A 34-years-old pregnant woman admitted in the emergency unit complaining about worsening right iliac fossa pain for 2 days. Acute appendicitis was the suspected diagnosis. Laboratory exams were ordered and results were within normal limits for infectious and inflammatory aspects. Ultrasound scan revealed a pregnancy in course without alterations and a thickness of the appendix wall without inflammatory signs in the surrounding tissue. Because the suspicion of acute appendicitis remained, a magnetic resonance was done and confirmed the diagnosis of a cecal appendix lipomatosis. Lipomatosis is the most frequent benign condition resulting from abnormal and increased proliferation of mature fat tissue in submucosal layers in the intracellular compartment. The more frequent clinic presentation of this condition is central medium portion of the body with predominance in the cephalic pole, more specifically the head, as well as in the dorsum. This problem is often related to the nodule or infiltrated unpainful tissue, which can cause symptoms secondary to the regional compression of joints or due to the rapid growth. In addition, lipomatosis may be presented in diffuse, asymmetric, or focal forms. When diffuse presentation may course with intestinal occlusion in different intensities, including total occlusion, digestive hemorrhage, diarrhea, vomiting, nausea, constipation, and pain in a variety degrees. In local or localized form, only few patients present symptoms and, in general, in asymptomatic cases, the lipoma exceeds 2cm in diameter.Lipomatosis with gastrointestinal presentation is, among all forms, the less frequent condition, and may occur in any portion of digestive tract, and the most frequent locations of these injuries of the colon, ileum, and jejunum.The goal of this report was to describe a rare manifestation of focal intestinal lipomatosis in the caecal appendix in a pregnant woman with low abdominal pain, as well as to provide a detailed description of main characteristics of this disease both in static and dynamic B-mode and doppler velocimetry ultrasound and sectional methods, such as computed tomography (CT) and magnetic resonance imaging (MRI). We believe that, considering the multiplicity of the presentation and the rarity of this specific form, to list characteristics of imaging in different methods may contribute to the practice of radiologists, particularly to those professionals working on emergency radiology by avoiding incorrect diagnosis, as well as unnecessary clinical-surgical management.A 34-year-old women in the second trimester of pregnancy was admitted to the emergency unit complaining about intensive moderate pain on lower portion of the abdomen with predominance to the right side for 3 weeks that worsened in the last 2 days. The patient did not present other symptoms such as fever, inappetence, nausea, or vomiting. Based on the abdominal pain diagnosis with predominance in the right Iliac fossa, laboratorial exams and a total abdomen ultrasonography (USG) were requested in the radiology emergency unit to assess inflammatory and infectious disease activities.The USG confirmed the pregnancy without evident alterations related to the pregnant uterus, to the placenta, and to the fetus   . The diThe laboratorial exams did not show alterations . Findings from the USG was not suggestive to acute inflammatory process, however they showed changes with benign aspects probably due to the fatty infiltration. A MRI exam was requested to complement the diagnosis.The MRI confirmed the findings described in the USG with focal appendicular parietal thickness without inflammatory signs   and 4 .  In this report, the MRI was conducted exclusively with the aim to confirm the non-inflammatory and benign nature of the appendicular injury in one pregnant patient.Among differential diagnosis of right iliac fossa pain are included a number of conditions such as appendicitis, diverticulitis, distal ureteral lithiasis, Crohn's disease, ovarian-tube inflammatory diseases, and ectopic pregnancy. Among appendicectomies, 4.5% to 15% are negative for appendicitis (with higher incidences of surgeries without inflammation findings in women). Such consideration is still relevant when findings from images are not conclusive for acute appendicitis and/or when inflammatory proofs are normal.The first report on intestinal lipomatosis focusing on caecal appendix dates back from 1956 in a study by Antoci, and in his study the definite final diagnosis was conducted by histopathologic analysis. One of the main limitations is the fact that this exam is operating dependent, which makes the knowledge by radiologists of imaging aspects of this condition even more important.Among currently available medical imaging methods, the USG is of the most commonly adopted exam in the emergency unit due to its low cost exam, little invasiveness, no radiation - a relevant aspect for women and, particularly, pregnant women - and with good diagnostic accuracy in experienced hands. The MRI is indicated, mainly, for patients with inconclusive ultrasonography findings and for those that ionizing radiation should be avoided.The CT also presents good accuracy, however, the use of ionizing radiation limits its application among pregnant women (as in the present case report) or among women wishing to become pregnant. The CT constitutes the most available, less expensive, and fastest method compared with the MRI.Findings of intestinal lipomatosis image vary based on the imaging method chosen, and the radiologist must recognize the different aspects in each one of the techniques. In the USG, intestinal lipomas presents as characterized marks the regular and homogenous parietal thickness with hyperechogenicity that derivates from presence of fat in submucosa layer. The decrease of compressibility of the organ with the use of transductor is present, however, this is quite less relevant compared with one inflamed appendix – a true acute appendicitis. In the case of intestinal lipomatosis, this aspects check in the within the appendiceal wall that is due to the fat infiltration that present hypoattenuating in a homogenous mode.In the CT, the characteristic of the image is a hypodense homogenous mass with attenuation between -80 to -120 units of the Hounsfield.i.e ., a malign inheritance of fat suppression, such as in case of liposarcoma instead of lipomatosis, occur for regularity and parietal homogeneity, presence of well-defined clival plans with fat plans, presence of adjacent organs and, particularly, lack of highlighting in the sequence after the use of gadolinium.In the MRI, the great specificity that determines the diagnosis of lipomatosis is the high intensity of the sign in images weighted in T1 and T2, with decrease in intensity of the signal in sequence with fat suppression. We obtained the definition of the presence of intracellular fat in intestinal wall, especially on in/out-phase series, which led to definition of the diagnosis without the need of the histological sample. The lack of malignity, Intestinal lipomatosis with focus in caecal appendix is an uncommon and rare condition associated with locoregional symptoms. Given the rarity of this disease, in some cases the diagnosis may not be conducted particularly due to the mild clinical findings and the often incidental diagnosis. Radiologists have a central role in the diagnosis workup, for this reason, they must understand aspects of images in a variety of methodologies, particularly ultrasonography, computed tomography, and magnetic resonance imaging. Given the prevalence of acute appendicitis in the emergency care, to differentiate an acute inflammatory process requiring intervention from a benign condition with a traditional follow-up is of highly importance both for an assertive report as well as to avoid invasive and unnecessary treatments. A lipomatose é uma condição mais frequentemente benigna, resultante da proliferação anormal e pronunciada de tecido adiposo maduro em camadas submucosas, no compartimento intracelular. Sua apresentação clínica mais frequente é na porção central mediana do corpo, com predomínio no polo cefálico, mais especificamente na cabeça, bem como no dorso.Trata-se, geralmente, de nódulo ou infiltrado tecidual indolor, podendo causar sintomas secundários à compressão regional de articulações ou decorrente de crescimento rápido.A lipomatose com apresentação gastrintestinal é, dentre todas as formas, a condição menos frequente, podendo ocorrer em qualquer porção do trato digestivo, sendo as localizações mais frequentes dessas lesões o cólon, o íleo e o jejuno.Na forma focal ou localizada, apenas uma minoria dos pacientes apresenta sintomas e, em geral, nos casos sintomáticos, os lipomas excedem 2cm em diâmetro.A lipomatose intestinal pode se apresentar nas formas difusa, salteada ou focal. Quando na apresentação difusa, pode cursar com oclusão intestinal, em diferentes intensidades, inclusive com quadros totalmente oclusivos, hemorragia digestiva, diarreia, vômitos, náuseas, constipação e dor, em graus variados.O objetivo deste relato foi descrever uma manifestação bastante rara da lipomatose intestinal focal no apêndice cecal em paciente do sexo feminino, gestante, com quadro de dor abdominal no baixo ventre, bem como pormenorizar as principais características de imagem dessa patologia, tanto ultrassonográficas, no modo B estático e dinâmico e dopplervelocimetria, quanto em métodos seccionais, como tomografia computadorizada (TC) e ressonância magnética (RM). Acreditamos que, considerando a multiplicidade de apresentações e a raridade dessa forma específica, listar as características de imagem nos diferentes métodos pode contribuir sobremaneira com radiologistas de modo geral, sobretudo aqueles com foco em radiologia de emergência, evitando diagnósticos equivocados, bem como condutas clínico-cirúrgicas desnecessárias.Paciente do sexo feminino, com 34 anos, no segundo trimestre de gestação, chega ao pronto atendimento com queixa de dor de moderada intensidade no andar inferior do abdome, com predomínio à direita, há 3 semanas, com piora acentuada nos últimos 2 dias. A paciente não apresentava outros sintomas além da dor referida, como febre, inapetência, náuseas ou vômitos. Diante do diagnóstico de dor abdominal com predomínio na fossa ilíaca direita, foram solicitados exames laboratoriais, para avaliação de atividade inflamatória e infecciosa, e ultrassonografia (USG) de abdome total, no setor de radiologia de emergência.A USG confirmou o quadro de gestação em curso, sem alterações evidentes relacionadas ao útero gravídico, à placenta e ao feto   . A avalOs exames laboratoriais não evidenciaram alterações . O conjunto de achados evidenciados à USG não foi sugestivo de processo inflamatório agudo, mas de alterações de aspecto benigno de provável natureza infiltrativa gordurosa. Foi solicitado exame de RM para complementar o diagnóstico.in-phase , com perda de sinal na sequência out-phase .Tal consideração é ainda mais relevante quando os achados de imagem não são conclusivos para apendicite aguda e/ou as provas inflamatórias são normais.O primeiro relato da lipomatose intestinal com foco no apêndice cecal data de 1956 por Antoci, sendo o diagnóstico final definido por meio de análise histopatológica.Uma de suas principais limitações é o fato de ser um exame operador-dependente, o que torna ainda mais importante o conhecimento dos aspectos de imagem dessa condição pelos médicos radiologistas.Dentro do rol de métodos de imagem disponíveis atualmente, a USG desponta como exame cada vez mais utilizado na emergência, visto que apresenta baixo custo, é pouco invasiva e sem radiação – aspecto particularmente relevante em pacientes do sexo feminino e grávidas –, com boa acurácia diagnóstica, em mãos experientes.A RM é reservada, mais frequentemente, aos pacientes com achados ultrassonográficos inconclusivos e nos quais a radiação ionizante deve ser evitada.A TC também apresenta boa acurácia diagnóstica, mas o uso de radiação ionizante limita sua realização em pacientes gestantes (como no caso em questão) ou com possibilidade de gravidez. Trata-se do método mais disponível, menos oneroso e de mais rápida realização que a RM.Os achados de imagem na lipomatose intestinal variam de acordo com o método de imagem empregado, devendo o radiologista conhecer os diferentes aspectos em cada uma das técnicas. Na USG, os lipomas intestinais apresentam, como marcas características, espessamento parietal homogêneo e regular, com hiperecogenicidade, que deriva da presença de gordura no plano da camada submucosa. A redução da compressibilidade do órgão com o uso do transdutor está presente, todavia bastante menos relevante quando em comparação com um apêndice inflamado – uma verdadeira apendicite aguda.No caso de lipomatose intestinal, esse aspecto é verificado no interior da parede apendicular, que, devido à infiltração adiposa, apresenta-se hipoatenuante, de modo homogêneo.Na TC, a característica de imagem é a de massa homogênea hipodensa com atenuação entre -80 a -120 unidades de Hounsfield.in/out-phase , obtemos a definição da presença de gordura intracelular na parede intestinal, fechando o diagnóstico, sem a necessidade de amostragem histológica. A ausência de malignidade, ou seja, de que se trata de uma linhagem maligna de acúmulo de gordura, como, por exemplo, no caso de um lipossarcoma ao invés de lipomatose, dá-se por regularidade e homogeneidade parietais, presença de planos clivais bem definidos com gordura e órgãos adjacentes e, sobretudo, ausência de realce nas sequências após o uso do gadolíneo.Na RM, a grande peculiaridade que determina o diagnóstico de lipomatose é a alta intensidade de sinal nas imagens ponderadas em T1 e T2, com queda da intensidade de sinal nas sequências com supressão de gordura. Especialmente nas series A lipomatose intestinal com foco no apêndice cecal é condição pouco frequente e raramente associada a sintomas locorregionais. Dada a raridade dessa apresentação, seu diagnóstico pode, por vezes, não ser realizado, sobretudo devido ao quadro frustro, por vezes com diagnóstico meramente incidental. O radiologista é um profissional fundamental para definir o diagnóstico, mas, para tanto, necessita dominar os aspectos de imagem nas diferentes metodologias, destacando-se a ultrassonografia, a tomografia computadorizada e a ressonância magnética. Dada a prevalência de apendicites agudas no âmbito do pronto-atendimento, saber diferenciar um processo inflamatório agudo, com necessidade de intervenção, de uma condição de curso benigno e com seguimento conservador, é de suma importância, tanto para um relatório assertivo, quanto para evitar condutas invasivas e desnecessárias.


The yellow fever is a systemic disease that was under control due to the effective campaigns against the vector and promotion of vaccines programs. However, since 1999, outbreaks appeared because of inefficient control of the vector, and led to the need of amplifying the immunization in large scale against the yellow fever virus, and consequently, raising the risk of adverse reactions to the vaccine. We report a case of previously healthy infant, who was referred to our care service, after 3 days with fever, chills, nausea and vomits, he received support therapy and was discharged from the hospital. After 24 hours of supportive measures, he was discharge. The patient returned to our service with general condition decline, strabismus, inability to control of cervical musculature and reduced force of the legs. The patient vaccine had received all vaccines from the calendar, and he was vaccinated for yellow fever 20 days before symptoms. During the hospitalization, liquor was collected, and ceftriaxone and aciclovir were administered. After negative cultures from the liquor, the antibiotics were suspended. The computed tomography of patient’s brain showed no alterations. Research for antibodies against yellow fever was requested, being positive for IgM in the liquor, and confirming the neurotropic disease associated with the yellow fever vaccine. On the fifth day of hospitalization, the patient showed improvement on the strabismus, cervical tonus, and musculature force. On the tenth day of hospitalization, patient showed complete improvement, and his laboratory exams no alterations. Subsequently, patient was discharged. The vaccine against yellow fever is safe, efficient and highly recommended, however it is not completely free from serious adverse reactions, including death. Aedes aegypti (in urban cycle) and Haemagogus (in wild cycle).1 This disease was under control since 1940 because of the effective campaigns against Aedes aegypti and to the vaccination programs for those living at risky areas or people who traveled to such areas. However, new outbreaks appeared since 1999, because of inefficacy of policies to control the vector. From 2008 to 2018, the vector started to spread in Southeast and Central east regions of Brazil.2Yellow fever (YF) is systemic disease with high morbimortality that is often found in tropical regions. YF is caused by the Flavivirus virus and transmitted by mosquitoes, such as 3Immunization in large scale against YF virus becomes a national need. This fact associated with own characteristics of vaccine against YF (VAYF), has led to important increase of risk of occurrence of adverse reactions (AR) to the vaccine.Because of the lack of data about AR associated with YF, we report a case of late neurotropic disease secondary to YF vaccine.This was a 9-month-old male infant, weighting 10.200g, who were previously healthy and who were from the municipality of Sao Paulo. Initially, the patient was admitted to the emergency room with a history of persistent fever (38°C), chill, nausea, and vomiting for 3 days. He received support therapy and was discharged. After 24 hours, the patient’s clinical picture evolved with worsening in his general status, strabismus, lack of control of cervical musculature and reduction of muscle strengths in lower limbs. At this time, the patient’s legal responsible sought to a referral hospital in the region.The legal responsible mentioned that patient had no history of previous hospitalizations, use of medications, allergies, hereditary diseases, contact with ill individuals or any remarkable changes during the last months of life. In relation to immunization card, the patient had received all vaccines required to his age, however, 20 days prior to hospitalization, he had received VAYF. However, no reactions occurred before the vaccination.During hospitalization process, supporting measures and complementary exams were requested   . After Instituto Adolfo Lutz, São Paulo (SP) to the antibody against YF that was positive to M immunoglobulin (IgM). The molecular research by polymerase chain reaction (PCR) for LCR virus was conducted for herpes-virus that found an undetectable result of genetic material.Among imaging exams, we requested computed tomography (CT) of the skull that showed lack of neurological changes. A sample of LCR was forwarded to After clinical, epidemiological and laboratorial diagnosis of neurotropic disease associated to YF vaccine (serious AR), the treatment of supporting was maintained and a neurological observation of the patient was conducted. After fifth day of hospitalization, the patient had improvement in strabismus, cervical tonus and muscular strength, and he end up standing without support and help. After 10 days of hospitalization, he had total improvement of clinical picture, was active, and responded to treatment, with integral neuropsychomotor development to his age, without complaints and no changes laboratorial tests. After that, the patient was discharged.5Inability to control of YF transmission by combating the vector in Brazil led to need to amplify of vaccine covering to prevent the dissemination of virus, and prevent the appearance of new cases. However, because urban areas are more populated, there is need to develop strategies to increase availability of vaccine. In July 2016, the World Health Organization (WHO) reported that fractioning the vaccine dose for 1:10 of the standard dose already promoted similar protection to complete dose. There are records of success in control of YF outbreaks after the campaigns promoted in 2016 using fractionated doses in city of Kinshasa, Democratic Republic of the Congo. In this sense, in 2018, Brazil adopted fractionated 1:5 of the standard dosage in states of Sao Paulo, Rio de Janeiro, and Bahia. This adoption was authorized only for individuals aged between 2 and 59 years, who were still not vaccinated. We highlight that, pregnant women who do not vaccinated and live at risky areas, and children aged between 9 months and 2 years should receive the standard dosage. Infants who were breastfeeding and who were younger than 6 months should also be vaccinated and breastfeeding should be suspended for 10 days.6 In this case report, a previous health infant developed signs and symptoms of neurotropic disease associated with VAYF after 20 days of VAYF administration. The risk of neurotropic disease development after VAYF is 1:8000, and this is more prevalent in vulnerable groups, such as newborns, infants and immunocompromised individuals.7 We should highlight that published literature shows a mean time of AR after VAYF ranging between 7 and 27 days. Therefore, our patient was near to limit of time ranging expected to the reported clinical manifestation.8The VAYF has been safety administer in human since 1937. In general, VAYF is well tolerated and efficient. However, this can lead to severe AR, such as viscerotropic and neurotropic diseases.Initially, although there are suspicion of reaction to the vaccine, we opted to keep ceftriaxone and acyclovir until tobtaining of negative results of cultures and in specific tests for main agents that was causing meningoencephalitis based on patient’s age range (bacteria and herpes-virus), as well as study of antibodies against YF virus.In the described case, there are clear evidences that vaccine against YF virus was the reason of the neurotropic disease, considering the reactions found, although late, they occurred within the time described in the published literature. Tests for other possible causing agents of meningoencephalitis were excluded, and a positivity of specific IgM was found for YF virus in LCR of the patient. Although an increase was seen in serum IgM after VAYF, it would be unlikely that serum IgM would overpass the hemato liquor barrier due to the fact that IgM molecule would be of high molecular weight, which reinfores the initial suspicion.i.e. , between 3 to 5 days after appearance of the symptoms. However, fatal cases of neurotropic disease associated with VAYF were also described.9Clinical evolution of the patient was favorable, with recovery of neurologic deficits in a short period of time. In a case series of neurotropic disease associated with VAYF, all patients had full neurological recovery during the hospitalization, Although the vaccine against yellow fewer is safe, efficient and strongly recommended to those at risk areas, the vaccine is not free of causing serous adverse events and potentially lethal reactions. The lethality of yellow fever is extremely higher than the side effects that may be triggered by the vaccination, being side effects considered rare. Flavivirus e transmitida por mosquitos, como Aedes aegypti (no ciclo urbano) e Haemagogus (no ciclo silvestre).  Essa doença estava controlada desde 1940, graças às efetivas campanhas de combate ao Aedes aegypti e aos programas de vacinação para moradores de áreas de risco ou pessoas que viajam para estes locais. No entanto, novos surtos começaram a surgir em 1999, devido à ineficácia das políticas de controle do vetor e, posteriormente, em 2008 e 2018, nas Regiões Sudoeste e Centro-Oeste do Brasil.  A febre amarela (FA) é uma doença sistêmica, de alta morbimortalidade, típica de áreas tropicais, ocasionada pelo vírus   A ampliação da imunização em larga escala contra o vírus da FA tornou-se necessária no território nacional. Este fato, associado às características própria da vacina contra FA (VCFA), ocasionou considerável aumento do risco de ocorrência de reações adversas (RA) à vacina.Mediante a lacuna de registros de ocorrências de RA graves à vacina da FA, o presente estudo se propôs a relatar um caso de doença neurotrópica tardia decorrente da vacina da FA.Lactente de 9 meses de idade, sexo masculino, pesando 10.200g, previamente saudável e proveniente de um município do estado de São Paulo. Inicialmente, o paciente foi levado a um pronto atendimento com história de febre persistente (38°C), calafrios, náuseas e vômitos há 3 dias, recebendo terapia de suporte e alta. Após 24 horas, ele evoluiu com queda do estado geral, estrabismo, falta de controle da musculatura cervical e redução da força muscular em membros inferiores, procurando, desta vez, o serviço de um hospital de referência da região.A responsável referiu ausência de internações prévias, uso de medicações, alergias, doenças hereditárias na família, contato com indivíduos doentes ou quaisquer alterações perspectivas e progressivas durante os últimos meses de vida. Em relação ao caderno de vacinação, encontrava-se completo para idade, tendo recebido, 20 dias antes, VCFA. Foram negadas quaisquer reações ocorridas anteriormente às vacinas administradas.Durante o processo de admissão hospitalar, foram instituídas medidas de suporte e realizados exames complementares   . Após rDentre os exames de imagem, solicitou-se tomografia computadorizada (TC) de crânio, que evidenciou ausência de alterações neurológicas. Uma amostra do LCR foi encaminhada ao Instituto Adolfo Lutz, em São Paulo (SP), para a pesquisa de anticorpos contra o vírus da FA, que retornou positiva para imunoglobulina M (IgM). A pesquisa molecular por meio da reação em cadeia da polimerase (PCR) para vírus no LCR foi realizada exclusivamente para herpes-vírus, que resultou em análise indetectável do material genético.Após diagnóstico clínico, epidemiológico e laboratorial de doença neurotrópica associada à vacina da FA (RA grave), o tratamento de suporte foi mantido e foi realizada observação neurológica do paciente. A partir do quinto dia de internação hospitalar, o paciente evoluiu com melhora do estrabismo, do tônus cervical e da força muscular, chegando a se manter em pé sem auxílio e apoio. Ao décimo dia de internação hospitalar, encontrava-se em melhora total do quadro, ativo, contactuante, com desenvolvimento neuropsicomotor íntegro para a idade, sem queixas e alterações laboratoriais, seguindo com alta hospitalar.  , 5 A ineficácia do controle da transmissão da FA por meio do combate ao vetor no Brasil levou à necessidade de ampliação da cobertura vacinal para coibir a disseminação do vírus e prevenir o surgimento de novos casos. Contudo, como as áreas urbanas são mais populosas, foi necessário desenvolver estratégias para aumentar a disponibilidade da vacina. Em julho de 2016, a Organização Mundial da Saúde (OMS) evidenciou que o fracionamento da vacina para 1:10 da dose padrão já promoveria proteção similar à da dose padrão. Há registros de sucesso no controle do surto da FA a partir de campanhas utilizando doses fracionadas na cidade de Kinshasa, na República Democrática do Congo, em 2016. Neste sentido, foi utilizado o fracionamento de 1:5 da dose padrão nos estados de São Paulo, Rio de Janeiro e Bahia em 2018. Este esquema foi autorizado apenas para indivíduos entre 2 e 59 anos, ainda não vacinados. Ressalta-se que, as gestantes pertencentes a áreas de risco não vacinadas e crianças entre 9 meses e 2 anos deveriam receber a dose padrão. Lactantes que estivessem amamentado menores de 6 meses deveriam ser vacinadas suspendendo a amamentação por 10 dias.  Neste caso, um lactente previamente hígido desenvolveu sinais e sintomas da doença neurotrópica associada à VCFA após 20 dias da administração. O risco de desenvolvimento de doença neurotrópica pós-VCFA é de 1:8.000, sendo mais prevalente em grupos vulneráveis, como recém-nascidos, lactentes e indivíduos imunocomprometidos.  Cabe salientar que a literatura mostra tempo médio de RA após a VCFA entre 7 e 27 dias, evidenciando que o lactente deste caso esteve próximo ao limite da faixa de tempo esperada para a referida manifestação clínica.  A VCFA tem sido administrada em humanos com segurança desde 1937. Em geral, é bem tolerada e muito eficaz. Entretanto, ela pode levar à RA graves, como as doenças viscerotrópica e neurotrópica.Inicialmente, apesar da suspeita de reação à vacina, optou-se por manter ceftriaxona e aciclovir até que fossem obtidas culturas e testes específicos negativos para os principais agentes causadores de meningoencefalites nesta faixa etária (bactérias e herpes-vírus), bem como a pesquisa de anticorpos contra o vírus da FA.No caso descrito, existiam evidências claras de que o vírus vacinal da FA foi causador da doença neurotrópica, visto que as reações encontradas, apesar de tardias, ocorreram dentro do tempo descrito na literatura, os testes para outros possíveis agentes causadores de meningoencefalites foram descartados, e ocorreu a positividade da IgM específica para o vírus da FA no LCR do paciente. Importante ressaltar que, apesar de ocorrer aumento da IgM sérica após a VCFA, seria improvável que ela ultrapassasse a barreira hematoliquórica, pelo fato de a molécula de IgM ser de grande peso molecular, reforçando a suspeita inicial.deficit neurológico em curto prazo de tempo. Em uma série de casos de doença neurotrópica associada à VCFA, todos os pacientes apresentaram recuperação neurológica completa durante a internação, isto é, entre 3 a 5 dias do início dos sintomas. Entretanto, casos fatais de doença neurotrópica associada à VCFA também foram descritos.  A evolução clínica do paciente foi favorável, com recuperação do Apesar da vacina contra febre amarela ser segura, eficaz e fortemente recomendada em áreas de risco, não é isenta de reações adversas graves e potencialmente fatais. Deve-se levar em conta a letalidade pela febre amarela infinitamente maior às reações adversas desencadeadas pela vacinação, sendo ainda consideradas raras.


To determine the efficacy and safety of the use of cryotherapy, cold knife or thermocoagulation compared to Loop Electrosurgical Excision Procedure (LEEP) for the treatment of cervical intraepithelial neoplasia.Systematic review with meta-analysis of randomized controlled trials in women with cervical intraepithelial neoplasia undergoing treatment with cryotherapy, cold knife, or thermo-coagulation compared with LEEP, to estimate its efficacy and safety. The search was conducted on MEDLINE/PUBMED, Cochrane Central Register of Controlled Trials (CENTRAL) and Scopus, until September 2018.The total of 72 studies were identified, of which only 8 studies met the inclusion criteria. The treatment of CIN with cold knife decreases the risk of residual disease compared with LEEP . The management of premalignant lesions with cryotherapy, compared with LEEP, increases the risk of disease recurrence by 86% , increases the risk of infections  and reduces the risk of minor bleeding by 51%  %, 0.40–0.59, p ≤ 0.001).The treatment of premalignant lesions of cervical cancer with cold knife reduces the risk of residual disease. Nevertheless, cryotherapy reduces the risk of minor bleeding in the 24 hours after treatment and increases the risk of recurrence of disease and infections. However, cervical cancer still ranks as the second leading cause of death and the second most common cancer in the female population in low and middle income countries1. Cervical intraepithelial neoplasia (CIN) is a premalignant lesion of cervical cancer, histologically divided as CIN1, CIN2 and CIN3. Both these premalignant lesions and cancerin situare attributed to human papillomavirus (HPV)3. According to the International Agency for Research on Cancer (IARC), report of 20184, in Peru, oncogenic HPV types 16 and 18 are found in 6.6% of patients with normal cytology, 27.3% with CIN1, 53.1% with CIN2-3 and 65.9% with cancerin situ. Early diagnosis and management of these pre-malignant lesions helps reduce the natural progression of these lesions into cervical uterine cancer. Monitoring of CIN2 and CIN3 histological lesions becomes a fundamental task in public health given that 31.0% of these evolve into cancer in the following 30 years5. Timely and appropriate therapeutic intervention can reduce this risk. Some authors have shown in monitoring cohorts of 10–20 years that the post-treatment rate of premalignant lesions decreases more than 30.0% during the first 10 years7.Cervical cancer is the fourth most common type of cancer and the fourth leading cause of death in women worldwide8, cryotherapy treatment is recommended for patients with CIN2+ lesions. If the patient is not eligible for this ablative therapy, the use of LEEP is recommended. However, excision and ablation procedures may be associated with adverse outcomes. Therefore, the objective of this systematic review and meta-analysis was to assess the effectiveness and safety of treating CIN with cryotherapy, cold cone or thermocoagulation compared to LEEP.For the treatment of premalignant cervical lesions, both ablative methods  and excisional methods , cold cone) can be effective. As recommended by the World Health Organization guidelines in the clinical guide published in 20159.PRISMA  guidelines were applied in the development and reporting of this systematic reviewRandomized controlled trials (RCT) were considered eligible (as the objective was to assess efficacy and safety) that met the following criteria: study population women over 18 years old with diagnosed cervical intraepithelial neoplasia and treatment interventions with cryotherapy, cold cone, or thermocoagulation and LEEP as comparator. Studies were excluded if participants were pregnant women, women with HIV (Human Immunodeficiency Virus) infection, women with symptoms or a history of treatment and monitoring of cervical cancer.The variables to assess effectiveness were: residual disease (in less than six months), recurrent disease (in more than six months) and positive margins. Major bleeding , minor bleeding , mortality associated with treatment, cervical stenosis, pain in treatment area, infections related to the procedure  and damage to other organs or need for other surgeries were assessed.We reviewed the MEDLINE/PUBMED, Cochrane Central Register of Controlled Trials (CENTRAL) The Cochrane Library and Scopus databases, using “Medical Subject Headings (MeSH)” or equivalent terms and text word terms. Articles in English and Spanish were included. A preliminary search strategy was created for MEDLINE/PUBMED. The remaining searches were tailored to individual databases , and th#1  OR  AND )#2 “Loop Electrosurgical Excision Procedure”[tiab] OR “Large loop excision of the transformation zone”[tiab] OR “LEEP”[tiab] OR “LLETZ”[tiab]#3 “cryotherapy”[MeSH Terms] OR cryotherapy[tiab]#4 “cold coagulation”[tiab]#5 “conization”[MeSH Terms] OR “conization”[tiab]#6 “Randomized Controlled Trial” [pt] OR “Randomized Controlled Trial”[tiab]#7 #3 OR #4 OR #5#8 AND #2 AND #7#9 #8 AND #6For the databases Scopus, and The Cochrane Library the search strategy was developed with the terms: “Uterine Cervical Neoplasms,” “Loop Electrosurgical Excision Procedure” and “Randomized Controlled Trial.”Two reviewers independently assessed study eligibility based on titles and abstracts (YHR and NBC); discrepancies were solved by a third reviewer (JG). Titles and abstracts of all selected references were independently assessed by applying the objectives and research question (PICO). We manually reviewed all references in the selected full texts.10.According to the search criteria in the different pre-selected databases, the references of each database that met the search criteria were exported to the Zotero software. Duplicates were eliminated and the required information  was extracted independently. Review Manager 5.3  was used to extract the main data11, following the methodology of the Cochrane Collaboration. This assessment included the domains: sequence generation, assignation concealment, blinding, incomplete outcome data, and selective outcome reporting and other sources of bias.To assess the risk of bias of each of the studies, we used the tool proposed by Higgins12methodology was used to assess the certainty of the evidence for each outcome. This assessment included the risk of bias, inconsistency, imprecision, indirect evidence and other considerations13.The GRADE 2> 50%). Heterogeneity tests  were performed for each of the outcomes. Heterogeneity was accepted if I2> 50% and 0.1 p was selected as the cutting point for rejecting the null hypothesis of the study’s homogeneity14.Quantitative synthesis of eligible studies for binary outcomes was performed using a fixed effects model allowing the estimation of pooled RR and 95% confidence intervals of the effect of treatments for CIN from similar studies. Random effects sensitivity analyses were performed if the results were heterogeneous  and six using additional records identified by other sources. After eliminating duplicates, 51 records were left for abstract reading, with 42 articles eliminated. After applying the selection criteria and after reading the full text, eight original articles were selected15. The arng bias . A bett19, two studies assessed treatment with cryotherapy compared to LEEP18. No studies were identified assessing treatment of CIN with thermocoagulation compared with LEEP. Regarding the comparison between Cold Cone versus LEEP, the certainty of the evidence was very low for all outcomes . The studies showed no significant heterogeneity (P = 0.65 and I 2 = 0%) (Three of the six included studies assessed disease recurrence  2 = 0%) .21 . Residual disease was reported in 6.1% of patients treated with cold cone and in 11.2% of those treated with LEEP. Meta-analysis of all four studies showed that patients treated with cold cone were less likely to have residual disease compared to those treated with LEEP . The studies showed no significant heterogeneity (P = 0.88 and I 2 = 0%)  .21 . Cases were reported with both cold cone and LEEP use. In patients treated with cold cone, 16.1% of cases were reported and in those treated with LEEP 21.3% of cases were recorded. The meta-analysis of the four studies showed that there is no statistically significant risk of positive margins in patients treated for CIN with cold cone compared to LEEP  (2 = 54%), so a sensitivity analysis using random effects was performed, and there was no significant change in result .Four studies assessed positive margins  = 0.14) . The stu21 . The prevalence of minor bleeding in patients treated with cold cone was 5.7% and in those treated with LEEP 5.4%. After meta-analysis of the five studies, the risk of minor bleeding during the first 24 hours after treatment in patients treated with cold cone versus LEEP was not statistically significant . No significant heterogeneity of the included studies was identified (P = 0.92 and I 2 = 0%) (Four included studies assessed this outcome  2 = 0%) .19 . 8.2% of patients treated with cold cone reported minor bleeding events after 24 hours of treatment, the prevalence of this event in patients treated with LEEP was 8.8%. After meta-analysis of the studies, the risk of minor bleeding after the first 24 hours after treatment in patients treated with cold cone versus LEEP was not statistically significant . No significant heterogeneity of the included studies was identified (P = 0.97 and I 2 = 0%) (Two studies assessed minor bleeding after the first 24 post-treatment  2 = 0%) .19 . The prevalence after cold cone treatment was 6.9% and 6.5% in patients treated with LEEP. The meta-analysis showed an increased risk of cervical stenosis in women treated with cold cone versus LEEP, however this result was not statistically significant . Giacalone et al. 15 did not identify cases of cervical stenosis in any of the patients treated with cold cone or LEEP. The studies showed low heterogeneity (P = 0.30 and I 2 = 5%)  .19reported one case of infection at the location of surgery in each group. The six studies assessed reported no major bleeding or pain secondary to cold cone treatment or LEEP.Dugan et al.18 . Both studies reported 14.7% disease recurrence in patients treated with cryotherapy and 7.7% of those treated with LEEP. The meta-analysis showed an increased risk of disease recurrence in women treated with cryotherapy compared to those treated with LEEP  (2 = 53%) so a sensitivity analysis using random effects was performed, and there was no significant change in outcome .For the comparison of CIN treatments with Cryotherapy versus LEEP, we identified two studies  = 0.01) . The stu2 = 0%) (2 = 0%) . The studies showed no heterogeneity (P = 0.91 and I 2 = 0%) . The pre(2 = 0%) .2 = 46%) . No significant heterogeneity was identified from the included studies (P = 0.17 and I 2 = 46%) .18 did not report cases of cervical stenosis in any of the treatment groups. However, Mitchell et al. 17 reported two cases in the cryotherapy treated patients (139) and one case in the group of patients treated with LEEP (130), with a nonsignificant risk of cervical stenosis if treated with cryotherapy compared to LEEP   .2= 0%).The two studies identified reported cases of pain secondary to treatment. The prevalence of pain in patients treated with cryotherapy was 23.9 percent and 27.5 percent in those treated with LEEP. The meta-analysis did not show a significant risk of pain secondary to cryotherapy treatment compared to LEEP . The studies showed no heterogeneity (P = 0.50 and I2 = 0%) . The studies showed no heterogeneity (P = 0.87 and I 2 = 0%) .24, we found that there is a lower risk of residual disease in patients treated with cold cone compared to LEEP. This finding may suggest that the technique used could be related to the depth of the extracted tissue, revealed in the positivity of the margins, which Jin et al.25in their meta-analysis, point out as a prognostic factor for recurrence and/or residual disease. The systematic review of El-Nashar et al.26showed a lower probability of postoperative bleeding and cervical stenosis in the management of CIN with LEEP. Their results show an increase of up to two times in the incidence of disease recurrence in patients treated with LEEP compared to those who were treated with cold cone. These results are at odds with our findings. We have not identified any differences in the management of premalignant lesions with these two methods for the same outcomes. This discrepancy can be attributed to the difference in the types of studies included in both reviews. The study by El-Nashar et al.26included both randomized controlled trials and observational studies and did not perform stratified analyses for each of these types of studies. Since the aim of our study was to assess efficacy and safety, our systematic review was restricted to the assessment of RCT.In this systematic review, we identified few randomized controlled studies that assessed treatment of CIN with cryotherapy or cold cone compared to LEEP . The studies were of moderate methodological quality. No significant heterogeneity was identified among the studies assessed for each of the efficacy and safety outcomes, except for positive margins in the studies comparing cold cone versus LEEP and for disease recurrence for the studies comparing cryotherapy to LEEP. Meta-analysis of data from the included studies showed that cold cone use decreases the risk of residual disease compared to LEEP. While the use of cryotherapy increases the risk of disease recurrence and infection; however, it reduces the risk of minor bleeding compared to LEEP treatment. In contrast to the study by Jiang et al.27. Our review also includes the study by Mitchell et al.17finding a nearly doubled rate of disease recurrence with the use of cryotherapy compared to LEEP. Therefore, our study is consistent with the evidence of increased risk of disease recurrence with the use of cryotherapy compared to LEEP. Similarly, D’Alessandro et al.28have published a systematic review assessing the management of CIN with LEEP and cryotherapy. The results of this study show a lower risk of disease recurrence in patients treated with LEEP compared to those treated with cryotherapy . This finding is similar to our review where we found the effectiveness of LEEP use to be greater relative to cryotherapy, as we identified an increased risk of disease recurrence with the use of cryotherapy. Our study did not include Smith et al.29because they assessed patients with HIV, as well as the Singh et al.30study because it was an observational study. It is essential to note the context in which the two included studies conducted the treatments: the professionals were health care workers specially trained in the use of both methods, and the care centers were specialized units that could increase the chances of success of the procedures. These are important points to consider when planning their implementation. The use of cold cone would be the best option compared to LEEP in patients with CIN, in terms of residual disease. On the other hand, the use of LEEP would be the best option compared to cryotherapy in terms of recurrence and post-operative infection. However, this evidence is of very low certainty, according to GRADE methodology. The true effect may be substantially different. More randomized controlled studies are needed, as well as strict standardized monitoring criteria to establish more reliable conclusions to assess the long-term effectiveness and safety of these methods. This meta-analysis assesses two treatment methods for CIN (cold cone and cryotherapy) compared to LEEP, including only randomized controlled studies to assess their efficacy and safety. It thus updates the evidence available to date. The main limitation of this review is that there are few randomized controlled studies, dating back more than 15 years and with short monitoring time. However, our systematic review addresses extensively the efficacy and safety outcomes with a specific analysis for each of them, thus providing a more refined analysis and better evidence for decision making in the therapeutic management of cervical intraepithelial neoplastic lesions.Our study assessed the effectiveness and safety of managing CIN with cryotherapy compared to LEEP. A previous systematic review of controlled studies suggests that the rate of disease recurrence (≥ 6 months post-treatment) may be lower after management of CIN with LEEP compared to cryotherapy  1. Sin embargo, el cáncer de cuello uterino se posiciona aún como la segunda causa de mortalidad y el segundo tipo de cáncer más común en la población femenina en los países de bajos y medianos ingresos1. La neoplasia intraepitelial cervical (NIC) es una lesión premaligna del cáncer de cuello uterino, histológicamente dividida como NIC1, NIC2 y NIC3. Tanto estas lesiones premalignas como el cáncerin situson atribuidos al virus papiloma humano (VPH)3. De acuerdo con el reporte de la Agencia Internacional de Investigación del Cáncer (IARC) del 20184, en el Perú, los tipos oncogénicos 16 y 18 de VPH se encuentran en el 6,6% de pacientes con citología normal, en el 27,3% de NIC1, en el 53,1% de casos de NIC2-3 y en el 65,9% de cáncerin situ. El diagnóstico y manejo precoz de estas lesiones premalignas contribuyen a disminuir el avance natural de estas lesiones hasta convertirse en un cáncer cérvico uterino. El seguimiento de las lesiones histológicas NIC2 y NIC3 se convierte en una tarea fundamental en salud pública dado que el 31,0% de estas evolucionan a cáncer en los 30 años siguientes5. Una intervención terapéutica oportuna y adecuada puede disminuir este riesgo. Algunos autores han evidenciado en cohortes de seguimiento de 10–20 años que la tasa postratamiento de las lesiones premalignas disminuye en más del 30,0% durante los 10 primeros años7.El cáncer de cuello uterino es el cuarto tipo más común de cáncer y la cuarta causa de mortalidad en las mujeres a nivel mundial8, en las pacientes con lesiones NIC2+, recomienda el tratamiento con crioterapia. Si no es elegible para esta terapia ablativa, se recomienda el uso del LEEP. Sin embargo, los procedimientos de escisión y ablación podrían asociarse con resultados adversos. Por lo tanto, el objetivo de esta revisión sistemática y meta análisis fue evaluar la eficacia y la seguridad del tratamiento de NIC con crioterapia, cono frio o termo coagulación en comparación con LEEP.Para el tratamiento de las lesiones premalignas cervicouterinas, tanto los métodos ablativos  como los métodos de escisión , cono frío) pueden ser eficaces. Según lo recomendado por las pautas de la Organización Mundial de la Salud en la guía clínica publicada el 20159.Se siguieron las pautas de PRISMA  para el desarrollo y reporte de esta revisión sistemáticaSe consideraron elegibles ensayos controlados aleatorizados (ECA)  que cumplieron los siguientes criterios: población de estudio mujeres mayores de 18 años con diagnóstico de neoplasia intraepitelial cervical e intervenciones de tratamiento con crioterapia, cono frio, o termo coagulación y LEEP como comparador. Se excluyeron estudios si las participantes fueron mujeres embarazadas, mujeres con infección por VIH (Virus de Inmunodeficiencia Humana), mujeres sintomáticas o con antecedente de tratamiento y seguimiento por cáncer de cuello uterino.Las variables para evaluar eficacia fueron: enfermedad residual (en menos de seis meses), enfermedad recurrente (en más de seis meses) y márgenes positivos. Para valorar seguridad, se evaluaron: sangrado mayor , sangrado menor , mortalidad asociada al tratamiento, estenosis cervical, dolor en zona de tratamiento, infecciones relacionadas al procedimiento  y daño de otros órganos o necesidad de otras cirugías.The Cochrane Libraryy Scopus, Se utilizaron términos “Medical Subject Headings (MeSH)” o equivalentes y los términos de palabras de texto. Se incluyeron artículos en idioma inglés y español. Se creó una estrategia de búsqueda preliminar para MEDLINE/PUBMED. Las demás búsquedas se adaptaron a las bases de datos individualmente almente , la bús#1  OR  AND )#2 “Loop Electrosurgical Excision Procedure”[tiab] OR “Large loop excision of the transformation zone”[tiab] OR “LEEP”[tiab] OR “LLETZ”[tiab]#3 “cryotherapy”[MeSH Terms] OR cryotherapy[tiab]#4 “cold coagulation”[tiab]#5 “conization”[MeSH Terms] OR “conization”[tiab]#6 “Randomized Controlled Trial” [pt] OR “Randomized Controlled Trial”[tiab]#7 #3 OR #4 OR #5#8 AND #2 AND #7#9 #8 AND #6Para las bases de datos Scopus, y The Cochrane Library se elaboró la estrategia de búsqueda con los términos: “Uterine Cervical Neoplasms”, “Loop Electrosurgical Excision Procedure” y “Randomized Controlled Trial”.Dos revisores evaluaron independientemente la elegibilidad de los estudios según títulos y resúmenes (YHR y NBC); las discordancias fueron resueltas por un tercer revisor (JG). Se evaluó independientemente los títulos y resúmenes del total de referencias seleccionadas aplicando los objetivos y la pregunta de investigación (PICO). Se revisó manualmente todas las referencias de los textos completos seleccionados.10.De acuerdo con los criterios de búsqueda en las distintas bases de datos preseleccionadas, las referencias de cada base que cumplieron con los criterios de búsqueda fueron exportadas al software Zotero. Se eliminaron los duplicados y la información requerida  fue extraída de forma independiente. Para la extracción de los datos principales, se utilizó el programa Review Manager 5.3 11, siguiendo la metodología de la Colaboración Cochrane. Esta valoración incluyó la evaluación de los dominios: generación de la secuencia, ocultación de la asignación, cegamiento, datos de resultado incompletos, notificación selectiva de los resultados y otras fuentes de sesgo.Para valorar el riesgo de sesgo de cada uno de los estudios, se utilizó la herramienta propuesta por Higgins12para evaluar la certeza de la evidencia de cada desenlace. Esta valoración incluyó el riesgo de sesgo, inconsistencia, imprecisión, evidencia indirecta y otras consideraciones13.Se utilizó la metodología GRADE 2> 50%). Se realizaron pruebas de heterogeneidad (utilizando la prueba de chi-cuadrado de la heterogeneidad y la prueba estadística I2) para cada uno de los resultados. La heterogeneidad fue aceptada si I2> 50% y se seleccionó un p de 0,1 como punto de corte para el rechazo de la hipótesis nula de la homogeneidad del estudio14.Se realizó la síntesis cuantitativa de los estudios elegibles para los resultados binarios utilizando un modelo de efectos fijos permitiendo estimar el RR agrupado y sus intervalos al 95% de confianza. del efecto de los tratamientos para NIC de estudios similares. Se hicieron análisis de sensibilidad con efectos aleatorios si los resultados presentaron heterogeneidad  y seis a través de registros adicionales identificados a través de otras fuentes. Luego de eliminar duplicados, quedaron 51 registros para lectura de resúmenes, eliminándose 42 artículos. Tras la aplicación de los criterios de selección y luego de la lectura a texto completo, se seleccionaron ocho artículos originales15. El artreporte . Pudo o19, dos estudios evaluaron el tratamiento con crioterapia en comparación con LEEP18. No se identificó ningún estudio que evaluara el tratamiento de NIC con termo coagulación en comparación con LEEP. En relación con la comparación entre Cono Frío versus LEEP, la certeza de la evidencia fue muy baja para todos los desenlaces . Los estudios no mostraron heterogeneidad significativa   .21 . Se reportó enfermedad residual en 6,1% de las pacientes tratadas con cono frio y en 11,2% de las tratadas con LEEP. El meta análisis de los cuatro estudios mostró que las pacientes tratadas con cono frio tienen menor probabilidad de presentar enfermedad residual en comparación de las tratadas con LEEP . Los estudios no mostraron heterogeneidad significativa   .21 . Se reportaron casos tanto con el uso de cono frio como con LEEP. En las pacientes tratadas con cono frio, se reportaron 16,1% de los casos y en las tratadas con LEEP se registraron 21,3% de los casos. El meta análisis de los cuatro estudios mostró que no existe un riesgo estadísticamente significativo de presentar márgenes positivos en pacientes en tratamiento de NIC con cono frio en comparación con LEEP  (2 = 54%), por lo que se realizó un análisis de sensibilidad aplicando efectos aleatorios, y no hubo cambios significativos en el resultado .Cuatro estudios evaluaron márgenes positivos  = 0,14) . Los est21 . La prevalencia de sangrado menor en las pacientes tratadas con cono frio fue 5,7% y en las tratadas con LEEP de 5,4%. Después de realizar el meta análisis de los cinco estudios, el riesgo de presentar sangrado menor durante las primeras 24 horas posteriores al tratamiento en las pacientes tratadas con cono frio versus LEEP no fue estadísticamente significativo . No se identificó heterogeneidad significativa de los estudios incluidos   .19 . El 8,2% de las pacientes tratadas con cono frio reportaron eventos de sangrado menor después de las 24 horas del tratamiento, la prevalencia de este evento en las pacientes tratadas con LEEP fue de 8,8%. Después de realizar el meta análisis de los estudios, el riesgo de presentar sangrado menor después de las primeras 24 horas posteriores al tratamiento en las pacientes tratadas con cono frio versus LEEP no fue estadísticamente significativo . No se identificó heterogeneidad significativa de los estudios incluidos   .19 . La prevalencia después del tratamiento con cono frio fue de 6,9% y de 6,5% en las pacientes tratadas con LEEP. El meta análisis mostró mayor riesgo de estenosis cervical en mujeres tratadas con cono frio versus LEEP, sin embargo, este resultado no fue estadísticamente significativo . Giacalone y cols. 15 no identificaron casos de estenosis cervical en ninguna de las pacientes tratadas con cono frio o LEEP. Los estudios mostraron una baja heterogeneidad   .19reportaron un caso de infección en el sitio de operación en cada uno de los grupos. Los seis estudios evaluados no reportaron sangrado mayor ni dolor secundario al tratamiento con cono frio ni LEEP.Dugan y cols18 . Ambos estudios reportaron 14,7% de recurrencia de enfermedad en pacientes tratadas con crioterapia y 7,7% de las tratadas con LEEP. El meta análisis mostró mayor riesgo de recurrencia de enfermedad en mujeres tratadas con crioterapia en comparación con las tratadas con LEEP  (2 = 53%) por lo que se realizó un análisis de sensibilidad aplicando efectos aleatorios, y no hubo cambios significativos en el resultado .Para la comparación de tratamientos de NIC con Crioterapia versus LEEP, identificamos dos estudios  = 0,01) . Los est2 = 0%) (2 = 0%) . Los estudios no mostraron heterogeneidad  . La prev(2 = 0%) .2 = 46%) . No se identificó heterogeneidad significativa de los estudios incluidos  .18 no reportaron casos de estenosis cervical en ninguno de los grupos de tratamiento. Sin embargo, Mitchell y cols. 17 reportaron dos casos en las pacientes tratadas con crioterapia (139) y un caso en el grupo de pacientes tratadas con LEEP (130), con un riesgo no significativo de presentar estenosis cervical si son tratadas con crioterapia en comparación con LEEP   .2= 0%).Los dos estudios identificados reportaron casos de dolor secundario al tratamiento. La prevalencia de dolor en las pacientes tratadas con crioterapia fue 23,9% y de 27,5% en las tratadas con LEEP. El meta análisis no mostró un riesgo significativo de presentar dolor secundario al tratamiento con crioterapia en comparación con LEEP . Los estudios no mostraron heterogeneidad  . Los estudios no mostraron heterogeneidad  .24, evidenciamos que existe un menor riesgo de enfermedad residual en las pacientes tratadas con cono frio en comparación con LEEP. Este hallazgo puede sugerir que la técnica usada podría relacionarse con la profundidad del tejido extraído, revelado en la positividad de los márgenes, que Jin y cols.25en su meta-análisis, señala como un factor pronóstico de recurrencia y/o enfermedad residual. La Revisión sistemática de El-Nashar y cols.26evidenció menor probabilidad de sangrado post operatorio y estenosis cervical en el manejo de NIC con LEEP. Sus resultados muestran un incremento de hasta dos veces en la incidencia de recurrencia de enfermedad en las pacientes tratadas con LEEP en comparación con las que fueron manejadas con cono frio. Estos resultados están en discrepancia con nuestros hallazgos. No hemos identificado diferencias en el manejo de lesiones premalignas con estos dos métodos para los mismos desenlaces. Esta discrepancia puede ser atribuida a la diferencia de tipos de estudios incluidos en ambas revisiones. El estudio de El-Nashar y cols.26incluyó tanto ensayos controlados aleatorizados como estudios observacionales y no realizaron análisis estratificados para cada uno de estos tipos de estudios. Dado que el objetivo de nuestro estudio fue evaluar eficacia y seguridad, nuestra revisión sistemática se restringió a la evaluación de ECA.En esta revisión sistemática, identificamos escasos ensayos controlados aleatorizados que evaluaron el tratamiento de NIC con crioterapia o cono frío en comparación con LEEP . Los estudios tuvieron moderada calidad metodológica. No se identificó una heterogeneidad significativa entre los estudios evaluados para cada uno de los desenlaces de eficacia y seguridad, excepto para márgenes positivos en los estudios que comparaban cono frio versus LEEP y para recurrencia de enfermedad para los estudios que comparaban crioterapia con LEEP. El meta análisis de los datos de los estudios incluidos evidenció que el uso cono frio disminuye el riesgo de enfermedad residual en comparación con LEEP. Mientras que el uso de crioterapia incrementa el riesgo de recurrencia de enfermedad y de infecciones; sin embargo, reduce el riesgo de sangrado menor en comparación con el tratamiento con LEEP. En discrepancia con el estudio de Jiang y cols.27. Nuestra revisión incluye además el estudio de Mitchell y cols.17encontrando una tasa de recurrencia de enfermedad incrementada casi dos veces con el uso de crioterapia en comparación con LEEP. Por lo tanto, nuestro estudio es consistente con la evidencia de mayor riesgo de recurrencia de enfermedad con el uso de crioterapia en comparación con LEEP. Del mismo modo, D’Alessandro y cols.28han publicado una revisión sistemática evaluando el manejo de NIC con LEEP y crioterapia. Los resultados de este estudio evidencian un menor riesgo de recurrencia de enfermedad en pacientes tratadas con LEEP en comparación con las tratadas con crioterapia . Este hallazgo es similar al de nuestra revisión en el que evidenciamos que la eficacia del uso de LEEP es mayor en relación con crioterapia, dado que nosotros identificamos un mayor riesgo de recurrencia de enfermedad con el uso de crioterapia. Nuestro estudio no incluyó el estudio de Smith y cols.29ya que ellos evaluaron pacientes con VIH, ni el estudio de Singh y cols.30al ser un estudio de tipo observacional. Es fundamental destacar el contexto en el que los dos estudios incluidos realizaron los tratamientos: los profesionales fueron personal sanitario especialmente entrenado en el uso de ambos métodos y los centros de atención fueron unidades especializadas que podría incrementar las probabilidades de éxito de los procedimientos. Estos son puntos destacables a tener en cuenta al considerar su implementación. El uso de cono frío sería la mejor opción en comparación con LEEP en paciente con NIC, en términos de enfermedad residual. Por otro lado, el uso de LEEP sería la mejor opción en comparación con la crioterapia en términos de recurrencia e infección post operatoria. Sin embargo, esta evidencia es de muy baja certeza, según la metodología GRADE. El verdadero efecto puede ser sustancialmente distinto. Se requieren más estudios controlados aleatorizados, así como criterios estrictos de seguimiento estandarizados para establecer conclusiones más fidedignas que permitan valorar la eficacia y seguridad de estos métodos a largo plazo. Este meta análisis evalúa dos métodos de tratamiento de NIC (cono frio y crioterapia) en comparación con LEEP, incluyendo sólo ensayos controlados aleatorizados que permitan evaluar su eficacia y seguridad. Actualiza de este modo la evidencia disponible hasta la fecha. La principal limitación de esta revisión es que existen escasos ensayos controlados aleatorizados, datan de hace más de 15 años y tienen tiempos de seguimiento cortos. Sin embargo, nuestra revisión sistemática aborda ampliamente los desenlaces de eficacia y seguridad con un análisis específico para cada uno de ellos, aportando de este modo un análisis más fino y una mejor evidencia para la toma de decisiones en el manejo terapéutico de lesiones neoplásicas intraepiteliales cervicales.Nuestro estudio evaluó la eficacia y seguridad del manejo de NIC con crioterapia en comparación con LEEP. Una revisión sistemática previa de ensayos controlados sugiere que la tasa de recurrencia de enfermedad (≥ 6 meses post tratamiento) puede ser menor después del manejo de NIC con LEEP en comparación con crioterapia


To describe the human resources for health and analyze the inequality in its distribution in Mexico. Cross-sectional study based on the National Occupation and Employment Survey (ENOE in Spanish) for the fourth quarter of 2018 in Mexico. Graduated physicians and nurses, and auxiliary/technician nurses with completed studies were considered as human resources for health. States were grouped by degree of marginalization. Densities of human resources for health per 1,000 inhabitants, Index of Dissimilarity (DI) and Concentration Indices (CI) were estimated as measures of unequal distribution. The density of human resources for health was 4.6 per 1,000 inhabitants. We found heterogeneity among states with densities from 2.3 to 10.5 per 1,000 inhabitants. Inequality was higher in the states with a very low degree of marginalization (CI = 0.4) than those with high marginalization (CI = 0.1), and the inequality in the distribution of physicians (CI = 0.5) was greater than in graduated nurses (CI = 0.3) among states. In addition, 17 states showed a density above the threshold of 4.5 per 1,000 inhabitants proposed in the Global Strategy on Human Resources for Health. That implies a deficit of nearly 60,000 human resources for health among the 15 states below the threshold. For all states, to reach a density equal to the national density of 4.6, about 12.6% of human health resources would have to be distributed among states that were below national density. In Mexico, there is inequality in the distribution of human resources for health, with state differences. Government mechanisms could support the balance in the labor market of physicians and nurses through a human resources policy. Anand and Bärnighausen criticize the conceptual framework of health systems proposed by the World Health Organization (WHO), which considers human resources for health (HRH) as one of the building blocks of the system1. They propose a conceptual framework in which human resources are the core of health systems3. The fulfillment of goals and patient satisfaction depend on the HRH, since they provide preventive and curative care, as well as information on diagnosis, treatment and monitoring, and decide which technology and/or drug to use. Therefore, their size, composition and distribution are very relevant to ensure the population’s access to health services3.Human resources working in health institutions are considered one of the fundamental components for the proper performance of health systems4. In 2004, the Joint Learning Initiative, [JLI] recommended a density of 2.5 per 1,000 inhabitants to achieve 80.0% measles immunization coverage and deliveries performed by health personnel5. Under the Millennium Development Goals (MDG), the 2006 WHO Global Report suggested a minimum threshold of 2.3 physicians, nurses and midwives per thousand inhabitants to reach 80.0% of deliveries performed by qualified personnel; 57 countries did not reach such an indicator4.The availability of HRH, measured by density per number of inhabitants, has been used as a health coverage indicator. A positive relationship has been found with some interventions, such as vaccination or births performed by qualified personnel6, the WHO established a density of 4.5 physicians, nurses and midwives per 1,000 inhabitants as the minimum threshold required for the implementation of the Global Strategy on Human Resources for Health (GSHRH) under Universal Health Coverage (UHC)7. Unlike the 2006 indicator, this threshold includes 12 indicators related to UHC and SDG targets. With this indicator, the WHO predicted that 18 million more health workers would be needed in low-middle-income countries to achieve SDG8, although it became an emphasis that it should not be a target for all countries given their differences in health needs7.In 2016, under the Sustainable Development Goals (SDG)Seguro Popular de Salud  in 2003, to provide financial protection to the population excluded from social security9. At the end of 2017, 53.5 million Mexicans were affiliated with PHI10. In 2005–2016, public spending on health per capita increased by 31.0%, and the density of physicians and nurses per thousand inhabitants increased by 34.0 and 32.0%, respectively. Despite these advances, the public health system faces problems of accessibility and quality in care, which can be explained by the lack of an explicit policy on human resources for health11 and by the imbalance between the health needs of the population and human and financial resources12.In Mexico, the federal government launched the public health insurance known as Secretaría del Trabajo y Previsión Social  makes periodic estimates of the number of graduated physicians and nurses who are employed13; however, these estimates do not show whether employed professionals practice the medical profession nor specify the length of the working day. Other sources of information such as the Organization for Economic Cooperation and Development (OECD) indicate for Mexico a density of 2.4 and 2.9 physicians and nurses, respectively, in 2017. However, these data include intern physicians (undergraduate) and residents , use different sources of information and recognize the possibility of duplication14. In both cases, the HRH density indicator may be overestimated, and it is not possible to estimate the professional deficit that is necessary to reach the 4.5 threshold recommended in GSHRH. Therefore, this study aimed to describe the HRH and analyze it’s inequal distribution in Mexico.At national level, the 15. Databases are publicly available and do not contain identifiable information about individuals.Cross-sectional study based on secondary data analysis to describe characteristics of the physicians and nurses. The National Occupation and Employment Survey , conducted by the National Institute of Statistics and Geography  was used. ENOE has a probabilistic, two-phased, stratified and clustered design. It is carried out quarterly, has national and state geographic coverage, and it aims to provide information on the occupational characteristics of the population aged 15 and olderENOE-based inequality indicators were constructed for the fourth quarter of 2018 (quarter IV-2018). All professionals with medical or nursing studies who reported completing their undergraduate studies at the time of the survey were considered Human Resources for Health (HRH) or health workers. We also included those who studied nursing at the technical level (auxiliary nursing).Employed (Emp): physicians and nurses who worked 20 hours or more a week performing functions according to their proffesional training in the health area, or performing administrative functions in the health sector.Unemployed (Une): physicians and nurses who looked for a job because they did not have an economic activity.Quantitative underemployment (QuantiUn): physicians and nurses employed less than 20 hours a week and with functions according to their profession, or who exercised the health profession as a secondary job.Qualitative underemployment : physicians and nurses employed but with functions or activities outside their professional training, regardless of working hours per week.Economically Active Population (EAP): physicians and nurses employed, underemployed and unemployed.Densities of Human Resources for Health per 1,000 inhabitants:a.Density of employed human resources (DHRH): b.Density of Human Resources EAP: In both cases, the HRH deficit was obtained from the threshold recommended in GSHRH according to the following formulas:c.Employed deficit: d.EAP Deficit: Socio-economic factors  in both professions were analyzed, and state densities of human resources for health of 1) employed health personnel per 1,000 inhabitants (DHRH), and 2) economically active population (EAP) per 1,000 inhabitants were estimated. In both cases, densities were compared with the density of 4.5 per 1,000 inhabitants recommended in GSHRH, and the number of health workers needed to meet this threshold was estimated.19. It is estimated using the formula sjh is the proportion of HRH in state j with respect to the national total of HRH, and sjp is the proportion of the population in state j with respect to the national population. In this study, the ID was interpreted as the proportion (or percentage) of workers who would have to be redistributed among states so that everyone had the same DHRH.The Index of dissimilarity (ID) is one indicator used in the analysis of health inequalities19. In this study, curves were elaborated considering states as an analysis unit. The proportion of HRH in state j with respect to the national total of HRH (sjh) was estimated, and the proportion of Disability-Adjusted Life Year (DALY) in state j was estimated from the national total of DALYs (sjd). The concentration curve plots the cumulative proportion of DALY by the states  with the accumulated proportions of HRH in the Y-axis. If workers are equally distributed among states according to their percentage of the national disease burden, the concentration curve matches the diagonal joining the points (0.0) and (1.1), which is called the equality line. The area between the CC and the equality line is the Concentration Index (CI) and the higher the absolute value of the larger IC, higher the inequality. A scatter plot was built between the DHRH per 1,000 inhabitants and the DALY per 100 thousand inhabitants in each state18. In addition, another dispersion plot was built between the DHRH per 1,000 inhabitants and the Gross Domestic Product (GDP) per capita, and the Spearman’s correlation was estimated.Another index used in the analysis of health inequalities is the index from the Concentration Curve (CC)20. The classification and grouping of states according to degree of marginalization comes from the classification proposed by CONAPO21. Data on the Gross Domestic Product (GDP) were obtained from the INEGI website22. DALY information was obtained from global disease burden estimates conducted by the Institute for Health Metrics and Evaluation (IHME)23.The three inequality indicators in the distribution of human resources at the national level and by states grouped by degree of marginalization were used: the DHRH per 1,000 inhabitants, the ID and the CI. Population size information comes from the population projections of the National Population Council  available on the website of the Directorate-General for Health Information  of the Ministry of HealthThe analyses were conducted using the survey weights, and its complex design was considered using the SVY module of the STATA MP 13.0 package. Pearson Chi-square tests assess the differences in distribution between the type of profession (medicine or nursing) and its socioeconomic factors considering p < 0.05 for statistical significance and confidence intervals at 95% (95%CI).In 2018, there were 413,000 physicians and 714,000 nurses in Mexico, of whom 62.9% and 44.4%, respectively, were employed 20 hours or more in the health sector , which iThe density of health professionals (DHRH) per 1,000 inhabitants was 4.6 , exceeding the threshold of 4.5 recommended in GSHRH . Howeverper capita . This coincided with what was described above, according to which the groups of entities of very low and very high marginalization had higher and lower DHRH, respectively  with the smallest proportions of DALY concentrated less than 25.0% of the entire workforce, while five of them  concentrated more than 40.0% (CI = 0.4). This pattern was mainly caused by the inequality in the distribution of medical personnel (CI = 0.5) and technical nursing (CI = 0.5), and to a lesser extent to the distribution of professional nursing (CI = 0.3) . In addiectively .Seventeen states reached a density of 4.5  and 3b. 24. While, according to GSHRH criteria, the density of health workers could be considered acceptable, inequality within the country is reflected in the variability among states, particularly those with high marginalization that do not reach the threshold. Considering that OECD data include interns and residents, and there is the possibility of double counting of physicians and nurses working simultaneously in the public and private sector, the availability of HRH for lower-density areas is likely to be below current demand and with a larger deficit for future years. In this sense, requirement projections by medical specialists in Mexico have estimated that health needs arising from population aging will require more specialists in internal medicine and surgery than in pediatrics, which will imply a growing challenge for the provision of services25.Our study shows a disadvantage of Mexico in the availability of HRH compared with the average of OECD countries26. Our results could reflect other weak areas of the health system itself, such as insufficient equipment or required inputs, poor quality of care, as well as conditions typical of the demographic and epidemiological transition. The consequences of these multiple factors are chronic-degenerative health needs that lead to disability for a greater proportion of the population27.A relevant finding was the lack of consistency in the relation between the density of health workers and DALY rates. As has been documented in other studies, a negative correlation would be expected, which would support evidence of having more health professionals to reduce the burden of disease28, due to their high economic development, which provide better job opportunities and better income expectations29; or 2) the distribution of the number of students enrolled at universities across the country where six states, of very low or low marginalization, concentrate to 50.0% and 35.0% of the enrollments of medical and nursing students in the 2017–2018 school year, respectively; in contrast, three very high-marginalization entities account for 15.7% of registered nursing students and 6.5% of medical students30. These imbalances in the distribution of human resources pose a challenge to the health system as the population living in areas of high degree of marginalization is less likely to have access to health services.By contrast, the positive relationship between DHRH and state GDP could be explained by the following reasons: 1) qualified medical personnel can switch residency to Mexican regions with attractive cities for medical mobility31, but are not considered in the estimation of the 4.5 per 1,000 Inhabitants threshold; c) the estimation of employment rates does not include physicians and nurses in health teaching and research activities. Therefore, they may have included as underemployed, and 5) ENOE is a national and state representative survey of the entire population over 15 years; medical and nursing staff account for less than 2.0% of the population, which could be construed as a weakness in outcomes at the state level. However, given the random design of ENOE and the sample sizes are large for both professions, representativeness can be assumed for this subgroup.Limitations of this analysis are the difficulties in identifying labor mobility, which may affect the estimation of state densities over time, and limitations from ENOE: a) it is not possible to distinguish between levels of care or between insurance schemes, which prevents more precise inequalities among population groups or health needs; b) midwives were not included, since it is not possible to identify them in the survey, nor were other categories of health personnel such as dentists, pharmacists, laboratory technicians or community promoters, who are also considered a health workforceIn brief, the results of this study indicate inequality in the distribution of HRH across states, which may potentially be linked to the number of enrollment offered in educational institutions, the preference of health personnel to be placed into areas with better living conditions, and greater availability of sources of work in states with greater health infrastructure. The establishment of a new human resources policy is a priority that, based on the health needs of the population, articulates the training of physicians, nurses, and other health professionals for incorporation into health institutions, considering the areas of greatest demand. In addition, it is necessary to regulate professional practice, which encourages balance in the public and private labor market. 2. Anand y Bärnighausen hacen una crítica al marco conceptual de los sistemas de salud propuesto por la Organización Mundial de la Salud (OMS) que considera a los recursos humanos en salud (RHS) como uno de los bloques del sistema1. Proponen un marco conceptual en el que los recursos humanos son el centro de los sistemas de salud3. El cumplimiento de las metas y la satisfacción de los pacientes dependen de los RHS, dado que son ellos quienes realizan las actividades de provisión de servicios preventivos y curativos, entregan información sobre el diagnóstico, tratamiento y seguimiento, y deciden qué tecnología y/o medicamento utilizar, por lo cual su tamaño, composición y distribución son muy relevantes para asegurar el acceso de la población a los servicios de salud3.Los recursos humanos que laboran en las instituciones de salud son considerados uno de los pilares para el adecuado desempeño de los sistemas de salud4. En 2004, la Iniciativa Conjunta de Aprendizaje , recomendó una densidad de 2,5 por 1.000 habitantes para alcanzar una cobertura de 80,0% de inmunización contra el sarampión y partos atendidos por personal de salud5. En el marco de los Objetivos de Desarrollo del Milenio (ODM), el informe mundial de la OMS de 2006 sugirió un umbral mínimo de 2,3 médicos, enfermeras y parteras por cada mil habitantes para alcanzar un 80,0% de partos atendidos por personal calificado; 57 países no alcanzaban tal indicador4.La disponibilidad de RHS, medida a través de la densidad por número de habitantes, ha sido relacionada con indicadores de cobertura. Se ha encontrado una relación positiva con algunas intervenciones como cobertura de vacunación o cobertura de partos atendidos por personal calificado6, la OMS estableció una densidad de 4,5 médicos, enfermeras y parteras por 1.000 habitantes como umbral mínimo requerido para la implementación de la Estrategia Global sobre Recursos Humanos para la Salud (EGRHS) en el marco de la cobertura universal de salud (CUS)7. A diferencia del indicador de 2006, este umbral contempla 12 indicadores relacionados con metas de la CUS y los ODS. Con este indicador, la OMS pronosticó que se necesitarían 18 millones más de trabajadores de la salud en los países de ingreso medio-bajo para alcanzar los ODS8, aunque se hizo enfasis en que este no debe representar una meta para todos los paises dadas sus diferencias en las necesidades de salud7.En 2016, en el marco de los Objetivos de Desarrollo Sostenible (ODS)9, con un logro de afiliación de 53,5 millones de mexicanos hacia finales de 201710. Adicionalmente, en el período 2005–2016, el gasto público en salud per cápita aumentó 31,0% y la densidad de médicos y enfermeras por cada mil habitantes se incrementó en 34,0 y 32,0%, respectivamente. A pesar de estos avances, el sistema público de salud enfrenta problemas de accesibilidad y calidad de atención, que pueden ser explicados por la carencia de una política explícita de recursos humanos en salud11, y por el desequilibrio entre las necesidades de salud de la población y los recursos humanos y financieros12.En México, el gobierno federal lanzó en 2003 un seguro público de salud conocido como Seguro Popular de Salud (SPS) para brindar protección financiera a la población excluida de la seguridad social13; no obstante, estas estimaciones no muestran si los profesionales ejercen la profesión médica ni se especifica la duración de la jornada laboral. Otras fuentes de información como la Organización para la Cooperación y el Desarrollo Economicos (OCDE) reportaron para México una densidad de 2,4 y 2,9 médicos y enfermeras, respectivamente, en 2017. Sin embargo, estos datos incluyen a médicos internos (pre-grado) y residentes , utilizan datos provenientes de distintas fuentes de información y en ellas se reconoce la posibilidad de duplicación14. En ambos casos, el indicador de densidad de RHS puede estar sobreestimado y no es posible calcular el déficit de profesionales que son necesarios para alcanzar el umbral de 4,5 recomendado en la EGRHS. Por lo anterior, el presente estudio tuvo como objetivo describir los RHS y analizar la desigualdad en su distribución en México.A nivel nacional, la Secretaría del Trabajo y Previsión Social (STPS) realiza estimaciones periódicas del número de médicos y enfermeras con licenciatura que están empleados15. Las bases de datos están disponibles públicamente y no contienen información identificable de los individuos.Estudio transversal realizado a partir de análisis secundario de datos para describir características del personal médico y de enfermería. Se utilizó la Encuesta Nacional de Ocupación y Empleo (ENOE), realizada por el Instituto Nacional de Estadística y Geografía (INEGI). La ENOE tiene un diseño probabilístico, biétapico, estratificado y por conglomerados, se levanta trimestralmente, tiene cobertura geográfica nacional y estatal, y su objetivo es proporcionar información sobre las características ocupacionales de la población de 15 años y másSe construyeron indicadores de desigualdad con base en la ENOE del cuarto trimestre de 2018 (trimestre IV-2018). Todas las personas con estudios en medicina o enfermería que refirieron haber terminado sus estudios de licenciatura al momento de la encuesta fueron consideradas Recursos Humanos en Salud (RHS) o personal sanitario. También se incluyeron a quienes estudiaron enfermería a nivel técnico (enfermería auxiliar).Personal empleado/ocupado (Emp): personal sanitario que trabajaba 20 horas o más a la semana realizando funciones de acuerdo a su formación acádemica en el área de la salud, o realizaba funciones administrativas en el sector salud.Personal desempleado (Des): personal sanitario que en la semana de referencia de la encuesta buscó trabajo porque no estaba vinculado a una actividad económica.Personal con subempleo cuantitativo (SubCt): personal sanitario empleado/ocupado menos de 20 horas a la semana y con funciones de acuerdo a su profesión, o bien, que ejercía la profesión sanitaria como un empleo secundario.Personal con subempleo cualitativo (SubCl): personal sanitario empleado/ocupado pero con funciones o actividades ajenas a su formación acádemica, independientemente de las horas laborales por semana.Población Económicamente Activa (PEA): personal sanitario empleado, subempleado y desempleado.Densidades de Recursos Humanos en Salud por 1.000 habitantes:a.Densidad de recursos humanos empleados (DRHS): b.Densidad de recursos humanos PEA: En ambos casos, se obtuvo el déficit de RHS respecto al umbral recomendado en la EGRHS de acuerdo con las siguientes fórmulas:c.Déficit de empleados: d.Déficit de PEA: Se analizaron los factores socioecónomicos  en ambas profesiones, y se calcularon las densidades de recursos humanos en salud por entidad federativa de 1) personal sanitario empleado por 1.000 habitantes (DRHS), y 2) población económicamente activa (PEA) por 1.000 habitantes. En ambos casos, se compararon las densidades con el umbral de 4,5 por 1.000 recomendado en la EGRHS y se estimó el número de trabajadores de la salud necesarios para alcanzar dicho umbral.19. Su cálculo proviene de la fórmula sjh es la proporción del personal sanitario en el estado j respecto al total nacional, y sjp es la proporción de la población en el estado j respecto a la población nacional. En este estudio, el ID se interpretó como la proporción (o porcentaje) de trabajadores que tendrían que redistribuirse entre los estados para que todos tuvieran la misma DRHS.El índice de disimilitud (ID) es uno de los indicadores usados en el análisis de las desigualdades en salud19. En este estudio, se construyeron las curvas considerando a los estados como unidad de análisis. Se calculó la proporción de RHS en el estado j respecto al total nacional (sjh), y se calculó la proporción de los Años de Vida Saludable perdidos por Discapacidad (AVISA) en el estado j respecto al total nacional (sjd). La curva de concentración grafica la proporción acumulada de AVISA por los estados  con las proporciones acumuladas de RHS. Si los trabajadores están igualmente distribuidos entre los estados, de acuerdo con su porcentaje de la carga de la enfermedad nacional, la curva de concentración coincide con la diagonal que une los puntos  y , llamada línea de igualdad. El área entre la CC y la línea de igualdad es el Índice de Concentración (IC) y entre mayor sea el valor absoluto del IC más grande es la desigualdad. Se construyó un gráfico de dispersión entre la DRHS por 1.000 habitantes y los AVISA por 100 mil habitantes en cada estado18. Adicionalmente, se construyó otro gráfico de dispersión entre la DRHS por 1.000 habitantes y el Producto Interno Bruto (PIB) per cápita, y se estimó la correlación de Spearman.Otro índice usado en el análisis de las desigualdades en salud es el índice que proviene de la Curva Concentración (CC)20. La clasificación y agrupación de los estados según grado de marginación proviene de la clasificación propuesta por CONAPO21. Los datos del Producto Interno Bruto (PIB) se obtuvieron de la página electrónica del Instituto Nacional de Estadística y Geografía (INEGI)22. La información de los AVISA se obtuvo de las estimaciones de la Carga Global de la Enfermedad realizadas por el Instituto de Métricas y Evaluación de la Salud de 2017 23.Se utilizaron los tres indicadores de desigualdad en la distribución de recursos humanos a nivel nacional y por estados agrupados por grado de marginación: la DRHS por 1.000 habitantes, el ID y el IC. La información del tamaño de la población proviene de las proyecciones de población del Consejo Nacional de Población (CONAPO) disponibles en la página electrónica de la Dirección General de Información en Salud (DGIS) de la Secretaría de SaludLos análisis se realizaron utilizando los factores de expansión de la encuesta y se consideró su diseño complejo utilizando el módulo SVY del paquete STATA MP 13.0. Pruebas Chi-cuadrada de Pearson evalúan las diferencias en la distribución entre el tipo de profesión (medicina o enfermería) y sus factores socioeconómicos considerando p < 0.05 para la significancia estadística e intervalos de confianza al 95% (IC95%).En 2018, había 413 mil médicos y 714 mil enfermeras en México, de los cuales 62,9% y 44,4%, respectivamente, estaban empleados 20 horas o más en el sector salud , equivalLa densidad de profesionales de la salud (DRHS) por 1.000 habitantes fue de 4,6 , superando el umbral de 4,5 recomendado en la EGRHS . Sin embper cápita . Esto coincidió con lo descrito anteriomente, según lo cual los grupos de entidades de muy baja y muy alta marginación tenían mayores y menores DRHS, respectivamente  con las menores proporciones de AVISA concentraron menos de 25,0% de toda la fuerza laboral, mientras que cinco de ellos  concentraron más de 40,0% . Este patrón fue originado principalmente por la desigualdad en la distribución del personal médico  y de enfermería técnica , y en menor medida a la distribución de la enfermería profesional  . Adicionivamente .Diecisiete entidades alcanzaron una densidad de 4,5 , 3a y 3b24. Si bien, de acuerdo a los criterios de la EGRHS, la densidad de trabajadores de la salud podría considerarse aceptable, la desigualdad al interior del país se refleja en la variabilidad entre estados, en particular aquellos con alta marginación que no alcanzan el umbral. Si se reconoce que en los datos de la OCDE se incluye a los médicos internos y residentes, y existe la posibilidad de doble conteo de médicos y enfermeras que trabajan simultáneamente en el sector público y privado, la disponibilidad de RHS para las áreas con menor densidad probablemente quedará por debajo de la demanda actual y con mayor déficit para años futuros. En este sentido, proyecciones de requerimiento de médicos especialistas en México han estimado que las necesidades de salud derivadas del envejecimiento poblacional requerirán mayor número de especialistas en medicina interna y cirugía que en pediatría, lo que implicará un reto creciente para la provisión de servicios25.Nuestro estudio muestra una desventaja de México en la disponibilidad de RHS respecto al promedio de los países pertenecientes a la OCDE26. Dicho resultado pudiera reflejar otras áreas débiles del propio sistema de salud, como insuficiencia en equipamiento o insumos requeridos, deficiencia en la calidad de la atención, así como condiciones propias de la transición demográfica y epidemiológica. Eso resulta en necesidades de salud crónico-degenerativas que derivan en discapacidad para una mayor proporción de la población27.Un hallazgo relevante fue la falta de consistencia en la relación entre la densidad de trabajadores de la salud y las tasas de AVISA. Se esperaría una correlación negativa, como ha sido documentado en otros estudios, que apoyaría la evidencia de contar con una mayor cantidad de profesionales de la salud para disminuir la carga de enfermedad28, que tienen mayor desarrollo económico y brindan mayores oportunidades laborales y expectativas de mejor ingreso29; o bien, 2) la distribución del número de matrículas registradas en las universidades a lo largo del país donde seis estados, de marginación muy baja o baja, concentran al 50 y 35,0% de las matrículas de estudiantes de medicina y enfermería en el ciclo escolar 2017–2018, respectivamente, y tres entidades de muy alta marginación concentran al 15,7% de los estudiantes de enfermería matriculados y 6,5% de los estudiantes de medicina matriculados30. Estos desequilibrios en la distribución de los recursos humanos representan un reto para el sistema de salud, ya que la población que vive en las zonas de alto grado de marginación presenta menor posibilidad en el acceso a los servicios de salud.En contraste, la relación positiva entre la DRHS y el PIB estatal podría ser explicada por las siguientes razones: 1) el personal médico calificado puede cambiar su residencia a las regiones de México con ciudades identificadas como focos de atracción en la movilidad médica31, pero que no se consideran en la construcción del umbral de 4,5 por 1.000 habitantes; c) la construcción de la tasas de empleo no contempla la posibilidad de que médicos y enfermeras pudieran dedicarse a actividades de docencia e investigación en salud, por lo que es muy posible que existan profesionales que son profesores e investigadores que estén incluidos en la categoría de personal subempleado, y 5) la ENOE es una encuesta representativa a nivel nacional y estatal de toda la población mayor de 15 años; el personal médico y de enfermería representa menos de 2,0% de la población, lo que podría interpretarse como una debilidad de los resultados a nivel estatal. Sin embargo, dado el diseño aleatorio de la ENOE y que los tamaños de muestra son grandes para ambas profesiones, se puede asumir representatividad para este subgrupo.Son limitaciones de este análisis la dificultad para identificar la movilidad laboral, que puede afectar la estimación de las densidades estatales en el tiempo, y limitaciones provenientes de la ENOE: a) no es posible distinguir entre niveles de atención ni entre esquemas de aseguramiento, lo que impide establecer de manera más precisa desigualdades entre grupos poblacionales o necesidades de salud; b) no se incluyó a las parteras debido a que no es posible identificarlas en la encuesta, y tampoco se incluyeron otras categorías de personal de salud como dentistas, farmacéuticos, técnicos de laboratorio o promotores comunitarios que también son considerados como fuerza laboral en saludLos resultados indican desigualdad en la distribución de los RHS a través de los estados, la cual puede estar potencialmente ligada al número de matrículas que se ofertan en las instituciones educativas, la preferencia del personal de salud para insertarse laboralmente en áreas con mejores condiciones de vida, y mayor disponibilidad de fuentes de trabajo en estados con mayor infraestructura en salud. Es prioritario el establecimiento de una nueva política de recursos humanos que, a partir de las necesidades de salud de la población, articule la formación de médicos, enfermeras y otros profesionales de la salud para su incorporación en las instituciones de salud considerando las áreas de mayor demanda. Además, es necesaria la regulación de la práctica profesional, que incentive el equilibrio en el mercado de trabajo público y privado.