#37; 1&#44;01&#8208;1&#44;18&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>85&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; O RRa para doen&#231;as renais mais eventos cerebrovasculares foi de 1&#44;28 &#40;IC 95&#37; 0&#44;99&#8208;1&#44;66&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>87&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; O RRa para doen&#231;as renais mais doen&#231;as hep&#225;ticas foi de 1&#44;46 &#40;IC 95&#37; 1&#44;10&#8208;1&#44;94&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>91&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; O RRa para eventos cardiovasculares mais doen&#231;as hep&#225;ticas foi de 1&#44;41 &#40;IC 95&#37; 1&#44;11&#8208;1&#44;80&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>95&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Riscos de comorbidades em &#243;rg&#227;os internos na psor&#237;ase leve e moderada&#47;grave</span><p id="par0065" class="elsevierStylePara elsevierViewall">Havia tr&#234;s estudos subdividindo os pacientes com psor&#237;ase em subgrupo leve e moderado&#47;grave&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">31&#44;32&#44;36</span></a> No total&#44; eles inclu&#237;ram 97&#46;285 pacientes com psor&#237;ase leve e 15&#46;016 pacientes com psor&#237;ase moderada&#47;grave&#46; O RRa de comorbidades em &#243;rg&#227;os internos foi de 0&#44;61 &#40;IC 95&#37; 0&#44;46&#8208;0&#44;81&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>94&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; para psor&#237;ase leve&#44; menor portanto do que o de pacientes com psor&#237;ase moderada&#47;grave &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S1 suplementar</a>&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">An&#225;lises de sensibilidade</span><p id="par0070" class="elsevierStylePara elsevierViewall">A sensibilidade &#233; um importante indicador da qualidade e heterogeneidade da literatura&#46; Um estudo foi exclu&#237;do de cada vez para estimar o efeito no RRa&#46; N&#227;o houve mudan&#231;a &#243;bvia nem diminui&#231;&#227;o significativa na heterogeneidade&#46; As an&#225;lises de sensibilidade foram realizadas para avaliar qual estudo forneceu maior heterogeneidade aos dados pelo gr&#225;fico de Galbraith&#46; Todos os estudos mostraram resultados est&#225;veis e confi&#225;veis &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S2 suplementar</a>&#41;&#46; Ap&#243;s avalia&#231;&#227;o cuidadosa&#44; concluiu&#8208;se que nem todos os estudos eram sens&#237;veis aos RRa e n&#227;o podiam ser exclu&#237;dos arbitrariamente&#46; Os resultados dos escores foram avaliados pela <span class="elsevierStyleItalic">Newcastle&#8208;Ottawa Quality Assessment Scale</span> para todos os estudos inclu&#237;dos na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46; Todos os estudos pontuaram pelo menos 6 pontos&#44; o que est&#225; de acordo com os requisitos para a continua&#231;&#227;o do estudo&#46; Por outro lado&#44; o comando Metaninf do <span class="elsevierStyleItalic">software</span> Stata foi utilizado para avaliar o impacto de um &#250;nico estudo&#46; Ap&#243;s a exclus&#227;o de um estudo de cada vez&#44; o ponto de estimativas n&#227;o ficou fora do IC de 95&#37; &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S3 suplementar</a>&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Vi&#233;s de publica&#231;&#227;o</span><p id="par0075" class="elsevierStylePara elsevierViewall">O gr&#225;fico de funil foi utilizado para analisar o vi&#233;s de publica&#231;&#227;o de 15 estudos&#46; O resultado do gr&#225;fico mostrou um certo grau de vi&#233;s de publica&#231;&#227;o&#46; O m&#233;todo de Egger foi utilizado para verificar e quantificar o gr&#225;fico de funil&#46; O valor de p foi verificado para determinar se havia vi&#233;s de publica&#231;&#227;o&#46; O valor T &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;854&#41; significou que n&#227;o houve vi&#233;s de publica&#231;&#227;o &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S4 suplementar</a>&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Qualidade dos estudos</span><p id="par0080" class="elsevierStylePara elsevierViewall">Em rela&#231;&#227;o &#224; qualidade de todos os estudos&#44; o escore na escala NOS variou de 6 a 8&#46; Foi determinado que seis estudos tinham baixo risco de vi&#233;s&#44; sete estudos tinham risco m&#233;dio de vi&#233;s e dois tinham alto risco de vi&#233;s &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">An&#225;lise de subgrupo</span><p id="par0085" class="elsevierStylePara elsevierViewall">As an&#225;lises de subgrupos foram conduzidas&#44; incluindo regi&#245;es &#40;pa&#237;ses ocidentais <span class="elsevierStyleItalic">vs</span>&#46; pa&#237;ses asi&#225;ticos&#41;&#44; per&#237;odo do estudo &#40;at&#233; 2000 <span class="elsevierStyleItalic">vs</span>&#46; ap&#243;s 2000&#41; e financiamento &#40;com <span class="elsevierStyleItalic">vs</span>&#46; sem&#41;&#46; A regi&#227;o pesquisada em tr&#234;s estudos foi a &#193;sia&#59;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">26&#44;27&#44;34</span></a> no restante foi o Ocidente&#46; Os resultados mostraram os pa&#237;ses asi&#225;ticos com RRa de 1&#44;09 &#40;IC 95&#37; 0&#44;95&#8208;1&#44;24&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; e 1&#44;24 &#40;IC 95&#37; 1&#44;12&#8208;1&#44;37&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; para os pa&#237;ses ocidentais&#46; O I<span class="elsevierStyleSup">2</span> foi de 55&#44;5&#37; e o valor de p foi de 0&#44;13 entre os subgrupos &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S5 suplementar</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Dois estudos n&#227;o apontaram claramente a dura&#231;&#227;o do estudo&#44;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">38&#44;40</span></a> e os demais foram divididos em dois grupos para discuss&#227;o posterior&#46; Os per&#237;odos de pesquisa de quatro estudos foram ao longo da d&#233;cada de 2000&#44;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">31&#44;33&#44;34&#44;36</span></a> e o RRa foi de 1&#44;04 &#40;IC 95&#37; 0&#44;89&#8208;1&#44;21&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>97&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; O RRa dos estudos restantes &#40;ap&#243;s 2000&#41; foi de 1&#44;31 &#40;IC 95&#37; 1&#44;17&#8208;1&#44;47&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>99&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; O I<span class="elsevierStyleSup">2</span> foi de 82&#44;7&#37; e o valor de p foi de 0&#44;02 entre os subgrupos &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S6 suplementar</a>&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Houve algumas pesquisas sem financiamento&#44;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">27&#44;32</span></a> enquanto o restante dos estudos foi financiado&#46; A an&#225;lise mostrou que o RRa de pesquisas n&#227;o financiadas foi de 1&#44;33 &#40;IC 95&#37; 1&#44;10&#8208;1&#44;62&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>99&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; e o RRa de pesquisas financiadas foi de 1&#44;18 &#40;IC 95&#37; 1&#44;09&#8208;1&#44;29&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; O I<span class="elsevierStyleSup">2</span> foi de 18&#44;7&#37; e o valor de p foi de 0&#44;27 entre os subgrupos &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S7 suplementar</a>&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Esses resultados de an&#225;lises de subgrupos&#44; incluindo regi&#245;es &#40;pa&#237;ses ocidentais <span class="elsevierStyleItalic">vs</span>&#46; asi&#225;ticos&#41;&#44; per&#237;odo de estudo &#40;at&#233; 2000 <span class="elsevierStyleItalic">vs</span>&#46; ap&#243;s 2000&#41; e financiamento &#40;com <span class="elsevierStyleItalic">vs</span>&#46; sem&#41;&#44; n&#227;o forneceram nenhuma fonte espec&#237;fica de heterogeneidade&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Metarregress&#227;o</span><p id="par0105" class="elsevierStylePara elsevierViewall">De acordo com as caracter&#237;sticas dos estudos inclu&#237;dos&#44; novas vari&#225;veis concomitantes foram geradas ap&#243;s a atribui&#231;&#227;o de vari&#225;veis <span class="elsevierStyleItalic">dummy</span> de acordo com as regi&#245;es &#40;pa&#237;ses ocidentais <span class="elsevierStyleItalic">vs</span>&#46; asi&#225;ticos&#41;&#44; per&#237;odo do estudo &#40;at&#233; 2000 <span class="elsevierStyleItalic">vs</span>&#46; ap&#243;s 2000&#41; e financiamento &#40;com <span class="elsevierStyleItalic">vs</span>&#46; sem&#41;&#46; O LogRR logar&#237;tmico de RR indicador de efeito de cada estudo era vari&#225;vel dependente&#46; As metarregress&#245;es foram todas realizadas &#40;p &#62; 0&#44;05&#41;&#44; mas n&#227;o houve fonte de heterogeneidade&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discuss&#227;o</span><p id="par0110" class="elsevierStylePara elsevierViewall">O presente estudo &#233; a primeira metan&#225;lise de risco de comorbidades relacionadas a &#243;rg&#227;os internos em pacientes com psor&#237;ase&#46; Esses riscos de comorbidade em &#243;rg&#227;os internos foram consistentes com os dados publicados anteriormente em n&#237;vel de doen&#231;a &#250;nica&#46; Por exemplo&#44; estudos anteriores mostraram que pacientes com psor&#237;ase tinham um risco maior de hipertens&#227;o &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;58&#44; IC 95&#37; 1&#44;42&#8208;1&#44;76&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">47</span></a> doen&#231;a renal em est&#225;gio terminal &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;29&#44; IC 95&#37; 1&#44;05&#8208;1&#44;60&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">48</span></a> acidente vascular cerebral &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;08&#44; IC 95&#37; 1&#44;00&#8208;1&#44;16&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">49</span></a> doen&#231;a hep&#225;tica gordurosa n&#227;o alco&#243;lica &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;15&#44; IC 95&#37; 1&#44;57&#8208;2&#44;94&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">24</span></a> e DPOC &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;90&#44; 95&#37; IC 1&#44;36&#8208;2&#44;65&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">21</span></a> Foi observado que os pacientes com psor&#237;ase tinham um risco significativamente maior de comorbidades em &#243;rg&#227;os internos do que a popula&#231;&#227;o geral&#46; Por exemplo&#44; o RRa de comorbidade foi de 1&#44;20 para o &#243;rg&#227;o cardiovascular geral&#44; 1&#44;75 para o f&#237;gado&#44; 1&#44;56 para o &#243;rg&#227;o cerebrovascular&#44; 1&#44;08 e 1&#44;05 para o &#243;rg&#227;o renal e &#243;rg&#227;os pulmonares&#44; respectivamente&#46; Em doen&#231;as cardiovasculares&#44; hep&#225;ticas e cerebrovasculares&#44; os riscos de comorbidades em &#243;rg&#227;os internos na psor&#237;ase foram acentuadamente maiores do que na popula&#231;&#227;o geral&#46; Embora n&#227;o houvesse diferen&#231;a significativa entre pacientes com psor&#237;ase e controles em rela&#231;&#227;o &#224;s doen&#231;as renais e pulmonares&#44; os resultados tamb&#233;m podem servir de refer&#234;ncia para pesquisas futuras&#46; Al&#233;m disso&#44; em compara&#231;&#227;o com pacientes com psor&#237;ase leve&#44; foi demonstrado que pacientes com psor&#237;ase moderada&#47;grave tinham um risco acentuadamente maior de comorbidades em &#243;rg&#227;os internos&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Estudos anteriores mostraram que pacientes com psor&#237;ase podem sofrer de duas ou mais comorbidades simultaneamente &#8211; por exemplo&#44; insufici&#234;ncia card&#237;aca combinada com doen&#231;a renal cr&#244;nica&#44;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">43</span></a> gota ou les&#227;o renal aguda combinada com hipertens&#227;o&#44; cirrose hep&#225;tica ou doen&#231;a cerebrovascular&#46;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">44&#8211;46</span></a> Para descobrir esses riscos combinados de comorbidades na psor&#237;ase&#44; foram reunidos dados de v&#225;rios &#243;rg&#227;os internos&#46; Observou&#8208;se que o RRa para doen&#231;as renais mais eventos cardiovasculares no mesmo paciente com psor&#237;ase era de 1&#44;09 &#40;IC 95&#37; 1&#44;01&#8208;1&#44;18&#41;&#44; 1&#44;28 &#40;IC 95&#37; 0&#44;99&#8208;1&#44;66&#41; para doen&#231;as renais mais eventos cerebrovasculares&#44; 1&#44;46 &#40;IC 95&#37; 1&#44;10&#8208;1&#44;94&#41;&#46;&#41; para doen&#231;as renais mais doen&#231;as hep&#225;ticas e 1&#44;41 &#40;IC 95&#37; 1&#44;11&#8208;1&#44;80&#41; para eventos cardiovasculares mais doen&#231;as hep&#225;ticas&#46; Esses valores mostraram que os pacientes com psor&#237;ase tinham riscos significativamente maiores de comorbidades em m&#250;ltiplos &#243;rg&#227;os&#44; n&#227;o apenas comorbidades em um &#250;nico &#243;rg&#227;o&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">A fim de analisar melhor a rela&#231;&#227;o entre os riscos de comorbidades em &#243;rg&#227;os internos na psor&#237;ase e o ano do estudo e a regi&#227;o dos pacientes&#44; foram comparados v&#225;rios conjuntos de dados&#46; Pelas caracter&#237;sticas diversas dos anos inclu&#237;dos nos estudos&#44; o ano de 2006 foi considerado o ponto de demarca&#231;&#227;o&#44; com base no princ&#237;pio da busca da m&#225;xima similaridade&#46; Seis grupos de dados significativos foram selecionados&#44;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">27&#44;30&#8211;32&#44;35&#44;37</span></a> e o RRa foi de 0&#44;23 &#40;IC 95&#37; 0&#44;05&#8208;1&#44;00&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; ap&#243;s a fus&#227;o de dados &#40;<a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S8 suplementar</a>&#41;&#46; Isso sugeriu que os pacientes com psor&#237;ase ap&#243;s o ano de 2006 eram mais propensos a sofrer de comorbidades em &#243;rg&#227;os internos&#46; Como foram inclu&#237;dos poucos estudos realizados no Oriente&#44; tr&#234;s grupos combinados com as caracter&#237;sticas dos estudos do Oriente foram utilizados para estudo comparativo&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">26&#44;27&#44;32&#8211;34&#44;39</span></a> Ap&#243;s a fus&#227;o dos dados&#44; o RRa foi de 1&#44;73 &#40;IC 95&#37; 1&#44;07&#8208;2&#44;77&#41;&#44; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100&#37;&#44; p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#59; <a class="elsevierStyleCrossRef" href="#sec0125">fig&#46; S9 suplementar</a>&#41;&#46; O resultado sugeriu que os pacientes asi&#225;ticos com psor&#237;ase eram mais propensos a sofrer de comorbidades em &#243;rg&#227;os internos&#46; Essas conclus&#245;es precisam de mais estudos para confirma&#231;&#227;o adicional&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A patog&#234;nese da psor&#237;ase e comorbidades em &#243;rg&#227;os internos pode ser mediada por certas citocinas representativas&#44; como interleucina&#8208;17 &#40;IL&#8208;17&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">50&#8211;53</span></a> interleucina&#8208;23 &#40;IL&#8208;23&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">54</span></a> e fator de necrose tumoral&#8208;&#593; &#40;TNF&#8208;&#593;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">55&#44;56</span></a> Elas podem chegar a qualquer local do corpo atrav&#233;s da circula&#231;&#227;o sangu&#237;nea e podem mediar respostas inflamat&#243;rias sist&#234;micas na psor&#237;ase&#46;<a class="elsevierStyleCrossRefs" href="#bib0710"><span class="elsevierStyleSup">57&#8211;61</span></a> As citocinas inflamat&#243;rias atuam em cada sistema juntas ou isoladamente&#46; Os efeitos s&#227;o gerados pelo mesmo mecanismo molecular e via inflamat&#243;ria imune&#46; Essas quest&#245;es precisam ser esclarecidas e ainda precisam de mais estudos&#46; Na verdade&#44; as citocinas envolvidas da patog&#234;nese de cada &#243;rg&#227;o interno podem ser as mesmas ou absolutamente diferentes&#46; Pesquisas existentes mostram que a principal citocina inflamat&#243;ria envolvida da psor&#237;ase com disfun&#231;&#245;es articulares ou diabetes &#233; o TNF&#8208;&#593;&#46; <a class="elsevierStyleCrossRefs" href="#bib0735"><span class="elsevierStyleSup">62&#8211;66</span></a> No entanto&#44; a citocina na psor&#237;ase envolvendo o sistema cardiovascular pode ser a IL&#8208;17 ou IL&#8208;23&#46;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">67&#8211;69</span></a> Tudo isso ainda precisa de mais investiga&#231;&#227;o&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">O presente estudo pode fornecer refer&#234;ncias para tratamentos cl&#237;nicos eficazes&#46; Ultimamente&#44; a terapia com anticorpos biol&#243;gicos desempenha um papel promissor no controle da morbidade e mortalidade da psor&#237;ase&#46; <a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">70&#8211;75</span></a> Se os mecanismos moleculares e as citocinas&#8208;alvo desreguladas nos &#243;rg&#227;os internos afetados forem diferentes&#44; ent&#227;o a escolha do anticorpo biol&#243;gico deve ser totalmente diferente&#46;<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">76&#8211;80</span></a> Nenhum anticorpo biol&#243;gico &#233; uma panaceia&#44;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">81&#8211;84</span></a> e deve&#8208;se tentar fornecer aos pacientes um plano de tratamento mais individualizado de acordo com as comorbidades em &#243;rg&#227;os internos afetados pela psor&#237;ase&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">H&#225; v&#225;rias limita&#231;&#245;es em nossa metan&#225;lise&#46; Primeiro&#44; h&#225; heterogeneidade&#46; Considerou&#8208;se que a heterogeneidade era normalmente distribu&#237;da e aceit&#225;vel&#46; A heterogeneidade estat&#237;stica n&#227;o afetou o resultado&#46; Observou&#8208;se que o &#237;ndice de heterogeneidade na metan&#225;lise de preval&#234;ncia geral sempre foi alto e estava relacionado ao grande n&#250;mero de objetos de estudo e &#224; natureza dos estudos observacionais&#46; Nesse estudo&#44; a an&#225;lise de subgrupo e metarregress&#227;o foram realizadas para tentar encontrar a fonte da heterogeneidade&#46; Tamb&#233;m foi utilizado o modelo de efeitos aleat&#243;rios para abordar a potencial heterogeneidade&#46; No entanto&#44; cada estudo foi qualitativamente semelhante &#224; an&#225;lise de todas as comorbidades em &#243;rg&#227;os internos e comorbidades em &#243;rg&#227;os individuais&#46; Em segundo lugar&#44; algumas an&#225;lises sistem&#225;ticas&#44; metarregress&#227;o e an&#225;lises de subgrupos n&#227;o apresentaram um alto poder estat&#237;stico devido ao pequeno n&#250;mero de estudos inclu&#237;dos&#46; Deve&#8208;se ter cuidado ao analisar esses dados&#46; Em terceiro lugar&#44; o tema do presente estudo &#233; novo e n&#227;o h&#225; estudos sobre comorbidades em &#243;rg&#227;os internos na psor&#237;ase&#46; A abordagem PECO &#233; diferente da express&#227;o PECO tradicional e pode causar confus&#227;o&#46; A popula&#231;&#227;o do estudo incluiu o grupo de exposi&#231;&#227;o mais o grupo controle&#44; ou seja&#44; a Popula&#231;&#227;o cont&#233;m Exposi&#231;&#227;o e Compara&#231;&#227;o&#46; Entretanto&#44; os resultados do presente estudo ainda podem servir de refer&#234;ncia para os m&#233;dicos no manejo das comorbidades da psor&#237;ase&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclus&#245;es</span><p id="par0140" class="elsevierStylePara elsevierViewall">Foi demonstrado que os pacientes com psor&#237;ase t&#234;m risco aumentado de comorbidades em &#243;rg&#227;os internos &#250;nicos e m&#250;ltiplos&#46; Isso n&#227;o foi relatado anteriormente na literatura publicada&#46; Esses resultados sugerem que deve haver controle da inflama&#231;&#227;o sist&#234;mica no tratamento&#44; principalmente para pacientes moderados&#47;graves&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Suporte financeiro</span><p id="par0145" class="elsevierStylePara elsevierViewall">Esse estudo recebeu suporte financeiro parcial da <span class="elsevierStyleItalic">National Natural Science Foundation of China</span> &#40;n&#176; 81771783&#44; 82073444&#41;&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Contribui&#231;&#245;es dos autores</span><p id="par0150" class="elsevierStylePara elsevierViewall">Xuemei Tang&#58; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#59; revis&#227;o cr&#237;tica da literatura&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; participa&#231;&#227;o intelectual em conduta proped&#234;utica e&#47;ou terap&#234;utica&#59; manejo dos casos estudados&#59; revis&#227;o cr&#237;tica do manuscrito&#59; elabora&#231;&#227;o e reda&#231;&#227;o do manuscrito&#59; an&#225;lise estat&#237;stica&#59; concep&#231;&#227;o e planejamento do estudo&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflito de interesses</span><p id="par0155" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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    "fechaRecibido" => "2021-07-05"
    "fechaAceptado" => "2021-10-04"
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          "palabras" => array:5 [
            0 => "Comorbidade"
            1 => "Metan&#225;lise"
            2 => "Psor&#237;ase"
            3 => "Revis&#227;o sistem&#225;tica"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A estreita rela&#231;&#227;o entre psor&#237;ase e doen&#231;as concomitantes &#233; amplamente aceita&#46; No entanto&#44; ainda falta uma an&#225;lise abrangente das comorbidades em &#243;rg&#227;os internos na psor&#237;ase&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">O objetivo foi apresentar o risco de comorbidades em &#243;rg&#227;os internos na psor&#237;ase comparando&#8208;o ao da popula&#231;&#227;o geral&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Uma busca foi realizada nas bases de dados Pubmed&#44; EMBASE e Cochrane para estudos que relatam comorbidades em &#243;rg&#227;os internos na psor&#237;ase <span class="elsevierStyleItalic">vs</span>&#46; na popula&#231;&#227;o geral&#46; Foram avaliados estudos observacionais que atenderam aos seguintes crit&#233;rios&#58; 1&#41; diagn&#243;stico de psor&#237;ase&#59; 2&#41; desfechos cardiovasculares ou renais ou hep&#225;ticos ou respirat&#243;rios ou cerebrovasculares&#59; 3&#41; grupo de compara&#231;&#227;o de indiv&#237;duos sem psor&#237;ase&#46; Riscos relativos agrupados &#40;RRa&#41; e intervalos de confian&#231;a de 95&#37; &#40;IC95&#37;&#41; foram calculados utilizando o modelo de efeito aleat&#243;rio&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Quinze estudos observacionais com 216&#46;348 pacientes com psor&#237;ase e 9&#46;896&#46;962 indiv&#237;duos da popula&#231;&#227;o geral foram inclu&#237;dos&#46; A popula&#231;&#227;o com psor&#237;ase apresentou maior risco de comorbidades em &#243;rg&#227;os do que a geral&#46; Comparando&#8208;se com a popula&#231;&#227;o geral&#44; o RRa para todas as comorbidades em &#243;rg&#227;os internos foi de 1&#44;20 &#40;IC 95&#37; 1&#44;11&#8208;1&#44;31&#41; na psor&#237;ase&#44; e o RRa foi menor em pacientes leves 0&#44;61 &#40;IC 95&#37; 0&#44;46&#8208;0&#44;81&#41; do que em pacientes moderados&#47;graves&#46; O RRa foi de 1&#44;20 &#40;IC 95&#37; 1&#44;11&#8208;1&#44;30&#41; para doen&#231;as cardiovasculares&#44; 1&#44;56 &#40;IC 95&#37; 1&#44;20&#8208;2&#44;04&#41; e 1&#44;75 &#40;IC 95&#37; 1&#44;33&#8208;2&#44;29&#41; para doen&#231;as cerebrovasculares e hep&#225;ticas&#44; respectivamente&#46; O RRa para eventos renais e cardiovasculares coexistentes foi de 1&#44;09 &#40;IC 95&#37; 1&#44;01&#8208;1&#44;18&#41;&#46; O RRa para eventos renais e cerebrovasculares coexistentes foi de 1&#44;28 &#40;IC 95&#37; 0&#44;99&#8208;1&#44;66&#41;&#46; O RRa para doen&#231;as renais e hep&#225;ticas coexistentes foi de 1&#44;46 &#40;IC 95&#37; 1&#44;10&#8208;1&#44;94&#41;&#46; O RRa para doen&#231;as cardiovasculares e hep&#225;ticas coexistentes foi de 1&#44;41 &#40;IC 95&#37; 1&#44;11&#8208;1&#44;80&#41;&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">H&#225; heterogeneidade&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#227;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A psor&#237;ase apresenta maior risco de comorbidades de &#243;rg&#227;os internos &#250;nicos e m&#250;ltiplos do que a popula&#231;&#227;o geral&#46; O presente estudo desperta a aten&#231;&#227;o para a psor&#237;ase como uma doen&#231;a inflamat&#243;ria sist&#234;mica&#46;</p></span>"
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          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Gr&#225;fico <span class="elsevierStyleItalic">Forest Plot</span> de risco de comorbidade espec&#237;fica em pacientes com psor&#237;ase em compara&#231;&#227;o com a popula&#231;&#227;o geral &#40;doen&#231;as cardiovasculares&#44; renais&#44; cerebrovasculares&#44; pulmonares&#44; hep&#225;ticas&#41;&#46;</p>"
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t" scope="col">Estudo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Pa&#237;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Per&#237;odo do estudo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Fontes de dados&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">M&#233;dia de idade&#44; &#40;a&#41;&#59; sexo feminino &#40;&#37;&#41;</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#176; de pacientes com psor&#237;ase</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N&#176; de Controles</th><th class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Comorbidades espec&#237;ficas&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">NOS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Psor&#237;ase&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Controle&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Todos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comorbidades&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Todos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comorbidades&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ahlehoff O&#44; 2011<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Dinamarca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2002 &#8208; 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The Danish National Patient Register</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&#44;5 &#40;12&#44;1&#41;&#59; 36&#44;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&#44;6 &#40;13&#44;5&#41;&#59; 38&#44;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">462&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">199&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#46;935&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">20&#46;356&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">DCV&#44; DR&#44; DP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ahlehoff O&#44; 2012<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dinamarca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1997&#46;01 &#8208; 2006&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The Danish National Patient Register</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&#44;1 &#177; 16&#44;9&#59; 49&#44;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#44;7 &#177; 19&#44;7&#59; 49&#44;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#46;558&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">530&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;478&#46;926&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55&#46;660&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DR&#44; DC&#44; DP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Armstrong AW&#44; 2013<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">32</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EUA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2004 &#8208; 2009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">University of California Davis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53 &#40;40&#8208;63&#41;&#59; 59&#44;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53 &#40;40&#8208;63&#41;&#59; 51&#44;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;078&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1776&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;234&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;616&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DC&#44; DP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Charlton R&#44; 2018<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1998&#46;01 &#8208; 2014&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The UK Clinical Practice Research Datalink</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49 &#40;39&#8208;59&#41;&#59; 50&#44;95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49 &#40;39&#8208;59&#41;&#59; 50&#44;95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8444&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#46;132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;051&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chiang CH&#44; 2011<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Taiwan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Before 2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Longitudinal Health Insurance Database 2007</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#44;3 &#177; 17&#44;4&#59; 43&#44;69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#44;5 &#177; 17&#44;4&#59; 22&#44;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;783&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1066&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;910&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feldman SR&#44; 2015<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">35</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EUA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2007&#46;01 &#8208; 2012&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The OptumHealth Reporting and Insights claims database</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#44;62&#59; 44&#44;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#44;62&#59; 44&#44;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;492&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">881&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;492&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">499&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DR&#44; DC&#44; DP&#44; DH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Khalid U&#44; 2015<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dinamarca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1997&#46;01 &#8208; 2011&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The Danish National Patient Register</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#44;3 &#40;15&#44;8&#41;&#59; 51&#44;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&#44;9 &#40;19&#44;9&#41;&#59; 5 0&#44;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&#46;665&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1292&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;036&#46;959&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">105&#46;321&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DR&#44; DP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> Lee S&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EUA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2010&#46;11 &#8208; 2015&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The US Department of Defense population</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#44;1&#59; 51&#44;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#44;1&#59; 51&#44;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;249&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2932&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#46;490&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#46;367&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CVD&#44; DC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Min C&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Coreia do Sul&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2002&#8208;2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The Korean National Health Insurance Service&#8208;National Sample Cohort</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NR&#59; 43&#44;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NR&#59; 43&#44;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;071&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5187&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">44&#46;284&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;298&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prasada S&#44; 2020<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EUA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2000&#46;01 &#8208; 2019&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The Northwestern Medicine Enterprise Data Warehouse</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#44;72 &#40;15&#44;95&#41;&#59; 51&#44;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#44;60 &#40;16&#44;65&#41;&#59; 57&#44;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;365&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1536&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;358&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;241&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Schell C&#44; 2015<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">38</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alemanha&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Eberhard Karls University T&#252;bingen</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#44;3 &#177; 15&#44;6&#59; 43&#44;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#44;1 &#177; 18&#44;6&#59; 60&#44;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">300&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">158&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">300&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">150&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DR&#44; DP&#44; DH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tollefson MM&#44; 2018<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EUA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2004&#46;01 &#8208; 2013&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Optum Laboratories Data Warehouse</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#44;0 &#40;4&#44;4&#41;&#59; 53&#44;52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#44;0 &#40;4&#44;4&#41;&#59; 53&#44;52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;957&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;957&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">646&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DCV&#44; DH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vena GA&#44; 2010<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">39</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">It&#225;lia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2001&#8208;2005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">The Health Search&#47;Thales Database</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#44;5 &#40;16&#44;5&#41;&#59; 47&#44;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#44;4 &#40;16&#44;4&#41;&#59; 52&#44;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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