The rs6296 polymorphism in the 5-HT1b receptor in Dutch men with lifelong premature ejaculation: a genetic case-control association study.

BACKGROUND: Lifelong premature ejaculation (LPE) is a rare sexual condition believed to be caused by genetic neurobiological disorders. AIM: In this study we sought to evaluate the genetic association between the rs6296 polymorphism of the 5-HT1b receptor and intravaginal ejaculation latency times (IELTs) in men with LPE compared with men in a control group. METHODS: This study was a prospective observational genetic case-control association study. The LPE definition of the International Society for Sexual Medicine (ISSM) 2013 was used. Patients were recruited in 2005-2009 while attending the department of Neurosexology, HagaZiekenhuis, the Netherlands. We obtained IELTs with the stopwatch method. Polymerase chain reaction (PCR) was used for genotyping rs6296. A randomly selected group of European Caucasian men from the 1000GENOMES project was used as a control group. OUTCOMES: Study outcomes included results of comparisons of analysis of variance (ANOVA) tests between genotypes and IELTs in study participants, genotypes of cases and controls determined with the chi-square test, and expressions of allelotype- and genotype-specific risks for LPE determined with odds ratios. RESULTS: In total, 67 men with LPE were included in this study. The geometric mean (SD) IELT was 32.0 (27.4) seconds and was non-normally distributed. Genotype frequencies consisted of 29 (43.3%) GG, 31 (46.3%) GC, and 7(10.4%) CC individuals in the LPE group. Log-transformed IELTs were not statistically significant (per ANOVA tests) in men with GG, GC, or CC genotypes (P = .54). Genotype frequencies consisted of 16 (6.6%) GG; 93 (38.8%) GC, and 131 (54.6%) CC individuals in the control group (n = 240). Significant differences were found when comparing allele (P = 1.02e-17) and genotype (P = 3.22e-16) frequencies in cases and controls using a chi-square test. A statistically significant increased risk for LPE was found for carriers of the G allele (OR 5.62; 95% CI 4.13-9.42). Statistically significant risks were also found for the CG genotype (OR 6.24; 95% CI 2.63-14.77) and the GG genotype (OR 33.92; 95% CI 12.79-89.93). CLINICAL IMPLICATIONS: By investigating polymorphisms in target genes the neuro-pathophysiology of LPE could be further elaborated, potentially leading to more effective treatment. STRENGTHS AND LIMITATIONS: This is to our knowledge the first study investigating rs6296 with regard to LPE. By using a strict definition for LPE (ISSM 2013) and using the stopwatch method for measuring IELTs, bias in selection of true LPE patients will be relatively low. This study is limited by a relatively small study population and the lack of IELT data in the control group. CONCLUSIONS: This study shows a genetic association in rs6296 in men with LPE compared with healthy controls. This result warrants attempted replication in future studies.

Target attainment and population pharmacokinetics of flucloxacillin in critically ill patients: a multicenter study.

PURPOSE: Insufficient antimicrobial exposure has been associated with worse clinical outcomes. Reportedly, flucloxacillin target attainment in critically ill patients was heterogeneous considering the study population selection and reported target attainment percentages. Therefore, we assessed flucloxacillin population pharmacokinetics (PK) and target attainment in critically ill patients. METHODS: This prospective, multicenter, observational study was conducted from May 2017 to October 2019 and included adult, critically ill patients administered flucloxacillin intravenously. Patients with renal replacement therapy or liver cirrhosis were excluded. We developed and qualified an integrated PK model for total and unbound serum flucloxacillin concentrations. Monte Carlo dosing simulations were performed to assess target attainment. The unbound target serum concentration was four times the minimum inhibitory concentration (MIC) for ≥ 50% of the dosing interval (ƒT>4xMIC ≥ 50%). RESULTS: We analyzed 163 blood samples from 31 patients. A one-compartment model with linear plasma protein binding was selected as most appropriate. Dosing simulations revealed 26% ƒT>2 mg/L ≥ 50% following continuous infusion of 12 g flucloxacillin and 51% ƒT>2 mg/L ≥ 50% for 24 g. CONCLUSION: Based on our dosing simulations, standard flucloxacillin daily doses of up to 12 g may substantially enhance the risk of underdosing in critically ill patients. Prospective validation of these model predictions is needed.

Extremely high unbound flucloxacillin concentrations in a patient with acute septic renal failure during continuous venovenous hemofiltration: Therapeutic drug monitoring to optimize treatment.

A 75-year-old female orthopedic patient with spondylodiscitis was admitted to the intensive care unit, where she developed severe acute renal injury (AKI) due to a Staphylococcus aureus bloodstream infection. Continuous venovenous hemofiltration (CVVH) was initiated as renal replacement therapy. According to physician experience and based on (inter)national guidelines and the severity of the infection, treatment with intravenous (IV) flucloxacillin at an initial continuous dose of 9 g/24h was started. The dose was increased to 12 g/24h because endocarditis could not be excluded. Therapeutic drug monitoring (TDM) was used to monitor flucloxacillin levels which are related to antibiotic efficacy and toxicity. Total and unbound flucloxacillin concentrations were measured following 24 hours of continuous infusion at three time points before regional citrate anticoagulation (RCA)-CVVH was initiated, at three time points in plasma, pre-filter, and post-filter, and in ultrafiltrate samples during RCA-CVVH treatment and 1 day following cessation of CVVH treatment. Extremely high total (up to 299.8 mg/L) and unbound (up to 155.1 mg/L) flucloxacillin concentrations were found in the plasma. This led to a dose decrease to 6 g/24h and subsequently to 3 g/24h. Antimicrobial target attainment against S. aureus was achieved by dosing IV flucloxacillin based on TDM. Based on these findings, we conclude that current dosing guidelines for flucloxacillin during renal replacement therapy need revision. We suggest a starting dose of 4 g/24h, which should be adjusted based on the TDM of the unbound flucloxacillin concentration.

Population pharmacokinetics of unbound ceftriaxone in a critically ill population.

OBJECTIVE: To develop a reliable 2-compartment population pharmacokinetic (PK) model for unbound ceftriaxone in a critically ill population and determine an optimal dosing regimen. MATERIALS AND METHODS: This was a prospective, single-center, observational study of critically ill patients treated with ceftriaxone. Unbound serum ceftriaxone concentrations were measured using validated ultrafiltration and ultra-performance liquid chromatography-tandem mass spectrometry. PK analysis and dosing simulations were performed using an iterative 2-stage Bayesian fitting procedure and Monte Carlo simulations. The PK/pharmacodynamics (PD) target was attained when unbound serum ceftriaxone concentrations exceeded 4 times the minimum inhibitory concentration (MIC) for ≥ 60% of the dosing interval (ƒT>4xMIC ≥ 60%). RESULTS: 91 patients were enrolled, and 173 unbound ceftriaxone concentrations were acquired. The population PK parameter estimates were hepatic clearance 5.2 ± 0.9 L/h/1.85m2, the unbound renal clearance of ceftriaxone divided by the creatinine clearance 0.61 ± 0.24, lean body mass corrected volume of distribution of the central compartment 0.82 ± 0.21 L/kg, and intercompartmental distribution rate constant from central to peripheral compartment 0.18 ± 0.08 h-1. Dosing simulations predicted ƒT>4 mg/L of 88% (95% CI: 69 - 100%) for 2,000 mg ceftriaxone once daily and ƒT>4 mg/L of 100% (95% CI: 100 - 100%) both for 1,000 mg twice daily and continuous infusion of 2,000 mg daily. CONCLUSION: We developed a reliable population PK model for unbound ceftriaxone in a critically ill population. Dosing simulations revealed ƒT>4 mg/L ≥ 60% for 1,000 mg twice daily and 2,000 mg once daily or by continuous infusion.

Iatrogenic topiramate poisoning in an ICU patient: Focus on topiramate peak time prolongation.

A 35-year-old man with generalized insults was admitted to the intensive care unit because of third-line treatment of persistent epileptic insults with antiepileptic drug therapy. Topiramate was added on top of his outpatient regimen in combination with intravenous antiepileptic drugs. Miscommunication and inappropriate topiramate dosing (2,500 mg twice) resulted in an acute topiramate intoxication. Toxicokinetic assessment showed toxic serum topiramate concentration of 55 mg/L and a dose-dependent shift of peak time tmax. According to our modulations, tmax follows Y = 0.0009X + 2.65, where X is the topiramate dose. Our results have important implications for effectiveness of gut decontamination modalities.

No effect of norepinephrine dose on anti-Xa activity in critically ill patients
.

OBJECTIVE: Low-molecular-weight heparins are frequently used to prevent venous thromboembolism. Vasopressor therapy may be associated with inadequate anti-factor Xa activity, thereby increasing the risk of venous thromboembolism. We aimed to assess the association between anti-factor Xa activity and norepinephrine dose in intensive care unit (ICU) patients treated with subcutaneous dalteparin for venous thromboembolism prophylaxis. MATERIALS AND METHODS: This was a prospective observational pilot study in adult ICU patients treated with dalteparin 5,000 IU subcutaneously once daily and norepinephrine > 0.25 µg/kg/min. Peak anti-factor Xa activity was monitored and dalteparin doses were adjusted following a predefined dose algorithm. RESULTS: From November 2016 to April 2018, 32 patients were included. No correlation was found between norepinephrine dose and anti-factor Xa activity (r = -0.01, 95% confidence interval = -0.47 - 0.27, p = 0.57). Furthermore, following dalteparin 5,000 IU once daily, 28% of the patients showed anti-factor Xa activity < 0.10 IU/mL. Higher body mass index (BMI) (p < 0.001) but not patients' norepinephrine dose, age, or serum creatinine were risk factors for anti-factor Xa activity < 0.10 IU/mL. Dose increments to 7,500 IU once daily resulted in anti-factor Xa activity ≥ 0.10 IU/mL in all 5 patients (p = 0.043). CONCLUSION: In this cohort of ICU patients, no association was found between norepinephrine dose and anti-factor Xa activity following subcutaneous dalteparin 5,000-IU administration once daily. Furthermore, nearly one-third of the patients showed anti-factor Xa activity below the target concentration for venous thromboembolism prophylaxis. Higher BMI was an independent risk factor for reduced anti-Xa activity.

Non-steroidal anti-inflammatory drugs increase urinary neutrophil gelatinase-associated lipocalin in recreational runners.

OBJECTIVES: To study the effects of running with/without the use of pain killers on urinary neutrophil gelatinase-associated lipocalin (uNGAL) and other parameters of kidney function in recreational runners. METHODS: Participants of the 10- and 21.1-km Weir Venloop race were enrolled and their urine samples collected before and after the run. Urine dipstick and other conventional tests used to assess kidney function were performed. The presence of ibuprofen, diclofenac, naproxen, and/or paracetamol was assessed by LC-MS/MS. uNGAL was measured with a two-step chemiluminescent immunoassay. RESULTS: NSAIDs/analgesics were detected in urine of 5 (14.4%) 10-km runners and 13 (28.9%) 21.1-km runners. Only half-marathon participants showed significant increases in uNGAL (pre: 11.7 [7.1-34.3] ng/mL; post: 33.4 [17.4-50.4] ng/mL; P = .0038). There was a significant effect of NSAID/analgesic use on uNGAL increase (F2, 76  = 4.210, P = .004). Post hoc tests revealed that uNGAL increased significantly in runners who tested positive for ibuprofen/naproxen compared to runners who did not use any medications (P = .045) or those who tested positive for paracetamol (P = .033). Running distance had a significant influence on the increase in uNGAL (F1, 53  = 4.741, P < .05), specific gravity (F1, 60  = 9.231, P < .01), urinary creatinine (F1, 61  = 10.574, P < .01), albumin (F1, 59  = 4.888, P < .05), and development of hematuria (χ2 (4) = 18.44, P = .001). CONCLUSIONS: Running distance and use of ibuprofen/naproxen were identified as risk factors for uNGAL increase in recreational runners.

Quantification of total and unbound cefuroxime in plasma by ultra-performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure.

BACKGROUND: Pharmacokinetic studies of cefuroxime by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) have been limited to measurements of total concentrations. Here, we developed a robust method for quantifying total and unbound cefuroxime concentrations using UPLC-MS/MS and ultrafiltration in critically ill patients with hypoalbuminemia and renal failure. METHODS: Method validation included accuracy, linearity, precision, repeatability, recovery, and limit of quantification (LOQ). Feasibility of the method was performed on samples obtained from randomly selected intensive care unit (ICU) patients. Total and unbound cefuroxime concentrations were quantified using UPLC-MS/MS. Sampling times were categorized as trough (180-1 min prior to administration), peak (10-30 min after administration), mid (30-360 min after administration), and continuous (sampling during administration). Pharmacokinetic/pharmacodynamic (PK/PD) targets were unbound cefuroxime concentrations above 4 times the minimum inhibitory concentration (32 mg/L). RESULTS: Intra-assay and inter-assay precision was <3%. Recovery was 99.7%-100.3%, and LOQ was 0.1 mg/L. We included 11 patients (median age 72 years (range 54-77). Median albumin serum concentrations and eGFR were 19 g/L (range 11-40 g/L) and 48 mL/min/1.73 m2 (range 7-115 mL/min/1.73 m2 ), respectively. Median trough and mid concentrations of total cefuroxime were 22.27 mg/L (range 5.42-54.03 mg/L) and 71.49 mg/L (range 53.87-73.86 mg/L), and median unbound fraction was 75.42% (range 27.36%-99.75%). Median unbound cefuroxime concentrations were 11.94 mg/L (range 3.85-32.39 mg/L) (trough) and 55.62 mg/L (range 10.03-62.62 mg/L) (mid). CONCLUSION: The method is precise and accurate according to ISO 15189 and within the clinical range of cefuroxime (0.5-100 mg/L). The method was applied in ICU patients and is suitable for TDM on unbound cefuroxime concentrations.

Population Pharmacokinetics of Cefuroxime in Critically Ill Patients Receiving Continuous Venovenous Hemofiltration With Regional Citrate Anticoagulation and a Phosphate-Containing Replacement Fluid.

BACKGROUND: Cefuroxime is frequently prescribed as an antimicrobial therapy in critically ill patients. The aim of this study was to develop a new intravenous dosing strategy for cefuroxime in critically ill patients undergoing continuous venovenous hemofiltration with regional citrate anticoagulation (RCA-CVVH) by analyzing its extracorporeal removal and pharmacokinetic (PK) parameters. METHODS: Nine critically ill patients treated with intravenous cefuroxime and RCA-CVVH and a phosphate-containing replacement fluid were investigated. Arterial and effluent samples were obtained from all patients and pre- and postfilter venous blood samples were obtained from a subgroup of 5 patients. Plasma cefuroxime levels were determined by ultraperformance liquid chromatography-mass spectrometry in plasma samples collected before and after intravenous infusion of either 1500 mg cefuroxime every 12 hours or 3000 mg continuously over 24 hours. Population PK analysis and dosing simulations were performed using nonlinear mixed-effects modeling and Monte Carlo simulations. RESULTS: The volume of distribution (VD) of cefuroxime in the central compartment, corrected for lean body mass, was 0.11 ± 0.056 L/kgLBMc, CVVH-mediated clearance was 49.5-50.6 mL/min, the mean elimination half-life (t½) was 90 minutes (77-103), and the mean sieving coefficient was 0.89 ± 0.01. A 2-compartment model with between-subject variability in clearance, VD, and t½ described these data adequately. Simulation of a standard dosing regimen (750 mg/12 hours) predicted failure to achieve the international target plasma cefuroxime concentration (32 mg/L). CONCLUSIONS: Cefuroxime clearance by RCA-CVVH was twice the reported clearance during standard CVVH. Our PK data predicted that a maintenance dose of 3000 mg cefuroxime, infused over 24 hours, would provide an optimal steady-state plasma concentration of 38.5 mg/L. The developed population PK model for cefuroxime has the potential to inform new dosing schedules in patients receiving cefuroxime during RCA-CVVH.

Possible pathophysiologic roles of neurotransmitter systems in men with lifelong premature ejaculation: a scoping review.

INTRODUCTION: Lifelong premature ejaculation (LPE) is a subtype of premature ejaculation. Genetic research on LPE has primarily focused on neurotransmitters such as serotonin, dopamine, and norepinephrine, whereas LPE treatment studies have focused on drugs such as selective serotonin reuptake inhibitors. However, findings from genetic association and pharmacotherapeutic studies have been inconsistent. OBJECTIVES: To provide a quality overview of neurobiological targets that are potentially associated with LPE by investigating genetic association and pharmacotherapeutic studies. METHODS: This scoping review was conducted per the PRISMA-ScR tool (Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews). Five databases were searched in March 2023 without timeline- or language-related restrictions. RESULTS: After deduplication, 3949 records were obtained for review. Following screening and full-text review with citation tracking, 52 studies were included: 18 genetic and 34 pharmacotherapy studies. Serotonergic targets, such as the serotonin transporter and pre- and postsynaptic serotonergic receptors, were most often associated with LPE in genetic and pharmacotherapeutic studies. Mixed results were found among polymorphisms within genetic studies. This mechanism is in accordance with pharmacotherapeutic studies, as the highest efficacy was found for potent serotonergic antidepressants. Successful treatment was also observed with medication acting on phosphodiesterase-5 enzyme, such as tadalafil and vardenafil. Analyses of other genetic association studies did not yield any further evidence for associated targets. CONCLUSIONS: This review is the first comprehensive scoping review on LPE. We found that serotonergic targets are most often associated with LPE, suggesting that the serotonergic pathway is a predisposing factor in LPE. Furthermore, there is some evidence for phosphodiesterase 5 inhibitors, which should be investigated. Other previously investigated neurobiological targets appear less likely to contribute to LPE. Future studies should focus on multiple targets, ideally in a genome-wide association study design.This review has been registered with the Open Science Framework (doi:10.17605/OSF.IO/JUQSD).

His452Tyr 5-HT2A polymorphism and intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation.

Lifelong premature ejaculation (LPE) may have heritable components. Selective serotonin reuptake inhibitors have been proven effective in prolonging intravaginal ejaculation latency time (IELT). Given that serotonergic pathways are involved in the ejaculation mechanism, we aimed to investigate whether His452Tyr, also known as the C1354T (RS6314) polymorphism of the 5-HT2A receptor, contributes to LPE pathogenesis and IELT differences among patients with LPE. Dutch Caucasian men with LPE (n = 65) attending the Outpatient Department of Neurosexology, HagaZiekenhuis for drug treatment for LPE in 2009 were selected and included in this case-control study. IELT during coitus was measured using a stopwatch, and all men were genotyped for the His452Tyr polymorphism. Analysis of variance (ANOVA) was performed to determine the association between the genotypes and IELTs. Mean IELTs with standard deviations were 29.7 (±20.9), 31.5 (±14.7), and 26.0 s, and the frequencies were 83.1%, 15.4%, and 1.5% for the CC, CT, and TT groups, respectively, with an average IELT of 29.9 s. No difference in mean IELT was observed between these groups. In the affected group, the frequencies of alleles C and T were 90.8% and 9.2%, respectively; whereas those among randomly selected European Caucasian male controls (n = 503) from the CEPH database were of 92.0% and 8.0%, respectively. No significant difference was observed between the groups. Therefore, no correlation was found between the His452Tyr polymorphism and IELT distribution in patients with LPE.

Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin.

BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin. OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD). METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts. RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor. CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.

Adult male patient with severe intellectual disability caused by a homozygous mutation in the HNMT gene.

Histamine is involved in various physiological functions like sleep-wake cycle and stress regulation. The histamine N-methyltransferase (HNMT) enzyme is the only pathway for termination of histamine neurotransmission in the central nervous system. Experiments with HNMT knockout mice generated aggressive behaviours and dysregulation of sleep-wake cycles. Recently, seven members of two unrelated consanguineous families have been reported in whom two different missense HNMT mutations were identified. All showed severe intellectual disability, delayed speech development and mild regression from the age of 5 years without, however, any dysmorphisms or congenital abnormality. A diagnosis of mental retardation, autosomal recessive 51 was made. Here, we describe a severely mentally retarded adolescent male born from second cousins with a homozygous mutation in HNMT. His phenotypic profile comprised aggression, delayed speech, autism, sleep disturbances and gastro-intestinal problems. At early age, regression occurred. Treatment with hydroxyzine combined with a histamine-restricted diet resulted in significant general improvement.

Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation.

INTRODUCTION: Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 minute, and has been postulated as a neurobiological dysfunction with genetic vulnerability for the short IELTs, related to disturbances of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor functioning. AIM: To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTLPR) and short IELTs in men with lifelong PE. METHODS: A prospective study was conducted in 89 Dutch Caucasian men with lifelong PE. IELT during coitus was assessed by stopwatch over a 1-month period. Controls consisted of 92 Dutch Caucasian men. All men with LPE were genotyped for a 5-HTT-promoter polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of 5-HTTLPR polymorphism were compared between patients and controls. Association between LL, SL, and SS genotypes, and the natural logarithm of the IELT in men with LPE was investigated. MAIN OUTCOME MEASURES: IELT measured by stopwatch, 5-HTTLPR polymorphism. RESULTS: In men with lifelong PE, the geometric mean, median, and natural mean IELTs were 21, 26, and 32 seconds, respectively. There were no significant differences in the 5-HTT polymorphism alleles and genotypes between 89 Dutch Caucasian men with LPE (S 47%, L 53%/LL 29%, SL 48%, SS 22%) and 92 Dutch Caucasian controls (S 48%, L 52%/LL 29%, SL 45%, SS 26%). In men with lifelong PE there was a statistically significant difference between LL, SL, and SS genotypes in their geometric mean IELT (P < or = 0.027); the LL genotypes had significantly shorter IELTs than the SS and SL genotypes. CONCLUSIONS: The 5-HTTLPR polymorphism is associated with significant effects on the latency to ejaculate in men with lifelong PE. Men with SS and SL genotypes have 100% and 90% longer ejaculation time, respectively than men with LL genotypes.

Men with subjective premature ejaculation have a similar lognormal IELT distribution as men in the general male population and differ mathematically from males with lifelong premature ejaculation after an IELT of 1.5 minutes (Part 2).

Men with Subjective premature ejaculation (PE) have complaints of PE but have normal intravaginal ejaculation latency time (IELT) durations. We found two previously published large epidemiological stopwatch-mediated IELT studies to encompass IELT details of men with Subjective PE, albeit this term was not mentioned in both studies or in reviews of them. In the current study we developed the mathematical formula of the IELT distribution of men with complaints of PE, as diagnosed by a clinician on basis of the DSM-IV-TR definition of PE, as reported in the two studies performed in the USA and Europe, respectively. The formula was calculated by investigation of the fitness of various well-known mathematical Probability Density distributions into the IELT distribution of the PE men and non-PE men of the two studies. The better the fitness the lower is the Goodnes of Fit (GOF). Another aim of the study was to investigate whether the IELT distribution of men with "complaints" of PE (Subjective PE) differs mathematically from the IELT distribution of the general male population and that of Lifelong PE. The overlap of the area under the curve (AUC) of the IELT distribution of the men with PE complaints and that of the general male population was calculated together with the cut-off point at which the AUC equals 10%. We found that the IELT distributions of the PE men in both studies were Lognormal distributions and that at the cut-off point at which the AUC is equal to 10% (p = 0.10) the IELT is 1.5 min, indicating that after 1.5 min the IELT distribution of males with complaints of PE becomes mathematically identical to that of the general male population. In conclusion, there is hard mathematical evidence that the IELT distribution of men with complaints of PE with normal IELT values (e.g., the Lognormal IELT distribution of Subjective PE) and the IELT distribution of men with Lifelong PE (e.g. the Gumbel Max IELT distribution) belong to two independent populations. According to the applied mathematical calculations Subjective PE starts after an IELT of 1.5 min and encompasses all higher IELT values. It may imply that the current IELT cut-off point in Lifelong PE should be 1.5 min instead of the approximate 1 min, as has previously been stated by ISSM and DSM 5.

Use of a confirmed mathematical method for back-analysis of IELT distributions: ejaculation time differences between two continents and between continents and men with lifelong premature ejaculation (Part 1).

Recently it was shown that a stopwatch-measured IELT distribution can be transformed to a mathematical formula of a specific mathematical type distribution. The IELT distribution of men in the general population is a Lognormal distribution whereas that of Caucasian men with lifelong premature ejaculation (PE) is a Gumbel Max distribution. In this article, we developed the mathematical formula of the IELT distribution of two other previously published stopwatch-mediated IELT studies in the general male population of the USA and Europe, respectively, by investigating the fitness of various well-known mathematical probability density distributions into the IELT distribution of the two studies. The better the fitness the lower is the goodnes of fit (GOF). We found that the lognormal distribution most accurately fitted the IELT distribution of 1405 men in the general population of the USA, and 1026 men in the general population of Europe, with a GOF of 0.056 and 0.061, respectively. The current study also shows that the Lognormal IELT distribution of two European studies in Caucasian males are quite similar but that the Lognormal IELT distribution of men in the USA deviates compared to the two European IELT distributions. As the USA study also included 25% of non-Caucasian males it may be speculated that ethnical factors play a role in this deviation of the IELT curve. In conclusion, the Lognormal distribution of the IELT distribution in USA and European general male populations reconfirms our previous finding of a Lognormal IELT distribution in two random samples of the general male population in four European countries and USA. The Lognormal IELT distributions of the general male population highly contrasts to the Gumbel Max IELT distribution in Caucasian males with lifelong PE, as has previously been found.