Impact of replacing or adding pregnancy-associated plasma protein-A at 11-13 weeks on screening for preterm pre-eclampsia.

OBJECTIVE: To assess whether pregnancy-associated plasma protein-A (PAPP-A) alters or provides equivalent screening performance as placental growth factor (PlGF) when screening for preterm pre-eclampsia (PE) at 11-13 weeks of gestation. METHODS: This was a secondary analysis of a non-intervention screening study of 6546 singleton pregnancies that were screened prospectively for preterm PE in the first trimester between December 2016 and June 2018. Patient-specific risks for preterm PE were estimated by maternal history, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), PlGF and PAPP-A. A competing-risks model with biomarkers expressed as multiples of the median was used. All women and clinicians were blinded to the risk for preterm PE. The performance of screening for preterm PE using PlGF vs PAPP-A vs both PAPP-A and PlGF was assessed by comparing areas under the receiver-operating-characteristics (AUC) curves. McNemar's test was used to compare detection rate at a fixed false-positive rate (FPR) of 10%. RESULTS: PlGF and PAPP-A were measured in 6546 women, of whom 37 developed preterm PE. The AUC and detection rate at 10% FPR using PlGF in combination with maternal history, MAP and UtA-PI were 0.854 and 59.46%, respectively. The respective values were 0.813 and 51.35% when replacing PlGF with PAPP-A and 0.855 and 59.46% when using both PAPP-A and PlGF. Statistically non-significant differences were noted in AUC when replacing PlGF with PAPP-A (ΔAUC, 0.04; P = 0.095) and when using both PAPP-A and PlGF (ΔAUC, 0.002; P = 0.423). However, on an individual case basis, screening using PlGF in conjunction with maternal history, MAP and UtA-PI identified three (8.1%) additional pregnancies that developed preterm PE and that were not identified when replacing PlGF with PAPP-A. Screening using PAPP-A in addition to maternal history and other biomarkers did not identify any additional pregnancies. CONCLUSION: On an individual case basis, adoption of a screening strategy that uses PAPP-A instead of PlGF results in reduced detection of preterm PE, consistent with previous literature. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Exploring the diagnostic utility of genome sequencing for fetal congenital heart defects.

OBJECTIVE: The diagnostic yield for congenital heart defects (CHD) with routine genetic testing is around 10%-20% when considering pathogenic CNVs or aneuploidies as positive findings. This is a pilot study to investigate the utility of genome sequencing (GS) for prenatal diagnosis of CHD. METHODS: Genome sequencing (GS, 30X) was performed on 13 trios with CHD for which karyotyping and/or chromosomal microarray results were non-diagnostic. RESULTS: Trio GS provided a diagnosis for 4/13 (30.8%) fetuses with complex CHDs and other structural anomalies. Findings included pathogenic or likely pathogenic variants in DNAH5, COL4A1, PTPN11, and KRAS. Of the nine cases without a genetic etiology by GS, we had outcome follow-up data on eight. For five of them (60%), the parents chose to keep the pregnancy. A balanced translocation [46,XX,t(14; 22)(q32.33; q13.31)mat] was detected in a trio with biallelic DNAH5 mutations, which together explained the recurrent fetal situs inversus and dextrocardia that was presumably due to de novo Phelan-McDermid syndrome. A secondary finding of a BRCA2 variant and carrier status of HBB, USH2A, HBA1/HBA2 were detected in the cohort. CONCLUSIONS: GS expands the diagnostic scope of mutation types over conventional testing, revealing the genetic etiology for fetal heart anomalies. Patients without a known genetic abnormality indicated by GS likely opted to keep pregnancy especially if the heart defect could be surgically repaired. We provide evidence to support the application of GS for fetuses with CHD.

Transperineal ultrasound assessment of fetal head elevation by maneuvers used for managing umbilical cord prolapse.

OBJECTIVE: To assess objectively the degree of fetal head elevation achieved by different maneuvers commonly used for managing umbilical cord prolapse. METHODS: This was a prospective observational study of pregnant women at term before elective Cesarean delivery. A baseline assessment of fetal head station was performed with the woman in the supine position, using transperineal ultrasound for measuring the parasagittal angle of progression (psAOP), head-symphysis distance (HSD) and head-perineum distance (HPD). The ultrasonographic measurements of fetal head station were repeated during different maneuvers, including elevation of the maternal buttocks using a wedge, knee-chest position, Trendelenburg position with a 15° tilt and filling the maternal urinary bladder with 100 mL, 300 mL and 500 mL of normal saline. The measurements obtained during the maneuvers were compared with the baseline measurements. RESULTS: Twenty pregnant women scheduled for elective Cesarean section at term were included in the study. When compared with baseline (median psAOP, 103.6°), the knee-chest position gave the strongest elevation effect, with the greatest reduction in psAOP (psAOP, 80.7°; P < 0.001), followed by filling the bladder with 500 mL (psAOP, 89.9°; P < 0.001) and 300 mL (psAOP, 94.4°; P < 0.001) of normal saline. Filling the maternal bladder with 100 mL of normal saline (psAOP, 96.1°; P = 0.001), the Trendelenburg position (psAOP, 96.8°; P = 0.014) and elevating the maternal buttocks (psAOP, 98.3°; P = 0.033) gave modest elevation effects. Similar findings were reported for HSD and HPD. The fetal head elevation effects of the knee-chest position, Trendelenburg position and elevation of the maternal buttocks were independent of the initial fetal head station, but that of bladder filling was greater when the initial head station was low. CONCLUSIONS: To elevate the fetal presenting part, the knee-chest position provides the best effect, followed by filling the maternal urinary bladder with 500 mL then 300 mL of fluid, respectively. Filling the bladder with 100 mL of fluid, the Trendelenburg position and elevation of the maternal buttocks have modest effects. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Expanded carrier screening using next-generation sequencing of 123 Hong Kong Chinese families: a pilot study.

INTRODUCTION: To determine the carrier frequency and common mutations of Mendelian variants in Chinese couples using next-generation sequencing (NGS). METHODS: Preconception expanded carrier testing using NGS was offered to women who attended the subfertility clinic. The test was then offered to the partners of women who had positive screening results. Carrier frequency was calculated, and the results of the NGS panel were compared with those of a target panel. RESULTS: One hundred twenty-three women and 20 of their partners were screened. Overall, 84 (58.7%) individuals were identified to be carriers of at least one disease, and 68 (47.6%) were carriers after excluding thalassaemias. The most common diseases found were GJB2-related DFNB1 nonsyndromic hearing loss and deafness (1 in 4), alpha-thalassaemia (1 in 7), beta-thalassaemia (1 in 14), 21-hydroxylase deficient congenital adrenal hyperplasia (1 in 13), Pendred's syndrome (1 in 36), Krabbe's disease (1 in 48), and spinal muscular atrophy (1 in 48). Of the 43 identified variants, 29 (67.4%) were not included in the American College of Medical Genetics and Genomics or American College of Obstetrics and Gynecology guidelines. Excluding three couples with alpha-thalassaemia, six at-risk couples were identified. CONCLUSION: The carrier frequency of the investigated members of the Chinese population was 58.7% overall and 47.6% after excluding thalassaemias. This frequency is higher than previously reported. Expanded carrier screening using NGS should be provided to Chinese people to improve the detection rate of carrier status and allow optimal pregnancy planning.

The current treatment landscape of irritable bowel syndrome in adults in Hong Kong: consensus statements.

OBJECTIVE: The estimated prevalence of irritable bowel syndrome in Hong Kong is 6.6%. With the increasing availability of pharmacological and non-pharmacological treatments, the Hong Kong Advisory Council on Irritable Bowel Syndrome has developed a set of consensus statements intended to serve as local recommendations for clinicians about diagnosis and management of irritable bowel syndrome. PARTICIPANTS: A multidisciplinary group of clinicians constituting the Hong Kong Advisory Council on Irritable Bowel Syndrome-seven gastroenterologists, one clinical psychologist, one psychiatrist, and one nutritionist-convened on 20 April 2017 in Hong Kong. EVIDENCE: Published primary research articles, meta-analyses, and guidelines and consensus statements issued by different regional and international societies on the diagnosis and management of irritable bowel syndrome were reviewed. CONSENSUS PROCESS: An outline of consensus statements was drafted prior to the meeting. All consensus statements were finalised by the participants during the meeting, with 100% consensus. CONCLUSIONS: Twenty-four consensus statements were generated at the meeting. The statements were divided into four parts covering: (1) patient assessment; (2) patient's psychological distress; (3) dietary and alternative approaches to managing irritable bowel syndrome; and (4) evidence to support pharmacological management of irritable bowel syndrome. It is recommended that primary care physicians assume the role of principal care provider for patients with irritable bowel syndrome. The current statements are intended to guide primary care physicians in diagnosing and managing patients with irritable bowel syndrome in Hong Kong.

Relationship between weight change and glycaemic control in patients with type 2 diabetes receiving once-weekly dulaglutide treatment.

AIM: To assess the relationship between weight change and glycated haemoglobin (HbA1c) change in dulaglutide-treated patients by analysing data from six head-to-head phase III AWARD clinical trials. METHODS: At 26 weeks, the relationship between weight and HbA1c was analysed in each trial rather than by pooling data because of differences in design and background therapy. The effect of baseline characteristics was also evaluated with regard to weight and HbA1c response. RESULTS: Across the studies, 87-97% and 83-95% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, had reductions in HbA1c levels, while 57-88% and 43-84% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, experienced weight loss. The majority (55-83%) of patients receiving dulaglutide 1.5 mg experienced weight loss and HbA1c reductions, while 41-79% of patients in the dulaglutide 0.75 mg arm lost weight and had reductions in HbA1c level. A weak and inconsistent correlation was observed between the changes in weight and HbA1c (range from -0.223 to 0.267) in patients treated with dulaglutide. The baseline characteristics of gender, age, duration of diabetes, HbA1c, body weight and BMI were not related to different combinations of weight and HbA1c responses. CONCLUSIONS: Dulaglutide is an effective treatment option across the type 2 diabetes treatment spectrum. Dulaglutide showed dose-dependent effects on both weight loss and HbA1c reduction. These effects had a weak correlation and appeared to be independent.

A modified compression model of spinal cord injury in rats: functional assessment and the expression of nitric oxide synthases.

STUDY DESIGN: Experimental study. OBJECTIVES: To investigate a modified compression model of spinal cord injury (SCI) in adult rats by using a room-air- inflated Fogarty balloon catheter. SETTING: Kaohsiung, Taiwan. METHODS: The rats were divided into injury, sham-operated and control groups. A 2-French Fogarty catheter was passed from the lumbar spine (L3-L4) epidurally, with a mini-laminectomy under the microscope, to the level of thoracic spine (T6-T7). The actual site of the catheter tip was confirmed with X-ray. The balloon of Fogarty catheter then was inflated with room air, 0.2 ml, for 10 min. Mini-laminectomy was performed without inserting the catheter in the sham-operated group. Quantitative neurological outcomes were evaluated with the Basso, Beattie and Bresnahan (BBB) locomotor rating scale daily. The gene expression of nitric oxide synthases (NOSs) of the spinal cord was investigated at the end of the functional assessment. RESULTS: The mean BBB locomotor scores were 10±1.85 and 10±1.85, respectively, on days 1 and 3 in the injury group, and 21 and 20.29±0.69, respectively, in the sham-operated group. There was a significantly increased gene expression of inducible NOS in the SCI group compared with the sham-operated group and control group. Endothelial NOS gene expression was not significantly different among the groups. CONCLUSION: The functional and molecular assessments show that this modified balloon-compression technique is a reproducible, simple and inexpensive model of SCI in rats.

A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder.

Epigenetic studies of DNA and histone modifications represent a new and important activity in molecular investigations of human disease. Our previous epigenome-wide scan identified numerous DNA methylation differences in post-mortem brain samples from individuals affected with major psychosis. In this article, we present the results of fine mapping DNA methylation differences at the human leukocyte antigen (HLA) complex group 9 gene (HCG9) in bipolar disorder (BPD). Sodium bisulfite conversion coupled with pyrosequencing was used to interrogate 28 CpGs spanning ∼700 bp region of HCG9 in 1402 DNA samples from post-mortem brains, peripheral blood cells and germline (sperm) of bipolar disease patients and controls. The analysis of nearly 40 000 CpGs revealed complex relationships between DNA methylation and age, medication as well as DNA sequence variation (rs1128306). Two brain tissue cohorts exhibited lower DNA methylation in bipolar disease patients compared with controls at an extended HCG9 region (P=0.026). Logistic regression modeling of BPD as a function of rs1128306 genotype, age and DNA methylation uncovered an independent effect of DNA methylation in white blood cells (odds ratio (OR)=1.08, P=0.0077) and the overall sample (OR=1.24, P=0.0011). Receiver operating characteristic curve A prime statistics estimated a 69-72% probability of correct BPD prediction from a case vs control pool. Finally, sperm DNA demonstrated a significant association (P=0.018) with BPD at one of the regions demonstrating epigenetic changes in the post-mortem brain and peripheral blood samples. The consistent multi-tissue epigenetic differences at HCG9 argue for a causal association with BPD.

Effect of silencing HIF-1α on proliferation, invasion and migration of glioblastoma U87 cells.

The objective of the study was to evaluate the effect of silencing hypoxia-inducible factor 1α (HIF-1α) on proliferation, invasion, and migration of glioblastoma U87 cells. HIF-1α-shRNA lentiviral vector was designed for liposome-mediated transfection into U87 cells. The efficiency of interference was assessed by RT-PCR and Western blot. Cell proliferation was measured by MTT assay. Cell migration was observed by the migration test. The capabilities of invasion and migration were detected using the Transwell model. The research involved experiments in the interference group (shRNA transfected), the control interference group (empty vector transfected), and the untreated (non-transfected) group. Compared with the control interference group and the untreated group, the expressions of HIF-1α mRNA and protein were significantly down-regulated, and the proliferation and invasion of U87 cells were significantly inhibited in the interference group. HIF-1α mRNA and protein are effectively suppressed by HIF-1α-shRNA in U87 cells, which appears to inhibit proliferation, invasion, and migration of U87 cells.

Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study.

We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 × 10(-6)mm(2)/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.

Enhancing collection efficiency in large field of view multiphoton microscopy.

Many multiphoton imaging applications would benefit from a larger field of view; however, large field of views (>mm) require low magnification objectives which have low light collection efficiencies. We demonstrate a light collection system mounted on a low magnification objective that increases fluorescence collection by as much as 20-fold in scattering tissues. This peripheral detector results in an effective numerical aperture of collection >0.8 with a 3-4 mm field of view.

Increased obese mRNA expression in omental fat cells from massively obese humans.

Obesity presents a significant challenge to the general health of affluent nations in terms of the number of people affected, the serious associated maladies and the lack of effective treatments. While common wisdom has held that obesity results from 'gluttony and sloth', a number of studies have indicated physiological causes of underlying the pathogenesis of obesity, with the degree of adiposity having a strong genetic component. Recently, the obese gene in the ob/ob mouse was cloned, along with its human homologue. The specific production of the obese protein by adipose tissue suggested that it may function in a feedback loop from fat tissue to the hypothalamus to control energy intake and/or energy expenditure, and that it may play a role in the pathogenesis of human obesity. In this study we report that obese mRNA expression is elevated in ex vivo omental adipocytes isolated from massively obese humans in the absence of an identifiable mutation. Therefore, we speculate that this increased expression may suggest that the massively obese are insensitive to the putative regulatory function(s) of the obese gene product.

Emollient molecule effects on the drying stresses in human stratum corneum.

BACKGROUND: Emollient molecules are widely used in skin care formulations to improve skin sensory properties and to alleviate dry skin but little is understood regarding their effects on skin biomechanical properties. OBJECTIVES: To investigate the effects of emollient molecules on drying stresses in human stratum corneum (SC) and how these stresses are related to SC components and moisture content. METHODS: The substrate curvature method was used to measure the drying stresses in isolated SC following exposure to selected emollient molecules. While SC stresses measured using this method have the same biaxial in vivo stress state and moisture exchange with the environment, a limitation of the method is that moisture cannot be replenished by the underlying skin layers. This provides an opportunity to study the direct effects of emollient treatments on the moisture content and the components of the SC. Attenuated total reflectance Fourier transform infrared spectroscopy was used to determine the effects of emollient molecules on SC lipid extraction and conformation. Results Emollient molecules resulted in a complex SC drying stress profile where stresses increased rapidly to peak values and then gradually decreased to significantly lower values compared with the control. The partially occlusive treatments also penetrated into the SC where they caused extraction and changes in lipid conformation. These effects together with their effects on SC moisture content are used to rationalize the drying stress profiles. CONCLUSIONS: Emollient molecules have dramatic effects on SC drying stresses that are related to their effects on intercellular lipids and SC moisture content.

Cement Equivalence of Metakaolin for Workability, Cohesiveness, Strength and Sorptivity of Concrete.

A series of concrete mixes with metakaolin (MK) content ranging from 0 to 30% and water/cementitious materials (W/CM) ratio varying from 0.30 to 0.50 were produced for performance testing. The results showed that adding MK up to 20% as ordinary Portland cement (OPC) replacement best improved the 28-day and 70-day cube strengths, whereas adding MK up to 30% as OPC replacement always increased the cohesiveness and decreased the sorptivity, but impaired the workability. Moreover, the cement equivalent factor (CEF), i.e. the equivalent mass of OPC per mass of MK added, for each performance attribute, including workability and cohesiveness, was evaluated. Whilst the actual CEF of MK was generally higher at a higher W/CM ratio and lower at a higher MK content, overall, the average CEFs were found to be 1.98, 2.17, 3.83, 1.93, 2.12, and 4.70 for slump, flow, cohesiveness, 28-day cube strength, 70-day cube strength, and sorptivity coefficient, respectively. These CEF values indicated that the MK is a highly effective cementitious material for improving the cohesiveness, strength, and durability. Moreover, it has been demonstrated that the CEFs for workability and cohesiveness are useful parameters in aiding the mix design of MK concrete.

Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) results from truncating mutations of the CDH1 (E-cadherin) gene. It is an autosomal dominant cancer susceptibility syndrome with a lifetime risk of diffuse gastric cancer (DGC) of 60-80%, with a mean age of onset of 37 years. There exists no adequate screening test for DGC. Early intramucosal diffuse/signet-ring cell carcinomas have been found in prophylactic total gastrectomy (PTG) specimens following normal preoperative endoscopy. Total gastrectomy has been advocated on a prophylactic basis. The aim of this study was to report our experience with PTG in 23 patients from the Canadian province of Newfoundland and Labrador. This is the largest series worldwide. METHODS: A retrospective study of consecutive patients undergoing PTG for HDGC was performed. All patients were confirmed to have a truncating mutation of the CDH1 gene. RESULTS: Twenty-three patients underwent PTG between February 2006 and November 2008. Major complications were found in 4/23 patients (17%), with no mortality. Two of 23 patients (9%) had positive mucosal biopsies on preoperative EGD. Twenty-two of 23 patients (96%) had evidence of diffuse/signet-ring carcinoma on final standardized pathological evaluation. Therefore, 21/23 (91%) were not picked up by preoperative EGD screening. CONCLUSIONS: PTG can be performed in patients with HDGC with a low rate of serious complications. Methods of reconstruction incorporating a pouch reservoir and preservation of the postgastric branches of the vagus nerves need to be explored. More refined penetrance estimates, effective screening protocols, and long-term psychological and functional outcomes following PTG require organized multicenter collaborative efforts.

Comparative studies of type X collagen expression in normal and rachitic chicken epiphyseal cartilage.

The levels of type X collagen in mineralizing normal chicken epiphyses and nonmineralizing rachitic chicken tibial epiphyses were measured and compared. Qualitative immunoperoxidase studies with anti-chick type X collagen monoclonal antibodies on sections from normal and rachitic cartilage demonstrated that the type X collagen levels in rachitic growth plates are reduced. Northern hybridization of mRNA and biosynthetic studies have confirmed that type X collagen synthesis in rickets is also decreased. In hypocalcemic rickets, the level of type X collagen mRNA is reduced by 80% whereas the level of type X collagen mRNA is only reduced by 50% in normocalcemic rickets. These observations provide additional evidence that type X collagen is involved in the process of cartilage mineralization and also suggest that the partial recovery of type X collagen synthesis in normocalcemic rickets may be related to the elevated plasma concentration of calcium. Calcium concentration may therefore play an important role in the control of type X collagen synthesis.

Macromolecular organization of chicken type X collagen in vitro.

The macromolecular structure of type X collagen in the matrices of primary cultures of chick hypertrophic chondrocytes was initially investigated using immunoelectron microscopy. Type X collagen was observed to assemble into a matlike structure with-in the matrix elaborated by hypertrophic chondrocytes. The process of self assembly was investigated at the molecular level using purified chick type X collagen and rotary-shadowing EM. It was shown that under neutral conditions at 34 degrees C, individual type X collagen molecules associate rapidly into multimeric clusters via their carboxy-terminal globular domains forming structures with a central nodule of carboxy-terminal domains and the triple helices radiating outwards. Prolonged incubation resulted in the formation of a regular hexagonal lattice by lateral association of the juxtaposed triple-helical domains from adjacent multimeric clusters. This extended lattice may play an important role in modifying the cartilage matrix for subsequent events occurring in endochondral bone formation.