The concentrations of Ni, As, Pb, Sr, Tl, Zn, Cu and Se showed significant differences among different age groups and the age-related concentration trends varied among these elements. There were significant differences in the urine concentrations of Zn and Sr between those subjects in the group who were frequently exposed to soil (exposed soil > 20 min/day) and those in the group who were not, indicating that people in regular contact with soil may be more exposed to metals. This study provides useful information for evaluating the levels of metal exposure among general populations.Metal pollution may lead to a variety of diseases; for this reason, it has become a matter of public concern worldwide. However, it is necessary to use biomonitoring approaches to assess the risks posed to human health by metals. In this study, the concentrations of 14 metal elements in 181 urine samples obtained from the general population of Gansu Province, China, were analyzed using inductively coupled plasma mass spectrometry. Eleven out of fourteen target elements had detection frequencies above 85%, namely, Cr, Ni, As, Se, Cd, Al, Fe, Cu and Rb. The concentrations of most metal elements in the urine of our subjects corresponded to the medium levels of subjects in other regional studies. Gender exerted a significant influence ( Metals, including essential and nonessential elements, are a group of substances that are widely distributed in the environment . Metals A growing body of evidence confirms the toxicity of some metal species. Chronic human exposure to exceedingly small doses of these metal species is associated with adverse health effects ,7,8. HumResearchers in many countries have carried out studies to assess metal exposure levels in different target populations. These studies have formed the basis for further metal exposure assessments in humans and other toxicology studies ,21,22. IGansu Province is located to the west of the Loess Plateau in Northwestern China . PreviouIn this study, therefore, we sought to measure the levels of 14 metal elements, including both non-essential elements  and essential elements , in urine samples obtained from the general population in Gansu Province, China. The concentration of metal elements in urine is influenced by environmental and physiological factors. We also studied the demographic factors that might influence the levels of metal concentration, including gender, age and lifestyle. This study was based on a regional exploratory study that provided useful information for evaluating the levels of metal elements among the residents of Northwestern China.The standards for six essential elements  and eight non-essential elements  were purchased from the General Research Institute for Nonferrous Metals . Nitric acid (69%) was purchased from CNW . Milli-Q (18.2 MΩ·cm) ultrapure water used to prepare the samples was obtained from a Milli-Q purification system .The participants in the current study were all from Jingyuan County, Gansu Province, China. In total, 181 participants aged 1–74 years were recruited from eight villages in the region during 2020 . All subHumans are exposed to elements mainly through dietary intake, respiratory tract inhalation, skin contact  and handn = 28); children ; adolescents ; and adults . For the analysis of the relationship between soil exposure and metal concentration, we considered the different lifestyles of people of different ages, and so we also divided subjects into a lower age group  and an older age group . We categorized age as either ≤11 years or >12 years because the latter is the cut-off age between participating and not participating in family farms in Jingyuan County. In the lower age group, participants were defined as exposed to the soil if they engaged in outdoor play for more than twenty minutes daily, or at least twice daily, in the previous year. In the older age group, participants were defined as exposed to the soil if they engaged in farm work for more than ten minutes daily, or at least once daily, in the previous year.For the analysis of the obtained data, we bore in mind that the metabolism of children and adults is different, and so we divided our study subjects into four categories: young children  nitric acid. Next, the resulting samples were digested by heating them at 40 °C in a water bath for one hour , where SG-adjusted is the urinary element concentration corrected by SG (μg/L), and SG-unadjusted concentration is the measured raw element concentration (μg/L). SGi is the measured SG value of the urine sample, and SGm is the median SG value in the study population.p-value correction were all carried out at the time of testing. All p-values were two-sided with a statistically significant level of 0.05.SPSS 23  software was used for statistical analysis. The element concentrations used for descriptive statistics were expressed as μg/L. Metal concentrations below the LOD were assigned with LOD divided by √2 ,49. The 2. Females represented 53.6% (n = 97) of the respondents. In the lower age group, 72.4% of the subjects (n = 42) had soil exposure as a result of playing outdoors. In the older age group, almost half of the subjects were exposed to soil due to farm work at home .Demographic data for the 181 participants are shown in The concentrations LODs and LOQs of the 14 metals in the urine of subjects are shown in According to a document issued by the Ministry of Health of the People’s Republic of China, the concentration of Pb in urine should not exceed 120 μg/L . This reCompared with previous studies ,39,53, tp < 0.01). Among these, there was a strong positive correlation between Fe and Al, and between Pb and Cr , indicating a similar pollution source. Previous studies have found that the levels of these different metals typically exhibit medium-strength correlation  [Spearman’s rank correlation coefficients between metals were of weak-to-moderate intensity . Spearmactively) ,55; thesctively) ,57. In vp < 0.05) in the urine of females  were significantly higher than in males . Contrarily, the concentration of Zn (p < 0.05) in the urine of males (503.1 μg/L) was significantly higher than in the urine of females (344.3 μg/L). Many studies have shown that exposure to metal elements  may involve remarkable gender differences [Box plots  show theferences ,59,60. Sferences . Other sferences ,61. Howeferences ,61 have p < 0.05)  . Overallp < 0.05)  . In the  < 0.05) . It can Compared to adults and adolescents, children may have higher levels of metals in their bodies because they have a higher basal metabolic rate ,69, a hip < 0.01)  . Zinc isEvery year, large quantities of metal elements are released into the environment from mining and agriculture. In Jingyuan County, the smelting and mining of non-ferrous metals in neighboring Baiyin City over the past 70 years have led to serious soil pollution with Cd, Cu, Pb and Zn . Diet anp < 0.05). Sr is considered a potential essential element [Urine concentrations of Sr in individuals engaged in farm work are shown in  element . However element . Some ex element .p < 0.05). Due to childhood-related behaviors, such as higher hand-to-mouth contact and closer contact with substances contaminated by elements via outdoor activities [Among participants in the lower age group, there was a significant difference in urine Zn concentration between those subjects exposed to soil and those not exposed (tivities ,43, chilMany essential metals are naturally occurring elements, and organisms have different needs for them . Higher In this study, we measured the concentrations of 14 metal elements in urine samples obtained from the general population in Jingyuan County, Gansu Province, China. This study was limited by incomplete questionnaire information but made up for the shortcomings of biological monitoring in the region. The levels of metal elements found in the study participants were comparable to those found in other studies using subjects from different regions of the world. We found certain correlations between the urinary concentrations of most of the targeted metals. High detection frequencies indicated that such pollutant elements are widespread and related to human exposure. Metallic elements are a natural component of the lithosphere, hydrosphere and atmosphere. As a result, they are also present in living organisms, including the human body. A number of factors, including gender, age and contact with soil, exerted a significant influence on concentrations of heavy metals. This study provides useful information on the levels of elements in human urine in Jingyuan County and evaluated various influence factors for different elements in terms of differences in urine element concentrations. Thereby, it offers improved insights into the relationship between the levels of exposure to metals and influencing factors for the general population in Northwestern China and provides clues to design further large-scale metal exposure level surveys in Northwestern China.


Menopausal hormone therapy (MHT) is used to alleviate the symptoms associated with menopause, despite the lack of recommendations for MHT in preventing dementia. Recent nationwide studies have explored the association between MHT and dementia risk, but the findings remain limited. This study aims to investigate the association between MHT and the incidence of Alzheimer’s disease (AD) and non-AD dementia using national population data from Korea.We conducted a retrospective study using data from the National Health Insurance Service in Korea between January 1, 2002, and December 31, 2019. Women over 40 years were eligible for this study and classified into the MHT or non-MHT groups. The MHT group consisted of women who used Tibolone (TIB), combined estrogen plus progestin by the manufacturer (CEPM), estrogen, combined estrogen plus progestin by a physician (CEPP), and transdermal estrogen during menopause. We compared the risk of dementia between the MHT and non-MHT groups.The study included 1,399,256 patients, of whom 387,477 were in the MHT group, and 1,011,779 were in the non-MHT group. The median duration of MHT was 23 months (range: 10–55 months). After adjusting for available confounders, we found that different types of MHT had varying effects on the occurrence of dementia. TIB  1.01–1.072) and oral estrogen alone  were associated with a higher risk of AD dementia. In contrast, there was no difference in the risk of AD dementia by CEPM , CEPP , and transdermal estrogen  use. The use of TIB, CEPM, and oral estrogen alone increased the risk of non-AD dementia , but there was no risk of non-AD dementia in the other MHT groups .Our findings indicate that MHT has varying effects on the incidence of AD and non-AD dementia. Specifically, TIB, CEPM, and oral estrogen alone increase the risk of non-AD dementia, while transdermal estrogen is not associated with dementia risk. It is essential to consider the type of MHT used when assessing the risk of dementia in women. The numThis trend seems more rapid in South Korea (hereafter Korea). Based on the government-led data, it is estimated that the number of people aged ≥65 years will reach 8.53 million in 2021 and is expected to exceed 12.98 million by 2030 and 19 million (accounting for 39.8% of the older adult population) by 2050 . AdditioMost studies have shown that women have a higher prevalence of dementia than men. This trend, which is generally explained by differences in sex hormones, education, and life expectancy, becomes more evident as age increases, because the prevalence of Alzheimer’s disease (AD) is higher in women aged >80 years than in men . These dMenopausal hormone therapy (MHT), which is prescribed for postmenopausal women with moderate to severe menopausal vasomotor symptoms, is not recommended to prevent dementia . AlthougAlthough recent nationwide studies have been conducted on the relationship between MHT and the risk of dementia, findings on this issue are limited. This study aimed to explore the risk of dementia and MHT using the Health Insurance Database of South Korea.2.2.1.We conducted a retrospective study based on the national population by investigating data from the National Health Insurance Service (NHIS) in Korea from January 1, 2002, to December 31, 2019. Korea’s health insurance system was integrated into a single system operated by the National Health Insurance Corporation in 2000 . Since t2.2.Using a database of clinical records from 2002 to 2011, only women aged >40 years were eligible for this study, and participants were recruited into the MHT and non-MHT groups. The MHT group included patients prescribed at least one MHT between 2002 and 2011, while the non-MHT group were those who underwent a national health examination at least once between January 1, 2002, and December 31, 2011, excluding those who received MHT between 2002 and 2019. Participants with previous diagnostic codes for cancer (any Cxx), dementia , or Parkinson’s disease (G20) before the 180th day from the start date of the study were excluded. Women diagnosed with menopause in 2002 and those aged <40 years were also excluded .2.3.The term ‘AD dementia’ used in this study is a clinical diagnostic term of AD dementia based on the ICD-10 code. AD dementia was defined based on diagnostic ICD-10 codes (F00 or G30) and non-AD dementia based on the codes , among patients who had visited three or more medical institutions. Total dementia (TD) was defined when the above two conditions are satisfied.2.4.In this study, MHT during menopause refers to the use of TIB, combined estrogen plus progestin by the manufacturer (CEPM), estrogen, combined estrogen plus progestin by a physician (CEPP), and transdermal estrogen. A detailed list of the MHTs is provided in 2.5.p <0.05 was considered statistically significant. All continuous data are presented as median [25th and 75th percentile], and categorical data are expressed as total number (%). Cox proportional hazard regression analysis, with or without adjustment for confounders, was used to analyze the associations between the variables and dementia. The pairwise deletion method was used when values were missing. All statistical analyses were carried out using SAS Enterprise Guide 6.1 (SAS Institute Inc.). To confirm the sensitivity analysis for evaluating the robustness of these results, we analyzed only participants prescribed medications by an obstetrics and gynecology specialist.A two-sided test was performed for all statistics, and a value of 2.6.This study was approved by the Institutional Review Board of the Sanggye Paik Hospital . Following the NHIS’s information protection policy, this study removed individual-identifying variables that could only be analyzed using virtual servers within the NHIS. Therefore, this study was conducted retrospectively using data obtained for clinical purposes, and the researcher could secure only the results. Furthermore, because it is impossible to specify any individual in the data, no possible harm can be caused. Moreover, this study did not require informed consent from the participants according to the Bioethics and Safety Act of South Korea.3.3.1.Of the 2,506,271 women who recorded menopause in the national health examination during the study period (2002–2011), we excluded those who had menopause in 2002 (washout period) and those under 40 years old. Women with any cancer type, previous dementia, or Parkinsonian syndrome within 180 days after the health examination or after the first MHT prescription were also excluded. Finally, data from 1,399,256 patients were included in this study. Among them, 387,477 were classified into the MHT group and 1,011,779 into the non-MHT group .The baseline characteristics of the women according to MHT exposure status are summarized in 3.2.Overall, the median duration of MHT was 23 months (range: 10–55 months). Only 23,145 (6%) women used hormone therapy for more than 10 years, whereas a shorter duration of MHT (shorter than 5 years) was observed in 297,801 (76.9%) women. According to the gynecology and non-gynecology specialties, physicians prescribed hormone therapy to 149,498 (38.6%) and 237,979 (61.4%) women, respectively. The detailed characteristics of the women receiving MHT in this study are shown in 3.3.The hazard ratio for the risk of dementia according to reproductive factors are shown in 3.4.In 4.We conducted a large cohort study of menopausal women undergoing MHT to determine the association between MHT use and the risk of dementia. Our study revealed that TIB and oral estrogen alone were associated with an increased risk of AD dementia. In contrast, CEPM, CEPP, and topical estrogen were not associated with an increased risk of AD dementia. In this analysis, the use of TIB, CEPM, and oral estrogen alone was found to be related to an increased risk of non-AD dementia and TD. However, topical estrogen was not associated with an increased risk of AD or non-AD dementia.A few studies have reported neither the benefit nor the risk of MHT concerning AD, which begins later than 65 or more than 5 years after menopause. A recent study that assessed the risks of developing TD and AD in women exposed to different types of MHT for different durations also reported no increased risks of developing dementia overall . FurtherThe most important finding of this study was that MHT had different effects on the incidence of AD and non-AD dementia. In this study, TIB, CEPM, and estrogen-only use were associated with an increased risk of non-AD dementia, consequently increasing overall TD incidence. Excluding CEPP, most oral hormone therapies  showed an increased tendency towards non-AD dementia occurrence. This is believed to be due to the accumulation of prothrombotic metabolites that may occur during the metabolic process of oral hormone therapy, leading to atherosclerotic effects, ischemia, and vascular cognitive decline . AlthougPrevious studies have reported the neuroprotective effects of estrogen on the brain, cognition, and dementia . EstrogeN = 2,506,272) compared with the current observational study. It included many TIB users, and TIB is widely used in Europe, Asia, and Korea . The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.J-SY and JP: conception and design of the study, acquisition of data, and final approval of the manuscript. J-SY, JL, and JP: analysis and interpretation of the data, drafting and revising the manuscript for content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Osteoarthritis (OA) is a common cause of lameness in sport horses with a significant economic impact. The prevention of OA is crucial since no effective treatment is available. This study aimed to apply untargeted metabolomic analysis to investigate the differences in synovial fluid (SF) composition between healthy and OA-affected joints in horses. SF collected from healthy (n.8) and OA (n.11) horses was analyzed using H-NMR analysis. Metabolomic analysis allowed 55 different metabolites to be identified and quantified in SF samples. Nineteen metabolites were found to be differently concentrated in OA compared to control horses. Synovial fluids from the OC group were found to be higher in 1,3-dihydroxyacetone but lower in tryptophan, phenylalanine, tyrosine, uridine, creatinine, creatine, glycine, choline, asparagine, glutamine, arginine, 3-hydroxybutyrate, valine, 2-hydroxyisovalerate, α-ketoisovaleric acid, 3-methyl-2-oxovalerate, 3-hydroxyisobutyrate, isoleucine, and methionine compared to the controls. A variety of SF metabolites significantly changed following joint disease, demonstrating the complex mechanism underlying osteoarthritis in horses and highlighting the value of applying the metabolomic approach in clinical research. Osteoarthritis (OA) is one of the most common causes of lameness in sport horses . This coThe pathogenesis of osteoarthritis involves both mechanical factors and chemical mediators, the latter represented by interleukins, enzymes, free radicals, and antibodies . Both meDuring OA, different pathobiological processes occur at the same time. Physical and/or biochemical damage of the articular cartilage and bone initiates the inflammation of the synovial membrane, articular bone surfaces, and fibrous joint capsule (synovitis and capsulitis). The synovial membrane is usually involved early in the process, but it remains unclear whether its modifications occur first or whether they are the result of cartilage degradation or lesions of the subchondral bone. Several cell types have been pointed out to be responsible for synovial inflammation, but studies have shown that much of the inflammation in the OA joint is attributed to synovial proinflammatory macrophages . CatabolAt present, no effective treatment has been identified, so therapy is aimed merely at managing lameness itself, with palliative systemic anti-inflammatory drugs and local injections of substances such as corticosteroids, hyaluronan, or interleukin receptor antagonist protein (IRAP) .A step forward in the prevention of osteoarthritis may come from its early diagnosis and from the possibility of monitoring its evolution to prevent the worsening of the horse’s clinical condition and preserve athletic activity . The sciSynovial fluid (SF) acts as a lubricant of the joints and therefore is at direct contact with the sore spots. For these reasons, in the diagnostic workup in addition to clinical and radiographic assessments, total proteins and white blood cells are routinely investigated by practitioners for the diagnosis of joint diseases ,11.In recent years, omics sciences, from genomics downwards to metabolomics, have granted a wealth of new diagnostic approaches in clinical and biomedical studies thanks to continuous developments in analytical techniques and bioinformatics ,13, thes1H-NMR spectroscopy in an untargeted manner and, promisingly, they identified as many as 55 metabolites, mainly pertaining to the chemical groups of amino acids and derivatives and to organic acids. The SF’s metabolome resulted in being extensively affected by sepsis, with 26 metabolites differently concentrated compared to nonseptic counterparts. In 2020, the same group confirmed the richness of information granted by metabolomics based on 1H-NMR by successfully studying palmar osteochondral disease [Among the omics platforms, metabolomics seems perfectly suited to biomarker identification, being the one dedicated to the characterization of low-weight metabolites, the so-called metabolome, the most directly altered by inflammatory processes . Metabol disease .1H-NMR on the water-soluble metabolome of SF also in the case of osteoarthritis. Unfortunately, the applications of this technique to the purpose are restricted to the work of Lacitignola et al. [These premises allow us to foresee the richness of information granted by a et al. , who lim1H-NMR in an untargeted manner to investigate as comprehensively as possible the differences in synovial fluid composition between healthy and OA-affected joints in horses.Considering the importance of obtaining an in-depth knowledge of equine osteoarthritis pathophysiology, we have applied Synovial fluid was collected from the metacarpophalangeal joints (fetlock) of 19 horses of different breeda, 11 animals affected by osteoarthritis (OA group), and 8 healthy horses slaughtered for meat production.Osteoarthritis was diagnosed in the OA Group  by a combination of clinical examination, radiographic and ultrasonographic findings, SF total protein, and cytology, as previously described .The day before slaughtering, the horses from Group C  were subjected to clinical and radiographic examinations to ascertain that animals were free of lameness and radiographic abnormalities.Briefly, after the proper preparation of the fetlock region, SF samples were obtained aseptically by arthrocentesis using a 21-gauge needle and a 2.5 mL syringe. Fetlock arthrocentesis was performed with the limb in flexion and with the needle inserted into the area between the third metacarpal bone and the suspensory ligament of the fetlock. The needle was introduced into the joint to a depth of about 1 cm [g for 5 min), the cellular component was eliminated, and, subsequently, the supernatant was transferred into another 1.5 mL tube. The samples were then frozen and stored at a temperature of −80 °C until analysis.The collected samples were then transferred to 1.5 mL tubes and processed within one hour of the aspiration procedure. Subsequently, the tubes were centrifuged , with the same described procedure occurred for group OA.All experimental procedures were approved by the Institutional Animal Care and Use Committee of Camerino University (Registration number: 1/2023) and were in accordance with the standards recommended by the EU Directive 2010/63/EU for experiments on animals.1H-NMR, a solution based on D2O was first created, set at pH 7.00 ± 0.02 by means of a phosphate buffer. It contained 3-(trimethylsilyl)-propionic-2,2,3,3-d4 acid sodium salt (TSP) 10 mmol/L, as an NMR chemical-shift reference, and NaN3 2 mmol/L, that avoided bacterial proliferation.To investigate the metabolome of synovial fluids by g for 10 min at 4 °C. An aliquot of 0.35 mL of supernatant was added to 0.35 mL of deionized water and to 0.1 mL of the above-described NMR solution. After a further centrifugation at the above conditions, a spectrometer AVANCE III , set at a frequency of 600.13 MHz and operated by the software Topspin (v3.5), was used to register the spectra at 298 K. Broad resonances’ signals due to large molecules were suppressed by a CPMG-filter, composed of 400 echoes spaced by 0.400 ms, and obtained with 180 pulses of 24 µs for a total filter of 330 ms. The residual signal from water was suppressed by presaturation. This was obtained by relying on the cpmgpr1d sequence, part of the vendor’s standard library of experiments. Each spectrum was the sum of 256 transients, sampled with 32,000 data points over a 7184 Hz spectral window, with an acquisition time of 2.28 s and a recycle delay of 5 s.Following Brugaletta et al. , each sa1H-NMR spectra were adjusted for phase and baseline in Topspin and then exported to ASCII format through the corresponding Bruker’s script. The subsequent steps were performed in R [The med in R  through med in R  and Chenmed in R , by relyt-test was subsequently applied to evaluate statistical differences in the concentrations of the various metabolites detected in the synovial fluid in the two groups of horses. Statistical analysis was not corrected for multiple testing. A p value ≤ 0.05 was considered statistically significant. Furthermore, the rPCA model and volcano plot were performed on the molecules found to be significantly different between AO and control samples.To ensure the normal distribution of the data, Box–Cox transformation was used . A t-tes1H-NMR allowed 55 different metabolites to be identified and quantified in SF samples , osteochondrosis (n = 6), and synovial sepsis (n = 7) in horses. The authors found higher concentrations of phenylalanine in the SF from nonseptic compared to septic joints, but no comparison was available with healthy joints for the lack of a control group. In this context, the role of phenylalanine in joint diseases and the meaning of its variation in horses needs to be clarified.Phenylalanine and tyrosine also showed a marked decrease in the OA group in our study. Phenylalanine, an essential amino acid, can be converted into tyrosine that, in turn, can be converted into L-DOPA, thyroxine, adrenaline, and norepinephrine. It is also involved in the regulation of enzyme activities. A study by Li and colleagues  analyzedp < 0.01) in the OA group compared to the controls. This nonessential amino acid is characterized by numerous functions, including the synthesis of proteins, in particular collagen and elastin, and plays a fundamental role in the synthesis of ATP. Collagen is the main protein of connective tissue, and its structural unit is tropocollagen, a protein formed by three polypeptide chains. All tropocollagen molecules are constituted by the same sequence of amino acids: glycine, proline, and a third amino acid or glycine, hydroxyproline, and a third amino acid. Since collagen  is the main protein constituting cartilage, its presence is a fundamental factor for the preservation of joints. In a study conducted in 2018 by Dai et al. [Glycine was lower  impairs cell proliferation and induces cell cycle arrest . On thisAnother nonessential amino acid, glutamine, decreased in the SF of the OA group. Biologically, this metabolite is involved in various biological functions, including the transporter of amino groups, precursor of glutamate and glutathione, energy support for lymphocytes, macrophages and enterocytes, stimulator of nucleotide synthesis, and the inducer of the expression of heat shock proteins (HSPs), capable of decreasing the inflammatory response by cytokines. Thermal shock proteins have a fundamental protective function, and a lack of these proteins can lead to cellular apoptosis and more extensive tissue damage . In 2017In our study, we found arginine, an amino acid classified as conditionally essential, less concentrated in the SF from the OA group. This metabolite has beneficial effects as it promotes the oxidation of fatty acids, increases the activity of lipolytic enzymes, and reduces insulin resistance . ArgininMethionine is an essential nonpolar amino acid with a strong antioxidant and protein structure stabilizing action . A recenCreatine and creatinine were found to be lower in the SF from the OA group compared to healthy subjects. Another study by Anderson and colleagues  found hiFinally, 1,3-Dihydroxyacetone was the only metabolite with a higher concentration in the SF of the OA group in comparison to the control group. To explain this, different theories can be adopted. First, this finding can be related to an alteration of energetic metabolism during the OA process as dihydroxyacetone phosphate (DHAP), the phosphorylated form, takes part in glycolysis and is an intermediate product of glucose metabolism. In addition to this, 1,3-Dihydroxyacetone has been demonstrated to be capable of enhancing GAG accumulation in cultured human articular chondrocytes and cartilage tissue, and it can be speculated that the increase in such metabolites represents an attempt from chondrocytes to attenuate the detrimental effect of OA. In 2001, Liu and collaborators  demonstrThe alteration in joint metabolism during OA can also explain the differences observed in other SF metabolites like 2-hydroxyisovalerate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, α-ketoisovaleric acid, and 3-methyl-2-oxovalerate, choline, uridine, and valine.2-hydroxyisovalerate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, and α-ketoisovaleric acid are organic hydroxy acids representing the intermediate metabolites of amino acid metabolism, found to be overexpressed during OA in human joints .On the human side, a number of studies have clarified that OA is responsible for an activation of specific amino acid metabolic pathways, causing an increase in the SF levels of organic acid as 2-hydroxyisovalerate, 3-hydroxybutyrate, and 3-hydroxyisobutyrate .In our study, we found a contrary trend of such metabolites during OA in horses.Adams and colleagues  recentlyHowever, a lower level of BCAAs and organic acid metabolites in media from the late-stage OA group may be explained by an alteration in BCAA metabolism with disease progression. Our findings support this hypothesis. Recently, the ratio of BCAA to the amino acid histidine was proposed as a biomarker for OA . In thatFrom a biochemical point of view, choline and uridine are methyl donors that can modulate methylation in different metabolisms. As an example, via betaine homocysteine methyltransferase, choline regulates the concentrations of S-adenosylhomocysteine and S-adenosylmethionine which have been shown to help the regeneration of cartilage tissue during OA, and dietary supplementation with SAMe represents a main strategy for cartilage restoration .Recently uridine has received attention for its anti-inflammatory properties and its potential as an antiarthritic therapy in an experimental model of rheumatoid arthritis (RA) . In thisFinally, lower concentrations of choline have been found in the OA group compared to the controls. This metabolite is involved in the cholinergic anti-inflammatory pathway that seemed to improve the progression of OA disease .The present study investigated the metabolomic profile of SF in horses affected by osteoarthritis and in healthy horses by demonstrating the variety of molecules that undergo significant changes during joint disease. We can speculate that the different concentration of certain metabolites could result from a reduced efficiency of homeostatic control mechanisms balancing pro- and anti-inflammatory pathways in OA joints. The possibility of identifying potential biomarkers and exploring the mechanism underlying osteoarthritis in horses represent the main reasons for promoting the application of the metabolomic approach in clinical research, and every metabolomic study will contribute towards reaching this goal.


Sleep problem is one of the major issues of cancer patients and may have detrimental effects on the ongoing treatment and recovery of patients. However, the evidence for the effect of light therapy on sleep problems in this population remained scarce. This study aimed to examine the effect of light therapy on self-reported and physiological measures of sleep quality of cancer patients. It also aimed to quantify the magnitude of the effect using a meta-analytical approach.Six databases were searched for randomized control trials (RCTs). The primary outcome was the sleep quality using the Pittsburgh sleep quality index (PSQI) measurement of self-reported scores, and the secondary outcomes included total sleep time and sleep efficiency measured by actigraphy. Meta-analyses were performed with the random effects model using the RevMan software. The standardized mean difference (SMD) of the PSQI scores and other measures with their 95% confidence intervals (CIs) were used for assessing the treatment effect (CRD42023370947).p = 0.006). Regarding total sleep time (p = 0.72) and sleep efficiency (p = 0.47), no significant effects of light therapy were found.Nine RCTs were identified and included in the study. Light therapy significantly improved the self-reported sleep quality with a reduction of the pooled PSQI score (SMD = −0.72; 95% CI: −1.24 to −0.21; Light therapy could improve self-reported sleep quality in cancer patients. However, due to the heterogeneity and small sample size of the included trials, the results should be interpreted cautiously. Trials with better designs and larger sample sizes are suggested to be conducted for a more definitive conclusion.Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=370947. It has Sleep disturbances and different sleep disorders  are common and considerable complaints of cancer patients. Pharmacological therapies   and nonpCompared with other non-pharmacological therapies, light therapy has been gaining attention because it is critical to all forms of life, and the circadian rhythms of human beings and other species are strongly affected by light . BiologiIn terms of the effectiveness of light therapy as a treatment option, there have been an increasing number of clinical trials investigating the effect of light therapy on sleep problems in patients with cancers , 24, 30.2.2.1.This study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The stuAccording to the PRISMA guidelines, the flow diagram of the study selection process, including the literature search, the reasons for exclusions, and the number of included studies was depicted see . Two autThe same two authors (LQY and ZYZ) independently screened all selected titles and abstracts, and read the full texts of relevant articles for eligibility. The eligibility criteria for inclusion were: (1) The studies are randomized controlled trials (RCTs) being published in English; (2) The participants were cancer patients or survivors; (3) Intervention measures were specifically bright light therapies, while the control measures were dim light therapies, placebo or usual care; (4) The primary outcomes were measured by the Pittsburgh Sleep Quality Index (PSQI); the secondary outcomes, namely the total sleep time and sleep efficiency at the end of the intervention, were assessed using physiological sleep measurement devices . Studies were excluded if they were: (1) not RCTs; (2) duplicated studies; (3) missing data on the primary and secondary outcomes; (4) not published in English; (5) the controls were not cancer patients; (6) the intervention measures included a combination of light therapy with another treatment , while the control group did not receive the same extra treatment. For duplicated studies, data were only extracted from the one with the most complete and updated information.2.2.Data were individually extracted and checked by authors YLQ and ZYZ independently using a predesigned data extraction form designed with Microsoft Excel. The following data of study characteristics were extracted: author, year of publication, country, sample size, age, gender, type of cancer, stage of cancer, the timeframe of diagnosis or therapy, previous treatment, intervention, and control descriptions, intervention duration, primary and secondary outcomes. The risk of bias was independently evaluated according to the Cochrane risk-of-bias assessment tool . Selecti2.3.p values, or t values), it would be performed. If the information was unavailable to assess the mean and SDs, the studies were excluded from the meta-analysis, although they had been included in the systematic review. The effect sizes were presented as the standardized mean differences (SMDs) between the intervention group with the light therapy and control groups with the corresponding 95% confidence intervals (CIs). Cohen’s classifications were used to categorize the effect sizes   was used to perform the meta-analysis. The mean and standard deviations (SDs) of the outcomes at the trial were extracted and estimated. If the studies did not report mean and SDs, the authors of the trials were contacted via email to request the information. According to Cochrane Handbook Version 6.3 and the previous study , 36, if  effect) . In thisogeneity . The ran3.3.1.Nine studies in total met all eligibility criteria and were included in the meta-analysis. These studies included a total of 451 participants, with 234 in the intervention group and 217 in the control group. Of these, five were conducted in the US , 39, 40,3.2.p = 0.006), suggesting light therapy might improve the overall sleep quality in cancer patients. However, the level of heterogeneity in the overall analysis was high , suggesting a considerable amount of variabilities in these studies.Nine studies were included in the meta-analysis reporting PSQI as the primary outcome , 39–44. p = 0.72), with insignificant heterogeneity issues .Six studies were included in the meta-analysis reporting total sleep time , 42–44. p = 0.47). The results indicated that the heterogeneity was low .Five studies were included in the meta-analysis reporting sleep efficiency , 43, 44.The forest plots of light therapy on PSQI and physiological sleep quality indexes were presented in 3.3.The results of the risk of bias assessment were summarized in 3.4.p = 0.01; n = 5)    (p > 0.05). As for total sleep time and sleep efficiency, the pooled effect size for the subgroups of all variables showed no significant differences between light therapy groups and control groups , and no significant subgroup differences of enhancing effects were found in total sleep time and sleep efficiency . The results of subgroup analyses were presented in The study’s authors further conducted subgroup analyses for PSQI, total sleep time, and sleep efficiency based on the following variables: country, gender, the number of participants, and light duration. Regarding the country, the effect size for PSQI showed a significant difference between the intervention group with the light therapy and control groups in the US  , 39, 40,; n = 4) . As for ; n = 6) , 39–41, ; n = 3) . Regardi3.5.I2 value of heterogeneity decreased slightly from 80 to 68%, however, the p-value was significant  and the trimmed sample . Hence, the sample size might not be the main reason, and there would be other sources of variabilities, such as the clinical characteristics of different samples. This is worthy of further research in the future. The results obtained on the risk of biases analyses suggested a heterogeneity issue with the outcome of PSQI scores. In addition, only a small number of trials were found on the topic and the sample sizes of most of these trials were small. This might render the meta-analyses lacking the power to demonstrate a true effect. Hence, these results should be interpreted with caution. As aforementioned, as a treatment option, light therapy could be considered complementary to the current pharmacological management of sleep problems in cancer patients  and different devices, which are shown to be lacking in the current research. Last but not least, future studies could apply cost-effectiveness analyses as part of the outcome measures.5.Light therapy has the potential to improve sleep quality and support mental health in cancer patients. However, this systematic review and meta-analysis found no evidence regarding the effects of light therapy on some physiological sleep indexes. Additionally, due to the heterogeneity, and small sample size of included RCT studies, future trials need to consider using a larger sample, different characteristics of participants, phototherapy intensities and devices, longer intervention, and follow-up durations, to obtain a more accurate estimation of the benefit of light therapy in sleep quality for cancer patients.The original contributions presented in the study are included in the article/LY and ZZ conducted the literature review, wrote and revised the manuscript. LY performed the statistical analysis. LL formulated the study objectives, conceptualized the study plan, supervised LY, and reviewed and edited the manuscript. All authors have read and approved the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The following indexes were determined for each subject: waist-to-hip ratio (WHR), waist-to-height ratio (WtHR), body mass fat index (BMFI), visceral adiposity index (VAI), and cardiometabolic index (CMI). Overall, the presence of MetS was detected in 544 patients (62%). Pearson correlation coefficients were calculated to evaluate the relationships between body composition indexes and metabolic characteristics of the women. Receiver operating characteristic (ROC) analysis was used to determine the best predictor for each adiposity index among metabolic risk factors. The ROC analysis showed VAI (AUC = 0.84) and CMI (AUC = 0.86) showed the best performance in predicting MetS. Differences were found between the ROC area of CMI and VAI with all other indexes (p < 0.05). The optimal cutoff point for early diagnosis of MetS was >0.92 for WHR, >0.76 for WtHR, >30.1 kg m−1 for BMFI, >1.94 for VAI, and >0.84 for CMI. In addition, VAI and CMI were the most sensitive and specific indexes compared with other indexes. In conclusion, VAI and CMI represent the most useful and reliable indexes to be used for detecting MetS in women suffering from obesity in clinical practice.Recent evidence shows that simple and inexpensive anthropometric measurements can be used to identify, at an early stage, women with obesity at increased risk of developing metabolic syndrome (MetS). Thus, the aim of this study was to compare the accuracy of five different indexes of adiposity and/or body composition in identifying MetS in a group of 876 women : 43.6 ± 6.1 kg m In the last decades, the number of obese adults has increased worldwide , and theBody mass index (BMI) is the most used index in clinical practice to predict the risk of developing a MetS . HoweverThe diagnosis of MetS integrates anthropometric and biochemical parameters . TherefoTherefore, the aim of the present study was to evaluate the capacity of five indexes  to identify the presence of MetS in a large group of women with obesity. Since WHR, WtHR, and BMFI consider only anthropometric measures, whereas VAI and CMI integrate anthropometric and biochemical parameters, we hypothesized that VAI and CMI would be the most useful and reliable indexes for detecting MetS in a large group of women with obesity.−2)), consecutively hospitalized for a multidisciplinary 3-week body weight reduction program at the Division of Metabolic Diseases, Istituto Auxologico Italiano, Piancavallo, Verbania, Italy, between April 2017 and April 2019 was performed. All subjects had a full medical history and physical examination, with routine hematology and biochemistry screens and urine analysis. All subjects were Caucasian. All of the subjects suffered from essential obesity, other genetic, organic, endocrine, or iatrogenic forms having been excluded. None of the subjects had taken weight loss drugs during the 12 months before enrollment into the present study. The study was approved by the Ethics Committee of Istituto Auxologico Italiano, IRCCS, (Milan), Italy . The study was performed in accordance with the Declaration of Helsinki and with the 2005 Additional Protocol to the European Convention of Human Rights and Medicine concerning Biomedical Research. At the admission to our institute, the patients signed an informed consent for the anonymous use of all the biochemical and anthropometric data collected during their hospitalization to be used for subsequent scientific research.A retrospective cohort study based on 876 women (aged 52.1 ± 13.8 (range 18–83) years) with severe obesity (BMI 43.6 ± 6.1 (range 30.7–72.9) kg mThe medical history and a physical examination of subjects were taken at the time of admission to the hospital. BM was measured to the nearest 0.1 kg with an electronic scale , with the subject dressed only in light underwear. Stature was measured to the nearest 0.5 cm on a standardized Harpenden stadiometer . BMI was calculated as weight (kg) divided by stature (m) squared . Waist cDiastolic and systolic blood pressures (BPs) were measured to the nearest 2 mmHg in the supine position after 5 min rest using a standard mercury sphygmomanometer with an appropriately sized cuff. The average of three measurements on different days was used.Baseline blood samples were drawn by venipuncture after a 12 h overnight fast. Measurements of glycemia, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) were performed by standard enzymatic methods .According to the International Diabetes Federation (IDF) criteria , a diagnThe following indexes were calculated according to the following formulas:WHR :WC (cm)/WtHR : WC (cm)BMFI : BMI  were first scrutinized for outliers using a cutoff of 4.5 standard deviation score. No patient was excluded on this basis. A Shapiro–Wilk test was used to assess the normality of each continuous variable. Continuous data were presented as mean and standard deviation. Anthropometric and metabolic data of women with MetS (MetS+) and without MetS (MetS−) were tested for statistical significance using two-tailed t-tests. Pearson correlation coefficients were calculated to assess the relationship between body composition indexes and SBP, DBP, TG, and HDL-C.p < 0.05. The data were analyzed using STATA 17.0.Receiver operating characteristic (ROC) curves were then generated to obtain the values of the area under the curve (AUC), with sensitivity, specificity, and 95% CI for each index as a predictor of MetS. In addition, for all the indexes, we calculated their sensitivity and specificity, their positive and negative predicted value , and their positive and negative likelihood ratio  to determine which index of body composition and/or adiposity was the most reliable in identifying MetS. ROC analysis was performed to identify the best predictor for each adiposity index among the metabolic risk factors. To identify the optimal cutoff, the Youden index  was calcp < 0.001). Women with MetS had significantly higher values of BMI , WC , FFM (kg) , SBP , DBP , TG , HDL-C , and glycemia  than those without MetS (p < 0.001). No difference was found for BM, HC, FM (kg), FM (%), and FFM (%) between the two subgroups , VAI and TG , CMI and HDL-C , and CMI and TG .The correlations between the different indexes and cardiometabolic parameters are shown in −1 for BMFI, >1.94 for VAI, and >0.84 for CMI. The percentages of women who would have been diagnosed with MetS using each of the indexes are the following: WHR, 35.2%; WtHR, 65.4%; BMFI, 35.2%; VAI, 66.4%; and CMI, 68.6%.The ROC curves and the area under the curve (AUC) comparing the predictive abilities of WHR, WtHR, BMFI, VAI, and CMI for MetS in women are shown in p < 0.001), VAI and all indexes , except for VAI vs. CMI (p = 0.002)). No difference was found between the ROC area of WHR vs. WtHR (p = 0.521).Differences were found between the ROC area of CMI and all other indexes  in detecting MetS.First, we observed that women with MetS were older than women without MetS, and WC was higher in obese women with MetS than in women without MetS. Overall, the presence of MetS was found in 544 patients (62%). Normally, the prevalence of MetS in postmenopausal women ranges from 32 to 58% . In addiSecond, to our knowledge, this is the first study conducted on women with obesity that showed higher predictive accuracy in identifying MetS with two different indexes, such as VAI and CMI. These results are consistent with previous studies showing that VAI and CMI performed significantly better than the other indexes in identifying MetS in adolescents with obesity  and adulBecause the diagnosis of MetS involves anthropometric and biochemical parameters , both VANevertheless, VAI and CMI were the most sensitive and specific indexes compared with the others. At the same time, the PPV for VAI and CMI was higher than for WHR, WtHR, and BMFI, even when NPV was considered. Overall, it was found that PPV was higher than NPV according to the prevalence of MetS in the study population. PLR and NLR were higher for the VAI and CMI indexes, suggesting that these two indexes better predict the probability of a true positive or negative outcome. In contrast to our results, Radetti et al.  showed tOur study presents, however, some limitations. First, longitudinal studies are required to measure the evolution over time of the ability of the different indexes to predict MetS in women with obesity. Second, we did not perform DEXA assessment  of body fat in our study due to the large number of participants, the high cost, and the X-ray exposure of this measurement. The use of WC as a marker of central obesity represents a potential bias in the present study. However, the examination of the patients was performed by a well-trained and experienced team, thus reducing the risk of significant misinterpretation.Further additional studies are needed to evaluate different indexes in the different BMI classes using DEXA in order to measure body composition in women with obesity.Finally, we selected in the present study only Caucasian women with obesity. Therefore, it is not possible to generalize our conclusions to other ethnic groups.On the contrary, the strength of this study lies in a large number of women with obesity who were recruited in a single third-level center for multidisciplinary obesity rehabilitation, examined by a well-trained staff of physicians, and with biochemical assessments by the same laboratory.In summary, VAI and CMI perform better than the other indexes in detecting metabolic syndrome. The two indexes simply require the evaluation of WC, height, and BMI, and the concomitant evaluation of two simple, easy, and routinely measurable biochemical parameters. Thus, the two indexes prove to be the best predictors of MetS that can be easily used in clinical practice. However, as mentioned above, our results will require to be confirmed with the use of better methods of body composition measurement, such as DEXA. Finally, it should be emphasized that all indexes mentioned in this study should be considered a support for clinicians to identify the presence of MetS without replacing clinical assessment.Finally, future studies are needed to determine whether changes in VAI and CMI over the years could be useful to ensure early detection of MetS and to determine the most appropriate therapeutic and rehabilitative approaches to assist clinicians in their daily clinical practice.


The current research examined the effect of Emotionally Focused Couples Therapy (EFCT) on perceived intimacy, affect, and dyadic connection in cancer survivor couples with relationship challenges.In this longitudinal replicated single-case study, positive and negative affect, intimacy, partner responsiveness, and expression of attachment-based emotional needs were reported every 3 days before and during treatment. Thirteen couples, with one partner having survived colorectal cancer or breast cancer, participated for the full duration of the study. Statistical analysis of the data was performed using randomization tests, piecewise regression, and multilevel analyses.Adherence to the therapeutic protocol was tested and found adequate. Compared with baseline, significant positive effects on affect variables were found during the therapeutic process. Positive affect increased and negative affect decreased. Partner responsiveness, perceived intimacy, and the expression of attachment-based emotional needs improved, but only in the later phase of treatment. Results at the group level were statistically significant, whereas effects at the individual level were not.This study found positive group-level effects of EFCT on affect and dyadic outcome measures in cancer survivors. The positive results warrant further research, including randomized clinical trials, to replicate these effects of EFCT in cancer survivor couples experiencing marital and sexual problems. Cancer is a severe stressor in people’s lives and can negatively impact the quality of the intimate relationship, including partnered sexuality, and the ability to connect to the important other . In the Receiving a cancer diagnosis and going through the process of diagnostic and curative interventions can have major negative effects on the patient’s physical and mental health and quality of life, as well as on the quality of life of the partner . The psyA secure and supportive partner relationship can bolster individuals in dealing with daily distress . ProblemEmotionally Focused Couples Therapy is an evidence-based approach to improve the quality of partner relationships, that was developed after microanalysis of therapeutic alteration processes . It is bThe main goals of EFCT are expanding constricted emotional responses that prime negative interaction patterns, restructuring interactions to enable partners to become more accessible and responsive to each other, and to foster positive cycles of comfort and caring . Therefod = 1.3, that was reported in several meta-analyses . We also hypothesized that, in the later stage of treatment , EFCT would promote improvement in the quality of the attachment bond of both partners, measured as higher levels of partner responsiveness, of expression of attachment-based emotional needs, and of perceived intimacy with the partner.The current longitudinal study with frequent repeated measurements used a R-SCED to investigate the therapeutic effect of EFCT for couples treated for cancer and experiencing relationship problems. Selected endpoints were emotion regulation, quality of the attachment bond, and perceived intimacy.Eligible participants had completed their primary treatment for colorectal or breast cancer between 12 months and 5 years prior and had not experienced recurrence of their cancer. Additionally, they were between 18 and 75 years of age and had a romantic partner for at least 3 months. Both partners had to agree to undergo treatment. Eligible couples screened positive for relationship distress, as measured using the Maudsley Marital Questionnaire  , lack ofCancer survivors in 11 Dutch hospitals and cancer centers involved in colorectal and breast cancer treatment were informed by their treating physician of the possibility to apply for participation in the study. Interested couples received information about the research aims, the treatment protocol, and the requirements for participation. Eligible patients then completed baseline assessment of relationship difficulties, intimacy problems, and unsupportive communication, and were asked to confirm if their partner agreed to undergo EFCT treatment and participate in the study. Ethical approval for this study was obtained from the ethical review board of the Zuyderland Hospital in Heerlen, Netherlands.For the current study, a protocol was developed based on the three stages of EFCT  and nine steps . The trepositive and negative affect (“I feel … cheerful/anxious”) , intimacy with four items , desire for sexual intimacy with two items , attachment-based emotional needs with three items (“At this moment…. I feel the need for my partner’s presence”), and partner responsiveness with four items . This questionnaire was used in previous research of the research team .” Both partners received a prompt on their mobile phones. They were instructed to complete the questionnaire independently and to discuss their responses only after completion, if they desired to do so. The ADQ is comprised of selected items from validated questionnaires, including the Positive and Negative Affect Schedule PANAS;  and the rch team .The 20-item Maudsley Marital Questionnaire (MMQ) was used to measure relationship dissatisfaction, sexual dissatisfaction, and general life dissatisfaction. It uses 9-point Likert scales (range 0–8). The MMQ is organized in three subscales: marital dissatisfaction, sexual dissatisfaction, and general life dissatisfaction. Higher scores indicate greater dissatisfaction. The reference time frame is past 2 weeks. Reliability statistics are satisfactory, with Cronbach’s alpha ranging from 0.60 to 0.88 .The 14-item Revised Dyadic Adjustment Scale (RDAS) was used to measure quality of relationship functioning. It uses 5- and 6-point Likert scales (range 0–5/0–6). The RDAS is organized in three subscales: consensus, satisfaction, and cohesion. Higher scores indicate greater stability and satisfaction. The reference time frame is “in the current relationship.” Reliability statistics are excellent, with Cronbach’s alpha of 0.90 .The 14-item Hospital Anxiety and Depression Scale (HADS) was used to measure levels of anxiety and depression complaints. It uses 4-point Likert scales (range 0–3). The HADS is organized in two subscales: depression, and anxiety. Higher scores indicate greater distress. The reference time frame is past weeks. Reliability statistics are satisfactory, with Cronbach’s alpha ranging from 0.67 to 0.93 .The questionnaires used to determine eligibility for the study  were repeated after treatment ending and after 26 weeks follow up. These questionnaires were used for descriptive purposes only. See To examine the level of adherence to the treatment protocol, two master-level students at the Open University, Netherlands, conducted procedural fidelity checks. Audio recordings of treatment sessions were compared to the steps described in the protocol of that particular session, as suggested by Confirmatory factor analysis of ADQ data  was performed to investigate the dimensions of the questionnaire and to confirm the factor structure in the multilevel data set. Correlations between the identified factors were calculated for all outcome measures  to understand the underlying associations between the various outcome measures. For these analyses, we used the Lavaan package in R .Consistent with the R-SCED design, individual results for each outcome variable were examined to evaluate the therapeutic effects of EFCT. Initially, piecewise regression (PWR) analyses were performed on individual data to evaluate and compare “before” and “during” treatment segments for the five outcome measures .Secondly, data of the couple were compared to assess whether changes on the determined outcome variables in one person would correlate to similar changes for their partner at the same time, using covariance calculations.Affect variable (combining positive affect and mirrored negative affect) and a Relationship Dynamic variable , according to the theoretical EFCT model. The focus in the first stage of EFCT is on de-escalation of negative emotions, and the focus in the subsequent stage is on creating more security in communication, improving the expression of emotional needs, and increasing partner responsiveness. Based on this therapeutic framework, a positive shift in affect level was expected to occur early in the therapeutic process, shortly after start of treatment; the positive shift in the level of the relationship dynamic outcome variable was expected to occur in the second stage of treatment. Hence, the “moment of change” for the statistical analysis for Affect was at the start of treatment (immediately following the baseline period), and for Relationship Dynamic outcome variables at the start of the second stage of treatment (after baseline and first treatment stage). Significance level for all statistical analyses was 05, unless stated otherwise.Thirdly, for group-level analysis, multilevel PWR  and multFor inclusion in the statistical analysis, participants had to have completed a minimum number of five measurements during baseline and five measurements after the start of treatment .Thirty heterosexual couples were screened for participation. Three couples did not start therapy due to personal circumstances . The average age of the remaining 27 couples was 58.7 years . The average duration of the relationship was 27.4 years .Of the 27 couples that were included for therapy, 21 couples completed all 12 therapy sessions according to the research protocol. The six couples who dropped out attended between one and six sessions. Reasons given for dropout were: end of the romantic relationship, other mental health issues, experiencing the therapy as too intense, or being unable to combine therapy and research requirements with work. Low compliance with assessments, despite repeated prompts to complete the ADQ, resulted in missing data and exclusion of the data of 8 couples from the statistical analyses. Thirteen couples completed the minimum number of five completed measurements during baseline and five measurements after the start of treatment .M = 9.5, SD = 4.1; Depression: M = 10.4, SD = 3.6; M = 22.1; SD = 12.5; M = 51.4; SD = 6.3; The average age of these 26 participants was 58.4 years (SD = 12.0) and average duration of the relationship was 28.3 years (SD = 18.5). Nine cancer survivors had colon cancer , two male survivors had rectal cancer, and two female survivors had breast cancer. The reported pre-treatment anxiety and depression levels were “borderline high” [Anxiety: 2 (0.000), CFI (0.924), TLI (0.910), RMSEA (0.048), and SRMR (0.051) all exceeded the required thresholds for a good model fit, see The adequacy of the operationalization of the constructs of positive and negative affect, perceived intimacy, expression of emotional needs, and partner responsiveness was evaluated using Confirmatory Factor Analysis (CFA). The CFA yielded a good model fit for the Affect and Dynamics Questionnaire (ADQ) used in this research. The Chipositive and negative affect, intimacy, partner responsiveness, and expression of attachment-based emotional needs were not statistically significant, based on the randomization test  and perceived intimacy (r = 0.46). This indicates that increases in reported positive affect in the patient over treatment time tend to be paired with similar increases in positive affect in the partner. Smaller correlations between patient and partner were observed for negative affect (r = 0.15) and partner responsiveness (−0.09). Attachment-based emotional needs had a large negative correlation (r = −0.46); indicating that increases in expression of attachment-based emotional needs in the one partner tended to be accompanied by a decrease in emotional needs expression in the other partner, see To examine effects at the partner level, results within the dyads were compared. Covariances for normal distributions between partners showed medium to large correlations for partner responsiveness and attachment-based emotional needs . This indicates an improvement on these variables over time from the combined baseline and first phase of treatment to the later phase of treatment. Effects on positive affect (p = 0.444), negative affect (p = 0.74), and on perceived intimacy (p = 0.174) were not significant, see At the group level, randomization tests revealed significant treatment effects on p = 0.002), but the effect on Affect was not significant (p = 0.652), see In multilevel PWR analysis the composite Affect and Relationship Dynamics variables both showed a significant change in the expected direction, i.e., Both Affect and Relationship Dynamics improved during treatment, see expression of attachment-based emotional needs and partner responsiveness. The effects on affect variables were not significant. These results imply that EFCT for cancer survivor couples who experience relational and sexual problems has positive effects on the participants’ expression of attachment-based emotional needs and on the responsiveness of partners to each other’s needs. These findings align with other research findings in the field of EFCT  between these factors. Intimacy showed a positive trend in most participants and a stable flat line for others. A possible explanation for the lack of a significant effect on intimacy is that several couples already experienced a high level of intimacy at baseline, leaving less room for improvement. Additionally, potentially other, cancer-related factors, such as physical discomfort or body image issues after surgery, might have interfered with achieving improvements in intimacy. Testing these hypotheses was outside the scope of this study but would add to the understanding of the dynamics of intimacy in couples after cancer treatment.Emotionally Focused Couples Therapy’s background theory postulates that partner responsiveness and intimacy are closely related factors. This corresponds with our finding of a high correlation  can be found below: The studies involving human participants were reviewed and approved by the Medisch Ethische Toetsingscommissie (METC)–Atrium–Orbis–Zuyd. The patients/participants provided their written informed consent to participate in this study.SD, JL, BO, AB, BA, and NA contributed to the conceptualization of the study. AB prepared the data collection. SD and PV performed the data analyses. SD, JL, BO, PV, and NA contributed to the writing and reviewing of the manuscript. All authors contributed to the article and approved the submitted version.


The prevalence of erectile dysfunction (ED) and premature ejaculation (PE) has been investigated in many population-based studies in different regions of the world. However, reliable data are lacking for Eastern Europe. Therefore, the aim of this study was to analyze the prevalence, effect on quality of life, and treatment-related behaviors for ED and PE in a population-representative sample of Polish men. We used an Internet interview format and rigorously adapted, widely accepted instruments for ED and PE evaluation. The study included 3001 men, representative for age and place of residence and adequate proportions of respondents from urban and rural areas. The prevalence of ED was 30.1–61.1%, and the prevalence of PE was 19.3–38.1%; there were no differences between urban and rural areas. Whereas the prevalence of ED increased with age, the prevalence of PE did not increase. More than 50% of respondents with ED and more than 60% of respondents with PE had concerns about their quality of life. However, less than one fourth of participants with ED and PE were seeking treatment, most of whom received treatment. The results of our nationwide analysis, reflecting the entire Polish population of men, are consistent with other epidemiologic studies of ED and PE and may support educational campaigns and health improvement programs in Poland. Both conditions lead to multiple issues in personal and social functioning, impairment of physical, mental, and emotional health, and finally to decreased overall well-being and quality of life2, and the overall PE prevalence being from 2 to 60%3. Such wide disparities are often due to differences in the selected study population, e.g., hospital- versus community- versus population-based, age, survey methodology, participant population size, data collection method, definition of disorder or symptoms, and culture or ethnicity.A substantial group of large epidemiological studies have been focused on evaluating ED and PE at the population level in many parts of the world. Perhaps interestingly, these studies yielded disparate results, with the overall ED prevalence varying from 3 to 76.5%4. Although there are some population-level analyses on ED from Central  and Eastern  Europe, these studies have been performed in single cities  or burdened with a significant selection bias in terms of sample representativeness . In sum, no large population-representative study in any country of this region has been conducted to reliably evaluate the prevalence of ED and PE. Indeed, experts stipulate that, for high-quality research, investigators should use generally accepted and professionally adapted instruments, ideally in surveying representative pools7. Population estimates of ED and PE are needed to increase general awareness, promote physical and mental health, and start appropriate educational programs. These data also tempt multidisciplinary frameworks for national health improvement programs and service deliveries instituted with appropriate allocation of resources by governments and healthcare systems.Despite the many existing epidemiological studies, reliable data for ED and PE are still lacking for Central and Eastern Europe. Even in large-scale and population-representative European studies conducted to ascertain the prevalence of ED or PE, countries from Central and Eastern Europe have not been included9; by land area, Poland is the third largest in Eastern Europe, after Russia and Ukraine, and the farthest east of the European Union countries10. Until now, no reliable and population representative study on ED and PE has been conducted in Poland. Poland and other Central and Eastern European countries are demographically unique, having homogeneous or even supra-ethnic uniformity; particularly for Poland, ≥ 99% of residents are Caucasian and ≥ 90% of residents are of Polish identity11. Such unique population features need to be considered when discussing population-based studies for any symptoms or disorders. Further, healthcare-related behavior may vary significantly between countries and regions because of local cultural norms that may inhibit individuals from admitting or discussing their health issues, especially when it comes to sensitive topics like sexual life12. Indeed, Central-Eastern Europe is often considered a distinct cultural entity, and Slavic people are culturally different from other European people13. Additionally, a relatively high number of people in Poland live in rural regions. Most data from elsewhere on prevalence, burden, and treatment-related behaviors for ED and PE may not be fully transferable to Poland because the epidemiological data originate from industrialized areas, including data publicized as being from low- or middle-income countries, with no comparisons between urban and rural areas. An analysis of treatment behaviors is particularly important for ED because medical attention for this condition may uncover other serious and asymptomatic morbidities early in the course of disease 1. Considering all these factors, our understanding of the prevalence and true burden of ED and PE in Poland is limited. Fortunately, the importance of population-based studies has gained attention in Poland and Central-Eastern Europe14. This new focus is related mainly to the increasing awareness of the detrimental impact of ED and PE on health-related quality of life. Therefore, the aim of this study was to reliably evaluate the prevalence, effect on quality of life, and treatment-related behaviors for ED and PE in a population-representative sample of adult men aged ≥ 18 years in all geographical regions of Poland.Poland is the largest country in Central Europe15.This study was a population-based, representative, and cross-sectional investigation performed to provide estimates (stratified by age and place of residence) of ED and PE in Poland (running title: ED POLAND). We followed standardized guidelines and well-established recommendations for reporting observational studies4. Because 93.33% of households in Poland had Internet access for 2022, with no significant differences between urban and rural areas , web interviews are justified for reliable population-based studies. Pilot web-surveys with cognitive debriefing comments (n = 200) were conducted before data collection to ensure that lay persons correctly understood the survey questions. All questions and terms were presented in Polish.We conducted computer-assisted web interviews (CAWI) between 1 September and 1 November 2022. Given the sensitive nature of the survey subject, and after considering the general applicability of large-scale studies on sex life, we implemented a CAWI system to guarantee the anonymity of the men respondents, to encourage their participation, and to avoid interviewer bias. We opted out of face-to-face interviews and telephone surveys because direct contact between interviewers and participants could have distorted our results. Moreover, previous studies have demonstrated that results from Internet surveys on sexual health  were not different from those obtained by other methods, such as telephone surveys or mailed questionnaires17. The quota controls included age and place of residence . For both urban and rural areas, we used definitions provided by the Central Statistical Office of Poland to appropriately cover these two types of regions: (1) urban areas (cities and towns) including areas located within the administrative boundaries of cities and towns; (2) rural areas (countryside) including areas outside the administrative boundaries of the cities, which consist of areas of rural gminas and rural parts of urban–rural gminas18.The most recent population census (2021) and the proportionate quota sampling method were employed to construct a population-representative sample of respondents 19. The IPSOS is a research agency with relevant international quality certificates  and prospective population-level databases of respondents, e.g., pre-existing Internet panels 19. The panel members, extracted by quota controls, were sent e-mail inviting them to participate in a confidential survey . A unique Uniform Resource Locator (URL) was sent to each participant. All responses, during the entire study period, were collected on a web server with appropriate Secure Sockets Layer (SSL) certificate that authenticates a website identity and enables an encrypted connection. During data collection, there were regular quality-control and stratification checks. After data collection, post-stratification weights were calculated to correct any imbalances based on differences in response rates that were not detected during data collection. The weights were computed by ranking the completed interviews to the marginals for the matching variables  before all statistical analyses. In addition, to exclude fraudulent responses, participants were excluded if they answered the survey too slowly (more than 10 min per page) and too quickly (a response time of less than 20% of the average response time).The IPSOS Poland administered the surveyGeneral demographic data were collected for each respondent, including age, level of education, employment status, and marital status.20, the most used2 and the consensual instrument for the evaluation of male sexual function1. PE was evaluated with the Premature Ejaculation Diagnostic Tool (PEDT)21, a valid screening instrument for PE22 that captures the essence of the multidimensional definition of PE1. Both questionnaires were rigorously translated and adapted into Polish24, and they are recommended by the European Association of Urology1.ED was assessed using the five-item International Index of Erectile Function (IIEF-5)Participants were also asked about their overall  and sex-specific  quality of life, treatment-related behaviors , relevant comorbidities  and lifestyle habits . All comorbidities were self-reported; we did not seek validation from medical records.The primary study objective was to estimate the prevalence of ED and PE in men aged ≥ 18 years in Poland. Because previous studies were based on different thresholds of IIEF-5 and PEDT scores to assess ED and PE prevalence, we decided to adapt diverse definitions of various score intervals to make our results reliably comparable with multiple studies. For ED prevalence, definition I: IIEF-5 score of 21 points or less; definition II: IIEF-5 score of 16 points or less. For PE prevalence, definition I: PEDT score of 9 points or more; definition II: PEDT score of 11 points or more.Secondary study objectives included the prevalence of different levels of ED severity , the effect of ED and PE on overall and sex-specific quality of life, the treatment behaviors for ED and PE, the correlations between ED/PE and relevant comorbidities/lifestyle habits, and the direct relation between ED and PE.p < 0.05. STATISTICA  was used to conduct data analysis.Quantitative variables were characterized by means, standard deviations, medians, minimum and maximum values (ranges), and 95% confidence intervals (CIs). Categorical variables were presented with numbers and percent. The Shapiro–Wilk test was used to test a normal distribution and the Leven (Brown-Forsythe) test was used to test the hypothesis of equal variances. Differences between two groups were tested with the Student t-test  or with the Mann–Whitney U test (model of unrelated variables) or with the Wilcoxon pair order test (model of related variables). Differences between more than two groups were tested with the F test (ANOVA) or Kruskal–Wallis test (model of unrelated variables) or with the Friedman test (model of related variables). When statistically significant differences between groups were obtained, post hoc tests were used . For categorical variables, Chi-square test was applied . The Pearson and/or Spearman correlation coefficients were calculated to establish relationships, strengths, and directions between variables. To analyse the effect of comorbidities and lifestyle habits on ED and PE, we also used logistic regression models. For regression models, we included results of the questionnaires as raw data (raw scores). Statistical significance was considered at 28. Thus, we computed the sample size based on the population age distribution, available from the recent census17, and expected ED/PE prevalence. Assuming a 95% confidence interval, we calculated that 2200 men in Poland would exceed the required sample size for estimating ED/PE prevalence. However, after analysing the recent census with general recommendations for future population-representative analyses, and after consulting with two independent teams of epidemiologists with relevant healthcare backgrounds, the sample size was raised to 3000 respondents. This increase in sample size provided smaller margins of error with no negative effects on any statistical analyses17. With a national sample of 3000, there was a 95% certainty that the overall survey results would be between ± 1–2% of what they would have been had we polled the entire adult male Polish population.For sample size calculation, we followed the methodology that was used in other population-based studies of ED/PEThe study was performed in compliance with Good Clinical Practice and in accordance with the Declaration of Helsinki. The Research Ethics Committee of Jagiellonian University Medical College, Krakow, Poland approved the study (1072.6120.331.2021); in addition, the study was registered with ClinicalTrials.gov (NCT05462171).All participants provided informed consent.In all, 3001 men from across the country participated in the survey (response rate: 51.7%). Given the large sample size, the respondents were categorized into six age groups, 18–24, 25–34, 35–44, 45–54, 55–64, and ≥ 65 . Most of the participants had at least secondary education, were employed, and married. More respondents lived in urban areas than in rural regions (75.8 vs. 24.2%). Table p < 0.0001, Spearman’s correlation coefficient R = −0.63). In all age groups, except for ≥ 65, ‘mild’ ED was the most prevalent ED severity category. In the ≥ 65 age group, ‘mild to moderate’ ED was the most prevalent group. In addition, the severity of ED increased with age .The prevalence of ED was 61.1% based on IIEF-5 score of 21 points or less (definition I), and the prevalence was 30.1% based on IIEF-5 score of 16 points or less (definition II). With both definitions, the prevalence of ED increased with age . However, other basic demographical parameters had important effects on ED prevalence. The prevalence of ED was lowest among men who had higher education, were employed, and married .We did not find any difference in ED prevalence across all geographical regions (voivodships) of Poland. There were also no significant correlations between ED prevalence and urban/rural status .The prevalence of PE was 38.1% based on PEDT score of 9 points or more (definition I), and the prevalence was 19.3% based on PEDT score of 11 points or more (definition II). There were no differences in PE prevalence between age groups . We did not observe correlations between PE and education, employment, and marital status .The PE prevalence did not differ across all geographical regions (voivodships) of Poland. There were also no significant correlations between PE prevalence and urban/rural status .We also found that the more severe the ED or PE, the worse the overall quality of life .We also found that the more severe the ED or PE, the worse the sex-specific quality of life (for ED: Among respondents with IIEF-5 score of 21 points or less (definition I), 16.1% (n = 295) were seeking treatment and most of them  received treatment. For respondents with IIEF-5 score of 16 points or less (definition II), 23.4% (n = 211) were seeking treatment, and, again, many of these persons received treatment . For the respondents who received treatment, most continued treatment  and most were satisfied with their therapy .p < 0.01), to continue the treatment (p = 0.0239), and to be satisfied with the treatment (p = 0.0037).We found that men with severe ED were more likely to seek treatment (p = 0.6978).Urban/rural status did not affect any treatment behavior for ED (Among respondents with PEDT score of 9 points or more (definition I), 14.4% (n = 165) were seeking treatment and most of them  received treatment. For respondents with PEDT score of 11 points or more (definition II), 15.4% (n = 89) were seeking treatment, and, again, most of these persons received treatment . For the respondents who received treatment, most continued  and were satisfied .p = 0.0001) and to continue the treatment (p = 0.0422).We found that men with severe PE were more likely to seek treatment (p = 0.7804).There were no differences between urban and rural areas in treatment behaviors for PE . The results are presented in Table We found a significant correlation between ED and PE; the likelihood of PE increased with the severity of ED  and the lowest prevalence in South America (up to 55.2%). The authors suggested that the geographical disparities in ED prevalence were likely determined by genetic, environmental, lifestyle, and, importantly, cultural factors. Our observation (n = 3001) of ED in 30.1–61.1% of men aged ≥ 18 appears broadly comparable with data from population-based studies performed in other countries and regions. Similarly, our analysis confirmed a trend of increasing ED prevalence with increasing age. However, although ED prevalence varies across countries and regions, we need to recognize that ED affects people worldwide, and it is a serious public health concern. Moreover, we need to consider that, to some extent, all factors that influence ED  do not appear to affect ED occurrence. As the population has become older, and as obesity, diabetes, and hypertension become more prevalent, ED is becoming more common.In a systematic review, Kessler et al. concluded that the global prevalence of ED was 13.1–71.2% as determined by studies based on the IIEF/IIEF-529. From 3,552 returned questionnaires, the authors estimated an ED prevalence of 42.7%. However, since this finding was reported, the investigation has been questioned because the results were not based on a population-representative sample but were based on clinical convenience samples of special patient populations. Critically, results of studies of clinical populations cannot be extrapolated to the general population25. Some experts correctly suggest that men who frequently visit their physicians are more likely to be diagnosed with ED, often because of their comorbidities. Further, Haczynski et al. did not exploit a widely used and rigorously adapted instrument to assess ED; instead, they used their own questions that were not universally vetted. Although the study of Haczynski et al. laid the foundations for ED research in Poland, recent improvements in assessing erectile function have triggered the need to determine the true burden of ED in Poland. This determination requires the use of a reliable and generally accepted questionnaire for ED evaluation of a representative pool of men. Finally, there has never been an assessment of seeking professional help, treatment receiving, treatment satisfaction, and treatment continuation for ED in Poland. In view of all these concerns, we instituted the ED POLAND study to assess the true burden of ED in Poland.Until now, only one study was conducted to assess the population burden of ED in Poland. In 2006, Haczyski et al. analyzed the data reported by 340 randomly chosen physicians who were asked to interview five to twenty consecutive patients aged at least 40 years about the presence of ED32, current diagnostic criteria are variable and largely rely on subjective measurements3. Further, experts recently proposed a new taxonomy for PE that encompasses other unaddressed and crucial clinical aspects of PE33. In addition, there is no consensus on normal ejaculatory latency time, perception of it varies by country, and diagnosis can further depend on whether it is assessed by patients or their partners. These limitations have impeded research on the prevalence of PE and the wide discrepancy in PE prevalence estimates has been well described1. The Global Study of Sexual Attitudes and Behaviors showed that approximately one-third of all men may have PE, but there were significant geographical differences34. The lowest prevalence was reported in the Middle East (12.4%), whereas the highest recorded prevalence occurred in Southeast Asia (30.5%). Notably, to assess PE, the study used only a single-item self-reported question about the reduction in ejaculatory latency time. Importantly, because bother is important for patient stratification, diagnosis, and treatment1, the current recommendation is that only individuals who report bothersome PE should be targeted  reduced ejaculatory latency time, (2) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy, (3) and perceived lack of control over ejaculation)33. As a patient’s perception of PE is both an important component of diagnosis or treatment success and often subjective and highly individual, validated screening instruments that include relevant symptom burden of the disease seem to be optimal in population-based analyses1. Interestingly, the evolution in methodology of studies to assess PE prevalence has been noted; whereas some older studies estimated PE prevalence from single questions that asked about early ejaculation or that used crude time-intervals to ejaculation 36, recent studies were based on validated instruments for PE screening39. Therefore, we used the PEDT, a questionnaire that has demonstrated high sensitivity and specificity in identifying PE1, and its validity has been widely accepted in estimating PE prevalence in other large population-based analyses39. With the PEDT, we revealed a PE prevalence of 19.3–38.1%. In the United States Global Online Sexuality Survey study that also was based on the PEDT, 49.6% of respondents were classified as having PE38. In contrast, with the same instrument the PE prevalence was 12.1% in a Korean cohort of married couples40. These results agree with those reported from Italy and Australia, where PEDT-assessed PE prevalence was estimated to be 15.6%41 and 16%42, respectively. When we consider differences in methods of measuring PE and study populations, overall PE prevalence in our study appears consistent with international analyses. Moreover, in our study, we did not find an association between PE prevalence and age, an observation consistent with other global analyses43.The prevalence of PE has not been analysed to an extent similar to that of ED. Because there is lack of a clear and universally accepted definition of PE44. Although these conditions are not life-threatening, they result in withdrawal from sexual intimacy and may lead to anxiety, depression, anger, frustration, poor self-esteem, guilt, and lack of confidence. In additions, partners of ED and PE patients may be negatively impacted by ED and PE due to relationship difficulties and sexual dissatisfaction. The occurrence of ED may even negatively affect work productivity because men with ED have higher rates of absenteeism due to psychosocial and physical reasons45. Generally, many studies demonstrated that men with ED and PE experience a deterioration in psychological, social, physical, and economic well-being compared with men who do not have these conditions44.We confirmed that ED and PE had negative effects on overall and sex-specific quality of life. Importantly, the degree of bother caused by ED and PE may be independent of how researchers define ED and PE46. The results of European Burden of Illness Study  showed that more than half of European men with self-reported ED did not discuss their condition with their physician47. For PE patients, a study from Turkey demonstrated that 22.4% of PE individuals were actively looking for treatment48. In Spain, a population-based study showed that only 16.7% of participants with PE were active in seeking information about the condition49. Barriers to seeking treatment include embarrassment, anxiety, social stigma, and treatment cost. In addition, often people are simply unaware that there may be treatment for their ailment; this issue is particularly important for men with PE. The knowledge about treatment-related behaviors may significantly support educational campaigns, health improvement programs, and resource allocation. Without adequate information about treatment, individuals cannot take optimal treatment seeking action. Finally, we can speculate that a true communication gap exists between Polish patients with PE or ED and their physicians.The low rate of treatment seeking despite the negative effects of ED and PE on multiple aspects of life is a significant public health concern. We showed that only 16.1–23.4% of respondents with ED and 14.4–15.4% of those with PE were seeking treatment. Fortunately, most of these individuals received treatment, they continued the treatment, and they were satisfied with the treatment. The low percentage of people with ED and PE who sought treatment has been reported elsewhere. An Asian study showed that only 21% of men with ED sought medical care33. Comorbidity of ED and PE has been reported51, and experts hypothesized a vicious cycle of ED and PE33. On the one hand, a man striving to control his ejaculation instinctively reduces his level of excitement, leading to ED. On the other hand, a man attempting to have an erection tries to increase his excitation, and the resulting overexcitement can undermine ejaculatory control52. Because the standard screening for ED and PE may lead to false positive results (up to 33%)53, experts propose introduction of the loss of control of erection and ejaculation as the primary definition of a disorder that is viewed as two deeply interrelated sexual symptoms33. Importantly, introducing this novel disorder may help to avoid consideration of ED and PE as completely separate entities.We investigated a significant correlation between ED and PE at the population level. Therefore, our results support recent recommendations based on the new taxonomic clinical entity of the loss of control of erection and ejaculation2, other studies have been based on a lower threshold of 16 points or less, e.g., the Boston Area Community Health Survey54. The threshold of 16 points or less combines patients characterized as ‘no ED’ and ‘mild ED’ and makes a stricter estimate of ED, sometimes even considered as a clinically significant ED25. For the same reason, i.e., to make our results broadly comparable and to present population estimates that can be compared with multiple studies, we adapted two thresholds of PEDT: 9 or more (the threshold that combined respondents with ‘probable PE’ and ‘PE’21), and 11 or more (a stricter definition that comprised only respondents with ‘PE’21). Importantly, other investigators used this approach of two different PEDT cut-offs in population-based studies of PE56. Thus, our population-based analysis, that was planned in line with the current guidelines and recommendations, provides a clear view of the prevalence and related effects of ED and PE in Poland.A strong point of our study was an adequate representation of the entire population, with well-balanced demographic characteristics, and appropriate proportions of urban and rural area participants. We also employed the recent census to stratify our variables. Because our sample size was large (n = 3001), the results were within ± 1–2% of statistical error for the national population, making our analysis one of the most accurate in the current literature of ED and PE prevalence for a single country. We used well-established and rigorously adapted diagnostic tools for ED and PE evaluation together with many other questions. Before conducting the study, we extensively reviewed the literature to select appropriate instruments and to adapt appropriate cut-offs for these instruments. Although some investigators who performed population-level studies adapted the most widely used IIEF-5 threshold of 21 points or less to recognise ED43. To evaluate overall and sex-specific quality of life, we used only single questions. We did not ask about all factors that may interfere with the quality of life  as we had to limit the number of questions in our survey to foster respondent compliance. Because this study was conducted in Poland, results may not be generalizable elsewhere, especially for treatment-related behaviors. However, similar findings on behaviors related to treatment have been reported in other countries.A main limitation of our study was the use of self-reports to measure ED and PE without medical evaluation. We did not also investigate the sexual orientation of respondents. In addition, we did not investigate the prevalence of lifelong and acquired PE. Nevertheless, because there is no consensus on definitions of lifelong and acquired PE, this assessment of lifelong and acquired PE was also omitted from other population-based studiesThis investigation was the first nationwide, population-representative epidemiological study of ED and PE performed in Poland. ED and PE were prevalent conditions and had negative effects on quality of life. However, less than one fourth of respondents with ED or PE were seeking treatment. Our findings agree with other epidemiologic reports of ED and PE conducted in different regions of the world, and our findings can support educational campaigns and health improvement programs for patients with ED and PE.