A 64-year-old male presented with spontaneous intracerebral hemorrhage and obstructive hydrocephalus without evidence of a third ventricular mass in 2019. The patient was lost to follow-up and re-admitted one year later for hydrocephalus secondary to a third ventricular mass. Imaging characteristics were consistent with a colloid cyst, which was the presumptive diagnosis. A transcallosal transchoroidal approach was utilized for cyst resection. The cyst wall was carefully incised, releasing flakey, partially solid contents which were grossly inconsistent with a colloid cyst. Due to the concern of iatrogenic cyst rupture in the setting of unknown diagnosis, the patient was placed on steroids post-operatively. Surgical specimens sent at the time of surgery were consistent with dermoid cyst. We present the first reported case of a third ventricular dermoid cyst in an adult initially misdiagnosed as a colloid cyst based on imaging characteristics. Dermoid cysts are benign lesions that represent around 0.04-0.7% of intracranial tumors ,2. Most When found within the ventricular system, dermoid cysts are typically located in the fourth ventricle ,5. ThereIn July of 2019, a 64-year-old male presented with non-ST elevation myocardial infarction (NSTEMI) who underwent cardiac catheterization. Shortly after the procedure, he had altered mental status with additional symptoms of nausea and emesis. A comparative computed tomography scan of the head (CTH) from 2008 demonstrated no abnormal findings and no evidence of a third ventricular mass Figure . CTH froAn EVD was placed, and the patient was started on a continuous insulin infusion for management of the DKA. An MRI was obtained which demonstrated a third ventricular lesion that was T1 hyperintense, showed homogenous contrast enhancement with an area of hypointensity, and was T2 heterogeneously hypointense without diffusion restriction Figures -2f.The patient underwent a right-sided interhemispheric transcallosal transchoroidal approach for removal of the presumed colloid cyst. The cyst wall was carefully incised, releasing flakey, partially solid contents which were inconsistent with the presumed imaging diagnosis of the colloid cyst. Multiple intra-operative specimens were sent to the pathology department for frozen and permanent preparation. The cyst was debulked. The ventricular system was carefully irrigated with meticulous attention in an effort to evacuate residual cyst components. At the conclusion of the case, the pathologist was unable to make a preliminary diagnosis, citing the need for further permanent preparation stains and analysis. Due to the concern of iatrogenic cyst rupture in the setting of unknown diagnosis, the patient was placed on steroids post-operatively.Based on tissue analysis, the lesion’s features were consistent with those of a dermoid cyst. It contained keratin debris, stratified squamous lining, acute inflammatory cells, and a focal area with a granular layer Figure . There wDermoid tumors are rare and benign lesions that usually occur along the midline. They rarely occur within the ventricular system and when they do, they are typically found in the fourth ventricle . They arDermoid cysts typically appear as non-enhancing, hypodense lesions on CT secondary to fat generated by sebaceous secretions ,3,5. RarThere are only two other reports of third ventricular dermoid cysts Table . The firIn comparison, our patient presented in his seventh decade and he had no report of progressive symptoms and had no evidence of a congenital anomaly or dermal sinus tract. The two previous cases had obvious dermoid cyst characteristics on imaging, such as hair or teeth. Imaging of our patient did not demonstrate such characteristics and more closely resembled a colloid cyst. Pertinently, in May 2008, our patient had a CT scan without any evidence of a third ventricular lesion, confirming that this was not a congenital lesion. This dermoid cyst may have developed from iatrogenically implanted ectodermally derived skin cells when the EVD was placed in July 2019. In Per et al.’s review of iatrogenically lumbar epidermoid cysts, the range between lumbar puncture and presentation was two to 23 years . If thisIn conclusion, dermoid cysts are rare, benign intracranial lesions. Our patient’s third ventricular lesion was initially misdiagnosed as a colloid cyst based on imaging characteristics and location with biopsy proving the lesion to be a dermoid cyst instead. Third ventricular dermoid cysts are very rare lesions that vary significantly in both clinical presentation and management. Our case demonstrates the first-reported third ventricular dermoid cyst in an adult.


No significant difference was noted in the BAP level; sSGA infants exhibited a significantly higher d-ROM level than control infants. sSGA infants showed a significantly increased OSI compared with control infants, and the BW z-score was inversely correlated with d-ROM levels and OSI in sSGA infants  but not in controls. In conclusion, sSGA infants, including preterm infants, exhibited higher oxidative stress at birth. The severity of fetal growth restriction was significantly correlated with oxidative stress levels at birth in sSGA infants.Severe small-for-gestational-age (sSGA) infants exhibit increased mortality and morbidity. Oxidative stress is suggested to be involved in intrauterine growth restriction. This retrospective study aimed to evaluate the oxidative stress level at birth in an sSGA population. Sera of 28 sSGA (sSGA group) and 31 non-sSGA (control group) infants, born at our hospital between March 2017 and March 2020, were evaluated. Oxidative stress (derivative of reactive oxidative metabolites: d-ROM level), biological antioxidant potential (BAP) level, and the ratio of d-ROM/BAP level (oxidative stress index: OSI) were measured. The sSGA group had a significantly lower birth weight (BW), BW z-score, head circumference, and height than the control group (all  Small-for-gestational-age (SGA) infants are smaller in size than normal for their gestational age infants; these infants usually experience intrauterine growth restriction as fetuses . In addiOxidative stress occurs when reactive oxygen species and free radicals exceed the antioxidant capacity, which can result in oxidative damage . In pretThis retrospective study was approved by the Institutional Review Board of the Kobe University Graduate School of Medicine . The patients’ parents provided written informed consent for the use of personal medical data. Gestational age was determined based on a dating ultrasound scan during the first trimester. sSGA was defined as a birth weight of <−2 SD for gestational age ,6. The s3 levels).Maternal and neonatal data were collected from electronic medical records. Maternal data included maternal age, threatened premature labor , prematp < 0.05. Analyses were performed using GraphPad Prism version 7.00 .Oxidative stress  and biological antioxidant potential (BAP) were measured using FREE Carrio Duo  and then compared between the groups. In addition, the oxidant to antioxidant (d-ROMs/BAP) ratio  was calp < 0.05). No significant differences were seen in maternal or neonatal blood gas data between the groups.The clinical characteristics of the infants are presented in p = 0.09, p = 0.03, p =0.03, Although no significant difference was found in BAP (sSGA: 2528 1725–3765) vs. control: 2376 (1947–2814) µM, 25–3765 vn = 12) population and compared the level of d-ROM, BAP, and OSI. No significant difference was found in d-ROM (preterm: 65 (24–282) vs. term: 90 (13–189) U.CARR, p = 0.72, p = 0.37, p > 0.99, We subsequently divided sSGA infants into preterm (GA: 31 (23–36) weeks; BW: 1117 (284–1792); n = 16) and term (GA: 39 (37–40) weeks; BW: 2155 (1696–2434); 2 = 0.300; p < 0.01 and R2 = 0.319; p = 0.02, respectively), although no correlation was observed in control infants  [Gveric-Ahmetasevic et al. measured the serum levels of malondialdehyde (MDA), an oxidative stress marker, in umbilical blood samples at birth and venous blood samples at 3 days after birth in 47 term SGA infants; they reported increased MDA levels in both umbilical arterial and venous blood of SGA infants compared with those of controls, despite no difference in MDA levels in venous blood samples taken at 3 days after birth . Similar < 0.01) . It is nBased on clinical observations, Hussain et al. reported that the BW z-score and the incidence of hypospadias were inversely correlated in an SGA population . SimilarIn this study, the serum level of d-ROM and OSI was significantly higher in sSGA infants than that in control infants; however, no significant difference was noted in the BAP level between the groups. Our results agree with the findings of Watanabe et al., who reported that preeclamptic women with growth-restricted fetuses had significantly increased cord blood levels of d-ROM, but no significant differences in BAP level, compared with those of preeclamptic women without growth-restricted fetuses . In addiFurthermore, previous studies regarding SGA and oxidative stress have not included preterm infants, and no reports have examined the level of oxidative stress at birth in preterm SGA infants ,9. PreviThe main limitations of this study were that it was a retrospective study using residual clinical samples with a relatively small sample size. However, the number of patients was similar to that in previous reports ,9, and wThe severity of fetal growth restriction was significantly correlated with the levels of oxidative stress markers at birth in sSGA infants, suggesting that oxidative stress might play an important role in the perinatal pathophysiology of sSGA infants.


BackgroundPremature birth is the most important cause of perinatal mortality and morbidity. This study aimed to evaluate mortality and morbidity in premature infants over a five-year period at a university hospital providing tertiary intensive care health services.MethodologyAll premature infants born alive at ≤37 gestational weeks and hospitalized in neonatal intensive care units were included in the study. Data such as maternal and perinatal characteristics, characteristics of the newborn, respiratory and related problems, neonatal morbidities, and causes of death were retrieved retrospectively from file records.ResultsA total of 1,780 patients  were included in the study. High-risk pregnancy was present in 55% of women. Respiratory distress syndrome (RDS) developed in 50.4% of the patients, intracranial hemorrhage in 8.4%, and necrotizing enterocolitis in 5.6%. Mortality was observed in 20.9% of the patients. The most frequent cause of death was RDS and related complications (11.8%), and 66.4% of mortality occurred during the early neonatal period, that is, the first 24 hours of life.ConclusionsHigh-risk pregnancies were significantly associated with neonatal morbidity and mortality. Therefore, the management of maternal health factors should be the priority for controlling neonatal mortality. Premature birth is the most important cause of perinatal mortality and morbidity worldwide. Although prenatal care standards have improved and access to healthcare has increased in many countries, the incidence of premature birth continues to rise .Although complete data on premature birth rates are not available in Turkey, it is estimated to be approximately 11.9% . It is iThe study was retrospectively conducted at a tertiary university hospital between January 1, 2003 and December 31, 2007. All premature infants born alive at ≤37 gestational weeks and hospitalized in neonatal intensive care units were included in the study. Patient data were obtained from file records.Maternal and perinatal characteristics, maternal age, number of pregnancies, birth via in vitro fertilization (IVF) techniques, mode of delivery, cause of premature birth , characteristics of the newborn (such as gender and birth weight), respiratory and related problems, respiratory distress syndrome (RDS), surfactant treatment application, pulmonary hemorrhage, neonatal morbidities, presence of early and late sepsis, intracranial hemorrhage (ICH), hemodynamically significant patent ductus arteriosus (PDA) and congenital heart diseases, necrotizing enterocolitis (NEC), causes of mortality, and hospitalization periods as obtained from patient files were recorded in the case report forms prepared by the researchers. Furthermore, according to their birth weight, patients were divided into the following subgroups: 501-750 g, 751-1,000 g, 1,001-1,500 g, 1,501-2,000 g, 2,001-2,500 g, and >2,500 g .DefinitionsInfants with a gestational age of 37 weeks or less were considered premature . RDS wasEarly neonatal sepsis  and late neonatal sepsis  were diagnosed using blood culture growth ,7. ICH wEthical issuesThis study was approved by the Chief Physician of the hospital due to the retrospective design of the study and followed the principles for human investigations outlined in the Second Declaration of Helsinki.Statistical analysisData were recorded and analyzed using SPSS version 16.0 . Descriptive statistics were recorded as quantity and ratios and mean ± standard deviation (SD). The Chi-square test was used for statistical assessment, and p < 0.05 was considered to be significant.The study included 1,780 patients . Overall, 65.8% of the patients were born via cesarean section, and 34.2% were born via spontaneous vaginal delivery. The lowest gestational age was 22 weeks. The mean hospitalization period of the patients was 20.3 ± 22.9 days. The distribution of patients by gestational weeks is shown in Table The mean maternal age was 26.2 ± 5.8 years, ranging between 15 and 50 years. The analysis showed that 75.1% of the neonates were delivered in the hospital’s tertiary gynecology-obstetrics unit. The antenatal steroid use rate was 28.1%. In total, 55% of the mothers had a history of high-risk pregnancy. Eclampsia/preeclampsia was present in 12.4% of the mothers, diabetes mellitus in 6.2%, urinary tract infection in 4.2%, and chorioamnionitis in 8.4% Table . The meaThe incidence of RDS by birth weight is shown in Table The total incidence of RDS was 50.4%, with rates of 94%, 60.4%, and 33% reported for babies born at <28 weeks, 28-32 weeks, and 32-37 weeks, respectively . No cause of death other than prematurity was determined in 372 patients (11%). The most frequent cause of death was RDS and related complications (11.8%). The mortality rate in the RDS patient group with birth weights of 501-750 g was significantly higher than those with other birth weights (p < 0.05). The mortality rate associated with RDS decreased as the birth weight increased Table .In addition, there was a statistically significant decrease in the mortality rates caused by ICH and NEC with an increase in birth weight (p < 0.05). Table In terms of mortality, 23.4% of the deaths were reported in the first 24 hours of life, 66.4% in the early neonatal period including the first 24 hours, 23.4% in the late neonatal period, and 10.2% in the postneonatal period. The highest mortality rate in the early neonatal period was in the group with birth weights of 501-750 g 78.5%). Table .5%. TablOverall, 7.5% of the patients were born via IVF. In total, 23.3% of the infants born via spontaneous pregnancy were born from multiple pregnancies. The rate of multiple pregnancies was 92.5% among infants born via IVF, and the difference was statistically significant (p < 0.05). Echocardiography was performed for 18.8% of the patients, and PDA was detected in 17.6% of the patients.Despite increasing innovation and technological advancement in the fields of neonatology and perinatology, premature birth rates are still rising. Approximately 80% of preterm deliveries are reported to occur spontaneously as preterm labor (50%) or preterm rupture of membranes (30%). The remaining 20% of preterm deliveries involve interventions for maternal or fetal problems including antenatal care follow-up , postnatRDS is an important concern among preterm infants and is a significant cause of neonatal mortality. While Jaberi et al. reported that RDS occurred in 23.8% of all premature neonates, Caner et al. showed a 40.6% incidence of RDS among premature neonates ,16. The An RDS incidence of 58.6% was reported for babies with a birth weight of >2,500 g in the present study, whereas the VON 2008 data indicated an incidence of 30% . High-riAntenatal steroid intake reduces the risk of RDS . HoweverIn this study, 51.4% of the premature infants born before the 32nd gestational week required surfactant therapy. Similarly, Heljić et al. showed that approximately 50% of premature infants born before the 30th gestational week require surfactant therapy . Dani etICH is a major complication linked to long-term neurological sequelae in preterm infants. Although the incidence of ICH has decreased following improvements in neonatal intensive care in recent years, it remains an important concern in preterm infants with very low birth weight. Handley et al. reported an incidence of ICH of 15% in preterm infants born at less than 32 gestational weeks . In a stTogether with an increase in the diagnosis of PDA in recent years, the rate of medical therapy in PDA decreased from 32% to 18% . EmiroglNEC is the most important gastrointestinal emergency in premature infants. Caner et al. determined a 6.6% incidence of NEC in infants younger than 37 gestational weeks . Horbar Multiple pregnancies via assisted reproductive techniques increase the incidence of preterm births. A previous study showed that the risk of premature birth increased by 16.2% among singletons, 55% among twins, and 76% among triplets, indicating that pregnancy status among infants born via assisted reproductive techniques may be a risk factor for premature birth . SimilarThere are several limitations to the present study. Because the patient data were collected retrospectively, no information regarding the number of antenatal steroid administration was available. In addition, maternal socioeconomic status, another crucial risk factor for neonatal mortality, was not investigated. A common risk factor of neonatal mortality, such as mothers, was also not analyzed.High-risk pregnancies are significantly associated with neonatal morbidity and mortality. Therefore, the management of maternal health factors represents a priority for controlling neonatal mortality.


The human population residing in monazite bearing Kerala coast are exposed to chronic low dose and low dose rate external gamma radiation due to Th232 deposits in its beach sand. The radiation level in this area varies from < 1.0 to 45.0 mGy/year. This area serves as an ideal source for conducting large-scale epidemiological studies for assessing risk of low dose and low dose rate radiation exposure on human population. The areas with a dose level of ≤1.50 mGy/year are considered as normal level natural radiation areas (NLNRAs) and areas with > 1.50 mGy/year, as high level natural radiation areas (HLNRAs). HLNRAs were further stratified into three dose groups of 1.51-3.0 mGy/year, 3.01-6.00 mGy/year and > 6.0 mGy/year. The present study evaluates the effects of chronic low dose radiation (LDR) exposure on the birth prevalence of Congenital Heart Diseases (CHD) among the live newborns monitored in hospital based prospective study from NLNRAs and HLNRAs of Kerala coast, India.Consecutive newborns were monitored from two hospital units located in the study area for congenital malformations. Referred CHD cases among the newborns screened were confirmed by conducting investigations such as pulse oximetry, chest X-ray, electrocardiogram and echocardiogram etc.P = 0.005) reduction was observed in the birth prevalence of CHDs among the newborns from HLNRA (1.28‰) as compared to NLNRA (1.79‰).Among the newborns screened, 289 CHDs were identified with a frequency of 1.49‰ among 193,634 livebirths, which constituted 6.03% of overall malformations and 16.29% of major malformations. Multiple logistic regression analysis suggested that the risk of CHD among the newborns of mothers from HLNRAs with a dose group of 1.51-3.0 mGy/year was significantly lower as compared to NLNRA , whereas it was similar in HLNRA dose groups of 3.01-6.00 mGy/year  and ≥ 6.0 mGy/year . The frequency of CHDs did not show any radiation dose related increasing trend. However, a significant (Chronic LDR exposure did not show any increased risk on the birth prevalence of CHDs from high-level natural radiation areas of Kerala coast, India. No linear increasing trend was observed with respect to different background dose groups. The frequency of CHD was observed to be 1.49 per 1000 livebirths, which was similar to the frequency of severe CHD rate reported elsewhere in India and was much less than the reported frequency of 9 per thousand. Congenital malformations are structural, functional or cosmetic disabilities present at the time of birth. They develop prenatally and are identified at the time of birth or before or after birth. Congenital heart diseases (CHD) are one of the most common major birth defects, which can involve the walls, valves, arteries or veins of the heart. The birth prevalence of CHD varies widely worldwide and ranges from 0.6 to 75 per 1000 live births  with conAbout 70-80% of CHD cases are multifactorial in origin, which include interaction of both genetic and environmental factors . SeveralIonizing radiation (IR) has clastogenic, teratogenic and carcinogenic potential for induction of somatic and germinal mutations. Both paternal and/or maternal exposure may induce germline mutations in the parental lineage. The induced mutations may have its impact during conception, pre-implantation, organogenesis and general intra-uterine development , 9, whicThe risk of parental exposure to IR below 100 mSv on birth prevalence of CHD in human population is not clearly established. Linear No Threshold (LNT) hypothesis, commonly used as basis for regulatory and safety purposes, considers any dose of IR is harmful whether it is acute or chronic, low or high dose. Human population exposed to IR provides direct evidence on hereditary effects or cancer incidence. There are large scale epidemiological studies such as Atomic Bomb (A-Bomb) survivors, Chernobyl and Fukushima Daiichi nuclear disaster affected population, population exposed to occupational and medical exposures and most importantly, those residing in HLNRAs of the world such as Yangjiang (china), Guarapari (Brazil), Ramsar (Iran) and Kerala (India). Even the largest epidemiological study involving children of survivors of the atomic bombings (A-Bomb) in Japan did not indicate any significant impact of acute radiation exposures in human population . No statAlthough the transgenerational and intra-uterine effect of LDR on the development of heart disease is poorly understood, somatic effect of IR was recognized in late 1960s  when thoThe study area is a narrow coastal belt in the state of Kerala (55 km long and 0.5 km wide) in southwest India extending from Neendakara (Kollam district) in the south to Purakkad (Alappuzha district) in the north. It has a patchy distribution of monazite in its beach sand that contains Th-232, and its decay products. Due to the uneven distribution of monazite in the beach sand, the level of radiation exposure varies extensively in this area, which ranges from < 1.0 to 45 mGy/year , 20. TheThe objective of the present study is to delineate the risk and/or effect of chronic LDR exposure on CHDs among the newborns from HLNRAs and the adjoining NLNRAs of Kerala coast.Screening of the newborns in hospital units located in NLNRA and HLNRA is described in detail elsewhere , 24. Bri2 and radiation dose level of each grid was estimated by taking the mean of several survey meter  readings taken across the length and breadth of the grid at 1 m height from the ground and the dose was assigned to all the newborns with parental residence in the grid. Areas with a radiation exposure level above 1.5 mGy/year were considered as HLNRA and those below 1.50 mGy/year, as NLNRA [The study area was divided into small grids of 100 mas NLNRA .Chi-square test, with Yate’s continuity correction where indicated, was used to compare the frequencies of CHD across different sub-groups. Multiple logistic regression using STATISTICA software  was emplDuring the period from August 1995 till December 2020, a total of 194,167 newborns were monitored from 192,822 deliveries, which include 1318 twins, 12 triplets and one quadruplet in hospital units of NLNRA and HLNRA of Kerala coast. Age at birth of the mothers ranged from 15 to 45 years with a mean age of 24.7 ± 3.8 years and about 83% were in the age group of 20-29 years. Majority (~ 92%) of the births was either from first (46.2%) or second (45.6%) gravida/delivery. The overall sex-ratio of the newborns monitored was 1042 males to 1000 females. Among these, congenital malformations were detected in 4668 (24.04‰) newborns of which 1774 (9.14‰) had major congenital malformations. About 59%  newborns were from HLNRA and 41% , from NLNRA. Major malformations (0.92% v/s 0.91%), stillbirths including born alive but died immediately after birth (0.38% v/s 0.34%), down syndrome (0.065% v/s 0.065%) and live singleton newborns with low birthweight of < 2500 g (8.13% v/s 8.15%) were observed to be similar in HLNRA and NLNRA, respectively. The prevalence of paternal smoking habit was 35% and it was not associated with the risk of any of the end-points considered. Maternal smoking was rare (< 1%) in the study population.A total of 533 infants were born dead, either as still birth or intrauterine death and were excluded from the analysis of congenital heart disease (CHD) among the live births. Among 193,634 live newborns, a total of 289 newborns were identified as CHDs  with a frequency 1.49‰ of which 23 newborns with CHD  died within few days without any physical stress. Though male newborns with CHD died immediately after birth, which is twice as often as their female counterpart, the difference was not statistically significant . CHD constituted 6.03% of overall malformations and 16.29% of major congenital malformations with serious structural, functional, or developmental disability. About 86% of the newborns had CHD alone and the remaining 14% had other major malformations involving central nervous, musculoskeletal, genitourinary, gastrointestinal, respiratory systems or syndromes.Maternal age at birth, gravida status, gender of the newborns and radiation dose levels at the area of parental residence were found to be associated with overall as well as major congenital malformations. However, the variation observed in the frequency of malformations across different religious groups was well within the limits of random fluctuation Table . While tP = 0.026) with increase in CHD after the maternal age at birth of 26 years and a statistically significant maternal age at birth related linear trend . Newborns of mothers with gravida status of 4 or more had the highest frequency of CHD (3.42‰) as compared to 1.33‰, 1.59‰ and 1.67‰ among mothers with gravida status of 1, 2 and 3, respectively (P = 0.057). Female newborns had relatively higher frequency of CHD (1.59‰) as compared to male newborns (1.40‰), but the difference was not statistically significant (P = 0.291). Newborns from consanguineous (1.83‰) and non-consanguineous marriage groups (1.49‰) had statistically similar frequency of CHD (P = 0.778). The variation in the CHD frequency across the three religious groups i.e., Hindu, Christian and Muslim as well as that among different ethnic groups within Hindu religious group was within the limits of chance fluctuations/ occurrences.Detailed analysis of the frequency of congenital heart disease (CHD) among live births was carried out among the newborns monitored. CHD was least frequent in the maternal age group of 20-21 years (0.86‰) and most frequent (1.92‰) in the age group of ≥30 years (Table P = 0.024). The overall frequency of CHD in HLNRA was 1.28‰, which was significantly (P = 0.005) different from the frequency 1.79‰ observed from NLNRA.The data was stratified based on background radiation level at the area of parental residence and was grouped as ≤1.50, 1.51-3.0, 3.01-6.0 and > 6.0 mGy/year. The CHD rates among the newborns of mothers belonging to these areas were 1.79‰, 1.30‰, 0.98‰ and 1.64‰ respectively (Table The odds ratio (OR) was estimated using multiple logistic regression analysis to assess the individual contributions of maternal age at birth, gravida status, gender of the newborn, consanguinity, religion and ethnicity together with background radiation dose to the risk of CHD and is depicted in Table The background dose at the parental residence was further subdivided to assess the dose response of CHD with respect to radiation dose. The odds of CHD in each dose group together with its 95% CI is depicted in Fig. Of the 193,634 live newborns, paternal age was not available for 55 cases and it was less than maternal age in 380 0.2%) cases. Hence, analysis was done on 193,199 newborns to find out the influence of paternal age at birth. As maternal age and paternal age were highly correlated, the effect of paternal age at birth was analysed by grouping the newborns whose paternal age is more than the maternal age by 4 years or less (36.9%), 5-9 years (54.1%) and ≥ 10 years (9%). The analysis was carried out separately in the maternal age groups of 15-19, 20-21, 22-23, 24-25, 26-27, 28-29 and ≥ 30 years. The risk of CHD among newborns whose paternal age is more than the maternal age by 5-9 years and ≥ 10 years relative to those who were within 4 years was assessed by using odds ratio. The results as depicted in Fig. % cases. The present study is a part of the newborn monitoring programme in the HLNRAs of Kerala coast, India to assess the influence of natural chronic low dose and low dose rate IR exposure directly on birth defects on offspring at birth. The study evaluated the symptomatic cases of CHD among consecutive new-borns at birth, detected by clinical examination of the baby and/or by further clinical investigations, where necessary. The study population has a high literacy rate and practices small family norms, where more than 90% of the mothers had a gravida status of 1 or 2. More than 80% of mothers had an age at delivery or child birth between 20 and 29 years with almost fully institutionalized delivery. Other reproductive parameters monitored during delivery was comparable to developed countries , 26. TheA study based on acute radiation exposure from the Chernobyl accident has not found any correlation between radioactive contamination and CHDs . In our The heart is considered as a radio-resistant organ, which is not influenced by doses up to 30 Gy . High doThe overall statistically significant reduction in the risk of CHDs in HLNRA as compared to NLNRA and the apparent reduction, though not statistically significant, at the dose levels of 1.51-2.50, 2.51-3.50, 3.51-4.50, 4.50-6.0 and 6.01-15.0 mGy/year  population and paternal age is usually greater than maternal age (99.8%). It may not be possible to vary one ‘keeping the other constant’ so as to apply regression techniques to estimate the individual contribution of maternal and paternal age on CHD. Hence, it was attempted to describe the effect of paternal age by comparing the risk of CHD among newborns whose paternal age was more than the maternal age by 5-9 years and ≥ 10 years relative to those who were within 4 years . Moreover, the availability of large sample size of newborns monitored in NLNRA and HLNRA in Kerala coast for the last three decades for delineating the effect of chronic LDR exposure on CHD is noteworthy. To our knowledge this is one of the largest studies on newborns in the World, where the risk of LDR exposure in human population and the offspring is assessed. No such data is available on birth prevalence of CHDs in a larger cohort of newborn population to delineate the effect of LDR.This study is based on monitoring 194,167 consecutive newborns at birth and the large sample size is the major strength of this study. The chance of under ascertainment of severe CHDs detectable at birth was remote in the study since all newborns were examined by the paediatricians of the collaborating hospitals and their observations were verified by medical doctors of LLRRL, BARC trained in detecting congenital anomalies. All the relevant concomitant information was recorded in pre-coded proforma during the stay of the woman in the hospital by staff nurses and medical doctors of the hospital. The data were scrutinized for completeness and consistency by medical and paramedical staff of LLRRL, who made regular visits to the participating hospitals. The uniqueness of the study population such as lower maternal age at birth, acceptance of small family norms, universal antenatal folic acid supplementation, higher literacy rate mediated health awareness and practices may have influence in reducing the prevalence of major cardiovascular anomalies. As only suspected cases of CHDs were referred for further investigation, chance of missing minor CHDs may not be ruled out. Radiation exposure profile in the natural high-level radiation scenario is quite complex due to local movement of the population coupled with the general Indian pattern of shift of residence of female to her husband’s place after marriage. One of the limitations of the study is that the average dose at the area of residence of the parents was used in the study as a surrogate for the actual dose. Since the radiation level in the region under study is purely due to primordial radioactivity, drastic change in radiation levels over the years was unlikely. Smaller sample size from the areas with higher radiation levels was another limitation of this study, which is the characteristics of this population.P = 0.005. There was no increasing trend with respect to chronic low dose and low dose background radiation exposure to this population.In conclusion, the study revealed that natural chronic low dose and low dose radiation exposure did not increase the incidence of CHD in HLNRA of Kerala coast as compared to the adjacent NLNRA. On the contrary, a reduction in the birth prevalence of CHDs were observed among the newborns of mothers hailing from areas with HLNRA (1.28‰) as compared to those from normal level natural radiation areas (1.79‰),


DTI had higher negative and positive predictive values than mpMRI to predict PCa  77.8% (58.6–97.0%), negative predictive value (NPV) 91.7% (80.6–100%) vs. PPV 46.7% (28.8–64.5%), NPV 83.3% (62.3–100%)). We conclude from this pilot study that DTI combined with T2-weighted imaging may have the potential to improve PCa detection without requiring contrast injection.In the prostate, water diffusion is faster when moving parallel to duct and gland walls than when moving perpendicular to them, but these data are not currently utilized in multiparametric magnetic resonance imaging (mpMRI) for prostate cancer (PCa) detection. Diffusion tensor imaging (DTI) can quantify the directional diffusion of water in tissue and is applied in brain and breast imaging. Our aim was to determine whether DTI may improve PCa detection. We scanned patients undergoing mpMRI for suspected PCa with a DTI sequence. We calculated diffusion metrics from DTI and diffusion weighted imaging (DWI) for suspected lesions and normal-appearing prostate tissue, using specialized software for DTI analysis, and compared predictive values for PCa in targeted biopsies, performed when clinically indicated. DTI scans were performed on 78 patients, 42 underwent biopsy and 16 were diagnosed with PCa. The median age was 62 (IQR 54.4–68.4), and PSA 4.8 (IQR 1.3–10.7) ng/mL. DTI metrics distinguished PCa lesions from normal tissue. The prime diffusion coefficient (λ Multiparametric magnetic resonance imaging (mpMRI), including anatomical, dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI), is an effective tool for the detection of prostate cancer (PCa) with sensitivity and specificity both over 80% ,2. MpMRIDiffusion weighted imaging (DWI) is an important component in prostate imaging reporting and data system ver.2 (PI-RADS2) ,8. DWI qDTI metrics have been shown to identify cancerous lesions in glandular organs, such as the breast and pancreas ,10. The As far as we know, previous studies of the utility of DTI for PCa detection have mostly analyzed only a part of the existing DTI metrics, and showed inconclusive, yet encouraging, results ,20,21,22In this pilot study, we applied a new standardized DTI protocol and a proprietary software to automatically process diffusion images recorded in 32 directions. We compared DTI results to DWI and mpMRI used in the standard clinical setting for PCa detection.The research protocol was approved by the Rabin Medical Center Institutional Research Ethics Committee , and signed informed consent was obtained from all subjects.Eighty (80) consecutive patients, 40–80 years old, planning to undergo prostate MRI for suspected PCa were recruited. Indication for MRI was elevated prostate-specific antigen (PSA). Men under 50 were screened using PSA due to family history. Study inclusion criteria were males undergoing evaluation for suspected prostate cancer using a 3T MRI scanner, able to provide informed consent. Exclusion criteria were contraindications to MRI, such as metallic implants. We applied a DTI protocol in addition to the standard mpMRI protocol. We collected respective clinical and pathological data for each patient. 2), SENSE factor 2.0, SPAIR fat suppression, two averages, scan time 4:54 min); 3. a DCE axial 3D, T1-weighted single-shot turbo field echo sequence with gadolinium injection .Standard clinical mpMRI scans were performed on a 3T-scanner  using 32-channel posterior and 32-channel anterior torso coils. The acquisition protocols included the following: 1. an axial T2-weighted turbo spin-echo sequence ; 2. an axial diffusion-weighted sequence using a single-shot echo-planar sequence  specializing in pelvic and abdominal imaging and experienced in prostate MRI reading and reporting. Malignant potential of lesions was stratified according to PI-RADS2 ,8. LesioFor comparison with DTI values, apparent diffusion coefficient (ADC) maps were also marked with regions of interest (ROIs) labeled according to the PI-RADS2 score, and the average ADC value was calculated for each ROI. This was performed retrospectively within the previously marked lesions.2, TR/TE = 4163/70 ms, SENSE factor (in-plane) of 2.6, 26 axial slices, 3 mm thick with a 0.3 mm gap, an in-plane resolution of 1.43 × 1.43 mm, and fat-saturation. The scan time for DTI was 4:36 min. A 2D axial DTI scan was added to the mpMRI protocol and acquired on the same 3T scanner, prior to contrast injection. The DTI protocol used monopolar spin-echo, echo-planar imaging with diffusion gradients in 32 directions at b values of 0 and 600 s/mm1, λ2, and λ3, sorted from highest to lowest [Data were analyzed using a dedicated DTI software, developed and supervised by H. Degani and her team in the Weizmann Institute of Science  . This DTo lowest ,24,25. WThe three diffusion coefficients served to calculate the mean diffusivity (Equation (1)), a measure of the diffusion averaged over all directions; two anisotropy metrics: maximal anisotropy (Equation (2)), the difference between the maximal and minimal diffusion coefficients; and fractional anisotropy (Equation (3)), which is a normalized measure of diffusion anisotropy, varying between 0  to 1 .Equations:1, λ2, λ3, MD, MA, and FA) [The software generated color-coded maps for the six DTI metrics (λ and FA) ,25. The We used a 3-level Likert scale  for categorizing the DTI findings. The final quantitative evaluation of the average values of the six DTI metrics within the ROI  was performed after unblinding and compared to the histopathological findings.Separate analyses were performed for the peripheral zone (PZ) and central gland (CG) due to the marked difference in diffusion metrics between these areas.®  system, with a combined targeted and systematic template.Prostate biopsies were performed when indicated by clinical exam, serum markers and standard mpMRI. Prostate biopsies were guided by the fusion of mpMRI data registered to trans-rectal ultrasound imaging using the NavigoFor the purpose of statistical analysis, non-cancerous proliferative lesions, such as high-grade prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP), were considered normal prostate tissue.Statistical analysis was performed using SPSS version 20 .t-test to evaluate differences in clinical, DWI ADC, and DTI metrics between normal tissue and cancerous lesions, using Bonferroni correction for multiple comparisons. We used the 3-level Likert scale to calculate specificity, sensitivity, negative predictive value (NPV), and positive predictive value (PPV) and compared them to those derived from the standard PI-RADS2 mpMRI scores. We performed receiver operating characteristic (ROC) curve analyses for the various DTI metrics and for conventional DWI ADC and calculated the area under the curve (AUC).We employed a Student’s DTI scans were successfully performed on 78 patients; 42 of them underwent biopsy, and 16 were diagnosed with PCa: eight had grade group 1 PCa, five had grade group 2 cancer, one had grade group 4 cancer, and two had grade group 5 cancer. The median age of the patients undergoing biopsies was 61.7 years (inter-quartile range: 54.4–68.4), and the median PSA was 4.8 (inter-quartile range: 1.3–10.7) ng/mL . We were1) values in the PZ and CG were (2.30 ± 0.32) × 10−3 mm2/s and (1.98 ± 0.11) × 10−3 mm2/s, respectively   . 1. FA was slightly but significantly increased in PZ cancer, with a similar trend for cancer in the CG as well. Overall, the primary diffusion coefficient, λ1, was (2.30 ± 0.34) × 10−3 mm2/s (mean ± SD) in normal PZ and (1.6 ± 0.33) × 10−3 mm2/s in PZ cancer (p < 0.00001), and (2.00 ± 0.14) × 10−3 mm2/s in normal CG versus (1.3 ± 0.12) ×10−3 mm2/s in CG cancer (p < 0.00001). The values of secondary and tertiary diffusion coefficients , mean diffusivity (MD), and anisotropy indices in cancer tissue were also significantly different from those in the corresponding normal tissue , with PCa threshold values below 2.1 × 10−3 mm2/s. For DWI ADC in the peripheral zone, the AUC was 0.89  for values below 1.7 × 10−3 mm2/s as a threshold for PCa (In a receiver operating characteristic (ROC) curve analysis , the AUC for PCa . This di1, vs. 0.89 (95% CI 0.79–0.98) for ADC values derived from DWI.In this study, we demonstrated that an automated analysis of an adapted DTI protocol may improve the accuracy of PCa detection by MRI. We assessed DTI using two scores: a 3-level Likert scale and a quantitative measurement of diffusion metrics. Both scores exhibited good accuracy for PCa detection, with the Likert score showing a PPV of 78–93% (vs. 47–56% with ADC) and NPV of 89–92% (vs. 75–83% with ADC). The AUC calculated from the quantitative measurement reached 0.97 (95% CI 0.94–1.0) for the best-performing DTI value, λDWI measures the average water diffusion in tissue over three directions, and consistently shows a higher rate of diffusion in the PZ than in the CG , and a hWe know from similar studies on the breast that DTI can anatomically track the ductal tree  and dete1, λ2, and λ3) are not clearly shown. In this study, we applied diffusion gradients in 32 directions, and calculated the three directional diffusion coefficients  and their derivatives . We were, therefore, able to study the detection efficiency of each DTI metric.Existing studies on DTI in the prostate generally use MRI manufacturer-supplied workstation DTI software ,19,20,21Previous studies show that ADC, or MD, is lower in PCa but disagree on FA. Some claim that FA values in PCa relative to normal prostate tissue are either higher ,14,16,231, detected PCa better than any other DTI or DWI metrics. Moreover, measuring and displaying all DTI coefficient values in one screen with T2-weighted images enabled an interpreter inexperienced in prostate DTI to reach better PPV and NPV than experienced radiologists using formal mpMRI. One other study published to date has looked at more than the standard DTI parameters and found that a model combining diffusion coefficients and their 15 various products significantly increased the AUC for prostate cancer detection, when compared to DWI or only MD and FA from DTI [From the existing literature, it appears that DTI has very little advantage over conventional DWI, since MD negates directionality and is generally equivalent to ADC from DWI, and FA results were, at best, inconclusive. However, we believe that MD and FA alone do not utilize the full potential of DTI. Our study shows that direct measurement of the primary diffusion coefficient, λfrom DTI . This st1, a measurement of diffusion in the fastest direction, displayed better results than MD, which measures average diffusion and is comparable to ADC in DWI.In our study, DTI performed better than DWI and mpMRI in detecting PCa lesions and in predicting both positive and negative biopsy results. This can either be due to the directionality of water diffusion, measured by DTI but not DWI, or due to the many repetitions of diffusion gradients (32) yielding a higher signal to noise ratio than the DWI protocol. The first theory is supported by the fact that λWe successfully performed DTI scans on all patients and received meaningful data on all DTI measurements. The additional scan time of 4.6 min was in line with earlier published works ,15,30,31The strengths of this study are its prospective design and the comparison of DTI, DWI, PI-RADS2, and pathological findings. Another important feature of this study is the use of an adapted standard protocol and DTI analysis software developed specifically for the research of DTI measurements. In contrast, most other studies on prostate DTI have used manufacturer-supplied workstation DTI software with a limited set of output metrics ,14,15,16The main study limitation was the small sample size. In addition, only patients with pathology were included in the analysis. It is possible that some patients with normal PSA and normal-appearing MRI had prostate cancer, limiting our ability to correctly estimate the false negative rate; however, we did not find it ethical to biopsy patients with negative MRI findings. This preliminary research showed the feasibility of DTI measurements of the prostate, suggesting that a specialized software assisted analysis of DTI metrics in combination with T2-weighted imaging may potentially improve PCa diagnosis without the need for contrast enhancement. Further validation studies are needed to verify the results of this pilot study.


Transcranial temporal interference stimulation (tTIS) is a novel non-invasive brain stimulation technique for electrical stimulation of neurons at depth. Deep brain regions are generally small in size, making precise targeting a necessity. The variability of electric fields across individual subjects resulting from the same tTIS montages is unknown so far and may be of major concern for precise tTIS targeting. Therefore, the aim of the current study is to investigate the variability of the electric fields due to tTIS across 25 subjects. To this end, the electric fields of different electrode montages consisting of two electrode pairs with different center frequencies were simulated in order to target selected regions-of-interest (ROIs) with tTIS. Moreover, we set out to compare the electric fields of tTIS with the electric fields of conventional tACS. The latter were also based on two electrode pairs, which, however, were driven in phase at a common frequency. Our results showed that the electric field strengths inside the ROIs  during tTIS are variable on single subject level. In addition, tTIS stimulates more focally as compared to tACS with much weaker co-stimulation of cortical areas close to the stimulation electrodes. Electric fields inside the ROI were, however, comparable for both methods. Overall, our results emphasize the potential benefits of tTIS for the stimulation of deep targets, over conventional tACS. However, they also indicate a need for individualized stimulation montages to leverage the method to its fullest potential. It is, however, not possible to reach deep brain structures non-invasively without stimulating the overlaying cortex. Currently, it is solely possible to target deep brain structures focally with an invasive brain stimulation technique, namely deep brain stimulation (DBS). DBS is used as a powerful therapeutical technique for several clinical disorders such as Parkinson’s disease6, treatment-resistant depression12, or Alzheimer’s disease15. However, DBS is based on a different mechanism of action (supra-threshold activation) as compared to non-invasive electric brain stimulation techniques, like tACS (sub-threshold modulation).Electric brain stimulation techniques, such as transcranial alternating current stimulation (tACS), are widely used to modulate human brain activity on a cortical level16. For tTIS, electric currents are applied through multiple electrode pairs at two different high frequencies  that are not in the range of regular neural frequencies  but they do penetrate the skull and brain tissue17. The applied currents stimulate with slightly different frequencies. The beat frequency of these two currents oscillates at fdiff (fdiff = f2 − f1), which represents the target stimulation frequency. This beat frequency is maximal when the two signals overlap with same strength and the field vectors have the same direction , without stimulating the overlaying cortex16. Furthermore, it was shown that tTIS over the left motor cortex led to motor activity in mice16. However, it could be challenging to translate knowledge gained in animal studies to humans: two-electrode tES is approx. 100-times stronger in the cortex of a mouse than in the human model. Generally, electric field strength due to tES strongly decreases from smaller to larger head sizes18. In contrast to mice, the human brain cannot be stimulated with supra-threshold field strength (as the mice in the tTIS study mentioned above16).Based on similar mechanism of action as tACS, transcranial temporal interference stimulation (tTIS) has been developed as a new non-invasive brain stimulation technique to electrically stimulate neurons at depth19 using a single neuron computational model. In this model, classical Hodgkin–Huxley squid neurons and some mammalian cells exhibited effects during temporal interference stimulation. However, some of the mammalian cells in the study did not show an effect to temporal interference stimulation. Another study showed that pure high frequency sinusoids resulted in a current balance between inward and outward current in single neuron models20. This current balance restrains the membrane potential from spiking. The fast-changing envelope, resulting when both high frequency sinusoids overlap, activates fast depolarizing currents without giving slow outward currents time to respond. This imbalance causes the neuron to fire (note that this study is based on a single neuron model and field strength achievable with available non-invasive electric brain stimulation techniques are far too week to cause neuron firing in humans). Other research investigated the suprathreshold and subthreshold membrane dynamics of neurons in response to interferential stimulation and the authors showed in a neuron model that tTIS was able to modulate spiking activity and facilitated phase synchronization similar to a relatively well-established brain stimulation technique, namely transcranial alternating current stimulation (tACS)21. Compared to conventional tACS, it should be noted though, that the modulatory effects were less potent for tTIS at similar field intensities, which is in line with other simulation work on the effect of electric stimulation with amplitude modulated signals22. A study based on hippocampal slices of rats showed that the spatial selectivity of tTIS  depends on phasic modulation of neural oscillations in deep brain structures23. Another study suggested that the mechanism of tTIS is based on an ion-channel mediated signal rectification process, instead of passive membrane filtering (as suggested in previous studies)24.The efficacy of tTIS to modulate neural oscillations in the human brain has not been investigated so far and current research is limited to animal studies, computational models and electric field simulations. The putative neurobiological mechanisms of tTIS has been investigated26. However, it was also shown that tTIS goes beyond superficial areas and may reach deeper areas26, in addition to producing more focal fields than conventional tES methods. A recent study proposed to use optimization algorithms to target desired ROI’s inside the brain when stimulating with tTIS27. With such algorithms, the authors showed that tTIS has the potential for focal non-invasive deep brain stimulation. Another study showed that optimal stimulation conditions with temporal interfering fields are inconsistent across subjects and suggested to consider individual anatomical differences28. However, the study is based on only three individual subjects and the used optimization algorithm seems to be time-consuming. Therefore, further research is needed to investigate the individual variability of the resulting electrical field during tTIS on a larger population.In addition to the investigation of the neurobiological mechanisms of tTIS, simulation studies focused on the exploration of the resulting electric fields during tTIS in humans. These showed that the stimulation intensity of tTIS might be similar to conventional transcranial alternating current stimulation (tACS)26 that aimed to optimize tTIS electrode montages for target field strength and focality investigated how different parameters influence the electric field of tTIS. Therefore, the electrode montages (88 electrode positions) and the stimulation current strength were systematically varied (146 M current patterns). Optimized electrode positions to maximize the electric field with tTIS in three brain regions were developed: the pallidum, the left hippocampus and the left motor cortex. However, optimal electrode placements were analyzed for a single subject, indicating the necessity for simulations across multiple subjects.A computational study31. Moreover, it was shown that neurons respond preferentially to stimulation when the field is oriented along the predominant direction of the neuron34. Therefore, the direction of the applied electric field has also to be considered when applying different brain stimulation techniques. Overall, the localization of the target (where are the neurons located that are related to the expected effect?), the strength of the electrical stimulation (which strength is needed in the target location?), and the preferred direction of the electric field (which direction of the electric field is needed in the target location?) have to be defined in order to achieve optimal stimulation effects with non-invasive electric brain stimulation techniques.In order to optimize stimulation effects of non-invasive electric stimulation techniques, important parameters that have a crucial influence on the effect have to be considered. These include the strength of the electric field and its direction. Stimulation effects are reported for electric field strength inside the human brain of approx. 0.1–0.3 V/m35, that leads to variable effects across subjects and studies. Due to the different brain anatomies across individuals, it might be beneficial to individually adjust electrode placement in order to target the region of interest (ROI) inside the brain and achieve similar stimulation effects across subjects and studies. In order to target deep brain structures , targeting the ROI precisely is inevitable in order to achieve comparable effects. A recent study investigated whether individual differences across subjects regarding the electrical field lead to different stimulation effects for tACS35. Since tTIS likely has a similar mechanism of action as tACS and, moreover, the electric fields of tTIS seem to be more focal26, it is important to investigate whether the electric fields also differ across subjects with the same electrode montage26. Individual differences of the electric fields due to tTIS could lead to variable stimulation effects. However, the variability of electric fields across individual subjects is nearly unknown for tTIS. Therefore, the aim of the current study is to investigate the variability of the electric fields due to tTIS across subjects. Due to similar underlying mechanisms of action, we set out to compare the electrical field of conventional tACS with the electrical field of tTIS.Effects of different non-invasive brain stimulation techniques are controversially discussed in current literature. This discrepancy might be in part due to the variability of electric fields due to different non-invasive brain stimulation techniques26. Since we expect physiological effects in the gray matter of the brain, we restricted our analysis to this compartment.To investigate the variability of the electric fields across subjects, the electric fields of three different electrode montages were simulated in order to target three different predefined regions-of-interest (ROIs) with tTIS. In a first step, we aimed to identify electrode montages that maximize the electric field inside the defined ROI, and simultaneously, minimize the electric field outside the ROI. Since efficient optimization algorithms are currently not available for tTIS, we adapted optimized electrode positions from the literature in order to target our ROIs with tTIS. The different electrode montages were simulated for different subjects and the resulting electric fields were compared. Additionally, the electric field simulations for tTIS were compared to the electric field simulations for conventional tACS, targeting the same ROIs, with optimized electrode positions for both stimulation techniques35). The data was initially acquired from 40 healthy volunteers (age: 24 ± 3 years), recruited at the Carl von Ossietzky University of Oldenburg and was counterbalanced for sex. All subjects were right-handed, without history of neurological and psychiatric disorder, non-smoker, medication free at the days of recordings and had normal or corrected to normal vision. Participants gave written informed consent. The study by Kasten et al.35 was approved by the committee for Research Impact assessment and Ethics of the University of Oldenburg and conducted in accordance with the declaration of Helsinki.To test the variability of the electric fields of tTIS across subjects, we simulated different electrode montages on structural MRI scans of 25 different subjects taken from an existing dataset . A T1-weighted 3-D sequence  with a slice thickness of 0.75 mm was used.36. A tetrahedral head mesh was created from the MRIs , we excluded 15 subjects due to obvious segmentation errors, resulting in 25 subjects . Default conductivities of the toolbox were used for the different compartments 36. The values of the conductivities represent average values from several references . They fall well within the range of conductivities observed in measurements from fresh or live tissues near body temperature for frequencies ranging from 0 to 100 kHz38. For the finite-element methods (FEM)-based electric field calculations, rubber stimulation electrodes with a diameter of 1 cm and conductivity of 29.4 S/m were placed at known 10–20 EEG system electrode sites. The electrically conductive, adhesive paste (conductivity of 1 S/m) underneath the electrodes were estimated with a thickness of 2 mm. SimNIBS 3.0 was used to simulate the electrical fields for each electrode pair separately. In order to investigate the distribution of the total electric field generated from the temporal interfering fields of two electrode pairs, further calculation steps were necessary. The spatial distribution of the envelope modulation amplitude was computed with the formula used by Grossmann et al.16Electric field simulations were performed with MATLAB R2018b and the SimNIBS 3.0 toolbox16 and Rampersad et al.26 and implemented in a MATLAB function (function is implemented in the SimNIBS toolbox).The equations were adapted from Grossman et al. 39  in order to predict the electric field distribution and strength of different brain stimulation techniques. Therefore, we simulated the electric field of different electrode montages targeting different ROIs on the MNI brain in order to investigate the spatial distribution and the strength of the electric field due to different electrode montages stimulating predefined ROIs with tTIS. The ROIs were defined as the left hippocampus, the left motor cortex and the thalamus  in the ROI. The authors also showed other electrode montages considering that neurons respond preferentially to stimulation when the field is oriented along the predominant direction of the neuron. However, the current study simulates the electrode montages that maximize the electric field strength in a given location over all directions. In addition, we aimed to simulate the electric field in order to target the thalamus. To this end, we simulated different electrode montages  and chose the electrode montage that maximizes the electric field inside the thalamus while minimizing the electric field outside the thalamus by visual inspection. We end up with the electrode positions F7/PO7, and F8/PO8  average brain40. Non-invasive electric brain stimulation with a current strength of 1 mA leads typically to an electric field of approx. 0.1–0.3 V/m inside the brain31. Since tTIS is based on similar mechanisms of action as tACS, we aim to achieve comparable electric field strength with tTIS than with well-known and established non-invasive brain stimulation techniques. Based on this knowledge, we characterized the focality of the different simulations: we calculated the proportion of voxel inside the ROI that exposed to field strength greater than 0.1 V/m, and 0.2 V/m. In order to complement our analyses with an index of focality, we also computed the proportion of voxels that exposed to field strength with greater than 0.1 V/m, and 0.2 V/m inside the whole gray matter volume.In order to characterize the electric field distribution and strength, we calculated the mean electric field inside the ROI’s, as well as the maximum of the electric field inside vs. outside the ROI by using the AAL-atlasTo evaluate the variability across subjects, we computed spatial correlations between different electric field simulations of the subjects and the predicted electric field, simulated on the MNI brain. Additionally, we computed spatial correlations across the electric field simulations of the different subjects and calculated characteristics of the electric fields , to target the left hippocampus is 0.1 . In order to target the left motor area with tACS, the optimal current ratio is 10 . The adapted electrode montages of tACS are visualized in Fig. In addition to the optimal electrode montages for tTIS, Rampersad et al.For the analysis, we investigated the amplitude of the low frequency envelope of tTIS  are visualized in Fig. The electric fields for both stimulation methods, tTIS and tACS, targeting the left motor area on the MNI brain are visualized in Fig. For tTIS, the electric field simulations targeting the left motor area are visualized for two representative subjects in Fig. The values for single subjects  are visualized in Fig. Overall, similar patterns are shown for both ROIs (left hippocampus and left motor area) regarding the parameter characterizing the electric field distribution and strength, when comparing tTIS with tACS: tACS resulted in only slightly stronger, or the same mean electric fields inside ROIs compared to tTIS, and only slightly higher, or the same maximal electric field inside the ROIs. However, tACS led to higher maximal electric field outside the ROI  regarding the parameter characterizing the electric field distribution and strength. However, similar to the results on the MNI brain for the thalamus: only 1.68% (std = 1.99) of the voxel of the whole gray matter volume expose to a field strength greater than 0.1 V/m for tTIS. In contrast, 39.53% (std = 18.62) of the voxel of the whole gray matter volume expose to a field strength greater than 0.1 V/m for tACS . In addition, when compared to tACS, tTIS stimulates more focally meaning that it induces much weaker co-stimulation of cortical areas close to the stimulation electrodes. Electric fields generated inside the ROI were, however, comparable for both methods.The variability of electric fields resulting from stimulation using the relatively new brain stimulation technique tTIS across different subjects has hitherto not been extensively studied. It is important, however, to investigate how the electric fields differ across subjects with the same electrode montageOverall, electric fields during tTIS targeting different ROIs  correlate highly across all subjects irrespective of the target ROI (averaged correlation coefficient across subjects ranging from 0.79 to 0.93). However, the individual correlation coefficients range from 0.57 to 0.94, indicating variability of the electric field distribution across individuals. A similar result can be seen when considering the strength of the electric field. The mean electric field across subjects ranged from 0.08 V/m to more than 0.13 V/m inside the different ROIs. On single subject level, the strength of the electric fields are highly variable, especially the proportion of voxels showing more than 0.1 V/m. For several subjects, more than 80% of the voxels inside the different ROIs are stimulated over 0.1 V/m, whereas in other subjects less than 10% of the voxels inside the ROIs exposed to field strength stronger than 0.1 V/m. The variability of the results indicates that a precise and individual electrode montage is necessary to achieve similar electric field strengths inside the target area across subjects.41. Therefore, further research to develop optimization algorithms (addressing single-channel and multi-channel tTIS strategies) could be promising in order to individually adjust the electrode montages and ensure consistent stimulation of relatively small deep brain targets. However, presumably due to the high conductivity of CSF, targeting deep brain areas precisely, without stimulating brain regions outside the ROI will likely remain challenging.It was shown that multi-channel tTIS increase the focality while reducing scalp sensations in computational modeling- and animal-experiments42. In addition, higher head-, skin-, and skull-volume seems to be associated with lower electric field strength inside the brain43. Since tTIS is based on similar mechanisms of action as conventional non-invasive electric brain stimulation techniques, similar anatomical characteristics are likely to be responsible for interindividual differences as well.Interindividual variability of electric fields have been investigated for established non-invasive electric brain stimulation techniques like tACS/tDCS in previous studies. Possible anatomical characteristics that affect the electric field distribution, and especially the focality, differently across subjects might be the thickness of cerebrospinal fluid26. Due to the development of different systematic optimization approaches, especially the tACS electrode montages could probably be optimized more effectively. While tTIS and tACS have comparable electric fields inside the ROI (mean/max inside ROI), the maximal electric field outside the ROI is higher for tACS. In addition, the proportion of voxels of the whole gray matter volume  is higher for tACS, especially noticeable for the thalamus. The direct comparison of the electric fields of tTIS and tACS are, however, challenging. Whereas the tACS stimulation waveform is close to a perfect sine wave (e.g. stimulation with 10 Hz), the envelope of the amplitude modulated signal of tTIS is not perfectly sinusoidal  is less problematic. With respect to research questions, the co-stimulation of tACS seems to be more problematic since the effects of stimulation cannot be ascribed solely to the stimulation of the deep brain structure26 are optimized for one single subject. Therefore, it would be especially promising for further research to develop an optimization algorithm to maximize the electric field inside the ROI, while minimizing the electrical field outside the ROI using tTIS. Additionally, since only T1 MRI scans were used for the current study, the accuracy of the skull segmentation could be improved, e.g. with an additional T2 MRI scan. However, we ruled out by visual inspection that low correlations with mean fields, as seen in some of the subjects, were cause by obvious segmentation errors. Moreover, since stimulation with high frequencies leads to less somatosensory sensations, a higher current could be used in order to target deep brain areas with tTIS. Lee et al.24 employed realistic finite head models for the optimization of tTIS. They suggested that customized tTIS based on numerical field analysis is expected to enhance the overall effectiveness of noninvasive deep brain stimulation.The results of the current study indicate that the maxima of the electric fields outside the ROIs are slightly higher than inside the ROIs, even when stimulating with tTIS . The use of optimization algorithms might address this issue in further studies. One major limitation of the current study is, that we did not use an optimization algorithm in order to target the defined ROIs. There might be electrode positions that target the ROI more precisely on the MNI brain. The used electrode montages by Rampersad et al.31, we used different thresholds in order to characterize the electric field distribution and strength. As there is no common agreement which stimulation intensities are required for tACS and tTIS to modulate brain activity, this approach describes the general coverage of the electric fields due to the different electric brain stimulation techniques. Therefore, we calculated the proportions of voxels that expose to field strength greater than 0.1 V/m, and 0.2 V/m. However, further research is needed to investigate this concern more precisely. Obviously, given the linear dependence of the electric field on the stimulation current, identical results for focality would be obtained for a threshold of 0.2 V/m, and 0.3 V/m when doubling the stimulation currents to 2 mA per electrode pair, which is still in a practically feasible range. Moreover, the electric fields were simulated for electrode montages that maximize the electric field strength in given locations (three different ROIs) over all directions . This does not consider that neurons respond preferentially to stimulation when the field is oriented along the predominant direction of the neuron. Overall, further research is needed to investigate precise parameters of the electric field that correlate with stimulation effects .It has to be noted that the robustness of the results of the current study is linked to the electric field threshold choice of 0.1 V/m resulting from a stimulation intensity of 1 mA per electrode pair. Based on literature45. However, also TMS of deeper structures suffers from a low focality and a substantial co-stimulation of more superficial structures46. tTIS addresses this issue by stimulating deep brain structures while reducing stimulation of the overlaying cortex. However, as shown in this study, individual electrode montages are necessary. In addition, the mechanisms of action differ between TMS (capable of supra-threshold stimulation) and tTIS (sub-threshold stimulation), suggesting that they might have partly complementary application profiles.Also the ability of transcranial magnetic stimulation (TMS) to reach deep brain structures has been tested and specific TMS coils have been made available that maximize the electric field intensities28, it is still unknown whether and how tTIS leads to stimulation effects in humans. More specifically, it is unclear whether tTIS works in humans similar to the experiments in mice41, due to the fundamental differences between mice and human regarding the size and anatomy of the brain. To this end, further research is essential in order to investigate the stimulation effects of tTIS in the human brain.Since current tTIS studies are limited to electric field simulations, animal studies, or computational models


Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy-related liver disease and is associated with an increased risk of adverse neonatal outcomes. Ursodeoxycholic acid (UDCA) is the most effective treatment. This study was aimed at investigating the adverse outcomes of ICP and evaluating the effects of treatment with UDCA in patients with ICP.  We included 114 women with ICP and 3725 women without ICP (no-ICP group) who delivered in our hospital between September 2017 and August 2019. The prevalence of ICP in this study was 3.15%. We matched each woman with ICP to five controls. Of all the 114 women with ICP, 73 (64.04%) received UDCA while 41 (35.96%) did not. Logistic multivariate regression analysis was used to compare the adverse outcomes between those with ICP and matched controls as well as between those who received UDCA (UDCA group) and those who did not (non-UDCA group).  Compared with controls, women with ICP were more likely to have preeclampsia , cesarean section , and preterm birth . Administration of UDCA reduced the rate of preterm birth .  ICP increased the risk of preeclampsia, cesarean section, and preterm birth. UDCA could reduce the rate of preterm birth. Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder , 2. Clinμmol/l , an165,136) . In addi165,136) . In our μmol/l [μmol/l, partially explaining the absence of stillbirth in our study. Nonetheless, the risk of stillbirth seems to increase after 37 weeks [Stillbirth is the most severe outcome that could be induced by ICP. In our study, no stillbirth was observed, which is not surprising as this outcome is very rare according to previous reports . In a reμmol/l . In our 37 weeks . To prev37 weeks , obstetrUDCA is the mainstay of treatment for ICP. In an 8-year case-control study in France, UDCA was administered to 43.6% of women with ICP and its prescription rate increased with the severity of bile acid elevation . Our stuThis study has several strengths including the comparison of comprehensive maternal and neonatal outcomes of ICP and the evaluation of UDCA in decreasing the adverse outcomes. Moreover, we explored the correlation of TBA with adverse pregnancy outcomes in the no-ICP group. However, it also has some limitations. First, this study is retrospective. Second, we did not distinguish emergency from elective cesarean section. Lastly, this is a single-center study, and the number of subjects was small. Hence, further prospective studies with a larger sample size are warranted to further explore the effect of TBA and ICP during pregnancy.In conclusion, ICP could result in preeclampsia, cesarean section, and preterm birth. Furthermore, UDCA could decrease the preterm birth rate. Further larger prospective studies are required to determine the adverse effect of ICP during pregnancy and the efficacy of UDCA.


To explore the longitudinal associations between prepartum fear of childbirth (FOC), birth experience, and postpartum mother-child-bonding, and the potential mediator role of the birth experience.Women from the prospective cohort study DREAM completed questionnaires during pregnancy, 8 weeks, and 14 months after the birth.n = 645 pregnant women from a large city in Eastern Germany participated in the study.A community sample of p < 0.001) which in turn predicted poorer mother-child-bonding both at 8 weeks  and 14 months postpartum . FOC also predicted mother-child-bonding at 14 months postpartum . Of note, this association was mediated by birth experience both at 8 weeks, indirect effect ab = 0.065, 95% CI , and 14 months postpartum, indirect effect ab = 0.043, 95% CI . These effects remained stable even when adjusting for potential confounders.In a regression analysis, FOC predicted negative birth experience (β = 0.208, This study suggests that the association between FOC and mother-child-bonding is mediated by birth experience, pointing to the importance of a woman's positive subjective experience.Findings reveal two targets for peripartum interventions for women at risk for poor mother-child-bonding, namely the implementation of FOC screenings during pregnancy, and birth experience as mediating factor between FOC and mother-child-bonding. Focusing on the mother's subjective birth experience could aid to identify women at risk for impaired bonding who might need additional support. With an estimated pooled prevalence rate of 14% –5. PrevaPrepartum FOC seems to not only predict the level of fear during birth, but is also associated with higher levels of postpartum FOC –32. AccoAnother factor influencing maternal bonding may be birth experience as it can have short- and long-term effects on the mother's postpartum well-being , 40 whicOther studies have focused on the mother's recalled labor pain  or distrHowever, the association between a women's subjective rating of her birth experience and postpartum mother-child-bonding remains understudied. If these two are indeed inter-related, enabling a positive birth experience could be a successful way to ensure a stronger bond between mother and child, thereby increasing the chance of positive child outcomes , 51.At this point, a potential link between prepartum FOC, birth experience, and postpartum mother-child-bonding needs further clarification. Especially the role of a negative birth experience could be of major importance as it might emphasize prior vulnerabilities of the mother, like FOC, and increase the risk of impaired mother-child-relationships , therefoThis study aims to explore the longitudinal associations between prepartum FOC, birth experience, and mother-child-bonding 8 weeks and 14 months postpartum. Furthermore, it will be analyzed whether the association between prepartum FOC and postpartum mother-child-bonding is mediated by birth experience.DResdner Studie zu Elternschaft, Arbeit und Mentaler Gesundheit”; DREAM). The DREAM study examines parental work participation, role distribution, stress factors, and how these affect peripartum outcomes and the long-term mental and somatic health of the family. Recruitment started in 2017 and finished at the end of 2020. Currently the study consists of six measurement points: T1 during pregnancy, T2 8 weeks after the anticipated birth date, T3 14 months, T4 2 years, T5 3 years, and T6 4.5 years after birth. Participants comprise a community sample of N = 3,865 parents from Dresden, Germany and surroundings who are expecting a child and are mainly recruited at information events of obstetrical clinics. Detailed information on the design of the study can be found in the study protocol , calm/worried and no fear/strong fear. In the DREAM study, each item generates scores of 0–100 with possible values being increments of 10. The two scores are then averaged to form a total score, where higher values indicate more fear. The reliability of the FOBS in the current study was excellent (Cronbach's α = 0.90).FOC was assessed using the German version of the Fear of Birth Scale  during Birth experience was assessed at T2 (8 weeks after the expected birth date) using the German version of the Salmon's Item List , a valinever (0) to always (5). Item scores are added to form the scores for each subscale and a total score ranging from 0 to 125. Higher values indicate more bonding difficulties. For this study, we used data from T2 and T3. The reliability of the PBQ was excellent for both T2 and T3 (Cronbach's α = 0.90).Mother-child-bonding was assessed using the German version of the frequently used Postpartum Bonding Questionnaire PBQ; , 62] whi whi62)] The following eight variables were selected as potential confounders, because they have been associated with FOC, birth experience, and mother-child-bonding in previous research: maternal age, parity, education, financial hardship, partnership satisfaction during pregnancy, maternal depressive symptoms during pregnancy, birth complications, and infant health status after birth. Except for financial hardship, birth complications, and infant health status after birth, which were measured at T2, all potential confounders were measured at T1 during pregnancy.Education was measured by an item, which asks about the professional qualification. Participants were then divided into one group without a university degree and one group with a university degree (bachelor's degree or higher).Financial hardship was measured by an item, which asks about financial problems during pregnancy or after the birth. It is part of a questionnaire asking about former and current critical life events and their burden based on the Life Event Questionnaire from the Avon Longitudinal Study of Parents and Children .never/very rare (0) to very often (3). The total score is generated by summation of all items and ranges from 0 to 27. The reliability of the PFB-K in the current sample was good (Cronbach's α = 0.80).Partnership satisfaction was measured by the validated German short version of the Partnership Questionnaire  which coMaternal depressive symptoms were measured by the German version of the Edinburgh Postnatal Depression Scale EPDS; , 66] whi whi66)] Birth complications and health status of the infant after birth were measured by questions based on the maternity records and the child's medical records. Complications during birth included the number of severe complications concerning the mother, e.g., failure to progress in labor, hemorrhage, perineal tear, vaginal/labial/clitoris tear, or premature or difficult abruption of the placenta. The infant's health status was measured dichotomously as complications during the first 3 days after birth  which led to a hospitalization of the child.p < 0.05 with 95% confidence intervals (CI). Due to missing data, n varied slightly between analyses.All analyses were conducted using IBM SPSS Statistics (Version 27.0). First, data were adjusted and checked for outliers. When items from psychometric scales were missing, they were replaced by the woman's mean value in cases where <20% of the items were missing. Second, descriptive analyses  for the sociodemographic characteristics of the sample and FOC, birth experience, mother-child-bonding, and the potential confounders were computed. Additionally, correlations between all variables were examined to identify statistically significant confounders. Third, associations between FOC, birth experience, and mother-child-bonding and the potential mediator role of birth experience were analyzed via ordinary least squares regression within the SPSS modeling tool PROCESS . The tooFor the interpretation of the mediated effect we followed the recommendations of Zhao et al.  and RuckAll parts of the study were approved by the Ethics Committee of the Faculty of Medicine of the Technische Universität Dresden (No: EK 278062015). The couples were informed about the aims and procedures of the DREAM study, the pseudonymization of their data, and their right to withdraw from the study at any time. All participants provided written informed consent.n = 645 women (SD = 3.9). Most were born in Germany (96.6%), in their third trimester of pregnancy (76.6%), expecting their first child (79.3%), and living in a stable partnership (99.4%). Compared to the general population in Dresden, the women in the sample had higher education, with 60.6% holding a university degree  consisted of 45 women . The meay degree . The mea2 = 5.76, p = 0.016) and had a 7.40 points, 95% CI , higher mean FOBS score than completers, t(708) = 2.62, p < 0.05, indicating more FOC. There were no differences between completers and non-completers regarding any other variable (tables on request).Dropout analyses were conducted for the predictor, the mediator, all potential confounders, and sociodemographic characteristics for completers vs. non-completers. Compared to completers, non-completers more often had no university degree  which in turn significantly predicted poorer mother-child-bonding at T2 . While FOC had no significant direct effect on mother-child-bonding at T2, the effect was mediated by the birth experience, completely standardized indirect effect ab = 0.065, 95% CI . p < 0.001). In this model, FOC had a significant direct effect on mother-child-bonding , but the effect was also mediated by the birth experience, completely standardized indirect effect ab = 0.043, 95% CI .Second, associations between FOC, birth experience, and mother-child-bonding were examined using ordinary least squares regression within PROCESS. Confounding variables which correlated with the two outcome variables can be found in the correlation matrix of This study aimed to explore the longitudinal associations between prepartum FOC, birth experience, and mother-child-bonding. We found that FOC significantly predicted a more negative birth experience, which in turn significantly predicted poorer mother-child-bonding at 8 weeks and 14 months postpartum. However, FOC did not have a direct effect on mother-child-bonding. Instead, the association was mediated by birth experience.FOC was a significant predictor for a more negative birth experience, even when adjusting for maternal education, parity, depressive symptoms during pregnancy, and birth complications (Model at 8 weeks postpartum) and maternal education, depressive symptoms during pregnancy, financial hardship, and partnership satisfaction (Model at 14 months postpartum). This finding is in line with previous research: On the one hand, endocrine stress parameters during pregnancy, like cortisol awakening response and higher plasma levels of adrenalin (which could both be influenced by FOC), may disrupt labor by interfering with uterine contractions  and thusA more negative birth experience was a significant predictor for poorer mother-child-bonding, both at 8 weeks and 14 months postpartum. However, the association was stronger 8 weeks postpartum, suggesting that the impact of birth experience on mother-child-bonding weakens over time. These results are consistent with previous research , 45, altExcept for 14 months postpartum when not considering the confounders, FOC was not a significant predictor for mother-child-bonding. At first glance, this finding contradicts previous research, which identified an association between FOC and constructs similar to postpartum mother-child-bonding. Especially the results of Klabbers et al.  who founUsing data from the prospective-longitudinal cohort study DREAM, we examined the longitudinal associations between FOC, birth experience, and mother-child-bonding from pregnancy to 14 months postpartum. By studying a large sample of German women, this study also contributed to the literature on FOC in Germany which is still scarce as most research focusses on populations from Scandinavia, Australia, and the UK , 4. AddiNevertheless, when interpreting the results, one should keep in mind the limitations of this study. Firstly, women who dropped out of the study had higher FOC and more often had no university degree than the women in the final sample. One explanation for the higher level of FOC could be that these women were more impaired and therefore dropped out of the study, which would mean that our results underestimate the effect of FOC on birth experience and mother-child-bonding. However, completers and non-completers did not differ from each other in their birth experience, their prepartum depression scores, their partnership satisfaction, or financial hardship, making it unlikely that their impairment was the reason to drop out. Additionally, the women who participated in the study had relatively low FOC levels. Although the mean scores were similar to populations in Sweden and Australia , 56, 57,Future research on the association between FOC, birth experience, and mother-child-bonding is needed to replicate these findings in more diverse samples including single mothers, less educated women, clinically impaired women, higher proportions of migrants, and LGBTQIA+ couples. Additionally, it should be tested whether there are differences in the described associations for nulliparous and multiparous women as parity was a significant confounder in our analyses. Regarding the improvement of women's birth experiences through altering their prepartum expectations, it should be investigated whether different strategies need to be followed for women with and without FOC. More precisely, women with FOC may profit from strengthening the belief in birth as a natural process, which their body can master, to escape the vicious circle described by Zar et al. . InsteadFindings clearly point to the need for FOC screenings in pregnancy to identify women at risk for a negative birth experience and connected postpartum mental health difficulties. However, such screenings are not part of routine clinical practice in Germany yet . This miAdditionally, women who experienced their birth as negative or traumatic need to be identified, as these mothers may need additional support in caring for and interacting with their babies as they are processing their birth experience. For this reason, it should also be investigated whether postpartum partner support can have a moderating effect on the development of bonding difficulties in mothers following a negative birth experience . Thus, wIn this study, FOC significantly predicted a more negative birth experience suggesting that a woman's expectation of her birth might be equally important for her birth evaluation as the course of labor and medical interventions. For this reason, it could be helpful to implement FOC screenings during the routine pregnancy check-ups to refer the affected women to a specialist offering a suitable intervention. Furthermore, in this study, a negative birth experience significantly predicted poorer mother-child-bonding at 8 weeks and 14 months postpartum, although the association was stronger at 8 weeks postpartum. This stresses the importance of support for women who perceived their birth as negative and might therefore be preoccupied with emotionally processing their experience and not able to properly bond with their babies. The results of this study also suggest that the association between FOC and mother-child-bonding is mediated by the birth experience, which further emphasizes the importance of a positive birth experience for all women. It could be promising to replicate and test these findings in more diverse samples, as well as comparing them to nulliparous and parous women.lara.seefeld@ukdd.de.The dataset analyzed during the current study is not publicly available due to legal and ethical constraints, as the study's informed consent did not include public sharing of participant data. The dataset is available from the corresponding author on reasonable request. Requests to access the datasets should be directed to This study involving human participants was reviewed and approved by the Ethics Committee of the Faculty of Medicine of the Technische Universität Dresden (No: EK 278062015). All participants provided written informed consent to participate in this study.LS, VW, and SG-N contributed to the conception and the design of the study. VW and MK conducted data cleaning and data preparation. LS and VW performed the statistical analyses. LS wrote the first draft of the manuscript. VW, MK, SK, and SG-N wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The DREAM study was funded by the German Research Foundation . This paper contributes to the EU COST Action 18211 supported by COST (European Cooperation in Science and Technology).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.