Embora tenha sido relatado que a dieta de jejum intermitente (JI) tem efeitos positivos na saúde do coração e na melhora da pressão arterial, ainda não foi suficientemente esclarecido como poderia ter esses efeitos positivos.Objetivo: Nosso objetivo foi avaliar os efeitos do JI no sistema nervoso autônomo (SNA) e no sistema renina-angiotensina (SRA), que estão intimamente relacionados à pressão arterial. Setenta e dois pacientes hipertensos foram incluídos no estudo, e os dados de 58 pacientes foram usados. Todos os participantes jejuaram por cerca de 15-16 horas por 30 dias. Os participantes foram avaliados com monitorização ambulatorial da pressão arterial de 24 horas e eletrocardiograma Holter antes e após o JI; também, amostras de sangue venoso de 5 ml foram coletadas para avaliação dos níveis séricos de angiotensina I (Ang-I) e angiotensina II (Ang-II) e da atividade da enzima conversora de angiotensina (ECA). Para análise dos dados, o valor de p < 0,05 foi aceito como significativo. Comparado ao pré-JI, observou-se queda significativa nas pressões arteriais dos pacientes no pós-JI. Um aumento na potência de alta frequência (AF) e na raiz quadrada média da soma dos quadrados das diferenças entre intervalos NN adjacentes (RMSSD) foram observados após o protocolo JI . A Ang-II e a atividade da ECA foram menores em pacientes após JI , e níveis decrescentes de Ang-II foram determinados como fatores preditivos para melhora da pressão arterial, como o aumento da potência de AF e RMSSD. Os presentes achados de nosso estudo demonstraram uma melhora na pressão arterial e a relação da pressão arterial com resultados positivos, incluindo VFC, atividade da ECA e níveis de Ang-II após o protocolo JI. Embora não haja causa subjacente definitiva na hipertensão essencial (primária), há superativação do SRA e instabilidade autonômica  na maioria dos casos. Existe uma interação complexa e bidirecional entre esses dois sistemas em condições fisiológicas e fisiopatológicas como a hipertensão. Além disso, os medicamentos anti-hipertensivos mais atuais visam suprimir a atividade excessiva desses dois sistemas.2A hipertensão continua sendo a principal causa evitável de doença cardiovascular (DCV) e morte em todo o mundo.3 O SRA clássico é uma série de interações enzima-substrato nas quais a proteína substrato angiotensinogênio é processada em uma reação de duas etapas pela conversão de renina e angiotensina enzima (ECA) para produzir hormônios peptídicos funcionais chamados angiotensina I (Ang-I) e angiotensina II (Ang-II), respectivamente. A Ang-II é a molécula mais funcional do SRA e desempenha um papel ativo em muitos processos fisiológicos e patológicos. Aumenta a pressão arterial principalmente por vasoconstrição, inflamação, secreção de vasopressina e aldosterona, estresse oxidativo, proliferação celular e ativação imunológica por meio de receptores tipo I (AT1) da superfície celular.4 Além disso, a Ang-II contribui para a regulação da pressão arterial modulando o sistema nervoso autônomo nos níveis central e periférico.5 A ativação do braço do receptor ECA/Ang-II/AT1 do SRA causa deterioração na regulação autonômica cardiovascular ao aumentar a condução nervosa simpática, inibindo o tônus parassimpático-vagal cardiovascular e diminuindo a sensibilidade do barorreflexo.6O SRA era originalmente conhecido como um sistema endócrino que regula a pressão sanguínea e o equilíbrio hidroeletrolítico.10Sabe-se que a combinação de terapias farmacológicas e não farmacológicas é oferecida para o manejo da hipertensão, incluindo modificações no estilo de vida, como dietas de forma eficaz. O jejum intermitente (JI) é uma das dietas populares que demonstraram ter um efeito positivo na pressão arterial, e os protocolos JI são classificados como alimentação com restrição de tempo (JRT), jejum em dias alternados (JDA), dieta 5:2, e jejum do Ramadã (JR).13 Além disso, uma diminuição na pressão arterial sistólica/diastólica foi relatada com o JI,14 mas ainda não há consenso sobre como o JI reduz a pressão arterial. Um dos possíveis mecanismos poderia ser uma diminuição do tônus simpático cardiovascular e um aumento do tônus parassimpático, o que corrige significativamente o desequilíbrio autonômico observado na maioria dos pacientes hipertensos.16 A modulação do SNA por JI também pode teoricamente causar supressão do vasoconstritor (ECA- Ang II-AT1 receptor) do SRA, dadas as interações do ANS e do SRA. Para apoiar esta hipótese, considerando as informações existentes na literatura, nosso estudo teve como objetivo avaliar 1. O efeito do JR na pressão arterial, 2. O efeito da JR no SRA medindo a atividade sérica da ECA e Ang-I e Ang- níveis II. 3. O efeito da JR no SNA medindo a variabilidade da frequência cardíaca (VFC) em pacientes hipertensos.Tem sido sugerido que o jejum intermitente melhora os fatores de risco cardiovascular por meio de três mecanismos possíveis: diminuição do estresse oxidativo, sincronização com o sistema circadiano e aumento da cetogênese.Society of Hypertension and Renal Diseases .17Em análises de poder, um bicaudal com tamanho de efeito de 0,5 pontos, um alfa de 0,05 e um poder de 0,80 precisou de um tamanho de amostra de apenas 34 para detectar esse efeito. Planejamos incluir cerca de 60 pacientes em nosso estudo, considerando o número de pacientes em um estudo realizado pela Setenta e dois pacientes com idade entre 40 e 60 anos, que procuraram o ambulatório de cardiologia, apresentavam hipertensão controlada, usavam apenas bloqueadores dos canais de cálcio do grupo diidropiridínico como tratamento anti-hipertensivo, faziam qualquer outro tratamento medicamentoso por qualquer motivo e estavam em jejum voluntário. Os dados de 58 pacientes foram usados excluindo 14 pacientes que pararam de jejuar por mais de 2 dias por motivos diversos e não compareceram para controle   .2 , hiperlipidemia, diabetes) que podem afetar a atividade do SRA e do SNA, aqueles com TFG < 50 e aumento duplo normal nos testes de função hepática, e que tinham doença cardiovascular, incluindo doença arterial coronariana, insuficiência cardíaca, insuficiência renal crônica e doença cerebrovascular foram excluídos do estudo. Pacientes em uso de drogas que podem afetar o SRA, a atividade do SNA  e PCR (estatina) também foram excluídos.Pacientes com pressão arterial desregulada, que apresentavam fatores de risco cardiovascular  fora do período de jejum; portanto, não há necessidade de um cálculo estrito de calorias. Para limitar a variabilidade da ingestão de calorias, os participantes foram aconselhados a seguir uma rotina de 30 dias de comer a refeição principal após o pôr do sol e uma refeição leve antes do nascer do sol. Os participantes tomaram a medicação antes do início da inanição.Os participantes foram verificados duas vezes, 5 dias antes do jejum e nos últimos 5 dias de jejum. Em seus controles, os participantes foram avaliados com monitoramento ambulatorial da pressão arterial de 24 horas e eletrocardiograma Holter. Em ambos os controles, amostras de 5 ml de sangue venoso foram coletadas entre 8:00 e 8:30 para testes bioquímicos.O consentimento informado assinado foi obtido de todos os participantes antes de participar do estudo. Este estudo foi aprovado pelo comitê de ética local do Hospital Municipal (2021/517).Amostras de sangue foram coletadas dos pacientes sentados após 20 minutos de repouso após 12 horas de jejum. A veia antecubital foi utilizada para obtenção da amostra de sangue. O soro e o plasma foram separados após as amostras serem centrifugadas por 10 minutos a 5000 rpm . Eles foram mantidos a -80 °C até que os ensaios dos parâmetros fossem realizados por um bioquímico clínico experiente.Os níveis séricos de angiotensina 1 e angiotensina 2 e a atividade da ECA foram estudados pelo método de ensaio imunoenzimático (ELISA) usando kits comerciais . Os níveis de Ang-I e Ang-II e a atividade da ECA foram analisados de acordo com as instruções do fabricante e expressos em ng/L, ng/L e U/L, respectivamente.Para avaliar a pressão arterial dos participantes, foram realizadas duas medidas de pressão arterial ambulatorial de 24 horas, 5 dias antes da JI e nos últimos 5 dias da JI. Foram obtidos os níveis médios de pressão arterial sistólica e diastólica de 24 horas e os níveis médios diurnos/noturnos de pressão arterial sistólica e diastólica. Para avaliar a variabilidade da frequência cardíaca (VFC), os dados do eletrocardiograma Holter de 24 horas foram obtidos duas vezes (modelo Ge: informações do software SEER 100 MARS). Os parâmetros e medidas da VFC foram feitos com base nos pareceres da European Society of Cardiology e da North American Society of Battery and Electrophysiology. O desvio padrão de todos os intervalos RR [NN] normais a normais (SDNN), a raiz quadrada média da soma dos quadrados das diferenças entre intervalos NN adjacentes (RMSSD), e o número de pares de intervalos NN que diferem em mais de 50 ms (pNN50) em 24 horas, potência de baixa frequência (BF), potência de alta frequência (AF) e a proporção dos dois (BF/AF) foram obtidos a partir de registros de ECG de 24 horas. Além disso, foram obtidas a frequência cardíaca máxima, a frequência cardíaca mínima, a frequência cardíaca média de 24 horas e a frequência cardíaca noturna média dos pacientes.Os dados foram analisados usando o IBM SPSS Statistics 21.0. A distribuição dos dados foi analisada por meio do teste Shapiro-Wilk e QQ Plot Normality. Frequências e porcentagens foram calculadas para variáveis categóricas. Variáveis contínuas com distribuição normal foram expressas como média e desvio padrão, enquanto variáveis contínuas com distribuição não normal foram expressas como mediana e intervalo interquartílico. Para comparar as variáveis, foram utilizados o teste t de amostras pareadas e o teste de Wilcoxon. Os efeitos preditivos dos parâmetros sobre a pressão arterial foram avaliados pelo método de análise de regressão linear. A adequação da regressão linear ao modelo de 6 etapas foi controlada em modelos para PAS e PAD . Altos níveis de correlação excluíram BUN, ácido úrico e níveis de colesterol total das análises. Um valor de p < 0,05 foi aceito como significativo nas análises estatísticas.Cinquenta e oito pacientes com HTA controlada entre as idades de 40-60 foram incluídos no estudo. As características dos pacientes são dadas na A Ang-I sérica foi menor, enquanto os níveis de Ang-II e ECA foram maiores nos hipertensos pré-JI do que nos hipertensos pós-JI   . Em pacConsiderando os efeitos do jejum intermitente no perfil lipídico IMC e PCR na literatura, as relações do IMC e TSH com os níveis de ECA e a hipótese do estudo, todos os dados foram  incluídos na análise de regressão para diminuir a pressão arterial sistólica e diastólica. O modelo de regressão foi estatisticamente significativo , e a diminuição da atividade da ECA e dos níveis de Ang-II, aumentando também o RMSSD e a potência de IC, foram avaliados como fatores preditivos para a diminuição da pressão arterial sistólica após a JI   . Além dPesquisas em humanos indicam que o JI pode ter vantagens cardiovasculares. O JI parece afetar positivamente inúmeras variáveis de risco cardiovascular, incluindo HTA, enquanto os mecanismos subjacentes são desconhecidos. Nosso estudo é um dos poucos que avaliaram os possíveis mecanismos subjacentes ao efeito da JR, um dos subtipos de JI, sobre a pressão arterial. É também o primeiro estudo em que os sistemas SRA e ANS, reconhecidamente importantes na regulação da pressão arterial, foram avaliados em conjunto. Os presentes achados de nosso estudo demonstraram os efeitos do JI na pressão arterial e na VFC. Outro fator principal que apresentou evolução positiva após o protocolo de JI foi a atividade da ECA e os níveis de Ang-II.18 Por outro lado, resultados conflitantes foram relatados em estudos que não encontraram nenhuma diferença.19 Além disso, benefícios cardiovasculares e metabólicos, como diminuição de TG, LDL, massa gorda e PCR, foram relatados no jejum terapêutico.20 Além disso, melhorias nos indicadores de saúde cardiovascular podem ser observadas 2 a 4 semanas após o início do JI em estudos animais.15 Em nosso estudo, em comparação com o pré-JI, foi observada uma diminuição significativa nas pressões arteriais médias sistólica e diastólica medidas em 24 horas e à noite em pacientes hipertensos pós-JI. Além das diferenças metodológicas entre os estudos, a inclusão de hipertensos controlados em nosso estudo pode ter levado a uma melhora mais significativa dos níveis pressóricos, uma vez que os casos resistentes foram excluídos. Não houve alteração estatisticamente significativa na glicemia de jejum, HgA1C, creatinina, GFR, BUN, colesterol total, LDL, HDL e níveis de TG, enquanto uma diminuição significativa foi observada nos níveis de PCR após a JI. No entanto, os níveis de PCR não foram avaliados como fator preditivo para melhorar os valores da pressão arterial nas análises de regressão. Além disso, não observamos nenhuma mudança estatisticamente significativa no IMC. Em um estudo de metanálise, foi relatado que o jejum intermitente teve efeitos positivos no IMC e na proporção de gordura.21 Por outro lado, considerando os estudos que os tempos de dieta são em sua maioria superiores a 1 mês, a razão pela qual não houve mudança significativa no IMC valores em nosso estudo podem ser a duração. É evidente a necessidade de novos estudos avaliando os efeitos do JI sobre o IMC em longo prazo.Estudos demonstraram que a terapia combinada com JR afeta positivamente a pressão arterial diurna em pacientes hipertensos.22 O RMSSD é a métrica chave no domínio do tempo usada para avaliar as alterações vagalmente mediadas observadas na VFC. Reflete a variação batimento a batimento na FC.23 As leituras de RMSSD ao longo de 24 horas estão altamente associadas com pNN50 e potência de AF.24 Estudos limitados investigaram os efeitos do JI na VFC em pacientes com HTA.26 Em um estudo, VFC foi avaliado duas vezes por registros ambulatoriais de Holter de 24 horas em jejum durante e após JI em 20 pacientes hipertensos com ritmo sinusal que variavam em fatores de estilo de vida. Considerando as variações estatisticamente significativas em SDNN, SDANN, BF e potência T entre os dois grupos, foi sugerido que a JR reduz a atividade do sistema nervoso simpático.25 Por outro lado, em outro estudo que incluiu 58 pacientes hipertensos, a JR aumentou significativamente a VFC e reduziu o estresse cardíaco entre os pacientes controlados por um aderente à medicação hipertensiva.25 Em nosso estudo, enquanto uma diminuição foi observada na Frequência Cardíaca Máxima após a JI, os valores da Frequência Cardíaca Mínima e da Frequência Cardíaca Média Noturna diminuíram, mas não se alteraram estatisticamente. Comparado ao pré-JI, um aumento na potência de IC e nos níveis de RMSSD e uma diminuição em BF/AF foram observados em pacientes hipertensos pós-JI. Como resultado importante, os aumentos de RMSSD e de potência de AF foram avaliados como fatores preditivos para a diminuição da pressão arterial sistólica após a JI.Pacientes com hipertensão essencial, especialmente aqueles não medicados, têm um aumento na atividade simpática e uma diminuição na atividade parassimpática do sistema nervoso autônomo.27 O efeito da Ang-II no aumento da pressão arterial e na retenção de sal e água é bem conhecido.28 Embora estudos em animais tenham relatado que o JI pode ter efeitos positivos no SRA em Na literatura, nenhum estudo avaliou os efeitos do JI sobre o SRA em pacientes hipertensos. Em um estudo com animais, Camelo et al.,29 levantaram a hipótese de que o JI reduz a pressão arterial e melhora o perfil lipídico em camundongos devido a um SRA local menos ativado no ventrículo esquerdo, independentemente do plano alimentar.29 Eles descobriram que a perda de peso causada pelo tratamento com JI resultou na regulação do SRA local, com o benefício do remodelamento do ventrículo esquerdo (VE) e redução da pressão arterial.29 Em outro estudo com ratos, foram investigados os efeitos dos esquemas de JI sobre o nível plasmático de Ang-II, a expressão dos receptores Ang-II e ECA2.30 Os animais idosos demonstraram ter maior índice de hipertrofia cardíaca. O coração e a aorta apresentaram maior expressão de AT1aR e menor expressão de AT2R. Aumentando os parâmetros declarados e o equilíbrio do SRA, “jejuar a cada dois dias” foi mais eficaz do que “jejuar um dia por semana”.30 Em nosso estudo, a Ang-I sérica foi maior, enquanto a Ang-II e a atividade da ECA foram menores nos pacientes hipertensos pós-JI do que nos pacientes hipertensos pré-JI, e a diminuição da atividade da ECA e os níveis de Ang-II foram determinados como fatores preditivos para a diminuição da pressão arterial sistólica após a JI. Além disso, a diminuição do nível de Ang-II foi um fator preditivo para a diminuição da pressão arterial diastólica após a JI. Outro ponto a ser enfatizado é que a atividade da ECA está associada ao IMC e às funções tireoidianas.32 Portanto, pacientes eutireoideos foram incluídos em nosso estudo e não houve alteração estatisticamente significativa no IMC e nos níveis de TSH antes e após a JI. Para controlar essas variáveis, os níveis de IMC e TSH foram adicionados à análise de regressão no modelo criado para a mudança da pressão arterial, e nenhuma relação significativa foi encontrada.A Ang-I é convertida em Ang-II pela ECA zinco metalopeptidase.Existem algumas limitações do nosso estudo. O número de participantes foi pequeno, pois apenas pacientes em uso de bloqueadores dos canais de cálcio do grupo diidropiridínico foram incluídos no estudo como tratamento anti-hipertensivo. Os participantes consistiam apenas em pacientes com hipertensão controlada e baixo risco cardiovascular. Futuros estudos abrangentes são necessários para determinar se as aplicações de FI são eficazes em pacientes com maior risco cardiovascular  com maior atividade de SRA e SNA.Em conclusão, os resultados do nosso estudo podem ser interpretados como: 1. A ativação do sistema parassimpático avaliada pela VFC desempenha um papel nos efeitos positivos do JI sobre a pressão arterial. 2. A diminuição dos níveis de Ang-II pode ser aceita como uma das razões para melhorar a hipertensão sobre a regulação da ativação do sistema simpático sobre o SRA. 1 Studies on the pathophysiological mechanism and optimal treatment of hypertension have focused mainly on the renin-angiotensin system (RAS) and the autonomic nervous system (ANS). Although there is no definitive underlying cause in essential (primary) hypertension, there is overactivation of the RAS and autonomic instability  in most cases. There is a complex and bidirectional interaction between these two systems in physiological and pathophysiological conditions such as hypertension. Also, most current antihypertensive drugs aim to suppress the excessive activity of these two systems.2Hypertension remains the leading preventable cause of cardiovascular disease (CVD) and death worldwide.3 Classical RAS is a series of enzyme-substrate interactions in which the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin-converting enzyme (ACE) to produce functional peptide hormones called angiotensin I (Ang-I) and angiotensin II (Ang-II), respectively. Ang-II is the most functional molecule of RAS and plays an active role in many physiological and pathological processes. It raises blood pressure mainly by vasoconstriction, inflammation, vasopressin and aldosterone secretion, oxidative stress, cellular proliferation, and immunological activation through cell surface type I (AT1) receptors.4 Also, Ang-II contributes to regulating blood pressure by modulating the autonomic nervous system at both central and peripheral levels.5 Activation of the ACE/Ang-II/AT1 receptor arm of the RAS causes deterioration in cardiovascular autonomic regulation by increasing sympathetic nerve conduction, inhibiting cardiovascular parasympathetic-vagal tone, and decreasing baroreflex sensitivity.6The RAS was originally known as an endocrine system that regulates blood pressure and fluid-electrolyte balance.10It is known that combining pharmacological and non-pharmacological therapies is offered to manage hypertension, including lifestyle modifications such as diets effectively. Intermittent fasting (IF) is one of the popular diets that has been shown to have a positive effect on blood pressure, and IF protocols are classified as time-restricted feeding (TRF), alternate-day fasting (ADF), 5:2 diet, and Ramadan fasting (RF).13 Also, a decrease in systolic/diastolic blood pressure was reported with IF,14 but there is no consensus yet on how IF reduces blood pressure. One of the possible mechanisms could be a decrease in cardiovascular sympathetic tone and an increase in parasympathetic tone, which significantly corrects the autonomic imbalance observed in most hypertensive patients.16 ANS modulation by IF may also theoretically cause suppression of the vasoconstrictor (ACE-Ang II-AT1 receptor) arm of the RAS, given the interactions of the ANS and the RAS. In order to support this hypothesis, considering the information in the existing literature, our study aimed to evaluate 1. The effect of RF on blood pressure, 2. The effect of RF on RAS by measuring serum ACE activity and Ang-I and Ang-II levels. 3. The effect of RF on ANS by measuring heart rate variability (HRV) in hypertensive patients.It has been suggested that IF improves cardiovascular risk factors through three possible mechanisms: decreasing oxidative stress, synchronization with the circadian system, and increasing ketogenesis.17In power analyses, a two-tailed with 0.5 point effect size, an alpha of .05, and a power of .80 needed a sample size of only 34 to detect that effect. We planned to include about 60 patients in our study, considering the number of patients in a study conducted by the Society of Hypertension and Renal Diseases.Seventy-two patients aged 40-60 years, who applied to the cardiology outpatient clinic, had controlled hypertension, used only dihydropyridine group calcium channel blockers as antihypertensive treatment, had any other drug treatment for any reason, and voluntarily fasted were included in our study. The data of 58 patients were used by excluding 14 patients who stopped fasting for more than 2 days for various reasons and did not come for control   .Patients with unregulated blood pressure, who had cardiovascular risk factors  that may affect RAS and ANS activity, those with a GFR <50 and a double-normal increase in liver function tests, and who had cardiovascular disease including coronary artery disease, heart failure, chronic kidney failure, and cerebrovascular disease were excluded from the study. Patients using drugs that may affect RAS, ANS activity , and CRP (statin) were also excluded.In our study, we used RF as the IF protocol. Participants fasted for about 15-16 hours from dawn to sunset for 30 days. There was no patient whose treatment was changed during IF. The reason for choosing the RF is that it is easy to apply, and there is no calorie restriction (ad libitum nutrition) outside the fasting period; therefore, there is no need for a strict calorie calculation. To limit calorie intake variability, participants were advised to follow a 30-day routine of eating the main meal after sunset and a light meal before sunrise. Participants took their medication before the onset of starvation.Participants were checked twice, 5 days before fasting and in the last 5 days of fasting. In their controls, participants were evaluated with 24-hour ambulatory blood pressure monitoring and Holter electrocardiography. In both controls, 5 ml venous blood samples were taken between 08:00 and 08:30 for biochemical tests.Signed informed consent was obtained from all participants before participating in the study. This study was approved by the local ethics committee of the City Hospital (2021/517).Blood samples were taken from the patients seated after a 20 min rest following 12h of fasting. The ante-cubital vein was used to obtain the blood sample. The serum and plasma were separated after the samples were centrifuged for 10 minutes at 5000 rpm . They were kept at −80 °C until assays for parameters were performed by an experienced clinical biochemist.Serum angiotensin 1 and angiotensin 2 levels and ACE activity were studied by enzyme-linked immunosorbent assay (ELISA) method using commercial kits . Ang-I and Ang-II levels and ACE activity were analyzed according to the manufacturer’s instructions and expressed as ng/L, ng/L, and U/L, respectively.In order to evaluate the blood pressure of the participants, two 24-hour ambulatory blood pressure measurements were made 5 days before IF and in the last 5 days of IF. 24-hour mean systolic and diastolic blood pressure levels and day/night mean systolic and diastolic blood pressure levels were obtained. To assess heart rate variability (HRV), 24-hour Holter electrocardiography data were obtained twice (Ge model: SEER 100 software information MARS). HRV parameters and measurements were made based on the opinions of the European Society of Cardiology and the North American Society of Battery and Electrophysiology. The standard deviation of all normal to normal RR [NN] intervals (SDNN), the root mean square of the sum of squares of differences between adjacent NN intervals (RMSSD), and the number of pairs of NN intervals that differ by more than 50 ms (pNN50) in 24 hours, low-frequency (LF) power, high-frequency (HF) power, and the ratio of the two (LF/HF) were obtained from 24-hour ECG recordings. In addition, the patients’ maximal heart rate, minimal heart rate, 24-hour mean heart rate, and mean nightly heart rate were obtained.The data were analyzed using IBM SPSS Statistics 21.0. The data distribution was analyzed using the Shapiro-Wilk test and Q-Q Plot Normality. Frequencies and percentages were calculated for categorical variables. Continuous variables with normal distribution were expressed as the mean and standard deviation, while continuous variables with non-normal distribution were expressed as the median and interquartile range. To compare variables, the paired-sample T-test and the Wilcoxon test were used. The predictive effects of parameters on blood pressure were evaluated using the linear regression analysis method. The suitability of the linear regression to the 6-step model was controlled in models for SBP and DBP . High correlation levels excluded BUN, Uric acid, and total cholesterol levels from analyses. A p-value <0.05 was accepted as significant in statistical analyses.Fifty-eight patients with controlled HT between the ages of 40-60 were included in the study. The characteristics of the patients are given in Serum Ang-I was lower, while Ang-II and ACE levels were higher in the pre-IF hypertensive patients than in post-IF hypertensive patients   . In hypConsidering the effects of intermittent fasting on lipid profile BMI and CRP in the literature, the relations of BMI and TSH with ACE levels, and the hypothesis of the study, all data were  included in the regression analysis for decreasing systolic and diastolic blood pressure. The regression model was statistically significant (p=0.032), and decreasing ACE activity and Ang-II levels, also increasing RMSSD and HF power, were assessed as predictive factors for decreasing systolic blood pressure after IF   . In addHuman research indicates that IF may have cardiovascular advantages. IF appears to positively affect numerous cardiovascular risk variables, including HT, while the underlying mechanisms are unknown. Our study is one of the few studies that evaluated the possible mechanisms underlying the effect of RF, one of the subtypes of IF, on blood pressure. It is also the first study in which the RAS and ANS systems, which are known to be important in blood pressure regulation, were evaluated together. The present findings of our study demonstrated the effects of IF on blood pressure and HRV. Another main factor that presented a positive outcome after the IF protocol was ACE activity and Ang-II levels.18 On the other hand, conflicting results were reported in studies that found no difference.19 In addition, cardiovascular and metabolic benefits, such as the decrease in TG, LDL, fat mass, and CRP, have been reported in therapeutic fasting.20 Also, improvements in indicators of cardiovascular health could be seen 2–4 weeks after the start of IF in animal studies.15 In our study, compared to pre-IF, a significant decrease was observed in the mean systolic and diastolic blood pressures measured at 24 hours and night in post-IF hypertensive patients. In addition to the methodological differences in the studies, including controlled hypertensive patients in our study may have led to a more significant improvement in blood pressure levels since resistant cases were excluded. There was no statistically significant change in fasting blood glucose, HgA1C, creatinine, GFR, BUN, total cholesterol, LDL, HDL, and TG levels, while a significant decrease was observed in CRP levels after IF. Although, CRP levels were not evaluated as a predictive factor for improving blood pressure values in the regression analyses. Also, we observed no statistically significant change in BMI. In a meta-analysis study, it was reported that intermittent fasting had positive effects on BMI and fat ratio.21 On the other hand, considering the studies that diet times are mostly over 1 month, the reason why there was no significant change in BMI values in our study may be the duration. It is obvious that there is a need for new studies evaluating the effects of IF on BMI in the long term.Studies have shown that combination therapy with RF positively affects daytime blood pressure in hypertensive patients.22 The RMSSD is the key time-domain metric used to assess the vagally mediated changes seen in HRV. It reflects the beat-to-beat variance in HR.23 RMSSD readings over 24 hours are highly associated with pNN50 and HF power.24 Limited studies investigated the effects of IF on HRV in patients with HT.26 In one study, HRV was assessed twice by ambulatory 24-hour Holter recordings at fasting during and after IF in 20 hypertension patients with sinus rhythm who varied in lifestyle factors. Considering the statistically significant variations in SDNN, SDANN, LF, and T power between the two groups, it was suggested that RF reduces the sympathetic nervous system’s activity.25 On the other hand, in another study that included 58 hypertensive patients, RF significantly increased HRV and reduced cardiac stress among patients controlled by an adherent to hypertensive medication.25 In our study, while a decrease was observed in Maximum Heart Rate after IF, Minimum Heart Rate and Night Average Heart Rate values decreased but did not change statistically. Compared to pre-IF, an increase in HF power and RMSSD levels and a decrease in LF/HF were observed in post-IF hypertensive patients. As an important result, RMSSD and HF power increases were assessed as predictive factors for decreasing systolic blood pressure after IF.Patients with essential hypertension, especially those who are unmedicated, have an increase in sympathetic and a decrease in the parasympathetic activity of the autonomic nervous system.27 The effect of Ang-II on raising blood pressure and salt and water retention is well-known.28 Although animal studies reported that IF might have positive effects on RAS in the literature, no study assessed the effects of IF on RAS in hypertensive patients. In one animal study, Camelo et al.29 hypothesized that IF lowers blood pressure and improves lipid profile in mice due to a less activated local RAS in the left ventricle, regardless of the dietary plan.29 They found that the weight loss caused by the IF treatment resulted in regulation of the local RAS, with the benefit of left ventricular (LV) remodeling and blood pressure reduction.29 In another study with rats, it was investigated the effects of IF regimens on the plasma level of Ang-II, the expression of Ang-II receptors, and ACE2.30 The elderly animals were shown to have a higher heart hypertrophy index. The heart and aorta had higher AT1aR expression and less AT2R expression. Increasing the stated parameters and RAS balance, “every other day fasting” was more effective than “fasting one day each week.”30 In our study, serum Ang-I was found to be higher while Ang-II and ACE activity were found to be lower in the post-IF hypertensive patients than in the pre-IF hypertensive patients, and decreasing ACE activity and Ang-II levels were determined as predictive factors for decreasing systolic blood pressure after IF. Also, decreasing Ang-II level was a predictive factor for decreasing diastolic blood pressure after IF. Another point to be emphasized is that ACE activity is associated with BMI and thyroid functions.32 Therefore, euthyroid patients were included in our study, and no statistically significant change was observed in BMI and TSH levels before and after IF. To control these variables, BMI and TSH levels were added to the regression analysis in the model created for the change in blood pressure, and no significant relationship was found.Ang-I is converted to Ang-II by the zinc metallopeptidase ACE.There are some limitations of our study. The number of participants was small, as only patients using dihydropyridine group calcium channel blockers were included in the study as antihypertensive treatment. Participants consisted only of patients with controlled hypertension and low cardiovascular risk. Future comprehensive studies are needed to determine whether IF applications are effective in patients with higher cardiovascular risk  with higher RAS and ANS activity.In conclusion, the results of our study could be interpreted as:1. Parasympathetic system activation evaluated through HRV plays a role in the positive effects of IF on blood pressure. 2. Decreasing the Ang-II levels could be accepted as one of the reasons for improving hypertension over regulating sympathetic system activation over the RAS.


Iron overload is connected with an expanded prevalence of thalassemia due to heart impairment. This considers pointing to survey changes in thalassemia's aortic elasticity due to iron deposition in the heart and liver of children.This case-control study was performed on 80 healthy and 160 thalassemia patients. The subjects gathered from educational pediatric hospital of Ali Asghar in Zahedan, Iran, from 2019 to 2021. Echocardiography parameters were measured. Ferritin, lipids profile, cardiac and liver MRI T2 * measured in patients only. Aortic elasticity parameters were aortic strain, aortic stiffness β index, aortic distensibility and pressure strain elastic modulus. Data analyzed by SPSS,p< 0.05 was considered as significant. Diastolic blood pressure (p<0.001), aortic diameter in diastole (p<0.001), aortic diameter in systole (p<0.001), ferritin (p<0.001), aortic strain (p<0.001), aortic distensibility(p<0.001), pressure strain elastic modulus (p<0.001) and aortic stiffness β index (p<0.001) were changed significantly in thalassemia patients compared to controls. From these variables, AoD, AoS, ferritin, AS and AD increased in thalassemia. Ferritin was higher in thalassemia patients with abnormal heart iron deposition (2131.89±1992.74 v.s 4887.66±3122.59 ng/ml). Considering the level of liver iron deposition, ferritin did not change in patients. Our highlighted variables did not change in patients based on the groups of ferritin.Concluded that AoD, AoS, ferritin, AS and AD increased in thalassemia patients. Ferritin increased in thalassemia with abnormal iron overload in the heart but did not change in the liver. Recommended MRI T2* to evaluate dynamic functions of liver and heart in thalassemia patients. Thalassemia is a blood disorder that was inherited from parents and characterized by abnormal hemoglobin , 2, more Iron overload is connected with expanded occurrence of transfusion-dependent (TDT) and non-transfusion-dependent thalassemia (NTDT) ,6. The mBetween the liver and heart, ferritin level is poorly correlated with heart iron overload compared to liver that this overload can be measured by MRI. Iron overload is caused by increased iron deposition in the human body and emerges as an important cause of congestive heart failure more common in thalassemia , and amoCardiac MRI T2 * has been proven to be quick and simple and robust with high positive value to predict cardiac dysfunction in asymptomatic thalassemia  such as Study Design: This case-control study was performed on 240 participants aged 5 to 39 years consisted of 80 healthy and 160 thalassemia as case group in Ali Asghar Hospitals of Zahedan in Sistan and Baluchistan provinces, Iran, from 2019 September to 2021 August. This study enrolled thalassemia patients who were asymptomatic 48-72 hours after packed red blood cell transfusions and received regular hemoglobin transfusions above 10 g / dl. Of the patients, only 80 people had heart and liver MRI T2 * due to iron deposits. Sampling of the controls was hospital base from those referred for the routine examinations.Criteria: Participants invalvular heart disease, rhythms, structural abnormalities, active infections, systemic inflammatory diseases, and renal failure were excluded from the study.MeasurementsBlood Pressure: Blood pressure (BP) levels were measured from the brachial artery at the level of the heart with a sphygmomanometer after resting for at least 5 minutes in the supine position. Three measurements, at least 2-minute apart, were performed, and the average of the closest two readings was recorded. A pressure drop rate of approximately 2 mm Hg/s was applied, and Korotkoff's phases I and V were used for systolic and diastolic BP levels. All BP measurements were made by a cardiologist. Echocardiography: The patient's important procedures were medical history, physical examination, chest x-ray, and echocardiography by a designated cardiologist. Echocardiography was performed on participants by the cardiologist using My Laboratory 60 with Transducer 3, 8 . To reach high accuracy of echocardiographic findings, the measurements were repeated 3 cycles and the average was taken into account. Participants underwent echocardiography without holding their breath. Echocardiographic results from M-mode (a diagnostic ultrasound representation of changes in echo over time indicating the depth of the echogenic interface with two-time axes and motion axes) are the diastolic diameter (AOD) of the aorta, the aortic. It was systolic diameter (AOS). The diameter of the aorta was measured as the distance between the inner edges of the anterior and posterior walls of the systolic and diastolic aorta. AOS was recorded when the aortic wall was fully opened. AOD was recorded at the same time that the QRS complex was seen on the electrocardiogram (ECG) recording. The measurements were made between three consecutive pulses and the average was calculated.Cardiac and liver MRI: To measure myocardial T2 *, standard ECG gating was used to synchronize scans with the cardiac cycle. Next, we took one short axis with a thickness of 10 mm, which was placed between the base of the left ventricle and the apex of the heart. Liver MRIT2 * was measured by imaging a single longitudinal slice (10 mm) through the center of the liver. Cardiac MRI T2 * results were categorized into severe (T2 * <10ms), moderate (10 <T2 * < 14 ms), and mild (14 < T2 * < 20> 20 ms) myocardial lesions. The results of liver T2* where acceptable liver iron was defined as LIC <3.5 mg/g, while mild, moderate, and severe were 3.5–7.0, 7.0–12.0, and >12.0, respectively . Then, 250 microns was isolated from serum samples to analyze ferritin by ELISA method/kit (USA).Aortic Elasticity Parameters: The systolic and diastolic diameters of the ascending aorta were recorded in M mode under the guidance of echocardiography and electrocardiography, approximately 3 cm above the aortic valve from the parasternal long axis. The systolic diameter of the aorta was measured at the time of maximal aortic advance, and the diastolic diameter was measured at the start of the QRS complex by electrocardiography  / height (m2).Ethical Approval: After approval, an informed consent was obtained from the participants or their legal guardians. This study was approved as a project (approved by the Research Commission and numbered 9397) and approved by the Ethics Commission of Zahedan Medical University in Zahedan, Iran (Ethics Number: IR.ZAUMS. REC.1398.410).Statistical Analysis: To analyze data, SPSS 20.0  applied. To assess distribution of continuous variables Kolmogorov–Smirnov test was used. Student’s t-test and Mann–Whitney U-test were applied to compare two mean values of quantitative variables with normal and non-normal variables. In comparing the variables in three or more groups, one-way analysis of variance and Kruskal Wallis tests applied. A p-value of < 0.05 was considered as statistically significant.The study population were 160 thalassemia patients with mean age of 21.61±7.22 ranged from 5 to 39 years and controls with mean age of 16.08 ±2.98 ranged from 11 to 24 years. Variables of AoD and AS had normal distribution (p>0.05) when all participants were considered. In the case of thalassemia participants, the variables of age, weight, AoD and AS were normal. All other variables had free distribution . AmongstDespite the fact that the side effects of thalassemia have particularly decreased recently, the patients still experience numerous difficulties . At presThe reason why this occurs, is due to the fact that patients with hepatic overload generally presented earlier than cardiac overload. In addition, the pressure accumulation represented by MRI T2* appears to establish a critical relationship with serum ferritin levels. Cheung et al.,  point by


Background: Current guidelines recommend prophylactic vasopressor administration during spinal anesthesia for cesarean delivery to maintain intraoperative blood pressure above 90% of the baseline value. We sought to determine the optimum baseline mean arterial pressure (MAP) reading to guide the management of spinal hypotension.Methods: We performed a secondary analysis of data collected from normotensive patients presenting for elective cesarean delivery in a tertiary care institution from October 2018 to August 2020. We compared the magnitude of hypotension in patients who reported nausea versus those who did not, using a case-control design. Baseline MAPs at last office visit, morning of surgery, or operating room  were determined. We calculated the duration and degree of hypotension using the area under the curve (AUC) when the MAP of the respective patient was below 90% of each baseline.Results: The patients who experienced nausea (n=45) had longer and more profound periods of hypotension than those who did not develop nausea (n=240). A comparison of AUC using MAP baseline at the last office visit or on the morning of surgery showed a statistically significant between-group difference, P=0.02, and P=0.005, respectively, and no significant between-group difference when 90% of the MAP baseline in the operating room was used.Conclusions: Patients had the highest preoperative MAP in the operating room and the AUC was similar for those with and without nausea when the pre-spinal MAP baseline was used. Therefore, maintaining higher intraoperative blood pressure using individual pre-spinal MAP as baseline should reduce intraoperative maternal nausea. Spinal hypotension during cesarean delivery occurs in up to 80% of patients . HypotenBaseline blood pressure is commonly defined as a single or average measurement obtained in the operating room before the administration of spinal anesthesia . In mostWe sought to determine the optimal baseline value to guide blood pressure control in patients presenting for elective cesarean delivery under spinal anesthesia. Specifically, this retrospective analysis explored different targets based on the blood pressure measured (i) at the last predelivery office visit, (ii) between 7 am and 12 pm on the day of the surgery, and (iii) in the operating room before the administration of spinal anesthesia, to determine which value was associated with the lowest incidence of nausea or vomiting. Our primary outcome was the presence or absence of nausea and vomiting associated with maintaining the mean arterial blood pressure (MAP) within 90% of one of the following three hemodynamic targets: baseline MAP at the last office visit, morning of surgery, or operating room .Following IRB approval (#2017P002304), with a waiver of patient consent, we performed a secondary post-hoc analysis of data collected in a previous investigation, to determine the optimal baseline blood pressure for the management of spinal hypotension during cesarean delivery. The original study was designed to collect precise data with the goal of creating an algorithm for the prediction of systolic blood pressure and the determination of the phenylephrine dose required to maintain hemodynamic stability after spinal anesthesia for cesarean delivery .Original study designThe original study collected data from women who had scheduled cesarean delivery at the Brigham and Women’s Hospital from October 2017 to August 2020 . PreciseAll data were obtained from the electronic health record. American Society of Anesthesiologists (ASA) class 2 and 3 patients were included who had cesarean delivery under spinal or combined spinal-epidural anesthesia; the latter mode of anesthesia was selected only if the epidural component had not been activated during the data collection period. All patients with cardiovascular disease , patients taking cardiovascular medications, those with inaccurate records, or patients who received vasopressors before the spinal anesthesia placement were excluded. Preoperative data collected included patient age, height, weight, gestational age, gravidity, parity, spontaneous rupture of membranes, contractions, and comorbidities . Intraoperative data collected consisted of medications , side effects , vital signs (heart rate and blood pressure), and Apgar scores of the neonate. The intraoperative data were collected for the period of five minutes before the spinal injection and continued for 20 minutes after injection or until delivery of the neonate, at intervals of one minute. When available on the weekdays, a research assistant was present in the operating room during the case, who acted as a scribe and assisted the clinical team in precisely documenting in the electronic record the administered medications, and the presence or absence of any intraoperative events. Should the patient spontaneously complain of nausea and/or vomiting, this was recorded; otherwise, the absence of nausea was documented.The clinical care of the patients followed standard institutional care. The premedication included oral sodium citrate 30 ml, metoclopramide 10-20 mg, and the preoperative intravenous administration of 500 ml lactated Ringer’s solution over 20 minutes. Upon arrival in the operating room, the patients were positioned in the sitting position, and standard monitors were applied, including noninvasive blood pressure, continuous electrocardiogram, and pulse oximetry using GE Carescape B650 monitor . The noninvasive blood pressure was measured in the sitting position until spinal anesthesia was complete and thereafter in the supine position, with the goal of measurement at one-minute intervals. Spinal anesthesia was induced using 1.4-2.0 ml 0.75% hyperbaric bupivacaine with 100-200 µg morphine and 10-15 µg fentanyl. The patient was immediately positioned supine with standard left lateral tilt. At the time of the spinal injection, a rapid bolus of 500-1,000 ml lactated Ringer’s solution was administered (co-load) in addition to the preoperative hydration. Prophylactic ondansetron 4 mg was administered intravenously after induction of spinal anesthesia. Prophylactic intravenous phenylephrine infusion at a rate of 40-60 µg/min was used. Vasopressor management was directed at maintaining the systolic blood pressure above 90 mmHg  using by titration of the intravenous phenylephrine infusion, supplemented by bolus phenylephrine 80-160 µg or, if the heart rate was lower than 60 beats per minute, a bolus of 5-10 mg ephedrine. Current secondary analysis study designFor purposes of this study, we selected all records in which a research assistant was present up to the delivery time, and there was documentation of the presence or absence of nausea and/or vomiting. Assuming 45% incidence of hypotension among patients with nausea, and 20% incidence of hypotension among patients without nausea, 80% power  required 37 patients with intraoperative nausea and 148 patients without nausea .In addition to the data collected above in the original study, we obtained from the medical record the blood pressure and heart rate recorded at the last outpatient visit and on the day of the surgery. To establish which baseline blood pressure reading would have been associated with the least nausea and vomiting, we defined the MAP taken at the last office visit as MAP_LV, the MAP in the morning of surgery as MAP_AM, and the MAP averaged for the last five minutes before the spinal administration as MAP_pre-spinal. These readings were obtained in the sitting position using a noninvasive blood pressure cuff. We also defined the BP target range as MAP 90% -110% of the baseline and investigated three different scenarios using MAP_LV, MAP_AM, and MAP_pre-spinal anesthesia as the baseline.Statistical analysisproject.org). For analysis purposes, the study population was divided into two groups: patients who reported nausea and/or vomiting (nausea) and those who did not (non-nausea). Missing blood pressure and heart rate values were linearly interpolated or extended. Continuous variables were not normally distributed and expressed as median (interquartile range), and categorical variables were defined as number/total number (%). We calculated the time and deviation from the target MAP values using the area under the curve (AUC) trapezoidal rule ,12. We sThere were 285 patients who met the inclusion criteria, all of whom were included in the present study. The patient characteristics are presented in Table Table Figure This study investigated the perioperative blood pressure time course in pregnant patients undergoing elective cesarean delivery. We explored three hypothetical hemodynamic targets based on the blood pressure measurements obtained at different times before the administration of spinal anesthesia, with the goal of decreasing the risk of intraoperative nausea and vomiting: MAP_LV, MAP_AM, and MAP_pre-spinal. We demonstrated that patients had the highest preoperative MAP in the operating room before the administration of spinal anesthesia . The duration and degree of hypotension was estimated using the AUC when the MAP of the respective patient was below 90% of each baseline. Patients who experienced nausea had longer and more profound periods of hypotension compared to the controls, as evidenced by the lower MAP after the administration of spinal anesthesia. Selecting a target for blood pressure during spinal anesthesia within 90% of the blood pressure measured at the last outpatient visit (MAP_LV) or on the morning of surgery (MAP_AM) resulted in more episodes of hypotension in the nausea group than in the group without nausea, i.e., significant between-group differences between the AUCs for patients with and without nausea. Therefore, selecting either of these low targets would result in overall lower blood pressure management and a higher incidence of nausea. In contrast, there was no significant between-group difference for AUC when selecting within 90% of the pre-spinal MAP values  as a hemodynamic goal. Thus, higher blood pressures would be maintained using MAP_pre-spinal baseline in both groups, which would result in the lowest incidence of hypotension and, respectively, nausea. These results suggest that MAP pre-spinal should be selected as the optimum baseline blood pressure for managing spinal hypotension to minimize nausea and vomiting during cesarean delivery. Our results agree with previous findings that blood pressure measured in the operating room immediately before administering anesthesia is higher than at the last office visit and on the morning of surgery -8,15. LaHypotension is the most common cause of intraoperative nausea in patients presenting for cesarean delivery under spinal anesthesia. The incidence of nausea in our cohort was 15.8%, similar to other studies in which patients have self-reported their symptoms . We beliProphylactic vasopressor infusions are recommended to avoid spinal hypotension . Most paOur recommendations should lead to the maintenance of higher intraoperative blood pressure than would be the case if the alternative baseline targets were used. In a similar fashion, a randomized trial of 25 parturients per group documented significantly lower rates of nausea when the blood pressure was maintained at 100% of the baseline, compared to 80% and 90% of baseline [This study was subject to some limitations. Due to the retrospective design, the patients’ blood pressure was maintained at a level deemed appropriate by the clinical team, and confounding variables may not have been excluded. In addition, maternal cardiac output and neonatal cord blood values were not monitored or tested in these elective cases. Missing MAP data in some patients required interpolation. We did not include hypertensive or preeclamptic patients, since blood pressure may be more labile and the response to vasopressors more variable. The nausea was self-reported by the patients, and, therefore, we may have underestimated the incidence. We utilized a research assistant as a scribe to document the patient-reported symptoms precisely. The small sample size may present a risk for selection bias; however, our incidence of nausea was similar to that reported in the literature, suggesting that under- or over-sampled either of the study groups was unlikely. Future larger studies using methods such as continuous cardiac output and blood pressure may generate further insights into the factors associated with nausea and vomiting. We selected only patients presenting for elective cesarean delivery, since obstetric emergencies may be associated with multiple factors such as hemorrhage, patient anxiety, and short anesthesia induction to delivery time, which may confound the results.Overall, we demonstrated that patients presenting for elective cesarean delivery had the highest preoperative MAP in the operating room before the administration of spinal anesthesia. Those who experienced nausea had longer and more profound periods of hypotension. There was no difference in AUC in the groups experiencing nausea versus no nausea, when 90% of the MAP baseline in the operating room was used. Based on these results, targeting higher intraoperative blood pressure using the individual preoperative MAP prior to spinal anesthesia as a baseline is preferable, to reduce intraoperative maternal nausea and vomiting.


Pelvic floor muscle weakness is a common cause of pelvic organ prolapse and urinary incontinence. Surgical repair of prolapse is commonly undertaken; however, the impact on pelvic floor muscle tone is unknown. The aim of this study was to compare the effect of anterior and posterior colporrhaphy on pelvic floor activation.p<0.05Patients aged under 70 undergoing primary anterior or posterior colporrhaphy were recruited. Intra-vaginal pressure was measured at rest and during pelvic floor contraction using the Femfit® device . Peak pressure and mean pressure over 3 s were measured in millimetres of mercury. The pre- and post-operative measurements were compared. The difference between the means was assessed using Cohen’s D test, with significance set at p=0.16) and change in mean pressure was −0.86 mmHg . Posterior colporrhaphy showed a significant increase in peak pelvic floor muscle tone of 7.2 mmHg  and mean pressure of 4.19 mmHg .A total of 37 patients completed pre- and post-operative analysis, 25 in the anterior colporrhaphy group and 12 in the posterior colporrhaphy group. Anterior colporrhaphy showed no significant change in pelvic floor tone. Change in peak pressure was −1.71mmHg (−5.75 to 2.33; Posterior colporrhaphy significantly improves pelvic floor muscle tone, whereas anterior colporrhaphy does not. Improved understanding of the impact of pelvic floor surgery may guide future management options for other pelvic floor disorders. Further work is needed to confirm the association of this improvement in pelvic floor disorders. Twenty-five percent of women develop pelvic floor muscle weakness after childbirth, which can result in pelvic organ prolapse (POP) and/or urinary incontinence (UI). Twelve percent of these women will require surgery. The pelvic floor is a group of muscles and fascia that supports the internal pelvic organs in the correct anatomical position. These muscles are important for bladder and bowel control, along with sexual function . ChildbiPelvic organ prolapse may present as a dragging sensation, vaginal laxity or palpable vaginal bulge and causes a range of bladder and bowel symptoms. The Pelvic Organ Prolapse Quantification (POP-Q) system  producesSurgery for POP involves reinforcing the supporting fascia and repositioning the pelvic organs to restore their normal anatomical positions . SurgeryA team at the Auckland Bioengineering Institute (ABI), Auckland University, have developed a novel intra-vaginal pressure sensor device  that measures pressure along the length of the vagina using eight sensors. The device was developed to measure pelvic floor muscle activation pressure and intra-abdominal pressure simultaneously, during a voluntary contraction, in order to assess the strength of the pelvic floor muscles. A proof-of-concept prototyping has already demonstrated that Femfit can provide reliable, objective measurements of a vaginal pressure profile and detect changes in pressure during pelvic floor contraction –7. The rAn objective assessment of changes in intravaginal pressure profiles pre- and post-surgery will provide a metric for assessing whether surgical intervention has improved the strength of the pelvic floor, or at least the ability of patients to perform a pelvic floor muscle contraction. This metric can be used objectively to assess the biomechanics of the pelvic floor, providing information on changes in anatomy and pelvic floor muscle strength following POP surgery and provide clinically valuable counselling pre-operatively.This study is aimed at determining if there are changes in vaginal pressures before and after surgery for POP using Femfit, and whether posterior colporrhaphy has more of an impact on pelvic floor activation pressure than anterior colporrhaphy.Patients were recruited prospectively from the urogynaecology clinic of a tertiary teaching hospital. The inclusion criteria required patients to be under 70 years of age, have a BMI of under 40 and for this to be primary prolapse surgery. Patients were excluded if they had had previous prolapse surgery, procidentia, vaginal infection or a contraindication to pelvic examination. Patients requiring both anterior and posterior compartment repair were also excluded. A sample size of 12 patients for each arm was calculated to provide sufficient power for this pilot study. Ethical approval for this study was obtained from the local research ethics committee (REC).The Femfit® Fig.  is a novAt the pre-operative clinic patients were asked to complete the electronic Personal Assessment Questionnaire - Pelvic Floor (ePAQ-PF) and details were collected regarding their POP-Q score and their MOS. They then had baseline measurements taken with the IVPSD. While the patient was supine, intra-vaginal pressure measurements were obtained, with pelvic floor muscles at rest to be used as a baseline, during pelvic floor activation (3-s “squeeze” × three occasions) and during coughing (three occasions). The data from coughing were not used in the analysis as it was felt to be irrelevant to this study. Provided that Femfit was not expelled because of vaginal prolapse, these measurements were repeated with the patient standing.All patients underwent surgery with three clinicians who use a standard technique of performing their anterior and posterior repair. Vaginal levator plication was not performed to avoid vaginal narrowing, as all women were sexually active.Twelve weeks post-operatively participants returned to the clinic to complete the ePAQ-PF again to assess clinical change following surgery. Details of patients’ actual POP surgery, any post-operative complications, and their post-operative POP-Q and MOS scores were obtained from the clinical notes. Pelvic examination was also undertaken as part of routine clinical care and intra-vaginal pressure profiles were additionally recorded. The post-operative vaginal pressure data collection followed the pre-operative protocol. The pressure data from Femfit® were interpreted by the team in the ABI. They identified which sensors corresponded to the pelvic floor and extracted these data along with the intra-abdominal pressures. Demographic and clinical data were collated onto an Excel spreadsheet.p<0.05.For each patient, the mean pressure exerted by the pelvic floor over 3 s and the mean peak pressure exerted were calculated pre- and post-operatively, both lying and standing. The results for both anterior and posterior colporrhaphy groups were collated to generate a mean peak pressure and 3-s mean pressure, pre-operatively and post-operatively, lying and standing. The difference between the means was assessed using Cohen’s D test with significance set at A sample size calculation demonstrated that a sample size of 12 patients recruited to each arm would be sufficient to reject the null hypothesis in a pilot study. Sixty-three patients were recruited with 37 (58%) completing analysis. This included 12 in the posterior repair arm and 25 in the anterior repair. The discrepancy in group size was because recruitment continued until there were 12 completed patients in each group. Of those excluded: 8 patients had no post-operative data, 12 withdrew from the study, 1 patient had both anterior and posterior repair, 2 patients had incomplete data and 3 had device data collection issues. None of the patients withdrew because they found the device difficult to tolerate and feedback on the device was that it was very comfortable when fitted. There were no adverse reactions from the device.Both groups were comparable in their parity, BMI, baseline MOS and grade of prolapse Table .Table 1Dp=0.16) and change in 3-s mean pressure was −0.86 mmHg (−4.38 to 2.66); p=0.31. In the posterior colporrhaphy there was a significant increase in peak pelvic floor muscle tone of 7.2 mmHg  and the change in 3-s mean pressure was 4.19 mmHg . There was therefore a significant increase in peak pelvic floor muscle contraction and mean contraction strength over 3 s in the posterior repair group, but in the anterior repair group no significant difference was seen.The results of the study are summarised in Tables With the patient standing there was no significant change in measured peak or mean pelvic floor contraction for either group.To our knowledge, this is the first study of its kind and the first use of the Femfit® in clinical practice. As a pilot study we found a consistent effect within groups and patients found the device and the protocol to be acceptable. We had a diverse group of patients in terms of age, BMI and parity. All of our patients were white, although this is unlikely to have affected the results.Although the fascial plication could have played a contributory mechanism, we do not feel that this was the main factor influencing the outcomes. Both anterior and posterior vaginal repairs involved fascial plication, but improvements were seen in only posterior repairs; hence, this explanation does not follow.We were limited by a high rate of patient withdrawal during the study, with 42% of those recruited not completing the analysis. This particularly affected the posterior repair arm with 15 out of 27 patients (56%) not completing the study. It is unclear why there was such a high withdrawal rate from the posterior repair arm but this will not have affected the statistical power of the results. As the study population consisted only of white women, it is difficult to extrapolate the results to other ethnic groups. In addition, all measurements were done in the early post-operative period; thus, it is difficult to know whether these improvements were sustained over time or whether they translated into better pelvic floor function with reduced urinary incontinence and/or improved sexual function, as patients had not resumed routine exercise or intercourse when they were seen post-operatively.This is the first study of its kind to assess measurement of pelvic floor muscle contraction before and after pelvic floor repair, to the best of our knowledge. It is unclear why there would be an effect seen with the patients supine but not standing. A study by Morgan et al.  found thIt is also possible that patients are better able to perform pelvic floor squeeze when lying supine, as they are able to isolate the movement with the rest of the abdominal and pelvic muscles relaxed. A previous study found that despite a significant increase in intravaginal pressure when stood there was no difference between the pelvic floor muscle squeeze when standing and that when lying supine . In thatThe hypothesis was that posterior colporrhaphy would increase pelvic floor muscle contraction strength because the nature of the surgery may draw together and reinforce component fibres of the pelvic floor. This seems to have been the case when the women were lying supine, although not when they were standing. The implications of this are unclear and further work is needed to understand the impact of this change on the functioning of the pelvic floor and the symptoms that patients may experience as a result of pelvic floor dysfunction (e.g. urinary incontinence). This device may be beneficial when teaching women pelvic floor exercises as they can get real-time feedback on their pelvic floor contraction and it allows their care provider to see how they are doing as well. There is an added benefit that this device is more reliable than subjective scoring, as it is an objective measure of pelvic floor contraction.Areas for future research include work to better understand the impact of pelvic floor activation pressure on symptoms associated with pelvic floor dysfunction and whether the changes seen here have a clinical implication. We are also using the Femfit® to study changes in pelvic floor tone during and after pregnancy to understand the impact of pregnancy on the pelvic floor and to better understand the underlying pathophysiology of postpartum pelvic floor dysfunction.


Acute kidney injury (AKI) can be caused by multiple factors/events, including acute coronary syndrome (ACS). Ceramides are involved in atherosclerosis progression, cardiovascular events, and renal damage. Almost no studies have been conducted on the relationship between ceramide concentrations and AKI events. Therefore, we evaluated the association between plasma ceramide level at admission and AKI in patients with ACS undergoing percutaneous coronary intervention.We enrolled 842 ACS patients from the Prospective Multicenter Study for Early Evaluation of Acute Chest Pain. AKI was defined using the criteria from the 2012 Kidney Disease: Improving Global Outcomes. Eleven C16–C26 ceramides were measured using the high-performance liquid chromatography interfaced to tandem mass spectrometer procedure. Logistic regression models were used to evaluate relationships between ceramides and AKI risk. The area under the receiver operating characteristic curves (AUC) was used to evaluate differences between ceramides.Overall, 139 (16.5%) patients developed AKI during hospitalisation. Patients who developed AKI had higher levels of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/21:0), Cer(d18:1/24:1), and Cer(d18:1/24:2) than patients who did not (P < 0.05). In risk-factor adjusted logistic regression models, these ceramides were independently associated with AKI risk (P < 0.05). Cer(d18:1/24:2) had the highest odds ratio of 3.503 . Ceramides had AUCs of 0.581–0.661 (P < 0.001) for AKI. Each ceramide combined with the Mehran risk score (AUC: 0.780) had AUCs of 0.802–0.808, greater than the Mehran risk score alone.Long-chain and very-long-chain ceramide levels may help determine the high AKI risk beyond traditional assessments.The online version contains supplementary material available at 10.1186/s12933-023-01831-6. Acute kidney injury (AKI) is a complex syndrome that is wildly considered a common and catastrophic complication of acute coronary syndrome (ACS) . The preCeramide is a type of complex sphingolipid; it is at the centre of sphingolipid synthesis and degradation metabolism. Ceramide consists of two hydrocarbon chains: the long-chain base of sphingosine and the saturated, or unsaturated, fatty acid of the C16–C26 chain length, linked to the C-2 position of the long-chain base of sphingosine via N-acylation –11, owinRecent studies have shown that increased levels of plasma ceramides are associated with chronic kidney disease, independent of common cardiovascular risk factors , 29. Onehttps://clinicaltrials.gov/ct2/home (Identifier: NCT04122573). This study was designed to evaluate whether the level of ceramides could predict AKI in patients with ACS undergoing primary PCI.The PEACP study was conducted to investigate new markers of diagnosis and prognosis for patients with acute chest pain using multiomics data by mass spectrometry detection. The PEACP study enrolled patients with acute chest pain from the chest pain centres of seven tertiary hospitals in China; it is registered at From November 2019 to April 2020, 3 610 patients with chest pain onset time < 24 h visited the acute chest pain centre: 923 patients were diagnosed with ACS and underwent PCI according to the diagnostic standard for non-ST-elevation ACS (NSTE-ACS) and ST-elevation myocardial infarction (STEMI), according to the American College of Cardiology and American Heart Association guidelines , 32. TheData were recorded prospectively by two independent researchers, including vital signs, chronic disease history, inpatient medications, imaging examination, and lab tests. Leukocytes, platelets, and hemoglobin was measured on a haematology analysis system . Serum creatinine, estimated glomerular filtration rate (eGFR), blood lipid, and blood glucose were conducted using the Architect c16000 analyser . Cardiac biomarkers were measured using an immunology analyser . The Global Registry of Acute Coronary Events (GRACE)  score anDiagnosis and staging of AKI were established using the Kidney Disease: Improving Global Outcomes (KDIGO) standard . Meetingg at 4 °C for 5 min, and 180 µL of the supernatant was transferred to an EP tube. The high-performance liquid chromatography interfaced with a tandem mass spectrometer (LC–MS/MS) procedure for ceramides testing has been showed in Supplementary materials in detail as reported previously [Blood samples (5 ml) were collected in EDTA tubes and stored at 4 °C for 30 min. To obtain plasma, blood samples were centrifuged at 1500 rpm for 10 min at 4 °C and then stored at −80 °C until further testing. Quality control (QC) was ensured by taking a mixture of 2 μL from each study sample. Ten microlitres of plasma were spiked before extraction with deuterated internal standards. The extraction of ceramide was performed as described previously . Brieflyeviously . The indThe endogenous plasma ceramide concentrations were derived from the obtained individual regression equations by calculating corresponding concentrations from the measured peak area ratios in samples. The precision (coefficient variance) and accuracy (relative error) for intra and inter for all 11 ceramides were within 10%; these were determined as previously described . The finBased on our pilot study, the incidence of AKI is approximately 15%. It is assumed that the area under the receiver operating characteristic curve (AUC) of ceramides for AKI is > 0.6, and to satisfy this difference with 80% power at 5% significance (2-tailed), a sample size of 546 is required. The sample size was calculated using MedCalc Statistical Software version 19.0.2 .2 test. Nonparametric continuous variables are expressed as medians (25th–75th) and compared using the Mann–Whitney U test. Parametric continuous variables are performed as means ± standard deviations and were compared using analysis of variance.Categorical variables are reported as frequency (%) and were compared by the χp < 0.05 indicated statistical significance. Data were analysed by SPSS Statistics  and R .The correlation between all 11 ceramides and common prognostic factors of ACS was determined using Pearson’s correlation analysis. Logistic regression models were used to evaluate whether the levels of ceramides were associated with the risk of AKI after adjustment for confounding factors, including age, sex, systolic blood pressure, heart rate, body mass index, statin use, hypertension, diabetes, hyperlipidemia, Killip class, white blood cell count, low-density lipoprotein cholesterol, total cholesterol, triglyceride, estimated glomerular filtration rate, high sensitive cardiac troponin T, N-terminal pro-brain natriuretic peptide, and Mehran risk score. The odds ratio was calculated per the standard deviation (SD) and interquartile range of ceramides. AUC was determined to assess the predictive power of the Mehran risk score, all ceramides, and the ratio of all ceramides to Cer(d18:1–24:0) for AKI and to investigate the incremental predictive value of ceramides over the Mehran risk score. A two-tailed p < 0.05) than patients without AKI  were men, and the average age was 66.9 ± 13.0 years. During the hospitalisation period, there were 75 (8.9%), 31 (3.7%), and 33 (3.9%) patients who developed AKI stages 1, 2, and 3, respectively. Table According to Spearman’s correlation analysis Fig. , all cerMedians and interquartile ranges of levels of ceramides in patients with and without AKI are shown in Table Figure ROC curve analysis was conducted to evaluate the discrimination of Mehran risk score and ceramides for AKI Table . These cIn this study, the incidence of AKI in patients with ACS was 16.5%, similar to those in previous meta-analysis reports (15.8%) and our previous retrospective study , 42. We Previous studies have confirmed the relationship between ceramides, cardiovascular disease progression, and adverse events –10. HoweGiven that ACS patients are often exposed to contrast agents during treatment, the Mehran risk score for the prediction of contrast-induced nephropathy after PCI was established in 2004 . SimilarThe application prospect of ceramides as biomarkers of AKI is that it may measure risk and guide interventions. Although randomised controlled trials regarding ceramides have not been reported, some studies have found that plasma ceramide levels could be reduced following aerobic exercise and statin therapy , 50. WhiFirst, although this was a multicentre, prospective study, owing to the relatively small sample size, additional studies are required to confirm these findings. Second, the first creatinine measure on admission was used as the baseline creatinine value, which may have been higher than the actual baseline creatinine for patients with ACS, even though only patients with onset time < 24 h were included; thus, the incidence of AKI may be underestimated, and the causality between ceramides and AKI remains inconclusive. Third, a control group of patients with CKD who did not develop AKI would have been useful, but the available data did not allow such analyses. Fourth, data for subgrouping AKI were not available. Fifth, although statins were administered to almost all patients with acute chest pain, this study did not collect data on the history of statin use, which may have impacted ceramide levels and the risk of AKI. Sixth, C12:0, C14:0, and > C26:0 ceramides were not examined in the present study, and whether they could be used for diagnosing AKI remains unknown. Seventh, ceramides have been associated with heart remodelling , 13, butLong-chain ceramides  and very long-chain ceramides (C24:1 and C24:2) were independently associated with the risk of AKI. These ceramides have a significant additional predictive value for AKI beyond traditional risk assessment tools. The ratio of Cer(d18:1/24:2) to Cer(d18:1/24:0) may be an indicator to identify AKI risk and guide effective clinical prediction, prevention, and intervention. The function of ceramide subtypes in cardiorenal diseases should be further researched.The authors report no disclosures relevant to the manuscript.Additional file 1: Figure S1. (A) Correlation analysis among all eleven ceramides. The value in the heat map is the correlation coefficient. * < 0.05; ** < 0.001; *** < 0.0001. (B) The average mass fraction of all eleven ceramides in ACS patients.Additional file 2: Table S1. Relationships between ceramides and acute kidney injury in patients with STEMI and NSTE-ACS according to multivariate Logistic regression analysis. Table S2. Relationships between ratio of ten ceramides to Cer(d18:1–24:0) and acute kidney injury in patients with acute coronary syndrome. Table S3. Predictive value of ratio of ten ceramides to Cer(d18:1–24:0) for patients with acute coronary syndrome.


Background: Low-grade inflammation is a significant component of chronic kidney disease (CKD). Systemic immune inflammation index (SII), a newly defined ratio combining neutrophil, lymphocyte, and platelet counts, has not yet been evaluated in the pediatric CKD population nor in the context of CKD progression or dialysis. Thus, this study aimed to analyze the complete blood cell count (CBC)-driven parameters, including SII, in children with CKD and to assess their potential usefulness in the prediction of the need for chronic dialysis. Methods: A single-center, retrospective study was conducted on 27 predialysis children with CKD stages 4–5 and 39 children on chronic dialysis. The data were analyzed with the artificial intelligence tools. Results: The Random Forest Classifier (RFC) model with the input variables of neutrophil count, mean platelet volume (MPV), and SII turned out to be the best predictor of the progression of pediatric CKD into end-stage kidney disease (ESKD) requiring dialysis. Out of these variables, SII showed the largest share in the prediction of the need for renal replacement therapy. Conclusions: Chronic inflammation plays a pivotal role in the progression of CKD into ESKD. Among CBC-driven ratios, SII seems to be the most useful predictor of the need for chronic dialysis in CKD children. Persistent low-grade inflammation is a hallmark of chronic kidney disease (CKD) ,2,3. TheThe increasing body of evidence suggests that the advanced production and decreased clearance of pro-inflammatory cytokines, as well as oxidative stress, are major causes of chronic inflammation under the conditions of impaired renal function ,4,5. OthAmong the above-mentioned components, platelets show the widest panel of activity due to the multiplicity of active substances released from the granules, stimulating leukocyte migration, reactive oxygen species (ROS) generation, phagocytosis, and thrombotic events . The plaThe engagement of such a spectrum of cell subsets in CKD-derived complications has initiated interest in their potential applicability as universally available biomarkers of systemic inflammation. Therefore, recent research has focused on the analysis of complete blood cell count (CBC) parameters and their derivatives in patients with CKD. Differences in the pattern of total and differential leukocyte count have been observed when comparing adult CKD patients with non-CKD counterparts and pre-dialysis with dialysis adults ,15,16,17The most recent studies have focused on the systemic immune inflammation index (SII), a newly defined ratio combining neutrophil, lymphocyte, and platelet counts. It is suggested as a prognostic indicator, comprehensively reflecting the inflammatory and immune status of patients with various renal diseases ,31,32,33However, SII was not evaluated in the pediatric CKD population nor in the context of CKD progression or outcome, such as the need for chronic dialysis. Moreover, despite the increasing role of machine learning methods in clinical practice, they have not been used in the analysis of CKD-related inflammation so far. Thus, this study aimed to analyze the complete blood cell count (CBC)-driven parameters, including SII, in children with CKD and to assess their potential usefulness in the prediction of the need for chronic dialysis, confronted with the predictive abilities of other indices of CKD-related complications, with the use of artificial intelligence tools. The study group consisted of 27 pre-dialysis children with CKD stages 4–5  and 39 patients on chronic dialysis . The patients’ age ranged from 5 to 18 years; children under 5 were excluded due to the different CBC profiles regarding neutrophil–lymphocyte proportions. The evaluated CBC parameters were hemoglobin, hematocrit, leukocyte, neutrophil, monocyte, lymphocyte, platelet counts, and mean platelet volume (MPV). CBC-driven ratios (neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII = [neutrophil count-lymphocyte count]/platelet count)) were then calculated and analyzed. Kidney function  served as a direct classifier of patient subgroups . The selected biochemical parameters  and blood gases were also evaluated. This database was used for further machine learning (ML) analysis.p value < 0.05 was considered significant.Results were expressed as minimal, mean, maximal values, and standard deviation. The null hypothesis of normality of distribution of analyzed variables was rejected by Shapiro–Wilk test. Thus, the analysis was performed with the use of nonparametric Mann–Whitney U test. Correlations were assessed by Spearman’s rank correlation coefficient. Statistical analysis was performed using the package Statistica ver. 13.3 . A Machine learning allows us to imitate simple decision-making processes and perform data classification based on previously calculated dependencies. These dependencies come from supervised learning, i.e., a person gives the correct labels for existing and available data, and the role of the program is to match the so-called hyperparameters to show the greatest possible discriminatory ability on the various input data that will be used to evaluate the models. Overcomplicating the model risks its overfitting to the data and ineffective prediction of the new data. Too little fit or too little complexity makes the model comparable to, or even worse than, the random classifier. An example of machine learning is the Random Forest Classifier, in which random decision trees are generated and then the so-called cost function is minimized in order to achieve the best fit in a compromise with flexibility. The final result is obtained by averaging the predictions from individual decision trees.The small data size may be an obstacle to the use of machine learning. The main aspect limiting the application is the difficulty in training a model. In this study, the training on a small set of training data was effective, so we used several measures to describe the predictive properties. Additionally, the Random Forest Classifier is a relatively simple model used on small datasets by other authors, which justifies our attempt to use it .The efficacy of the model can be characterized by its accuracy, area under the receiver operating curve (AUROC), precision, recall, F1-score, Matthews correlation coefficient (MCC), and Gini importance.Accuracy is the ratio of correct matches or classifications to all classifications made, which indicates how close the model’s predictions are to the true value.AUROC is the basic parameter defining the discriminating ability of the binary classifier.Precision is an information technology synonym for a positive predictive value and is defined as the ratio of true positives to all positive predictions.Recall is equivalent to sensitivity and determines the ratio of true positives to the sum of true positives and false negatives predictions.F1-score is the harmonic mean of the precision and recall. F1-score is a stat especially useful in unbalanced sets due to classes. However, it has a limitation that can be circumvented by using a broader statistic, such as Matthews correlation coefficient (MCC). MCC is a parameter that achieves a large value if the model performs well enough in all four fields of the confusion matrix . The useThe Gini feature importance determines how much a given feature contributes to dividing the set into classes. In other words, it is approximated by the probability of achieving a division that will allow the final classes to clarify themselves faster.The aim was to narrow the set of input parameters so that the high predictive power is secured and overfitting or overcomplicating could be avoided. Moreover, the Gini importance was measured in order to define the parameter with the largest share in the prediction.The primary database was randomized into a training and testing set in the ratio of 80:20, which is a proportion of the split commonly used and accepted in machine learning . Due to In the first step, a random forest model was built using all available parameters as input variables. Of note, serum creatinine and eGFR values were not included in the analysis because they primarily stratified the groups, and their implementation would oversimplify the model. The Gini feature importance was calculated, and the parameter with the smallest contribution to the prediction was chosen. In the next step, we built a model based on variables, among which we did not include the aforementioned parameter. In this way, we have iteratively reduced the number of input variables to 3. The algorithm stopped the reduction of the number of variables when the model quality deteriorated after reducing the input size. The analysis of generated decision trees was based on following the process of dividing the data set. This method can be used to discover new hypotheses or design algorithms. Within a single decision tree, the same variables are queried but with different cutoffs or in different variants, with previous and following conditions stored in the nodes. Finally, the partial results from all trees were collected, and the prevailing result has become the final one.p < 0.005). The significant correlations of CBC parameters concerned serum urea and all cell subtypes: erythrocytes , leukocytes , neutrophils , lymphocytes , monocytes , and platelets . Additionally, correlations with inflammation markers , CRP and NEU , MPV and serum albumin ) and bone turnover indices , MPV and cholecalciferol level ) were statistically significant. Consequently, CBC-driven ratios revealed significant correlations  achieved an AUROC of 0.8750, an accuracy of 87.50%, MCC of 0.7745, a precision of 0.9000, and a recall of 0.8750. Therefore, a larger database is required to test its efficiency.In our study, the RFC model built with the input variables of neutrophil count, MPV, and SII turned out to be the best predictor of the progression of pediatric CKD into end-stage kidney disease requiring dialysis. Out of these variables, SII showed the largest share in the prediction of the need for renal replacement therapy. Therefore, the model constructed with CBC-derived parameters outperformed those based on classical indices of CKD-related complications, like anemia, CKD–mineral-bone disease, or acidosis. These findings underline the importance of chronic inflammation in the deterioration of kidney function, which should not be neglected when compared to the influence of other risk factors. The role of persistent low-grade inflammation in adults with CKD has been vastly analyzed and discussed . ChronicChanges in the white blood cell count and proportion observed in adults with CKD included higher granulocyte and monocyte count and lower lymphocyte count ,13,37. TIn our study, no difference was reported in the leukocyte/granulocyte/monocyte count between the pre-dialysis and dialysis groups, although the tendency toward higher monocyte percentage in children on chronic dialysis vs. those with CKD 4–5 was noticeable. Moreover, correlations between all cell counts and indices of toxemia/inflammation were statistically significant.Consequently, the neutrophil-to-lymphocyte ratio (NLR) was proposed as a supplementary marker of CKD progression and the need for starting hemodialysis ,39,40. EMean platelet volume (MPV), platelet-to-lymphocyte ratio (PLR), and mean platelet volume-to-lymphocyte ratio (MPVLR) are other parameters derived from complete blood count of potential use in the assessment of CKD-related chronic inflammation. The dysfunction of platelets and changes in their functional properties observed in CKD patients indicate the modulating role of platelets in persistent inflammation. Platelets may interfere with the inflammation pathways due to their role in maintaining vascular integrity. Additionally, they are able to influence leukocyte function and monocyte differentiation by cell–platelet adhesion or by the release of soluble mediators, microparticles, and cytokines ,23. The In adult CKD patients on maintenance hemodialysis, the combination of NLR, MLR, and PLR was proposed for a more precise assessment of inflammation and all-cause mortality ,21. ReceThe diagnostic value of SII in pediatric nephrology has been investigated in children with urinary tract infections. Karakaya et al. assessed the role of CBC-derived parameters in predicting acute pyelonephritis and showed that SII was among the best predictors of the development of acute pyelonephritis . LikewisThe elevated SII has a predictive value for mortality risk among CKD non-dialyzed and hemodialyzed adults ,31. Lai Contrary to the adult population, pediatric patients with CKD were not tested for the SII values and their prognostic abilities. Thus, to the best of our knowledge, this study is the first to assess the link between SII and the progression of CKD in pediatric patients. SII in both subgroups correlated with CRP, alkaline phosphatase, serum albumin, and pH of blood gases. The computer program has been equipped with a simple heuristic algorithm that allows for optimally finding the best predictive model and flexibly scaling solutions to larger databases in other centers. The brute-force solution requires enormous computational complexity, although once the process of parallelization is introduced, the following stages do not cause particular problems. However, in other, broader applications, it is possible to speed up the evaluation of models and secure more effective adaptation of classifiers to growing data sets. We have empirically demonstrated the effectiveness of optimization techniques based on heuristics as opposed to previous brute-force applications . Moreover, it is possible to scale the developed models to new data, and this perspective seems essential in light of our preliminary results on the prediction of the type of dialysis (APD vs. HD) that requires testing on a larger dataset. Another step is the analysis of risk factors, with an emphasis on the use of Gini feature importance as a parameter indicating critical factors for classifying patients and discrimination in risk models. Other authors mention its use in the assessment of unrelated and COVID-19-related mortality in dialysis patients ,44. It wWe also have to acknowledge the limitations of our study. First, the size of the subject is limited by the small number of data and by the fact that it was conducted in a single center. Second, we evaluated only selected markers of inflammation and a limited number of parameters reflecting other CKD-related complications. Thus, this analysis did not cover all aspects of multilayer connections between inflammatory indices, markers of CKD, and blood cell count-derived ratios. Complete blood cell count-driven parameters provide simple and cost-effective insight into the inflammatory status of children with chronic kidney disease. Our study showed that the CBC-driven parameters, particularly neutrophil count, mean platelet volume, and systemic immune inflammation index, might be of added value while predicting the need for chronic dialysis in pediatric CKD patients. However, further studies in that field are required to assess their potential role in clinical practice.