Association of congenital uterine anomaly with abnormal placental cord insertion and adverse pregnancy complications: a retrospective cohort study.

OBJECTIVE: Congenital uterine anomalies during pregnancy increase the risk of pregnancy complications such as miscarriage, preterm delivery, fetal malpresentation, cesarean delivery, and fetal growth restriction. However, few studies have examined uterine anomalies in relation to perinatal complications other than those mentioned above. We investigated the association between pregnancies complicated by congenital uterine anomalies and various perinatal outcomes at our institution. METHODS: This retrospective cohort study was conducted from January 2009 to May 2021. We included cases of uterine anomalies, such as septate, bicornuate, unicornuate, and didelphic uterus. First, the perinatal complications and neonatal outcomes were compared between pregnancies complicated by uterine anomalies and those with normal uteri. Second, we conducted an analysis based on the type of uterine anomalies classified into two groups: the minor anomaly group consisted of anomalies limited to the uterine cavity, such as the septate uterus, whereas the major anomaly group included anomalies affecting the uterine shape, such as bicornuate, unicornuate, and didelphic uterus. We compared the incidence of perinatal complications among the major anomaly, minor anomaly, and normal uterus groups. RESULTS: During the study period, 45 pregnancies were complicated with uterine anomalies. The minor anomaly group included 11 patients and the major anomaly group included 34 patients. The incidence of fetal malpresentation was significantly higher in the uterine anomaly group than in the normal uterus group (18% vs. 3.7%, p = .04). Furthermore, the frequency of abnormal placental cord insertion was significantly higher in the uterine anomaly group (16% vs. 3.7%, p = .01). Examination based on the type of uterine anomaly revealed significant differences in cervical incompetence, malpresentation, cesarean section, and abnormal placental cord insertion. Cervical incompetence was more likely in patients with minor anomalies. In contrast, fetal malpresentation, cesarean section, and abnormal placental cord insertion were more likely in the major anomaly group. CONCLUSIONS: In addition to the findings reported in previous studies, abnormal placental cord insertion was more frequent in pregnancies complicated by uterine anomalies.

Differences in perinatal complications and serum hormone levels due to uterine endometrial preparation methods in frozen-thawed embryo transfer.

AIM: In frozen-thawed embryo transfer (FET), differences in endometrial preparation methods affect the incidence of perinatal complications. However, the underlying causes are unclear. We aimed to investigate whether serum E2, P4 levels are associated with perinatal complications. METHODS: This is a retrospective cohort study, involving 306 successful FET pregnancies from 2017 to 2022. Participants were divided into Natural Cycle (NC) and Hormone Replacement Cycle (HRC) group. We compared serum hormone levels, maternal backgrounds, and perinatal outcomes and complications. Furthermore, within the HRC group, serum hormone levels were compared for perinatal complications previously reported to show differences in incidence rates depending on the method of endometrial preparation. RESULTS: HRC exhibited significantly higher serum E2 levels during the implantation period, but lower P4 levels during ovulation, implantation, and pregnancy test period compared with NC. HRC also had significantly higher rates of postpartum hemorrhage (PPH) and placenta accreta spectrum (PAS). There was no association found between perinatal complications more likely to occur in HRC and serum E2, P4 levels. CONCLUSIONS: In HRC, there were more occurrences of PPH and PAS. Although serum E2, P4 levels during FET did not correlate with perinatal complications.

Quantification of the size of subchorionic hematoma causing pregnancy-related complications: a retrospective cohort study.

PURPOSE: This study aimed to establish criteria for defining "large" subchorionic hematoma (SCH) and assess its association with pregnancy complications. METHOD: This was a retrospective cohort study conducted at our institution between 2019 and 2020. We compared the size of SCH between the pregnancy-related complication and non-complication groups, using two measurement methods. Receiver operating characteristic (ROC) curve analysis determined cutoff values. Additionally, we compared the occurrence of pregnancy complications among three groups: large SCH group (above the cutoff value), non-large SCH group (below the cutoff value), and non-SCH group. RESULTS: Of 1305 singleton pregnancies managed during the study, 80 cases were diagnosed with SCH. Pregnancy complications occurred in 15 patients. The patients with pregnancy complications had significantly larger SCH sizes with both measurement methods. For each method, the cutoff values calculated from the ROC curve analysis were as follows: Method 1, 25% (area under the ROC curve [AUC], 0.662); Method 2, 30% (AUC, 0.624). In Method 1, we found a significantly higher occurrence of preterm delivery in the large SCH group (24.1%) than in the non-large SCH (4.2%) and non-SCH groups (5.3%; all p < 0.01). In Method 2, there was a significantly higher occurrence of preterm delivery in the large SCH group (33.3%) than in the non-large SCH (6.5%) and non-SCH groups (5.3%; all p < 0.01). CONCLUSION: Large SCHs may indicate a high risk of pregnancy-related complications. Among these, recognizing and managing cases that exceed the aforementioned cutoff value as high-risk cases may be beneficial for reducing pregnancy complications.

Pharmacokinetics, safety, and efficacy of daridorexant in Japanese subjects: Results from phase 1 and 2 studies.

Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. We report results from the first two randomised, double-blind clinical studies of daridorexant in Japanese subjects. In the Phase 1 study, daridorexant (10, 25, 50 mg) or placebo were administered in the morning for 4 days in 24 young (mean age 26.9 years) and 24 older (mean age 69.7 years) healthy Japanese adults. Daridorexant reached a peak plasma concentration within 1.0 h across every dose and age group. For all doses, the mean plasma concentration of daridorexant showed a similar change between the age groups. Exposure parameters increased dose-dependently with minimal/no accumulation upon repeated dosing. The terminal half-life was ~8 h. In the Phase 2, four-period, four-way crossover study, 47 Japanese subjects (mean age 50.4 years) with insomnia disorder were randomised to receive four treatments (daridorexant 10, 25, 50 mg, placebo) during four treatment periods, each consisting of two treatment nights (5-12 day washout between treatment periods). Subjects continued their fourth treatment for 12 further days. A statistically significant dose-response relationship (multiple-comparison procedure-modelling, p < 0.0001) was found in the reduction of polysomnography-measured wake after sleep onset (WASO; primary endpoint) and latency to persistent sleep (secondary endpoint) from baseline to days 1/2. Statistically significant dose-response relationships were also observed for secondary subjective endpoints from baseline to days 1/2 (sWASO, latency to sleep onset). All daridorexant doses were well tolerated, with no treatment discontinuations and no next-morning residual effects. These results supported further investigation of daridorexant in Japanese patients with insomnia disorder.

Prostaglandin F2α Affects the Cycle of Clock Gene Expression and Mouse Behavior.

Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor (Ptgfr) has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of Ptgfr-KO (B6.129-Ptgfrtm1Sna) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in Ptgfr-KO mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (Cry1), which is related to the circadian cycle. Moreover, the expression of Cry1, Cry2, and Period2 (Per2) mRNA were significantly altered in the mouse liver in Ptgfr-KO mice under DD. In the wild-type mouse, the plasma prostaglandin F2α (PGF2α) levels showed a circadian rhythm under a 12 h cycle of light-dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of Per2::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF2α is important for driving clock genes, thus suggesting the involvement of PGF2α- and Ptgfr-targeting drugs in the biological clock cycle.

Preeclampsia prediction model using demographic, clinical, and sonographic data in the second trimester of Japanese nulliparous women.

AIM: This study aimed to clarify the factors influencing preeclampsia (PE) development in nulliparous Japanese women and to develop a PE prediction model using second trimester sonographic and clinical data readily available to obstetricians. METHODS: This historical cohort study examined the obstetric records of nulliparous women who delivered at Yamanashi Prefectural Central Hospital from January 2019 to May 2023. A model was constructed to predict the PE development rate, with a focus on 796 nulliparous women. The assessed outcome was PE, excluding superimposed PE. Data on maternal age, assisted reproductive technology, mean arterial pressure, uterine artery notching, and umbilical artery resistance index were extracted. Multivariable logistic regression analysis was conducted on these five factors. RESULTS: The incidence of PE was 4.3% (34/796). Multivariable analysis indicated significant odds ratios for the association of PE with mean arterial pressure (adjusted odds ratio: 1.06, 95% confidence interval: 1.03-1.10) and uterine artery notching (adjusted odds ratio: 6.28, 95% confidence interval: 2.82-14.0) in nulliparous women. The PE prediction formula was established as follows: Probability of PE development (%) = (odds/1 + odds) × 100, odds = ex and x = -11.3 + 0.039 × maternal age (years) + 0.91 × assisted reproductive technology + 0.061 × mean arterial pressure (mmHg) + 1.84 × uterine artery notching + 1.84 × umbilical artery resistance index. The sensitivity and specificity of this model were 58.8% and 84.5%, respectively (area under the curve: 0.79). CONCLUSIONS: This study is the first to provide a prediction formula targeting the Japanese population. Our specialized model for nulliparous women could guide obstetricians to educate women regarding the precise prospect of PE development.

Similar Pharmacokinetics and Pharmacodynamics of Biosimilar SAR342434 Insulin Lispro and Japan-Approved Humalog Insulin Lispro in Healthy Japanese Subjects.

This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan-reference Humalog insulin lispro. This was a randomized, double-blind, 2-period, crossover study. Thirty-six healthy Japanese male subjects underwent a 10-hour euglycemic clamp following a single subcutaneous 0.3-U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration-time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR-time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR-AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product.

Ultrasonographic observation in combination with progesterone monitoring for detection of ovulation in Labrador Retrievers.

Although it is well known that the ovulation occurs during a period of time after LH surge in dogs, there are few reports of observing the entire process of development, ovulation and luteinization of each follicle. This study aimed to detect the ovulation kinetics by ultrasonography in combination with progesterone monitoring and therefore identify the time-range of the ovulation process in a dog. Daily transabdominal ultrasonography and progesterone monitoring were conducted for 24 natural oestrus cycles of Labrador Retrievers. Ovarian follicles were observed as anechoic structure with contours before ovulation. Ovulation (follicular collapse) was defined as when follicles became cloudy and contours obscure by transabdominal ultrasonography. Ultrasound imaging was capable of identifying the day of ovulation for 94.7% (178/188) of the follicles through the appearance of collapsed follicle or corpus luteum. Ovulation was observed between LH 0 (the day of LH surge) and LH 5, with 48.0%, 33.5% and 15.0% for LH 2, LH 3 and LH 1, respectively. The total number of ovulations on LH 2 and LH 3 accounted for 81.5% (141/173) of the total ovulation in 24 cycles examined. Ovulation occurred in 12 cycles for 2 d and for 3 d in 12 cycles. Seventeen cycles (70.8%) with multiple days of ovulation showed the largest number of ovulations on LH 2. The average follicle diameter 3 d before the LH surge was less than 5 mm, then exceeded 5 mm 2 d before the LH surge. The average follicle diameter at the time of ovulation (follicular collapse) was 6.1 ± 1.0 mm (n = 118). On the day before ovulation, the average diameters of the follicles ovulated on LH 1, LH 2 and LH 3 were 5.0 ± 0.7 mm, 5.8 ± 1.2 mm and 6.2 ± 1.3 mm, respectively. There was a significant difference in the follicle diameter between LH1 and LH2 (p < .001), LH2 and LH3 (p < .05), and LH1 and LH3 (p < .001). Suggesting that it is difficult to estimate the ovulation day based on follicle size. This study showed that combination of ultrasonography with progesterone monitoring could follow follicular development, ovulation and luteinization of the ovary in Labrador Retrievers. The direct visualization of the ovulation was achieved in a non-invasive, labour-friendly way. Furthermore, the time-range of the ovulation process was clarified in a dog. These results may contribute to an accurate understanding of the optimum timing of mating and improved breeding efficiency, including artificial insemination and embryo transfer for Labrador Retrievers.

Pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and Japan-approved NovoRapid in healthy Japanese subjects.

This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-Cmax), area under the plasma insulin concentration-time curve to the last quantifiable concentration (INS-AUClast), area under the GIR-time curve during the clamp (GIR-AUC0-10 h), and maximum GIR (GIRmax). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval [CI] 0.94-1.05) for INS-Cmax and 1.02 (90% CI 1.00-1.04) for INS-AUClast. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93-1.06) for GIR-AUC0-10 h and 1.01 (95% CI 0.95-1.08) for GIRmax. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80-1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.

Cerebrospinal Fluid Protein Concentration in Healthy Older Japanese Volunteers.

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in the older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in healthy older Japanese volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55-73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥65 years old) had higher CSF-TP concentration than the younger group (55-64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10-40 mg/dL). Conclusions: The reference interval of CSF-TP in the older population should be reconsidered for the precise diagnosis of neurological emergencies.

Statistical Analysis of the Axillary Temperatures Measured by a Predictive Electronic Thermometer in Healthy Japanese Adults.

Body temperature is important for diagnosing illnesses. However, its assessment is often a difficult task, considering the large individual differences. Although 37 °C has been the gold standard of body temperature for over a century, the temperature of modern people is reportedly decreasing year by year. However, a mean axillary temperature of 36.89 ± 0.34 °C reported in 1957 is still cited in Japan. To assess the measured axillary temperature appropriately, understanding its distribution in modern people is important. This study retrospectively analyzed 2454 axillary temperature measurement data of healthy Japanese adults in 2019 (age range, 20-79 years; 2258 males). Their mean temperature was 36.47 ± 0.28 °C (36.48 ± 0.27 °C in males and 36.35 ± 0.31 °C in females). Approximately 5% of the 20-39-year-old males had body temperature ≥37 °C, whereas 8% had a temperature ≥ 37 °C in the afternoon. However, none of the subjects aged ≥50 years reported body temperature ≥37 °C. In multivariable regression analysis, age, blood pressure, pulse rate, and measurement time of the day were associated with axillary temperature. Our data showed that the body temperature of modern Japanese adults was lower than that reported previously. When assessing body temperature, the age, blood pressure, pulse rate, and measurement time of the day should be considered.

SARS-CoV-2 Seroprevalence among Healthcare Workers in General Hospitals and Clinics in Japan.

Coronavirus disease 2019 (COVID-19) has become a serious public health problem worldwide. In general, healthcare workers are considered to be at higher risk of COVID-19 infection. However, the prevalence of COVID-19 among healthcare workers in Japan is not well characterized. In this study, we aimed to examine the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies among 2160 healthcare workers in hospitals and clinics that are not designated to treat COVID-19 patients in Japan. The prevalence of SARS-CoV-2 immunoglobulin G was 1.2% in August and October 2020 (during and after the second wave of the pandemic in Japan), which is relatively higher than that in the general population in Japan (0.03-0.91%). Because of the higher risk of COVID-19 infection, healthcare workers should be the top priority for further social support and vaccination against SARS-CoV-2.

Effect of quercetin on the motility of cryopreserved canine spermatozoa.

The addition of an antioxidant to cryopreservation solutions for preventing oxidative stress to sperm from several species, including that from humans, has been studied previously. Quercetin is a flavonoid contained in subarctic trees with freeze resistance and is known to be a strong antioxidant. Therefore, the effect of quercetin on the cryopreservation of dog spermatozoa was examined in this study. The proportions of total motile spermatozoa were significantly higher at 30, 60, 90, 120, and 150 min and at 60, 120, and 150 min after thawing in groups treated with 5 µg/ml and 10 µg/ml of quercetin dissolved in 0.1% DMSO added to the second extender based on skim milk compared to that in the control group, respectively. There were no differences between the experimental groups in the proportion of total motile spermatozoa during the observation periods. The proportion of total motile spermatozoa among those treated with 5 µg/ml of quercetin in 0.1% DMSO was improved by approximately 10-20% at 30-180 min after thawing compared to that in the control group. To evaluate the fertility of cryopreserved spermatozoa treated with quercetin, 2 × 108 spermatozoa were transcervically inseminated into bitches, and a total of 18 puppies were delivered in three bitches. These results indicated that supplementation of quercetin as a cryoprotectant to the skim milk-based extender improved the motility of cryopreserved spermatozoa from dogs compared to those of the control group. And fertility of cryopreserved spermatozoa with quercetin supplementation was proven with higher efficiency.

Pool walking may improve renal function by suppressing the renin-angiotensin-aldosterone system in healthy pregnant women.

This study aimed to examine the effect of pool walking on renal function in pregnant women. Fifteen pregnant women (mean gestational age, 37.8 weeks) walked in a pool (depth 1.3 m) for 1 h. A few days later, they walked on a street for 1 h. Within each activity, the starting and ending levels of plasma renin activity were measured. The total urine volume, creatinine clearance, and change in plasma renin activity levels between each activity were compared by Wilcoxon rank-sum test. The renin-angiotensin-aldosterone level was suppressed during pool walking: the mean starting and ending values of plasma renin activity and serum aldosterone were 6.8 vs. 5.5 ng/mL/h (p = 0.002) and 654 vs. 473 pg/mL (p = 0.01), respectively. The decreases in plasma renin activity and serum aldosterone levels were more evident in pool walking than in land walking (plasma renin activity, -1.27 vs. 0.81 ng/mL/h, p = 0.002; serum aldosterone, -180.9 vs. 3.1 ng/mL/h, p = 0.03), resulting in higher total urine volume (299 vs. 80 mL, p < 0.001) and creatinine clearance (161.4 vs. 123.4 mL/min, p = 0.03) in pool walking. Pool walking may improve renal function in pregnant women partly through the suppressed renin-angiotensin-aldosterone system.

Growth Patterns of Neonates Treated with Thermal Control in Neutral Environment and Nutrition Regulation to Meet Basal Metabolism.

Little is known about the growth patterns of low birth weight neonates (<2500 g) during standardized thermal control and nutrition regulation to meet basal metabolism requirements compared to those of non-low birth weight neonates (2500 g and above). We retrospectively identified 10,544 non-low birth weight and 681 low birth weight neonates placed in thermo-controlled incubators for up to 24 h after birth. All neonates were fed a 5% glucose solution 1 h after birth and breastfed every 3 h (with supplementary formula milk if applicable) to meet basal metabolism requirements. Maximum body-weight loss (%), percentage body-weight loss from birth to peak weight loss (%/day), and percentage body-weight gain from peak weight loss to day 4 (%/day) were assessed by multivariable linear regression. Overall, the growth curves showed a uniform J-shape across all birth weight categories, with a low mean maximum body-weight loss (1.9%) and incidence of neonatal jaundice (0.3%). The body-weight loss patterns did not differ between the two groups. However, low birth weight neonates showed significantly faster growth patterns for percentage body-weight gain: ß = 0.52 (95% confidence interval, 0.46 to 0.58). Under thermal control and nutrition regulation, low birth weight neonates might not have disadvantages in clinical outcomes or growth patterns.

Influence of genetic polymorphisms and habitual caffeine intake on the changes in blood pressure, pulse rate, and calculation speed after caffeine intake: A prospective, double blind, randomized trial in healthy volunteers.

The aim of this study was to investigate the contribution of gene polymorphisms, in combination with habitual caffeine consumption, to the effect of caffeine intake on hemodynamic and psychoactive parameters. A double-blind, prospective study was conducted with 201 healthy volunteers randomly allocated 2:1 to the caffeinated group (150 mL decaffeinated coffee with additional 200 mg caffeine) or decaffeinated group (150 mL decaffeinated coffee). We measured the changes in blood pressure (BP) and calculation speed upon coffee intake, stratifying with gene polymorphisms, e.g., those in adenosine A2A receptor (ADORA2A) and cytochrome P450 (CYP) 1A2, and daily caffeine consumption (≤90 mg/day and >90 mg/day). Overall, caffeine intake independently increased BP and calculation speed (p-values < 0.05), irrespective of the polymorphisms. In stratified analysis, a statistical significance within the caffeinated group was observed for the change in systolic BP in the stratum of CYP1A2 polymorphism with daily caffeine consumption ≤90 mg/day: change in systolic BP in the CYP1A2 rs762551 CC group (mean ± SD = 11.8 ± 5.9) was higher than that in the AA/CA group (4.1 ± 5.5). Gene polymorphisms may limitedly modify the effect of caffeine intake on hemodynamic parameters in combination with habitual caffeine consumption.

Optimal Thermal Control with Sufficient Nutrition May Reduce the Incidence of Neonatal Jaundice by Preventing Body-Weight Loss Among Non-Low Birth Weight Infants Not Admitted to Neonatal Intensive Care Unit.

BACKGROUND: Neonatal jaundice is strongly attributable to excess body-weight loss as a result of insufficient calorific intake. OBJECTIVES: To examine the incidence of neonatal jaundice (defined by use of phototherapy) and body-weight loss, as well as their association, among neonates under optimal thermal control with sufficient nutrition, a local protocol for temperature and nutritional regulation. METHODS: We retrospectively identified a cohort of 10,544 neonates (birth weight ≥2,500 g) placed in thermo-controlled incubators for 2 h immediately after birth. Neonates were fed with 5% glucose solution 1 h after birth and breastfed every 3 h (with supplementary formula milk if applicable) according to basal maintenance expenditure. Total serum bilirubin levels at day 4 (peak level) were assessed. Phototherapy was performed on the basis of total serum bilirubin level ≥18 mg/dL. Risk ratio (RR) and 95% CI for the use of phototherapy against maximum body-weight loss were estimated using Poisson regression with robust variance. RESULTS: Incidence of phototherapy use was low (0.3%) and the mean total serum bilirubin level was 8.5 mg/dL (SD 2.7 mg/dL), with a low mean maximum body-weight loss (1.9%) and low incidence of excess body-weight loss ≥7% (0.4%). Maximum body-weight loss was associated with risk of neonatal jaundice (RR 1.27; 95% CI 1.04-1.54), and became significant at approximately 4% of maximum body-weight loss. CONCLUSION: Optimal thermal control and sufficient nutrition may greatly reduce the incidence of neonatal jaundice by preventing neonatal body-weight loss.

Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration.

INTRODUCTION: To examine whether sex and polymorphisms of cytochrome P450 (CYP) 2B6 and UDP-glucuronosyltransferase (UGT) 1A9 affect the difference between predicted and measured plasma propofol concentration during continuous infusion by target-controlled infusion. RESULTS: Blood samples of 69 patients (48 men and 21 women) were obtained at 4 h after initial propofol infusion. Percentage performance error (PE) was calculated to assess the difference between measured and predicted propofol concentration. Regression coefficients (ß) and 95% confidence intervals (CI) of sex and the polymorphisms of CYP2B6 and UGT1A9 for PE were, separately and mutually, estimated with linear regression. Covariates included age and body mass index in the minimal adjusted model, and additionally included clinical factors (mean blood pressure, heart rate, volume of intravenous fluid, surgical site, surgical position, and pneumoperitoneum) in the full adjusted model. PE was higher in men than in women (28.7% versus 10.5%, p = 0.015). Female sex was inversely associated with PE: the minimal adjusted ß = - 8.84 (95% CI, - 16.26 to - 1.43); however, the fully adjusted ß with clinical factors became not significant. The average of PE did not differ between polymorphisms of CYP2B6 and UGT1A9, and ß of CYP2B6 516G>T polymorphisms mutually adjusted with female sex was not significant. Mean blood pressure, heart rate, and volume of intravenous fluid were independently associated with PE in the full adjusted model. CONCLUSIONS: Under 4 h anesthesia with propofol target-controlled infusion in our population, sex differences appeared to exist in the propofol concentration, which might be largely mediated by clinical factors, such as hemodynamic status. TRIAL REGISTRATION: UMIN-CTR UMIN000009015 , Registered 1 October 2012.

BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aß Peptides.

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human ß-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-ß (Aß) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aß peptide reductions were also seen at all doses, with CSF Aß42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-ß precursor protein ß also decreased following lanabecestat treatment. Suppression of CSF Aß peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease.