Nanosheet Particles with Defect-Free Block Copolymer Structures Driven by Emulsions Containing Crystallizable Surfactants.

Highly anisotropic-shaped particles with well-ordered internal nanostructures have received significant attention due to their unique shape-dependent photonic, rheological, and electronic properties and packing structures. In this work, nanosheet particles with cylindrical block copolymer (BCP) arrays are achieved by utilizing collapsed emulsions as a scaffold for BCP self-assembly. Highly elongated structures with large surface areas are formed by employing crystallizable surfactants that significantly reduce the interfacial tension of BCP emulsions. Subsequently, the stabilized elongated emulsion structures lead to the formation of BCP nanosheets. Specifically, when polystyrene-block-polydimethylsiloxane (PS-b-PDMS) and 1-octadecanol (C18-OH) are co-assembled within an emulsion, C18-OH penetrates the surfactant layer at the emulsion interface, lowering the interfacial tension (i.e., below 1 mN m-1 ) and causing emulsion deformation. In addition, C18-OH crystallization allows for kinetic arrest of the collapsed emulsion shape during solvent evaporation. Consequently, PS-b-PDMS BCPs self-assemble into defect-free structures within nanosheet particles, exhibiting an exceptionally high aspect ratio of over 50. The particle formation mechanism is further investigated by controlling the alkyl chain length of the fatty alcohol. Finally, the coating behavior of nanosheet particles is investigated, revealing that the deposition pattern on a substrate is strongly influenced by the particle's shape anisotropy, thus highlighting their potential for advanced coating applications.

Disrupted Rotational Perception During Simultaneous Stimulation of Rotation and Inertia.

Two vestibular signals, rotational and inertial cues, converge for the perception of complex motion. However, how vestibular perception is built on neuronal behaviors and decision-making processes, especially during the simultaneous presentation of rotational and inertial cues, has yet to be elucidated in humans. In this study, we analyzed the perceptual responses of 20 participants after pairwise rotational experiments, comprised of four control and four test sessions. In both control and test sessions, participants underwent clockwise and counterclockwise rotations in head-down and head-up positions. The difference between the control and test sessions was the head re-orientation relative to gravity after rotations, thereby providing only rotational cues in the control sessions and both rotational and inertial cues in the test sessions. The accuracy of perceptual responses was calculated by comparing the direction of rotational and inertial cues acquired from participants with that predicted by the velocity-storage model. The results showed that the accuracy of rotational perception ranged from 80 to 95% in the four control sessions but significantly decreased to 35 to 75% in the four test sessions. The accuracy of inertial perception in the test sessions ranged from 50 to 70%. The accuracy of rotational perception improved with repetitive exposure to the simultaneous presentation of both rotational and inertial cues, while the accuracy of inertial perception remained steady. The results suggested a significant interaction between rotational and inertial perception and implied that vestibular perception acquired in patients with vestibular disorders are potentially inaccurate.

Clinical profile and treatment outcomes of idiopathic intracranial hypertension: a multicenter study from Korea.

BACKGROUND: Currently, there is a relative lack of detailed reports regarding clinical presentation and outcome of idiopathic intracranial hypertension in Asians. This study aims to describe the clinical features and treatment outcomes of Korean patients with idiopathic intracranial hypertension. METHODS: We prospectively recruited patients with idiopathic intracranial hypertension from one hospital and retrospectively analyzed the medical records of 11 hospitals in Korea. We collected data regarding preceding medical conditions or suspected medication exposure, headache phenotypes, other associated symptoms, detailed neuroimaging findings, treatments, and outcomes after 1-2 and 3-6 months of treatment. RESULTS: Fifty-nine (83.1% women) patients were included. The mean body mass index was 29.11 (standard deviation, 5.87) kg/m2; only 27 patients (45.8%) had a body mass index of ≥ 30 kg/m2. Fifty-one (86.4%) patients experienced headaches, patterns of which included chronic migraine (15/51 [29.4%]), episodic migraine (8/51 [15.7%]), probable migraine (4/51 [7.8%]), chronic tension-type headache (3/51 [5.9%]), episodic tension-type headache (2/51 [3.9%]), probable tension-type headache (2/51 [3.9%]), and unclassified (17/51 [33.3%]). Medication overuse headache was diagnosed in 4/51 (7.8%) patients. After 3-6 months of treatment, the intracranial pressure normalized in 8/32 (25.0%), improved in 17/32 (53.1%), no changed in 7/32 (21.9%), and worsened in none. Over the same period, headaches remitted or significantly improved by more than 50% in 24/39 patients (61.5%), improved less than 50% in 9/39 (23.1%), and persisted or worsened in 6/39 (15.4%) patients. CONCLUSION: Our findings suggest that the features of Asian patients with idiopathic intracranial hypertension may be atypical (i.e., less likely obese, less female predominance). A wide spectrum of headache phenotypes was observed. Medical treatment resulted in overall favorable short-term outcomes; however, the headaches did not improve in a small proportion of patients.

The influence of dietary patterns on skin bacterial diversity, composition, and co-occurrence relationships at forearm and neck sites of healthy Korean adults.

AIMS: Diet and nutrition are important aspects of skin physiology and health. However, the influence of diet on the bacterial flora of different skin sites is not well understood. Therefore, we investigated the relationship between dietary patterns (DPs) and skin bacterial flora on the forearm (a dry site) and the neck (a sebaceous site) of healthy Korean adults. METHODS AND RESULTS: In metagenomics analysis, Shannon and Simpson indices were higher on the forearm than on the neck and were negatively correlated with the two dominant species, Cutibacterium acnes and Staphylococcus epidermidis, on two skin sites. In addition, the Simpson index of the forearm was positively associated with DP1 (characterized by a high intake of vegetables, mushrooms, meat, fish and shellfish, seaweed, and fat and oil), while that on the neck was negatively associated with DP2 (characterized by a high intake of fast food). A high intake of DP1 was associated with a lower abundance of dominant species, including C. acnes, and higher degrees of the co-occurrence network, whereas a high intake of DP2 was associated with the opposite pattern. CONCLUSIONS: Specific diets may impact both skin bacterial diversity and composition, as well as the co-occurrence of bacteria, which may vary across different skin sites.

Successful New Dental Implant Installation in a Healed Site of Medication-Related Osteonecrosis of the Jaw: A Case Report.

The purpose of this case report was to present a rare clinical case of successful new dental implant installation in the site of previously healed medication-related osteonecrosis of the jaw (MRONJ). An 80-year-old female patient with history of oral bisphosphonate (BP) therapy presented with pain and swelling of gingiva in the right posterior mandible. One of the 3 implants placed 15 years ago in the right mandibular posterior area was removed 6 months before the visit to our hospital, which led to worsening of the symptoms. After clinical and radiographic examination, the patient was diagnosed with stage 2 MRONJ. Along with antibiotic therapy, the patient underwent surgical intervention via sequestrectomy and removal of the remaining 2 implants. Adequate soft and hard tissue healing without any complications and signs of recurrence was confirmed, and implant installation with simultaneous bone grafting and prosthesis fabrication were done in the explantation sites of MRONJ. By the 7-year follow-up, no implant failure has been observed, and installation of implants was successful in the previously healed MRONJ site. Dental implant installation is possible in a patient with history of failed implant due to MRONJ. However, a careful treatment planning is needed before implantation in a previously healed site of MRONJ to reduce the potential risks of MRONJ recurrence and implant failure.

Parent-infant skin-to-skin contact reduces the electrical activity of the diaphragm and stabilizes respiratory function in preterm infants.

BACKGROUND: The physiological benefit of parent-infant skin-to-skin contact (SSC) is uncertain for preterm infants with ventilatory support. We aimed to investigate whether SSC stabilizes the respiration compared to incubator care in mechanically ventilated preterm infants. METHODS: The prospective observational study was performed in Turku University Hospital, Finland. Preterm infants were eligible if they were born before 36 weeks gestation and received respiratory support with either invasive or non-invasive neurally adjusted ventilatory assist (NAVA). SSC was applied as soon as possible after birth. Respiratory variables were collected from the ventilator log data, and SSC episodes were compared with matched control periods during incubator care. RESULTS: A total of 167 episodes of SSC were recorded from 17 preterm infants: 138 episodes during invasive NAVA and 29 episodes during non-invasive NAVA. During invasive NAVA, peak electrical activity of the diaphragm (Edi), minimum Edi, respiratory rate, time on backup ventilation, peak inspiratory pressure, and mean airway pressure were significantly lower in SSC than in incubator care. During non-invasive NAVA, peak Edi, minimum Edi, time on backup ventilation, and peak inspiratory pressure were significantly lower in SSC than in incubator care. CONCLUSIONS: SSC stabilized and improved the respiratory physiology in mechanically ventilated preterm infants. IMPACT: Skin-to-skin contact reduced work of breathing compared to incubator care in mechanically ventilated preterm infants. Skin-to-skin contact reduced the need for backup ventilation during neurally adjusted ventilatory assist in preterm infants. Skin-to-skin contact among ventilated preterm infants was not only safe but also stabilized and improved their respiratory physiology.

The effect of the multimodal intervention including an automatic notification of catheter days on reducing central line-related bloodstream infection: a retrospective, observational, quasi-experimental study.

BACKGROUND: A central venous catheter (CVC) is an important medical device, but it could be preceding infection and the risk of central line-associated bloodstream infection (CLABSI). CLABSI is a common healthcare-associated infection but results in high cost and mortality; therefore, various efforts to reduce CLABSI have been attempted. METHODS: This is a retrospective, observational, quasi-experimental study in the intensive care unit (ICU) of a single tertiary care hospital. We reviewed and analysed the data of CLABSI rates and days from the insertion to the removal of the temporary CVC between January 2018 and June 2021 with transient periods over 9 months. Sequentially, all patients with the CVC in the ICU underwent the following interventions: maximal barrier precaution, automatic notification of catheter days and 2% chlorhexidine gluconate bathing. A segmented regression analysis of interrupted time series was conducted to compare the CLABSI rates before and after the introduction of multimodal interventions. During study periods, the impact of interventions on CLABSI was evaluated using multivariate logistic regression analyses. RESULTS: A total of 76,504 patient-days, 28,312 catheter days and 66 CLABSI cases were reviewed in ICU-hospitalised patients. As additional interventions, the CLABSI rate declined from 3.1 per 1000 CVC days to 1.2 per 1000 CVC days in post-interventions. In the pre-intervention and post-intervention periods, 4146 patents had one more short-term CVC. In the multivariate logistic regression analyses, multimodal intervention was one of determinants reducing CLABSI rates (odds ratio (OR), 0.52 [95% confidence interval {CI}, 0.28-0.94]). Indwelling time of CVC over 10 days was the risk factor for CLABSI rates (OR, 6.27 [95% CI, 3.36-12.48]). Of the three interventions, the automatic notification of catheter days was associated with decreased median monthly total CVC days and duration of CVC days per patient. CONCLUSIONS: Multidisciplinary and evidence-based interventions could lead to a decrease in the CLABSI rates. Moreover, the automatic notification of catheter days of the electronic medical healthcare system has shortened the time of indwelling CVC.

Maternal antibiotic exposure during pregnancy is a risk factor for community-acquired urinary tract infection caused by extended-spectrum beta-lactamase-producing bacteria in infants.

BACKGROUND: This study aimed to investigate the risk factors for community-acquired urinary tract infection (UTI) caused by extended-spectrum beta-lactamase (ESBL)-positive bacteria in infants. METHODS: We retrospectively reviewed the medical records of infants aged < 1 year with first UTI from 2018 to 2019 at two tertiary centers in Korea. Data analyzed included clinical findings, birth history, delivery mode, milk type, use of postpartum care center, and previous use of antibiotics both in the patient and mother. RESULTS: Of 265 patients, 62 (23.4%) were diagnosed with first UTI caused by ESBL-positive bacteria at the median age of 3.6 (interquartile range (IQR) 2.3-5.4) months. Maternal use of antibiotics during pregnancy (29.0 vs. 10.3%, p < 0.001) and Klebsiella species (19.4% vs. 4.9%, p < 0.001) were significantly associated with ESBL-positive UTIs and remained valid in the multivariate analysis (odds ratio [OR], 3.40; 95% confidence interval [CI] 1.61-7.19, p = 0.001, and OR 5.26; 95% CI 2.03-13.13, p = 0.001, respectively). Previous antibiotic exposure of patients, previous hospitalization, prematurity, delivery mode, milk type, and use of postpartum care center were not significantly different between ESBL-positive and ESBL-negative groups. With respect to the clinical course of UTI, the ESBL-positive group presented a higher number of blood leukocytes (p = 0.041) and longer hospital stay (p < 0.001) than the ESBL-negative group. CONCLUSIONS: About one-fourth of infantile UTI cases were ESBL-positive. Prenatal antibiotic exposure of mothers and Klebsiella species were associated with community-acquired UTI caused by ESBL-positive bacteria.

Survey on the Status of Breastfeeding in Korean Medical Institution Workers.

BACKGROUND: Human breast milk is essential and provides irreplaceable nutrients for early humans. However, breastfeeding is not easy for various reasons in medical institution environments. Therefore, in order to improve the breastfeeding environment, we investigated the difficult reality of breastfeeding through questionnaire responses from medical institution workers. METHODS: A survey was conducted among 179 medical institution workers with experience in childbirth within the last five years. The survey results of 175 people were analyzed, with incoherent answers excluded. RESULTS: Of the 175 people surveyed, a total of 108 people (61.7%) worked during the day, and 33 people (18.9%) worked in three shifts. Among 133 mothers who stayed with their babies in the same nursing room, 111 (93.3%) kept breastfeeding for more than a month, but among those who stayed apart, only 10 (71.4%) continued breastfeeding for more than a month (P = 0.024). Ninety-five (88.0%) of daytime workers, 32 (94.1%) two-shift workers, and 33 (100%) three-shift workers continued breastfeeding for more than a month (P = 0.026). Workers in general hospitals tended to breastfeed for significantly longer than those that worked in tertiary hospitals (P = 0.003). A difference was also noted between occupation categories (P = 0.019), but a more significant difference was found in the comparison between nurses and doctors (P = 0.012). Longer breastfeeding periods were noted when mothers worked three shifts (P = 0.037). Depending on the period planned for breastfeeding prior to childbirth, the actual breastfeeding maintenance period after birth showed a significant difference (P = 0.002). Of 112 mothers who responded to the question regarding difficulties in breastfeeding after returning to work, 87 (77.7%) mentioned a lack of time caused by being busy at work, 82 (73.2%) mentioned the need for places and appropriate circumstances. CONCLUSION: In medical institutions, it is recommended that environmental improvements in medical institutions, the implementation of supporting policies, and the provision of specialized education on breastfeeding are necessary to promote breastfeeding.

Total Intravenous Anesthesia in a Malignant Hyperthermia-Susceptible Patient with Klinefelter Syndrome Undergoing Orthognathic Surgery.

ABSTRACT: A patient with Klinefelter syndrome and skeletal Class III malocclusion experienced a malignant hyperthermia-like reaction while undergoing orthognathic surgery. The patient fully recovered after prompt diagnosis and management, and surgery was reattempted under total intravenous anesthesia. The patient was discharged without any anesthetic complications and was satisfied with the surgical results. This is the first described case of a malignant hyperthermia-like event in a patient with Klinefelter syndrome. Total intravenous anesthesia may be safely administered in malignant hyperthermia-susceptible patients who require orthognathic surgery.

Genotype and Phenotype Differences in CADASIL from an Asian Perspective.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small-vessel disease caused by mutations in the NOTCH3 gene. Classical pathogenic mechanisms are associated with cysteine gain or loss, but recent studies suggest that cysteine-sparing mutations might have a potential role as a pathogen. In comparison with CADASIL patients in Western countries, there are several differences in Asian patients: (1) prevalent locus of NOTCH3 mutations (exons 2-6 [particularly exon 4] vs. exon 11), (2) age at symptom onset, (3) prevalence of cerebral microbleeds and hemorrhagic stroke, (4) clinical symptoms, and (5) severity of white matter hyperintensities and typical involvement of the anterior temporal pole in magnetic resonance imaging. Both ethnicity and founder effects contribute to these differences in the clinical NOTCH3 spectrum in different cohorts. More functional investigations from diverse races are needed to clarify unknown but novel variants of NOTCH3 mutations. This review may broaden the spectrum of NOTCH3 variants from an Asian perspective and draw attention to the hidden pathogenic roles of NOTCH3 variants.

Vestibular Perception in Time and Space During Whole-Body Rotation in Humans.

We investigated the vestibular perception of position, velocity, and time (duration) in humans with rotational stimuli including low velocities and small amplitudes. The participants were categorized into young, middle, and old age groups, and each consisted of 10 subjects. Position perception was assessed after yaw rotations ranged from 30 to 180° in both clockwise and counterclockwise directions. For each position, the rotation was delivered at two or more different velocities ranging from 15 to 120°/s. Position perception tended to underestimate the actual position and was similar during the slow and fast rotations. However, the trends of underestimation disappeared in the old age group. Velocity perception was evaluated by forcing the selection of the faster direction in each pair of rotations toward two positions (30° and 60°) with velocity differences from 0 to 20°/s. Velocity discrimination was similar between the rotation amplitudes or among the age groups. For duration perception, participants chose the rotation of longer duration for three test paradigms with different amplitudes (small vs. large) and durations (short vs. long) of rotation. The accuracy of discriminating duration was similar across the test paradigms or age groups, but the precision was lower in the older group and altered significantly according to the test paradigm. In conclusion, vestibular perception can be assessed using rotations of low velocities and small amplitudes. The perception of position and duration is affected by aging. The precision of duration perception can be influenced by the interactions between the amplitude and duration of motion.

Opsoclonus Following Downbeat Nystagmus in Absence of Visual Fixation in Multiple System Atrophy: Modulation and Mechanisms.

We report atypical opsoclonus in a patient with multiple system atrophy and propose a mechanism based on the patterns of modulation by visual, vestibular, and saccadic and vergence stimulation. Firstly, the 6-Hz opsoclonus mostly in the vertical plane occurred only after the development of downbeat nystagmus in darkness without visual fixation. Even after a substantial build-up, visual suppression of the opsoclonus was immediate and complete. Furthermore, the latency for re-emergence of opsoclonus in darkness was greater when the duration of preceding visual fixation was longer. Secondly, the effect of preceding downbeat nystagmus on the development of opsoclonus was evaluated by changing the head position. The opsoclonus did not occur in the supine position when the downbeat nystagmus was absent. After horizontal head shaking, the opsoclonus in the vertical plane gradually evolved into horizontal plane and resumed its vertical direction again after vertical head shaking. Thirdly, any opsoclonus was not triggered by imaginary saccades in the supine position. Lastly, combined vergence and saccadic eye movements during the Müller paradigm did not induce opsoclonus. From these findings of modulation, we suggest that the opsoclonus observed in our patient was invoked by vestibular signals. When the function of the omnipause neurons and saccadic system was impaired, the centrally mediated vestibular eye velocity signals may activate the saccadic system to generate opsoclonus. These atypical patterns of opsoclonus, distinct from the classic opsoclonus frequently observed in para-neoplastic or para-infectious disorders, may be an unrevealing sign of degenerative brainstem or cerebellar disorders.

Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Transgenic Mice Overexpressing PG1 Display Corneal Opacity and Severe Inflammation in the Eye.

Antimicrobial peptides (AMPs) are of interest as alternatives to antibiotics or immunomodulators. We generated and characterized the phenotypes of transgenic mice overexpressing protegrin 1 (PG1), a potent porcine cathelicidin. No obvious differences were observed between PG1 transgenic and wild-type mice in terms of growth, development, general behaviour, and the major immune cell population. However, PG1 transgenic mice intranasally infected with Staphylococcus aureus resulted in a reduction in microscopic pulmonary injury, improved clearance of bacteria, and lower proinflammatory cytokine secretion, compared to those of wild-type mice. On the other hand, approximately 25% of PG1 transgenic mice (n = 54/215) showed corneal opacity and developed inflammation in the eye, resulting ultimately in phthisis bulbi. Immunohistochemical analyses revealed that PG1 and its activator, neutrophil elastase, localized to the basal cells of the cornea and glands in eyelids, respectively. In addition, apoptosis indicated by a Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive signal was detected from flat cells of the cornea. Our study suggests that the expression regulation or localization of AMPs such as PG1 is important to prevent their adverse effects. However, our results also showed that the cytotoxic effects of PG1 on cells could be tolerated in animals, except for the eyes.

CRISPRi-Guided Metabolic Flux Engineering for Enhanced Protopanaxadiol Production in Saccharomyces cerevisiae.

Protopanaxadiol (PPD), an aglycon found in several dammarene-type ginsenosides, has high potency as a pharmaceutical. Nevertheless, application of these ginsenosides has been limited because of the high production cost due to the rare content of PPD in Panax ginseng and a long cultivation time (4-6 years). For the biological mass production of the PPD, de novo biosynthetic pathways for PPD were introduced in Saccharomyces cerevisiae and the metabolic flux toward the target molecule was restructured to avoid competition for carbon sources between native metabolic pathways and de novo biosynthetic pathways producing PPD in S. cerevisiae. Here, we report a CRISPRi (clustered regularly interspaced short palindromic repeats interference)-based customized metabolic flux system which downregulates the lanosterol (a competing metabolite of dammarenediol-II (DD-II)) synthase in S. cerevisiae. With the CRISPRi-mediated suppression of lanosterol synthase and diversion of lanosterol to DD-II and PPD in S. cerevisiae, we increased PPD production 14.4-fold in shake-flask fermentation and 5.7-fold in a long-term batch-fed fermentation.

Upregulation of cellulase activity and mRNA levels by bacterial challenge in the earthworm Eisenia andrei, supporting the involvement of cellulases in innate immunity.

To investigate whether earthworm cellulases contribute to the innate immune system, the responsiveness of cellulase activity and mRNA expression to bacterial challenge was examined by zymography and RNA sequencing. A zymographic analysis revealed that the activity levels of earthworm cellulases were upregulated in response to either a bacterial (Bacillus subtilis or Escherichia coli) or LPS challenge. After the challenge, significant increases in cellulase 1 and cellulase 2 activity levels were observed within 8-16 and 16-24 h, respectively. In the coelomic fluid, both activities were significantly upregulated at 8 h post-injection with B. subtilis. Based on RNA sequencing, cellulase-related mRNAs encoding beta-1,4-endoglucanases were upregulated by 3-fold within 6 h after B. subtilis injection. Our results clearly demonstrated that earthworm cellulases are upregulated by bacterial challenge at the mRNA and protein levels. These results support the view that earthworm cellulases act as inducible humoral effectors of innate immunity against bacterial infection.

Importin-11 is Essential for Normal Embryonic Development in Mice.

Importin-11 (Ipo11) is a novel member of the human importin family of transport receptors (karyopherins), which are known to mediate the nucleocytoplasmic transport of protein and RNA cargos. Despite its role in the transport of protein, we found that knockout of Ipo11 nuclear import factor affects normal embryonic development and govern embryo-lethal phenotypes in mice. In this study, we for the first time produced a mouse line containing null mutation in Ipo11 gene utilized by gene trapping. The Ipo11-/- embryos showed an embryonic lethal phenotype. The Ipo11-/- embryos showed a reduced size at embryonic day 10.5 (E10.5) when compared with Ipo11+/+ or Ipo11+/- embryos and died by E11.5. Whereas Ipo11+/- mice were healthy and fertile, and there was no detectable changes in embryonic lethality and phenotype when reviewed. In the X-gal staining with the Ipo11-/- or Ipo11+/- embryos, strong X-gal staining positivity was detected systematically in the whole mount embryos at E10.5, although almost no X-gal positivity was detected at E9.5, indicating that the embryos die soon after the process of Ipo11 expression started. These results indicate that Ipo11 is essential for the normal embryonic development in mice.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Population Pharmacokinetic Study of Prophylactic Fluconazole in Preterm Infants for Prevention of Invasive Candidiasis.

Fluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen. A pharmacokinetic model was developed using 301 fluconazole concentrations from 75 preterm infants with a baseline body weight (WT) ranging from 0.5 to 1.5 kg and an estimated glomerular filtration rate (eGFR) ranging from 12.9 to 58.5 ml/min/1.73 m2 Eligible infants received an intravenous or oral dose of 3 mg/kg of body weight of fluconazole, twice weekly with a ≥72-h dose interval, for 4 weeks. The model was qualified with basic goodness-of-fit diagnostics, visual predictive checks, and bootstrapping. The fluconazole pharmacokinetics was well described with a one-compartment linear model with a proportional residual error. The population clearance (CL) and volume of distribution (V) were derived as 0.0197 × (WT/1.00)0.746 × (eGFR/25.0)0.463 × exp(η) and 1.04 × WT × exp(η), respectively. Such covariate analyses augment the awareness of the need for personalized dosing in preterm infants. (This study has been registered at ClinicalTrials.gov under identifier NCT01683760).