COVID-19 vaccination and transmission patterns among pregnant and postnatal women during the fifth wave of COVID-19 in a tertiary hospital in Hong Kong.

INTRODUCTION: Vaccination is a key strategy to control the coronavirus disease 2019 (COVID-19) pandemic. Safety concerns strongly influence vaccine hesitancy. Disease transmission during pregnancy could exacerbate risks of preterm birth and perinatal mortality. This study examined patterns of vaccination and transmission among pregnant and postnatal women during the fifth wave of COVID-19 in Hong Kong. METHODS: The Antenatal Record System and Clinical Management System of the Hospital Authority was used to retrieve information concerning the demographic characteristics, vaccination history, COVID-19 status, and obstetric outcomes of women who were booked for delivery at Queen Mary Hospital in Hong Kong and had attended the booking antenatal visit from 1 July 2021 to 30 June 2022. RESULTS: Among 2396 women in the cohort, 2006 (83.7%), 1843 (76.9%), and 831 (34.7%) had received the first, second, and third doses of COVID-19 vaccine, respectively. Among 1012 women who had received the second dose, 684 (67.6%) women were overdue for their third dose. There were 265 (11.1%) reported COVID-19 cases. Women aged 20 to 29 years had a low vaccination rate but the highest disease rate (19.1%). The disease rate was more than tenfold higher in women who had no (20.3%) or incomplete (18.8%) vaccination, compared with women who had complete vaccination (2.1%; P<0.001). CONCLUSION: Acceptance of COVID-19 vaccination was low in pregnant women. Urgent measures are needed to promote vaccination among pregnant women before the next wave of COVID-19.

Application of multiple stable isotopes to aid identification of the origin of regional and organic animal products in Hesse, Germany.

There is an increasing global demand for regional and organic produce. However, the growth of these markets depends on consumers' trust. Thus, novel methods must be developed to aid the verification of the origin of produce. We built on our previous study to identify the geographical origin and production method of animal-derived food products. Thirty-samples of eggs, 99 of milk, 34 of beef, and 62 of pork were collected from different regions in central Germany and analysed for their stable isotopic composition. The analysis followed a single-variate authentification approach using five isotope signatures, δ18O, δ2H, δ13C, δ15N, and δ34S. The best-performing indicators for verification of the geographical origin were δ15N and δ34S for beef; δ18O, δ2H, and δ13C for milk, and δ2H and δ13C for pork. These tracers indicated statistically significant differences among regions with the exception of pork; the results recorded for eggs were inconclusive. It was possible to distinguish between production methods by means of δ15N and δ34S (beef); all five tracers (eggs), and δ13C, δ15N, and δ34S (milk). This study demonstrated how the analysis of stable isotopes can be employed to determine the geographic region of origin and production method of animal-derived products in Germany.

Assessment of multiple stable isotopes for tracking regional and organic authenticity of plant products in Hesse, Germany.

As demand for regional and organically produced foodstuff has increased in Europe, the need has arisen to verify the products' origin and production method. For food authenticity tracking (production method and origin), we examined 286 samples of wheat (Triticum aestivum), potatoes (Solanum tuberosum), and apples (Malus domestica) from different regions in Germany for their stable isotope compositions of oxygen, hydrogen, carbon, nitrogen and sulphur. Single-variate authentication methods were used. Suitable isotope tracers to determine wheat's regional origin were δ18O and δ34S. δ13C helped to distinguish between organic and conventional wheat samples. For the separation of the production regions of potatoes, several isotope tracers were suitable (e.g. δ18O, δ2H, δ15N, δ13C and δ34S isotopes in potato protein), but only protein δ15N was suitable to differentiate between organic and conventional potato samples. For the apple samples, 2H and 18O isotopes helped to identify production regions, but no significant statistical differences could be found between organically and conventionally farmed apples. For food authenticity tracking, our study showed the need to take the various isotopes into account. There is an urgent need for a broad reference database if isotope measurements are to become a main tool for determining product's origin.

Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine.

BACKGROUND: Intranasal dexmedetomidine produces safe, effective sedation in children and adults. It may be administered by drops from a syringe or by nasal mucosal atomisation (MAD NasalTM). METHODS: This prospective, three-period, crossover, double-blind study compared the pharmacokinetic (PK) and pharmacodynamic (PD) profile of i.v. administration with these two different modes of administration. In each session each subject received 1 µg kg-1 dexmedetomidine, either i.v., intranasal with the atomiser or intranasal by drops. Dexmedetomidine plasma concentration and Ramsay sedation score were used for PK/PD modelling by NONMEM. RESULTS: The i.v. route had a significantly faster onset (15 min, 95% CI 15-20 min) compared to intranasal routes by atomiser (47.5 min, 95% CI 25-135 min), and by drops (60 min, 95%CI 30-75 min), (P<0.001). There was no significant difference in sedation duration across the three treatment groups (P=0.88) nor in the median onset time between the two modes of intranasal administration (P=0.94). A 2-compartment disposition model, with transit intranasal absorption and clearance driven by cardiac output using the well-stirred liver model, was the final PK model. Intranasal bioavailability was estimated to be 40.6% (95% CI 34.7-54.4%) and 40.7% (95% CI 36.5-53.2%) for atomisation and drops respectively. Sedation score was modelled via a sigmoidal Emax model driven by an effect compartment. The effect compartment had an equilibration half time 3.3 (95% CI 1.8-4.7) min-1, and the EC50 was estimated to be 903 (95% CI 450-2344) pg ml-1. CONCLUSIONS: There is no difference in bioavailability with atomisation or nasal drops. A similar degree of sedation can be achieved by either method. CLINICAL TRIAL REGISTRATION: HKUCTR-1617.

Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia.

To investigate the genetic etiology of anophthalmia and microphthalmia, we used exome sequencing in a Caucasian female with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, ventricular and atrial septal defects, and growth delays. We found two sequence variants in SALL4 - c.[575C>A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G>C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency for SALL4 due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities. Our report is the first description of structural eye defects associated with two missense variants in SALL4 inherited in trans; the absence of reported findings in both parents suggests that both sequence variants are hypomorphic mutations and that both are needed for the ocular phenotype. SALL4 is expressed in the developing lens and regulates BMP4, leading us to speculate that altered BMP4 expression was responsible for the eye defects, but we could not demonstrate altered BMP4 expression in vitro after using small interfering RNAs (siRNAs) to reduce SALL4 expression. We conclude that SALL4 hypomorphic variants may influence eye development.

Intrarenal abscess caused by community-associated methicillin-resistant Staphylococcus aureus in a transplanted kidney.

Emergence of multidrug-resistant bacteria is important in solid organ transplant recipients, because it can jeopardize patient and graft survival. Methicillin-resistant Staphylococcus aureus (MRSA) infections are not rare in kidney transplant recipients. On the other hand, infections related to community-associated MRSA (CA-MRSA) strains are seldom reported in the literature. Herein, we report the first patient, to our knowledge, with CA-MRSA renal graft abscess who was successfully treated with drainage and parenteral antibiotics.

Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles.

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Who Smells? Forecasting Taste and Odor in a Drinking Water Reservoir.

Taste and odor problems can impede public trust in drinking water and impose major costs on water utilities. The ability to forecast taste and odor events in source waters, in advance, is shown for the first time in this paper. This could allow water utilities to adapt treatment, and where effective treatment is not available, consumers could be warned. A unique 24-year time series, from an important drinking water reservoir in Saskatchewan, Canada, is used to develop forecasting models of odor using chlorophyll a, turbidity, total phosphorus, temperature, and the following odor producing algae taxa: Anabaena spp., Aphanizemenon spp., Oscillatoria spp., Chlorophyta, Cyclotella spp., and Asterionella spp. We demonstrate, using linear regression and random forest models, that odor events can be forecast at 0-26 week time lags, and that the models are able to capture a significant increase in threshold odor number in the mid-1990 s. Models with a fortnight time-lag show a high predictive capacity (R(2) = 0.71 for random forest; 0.52 for linear regression). Predictive skill declines for time lags from 0 to 15 weeks, then increases again, to R(2) values of 0.61 (random forest) and 0.48 (linear regression) at a 26-week lag. The random forest model is also able to provide accurate forecasting of TON levels requiring treatment 12 weeks in advance-93% true positive rate with a 0% false positive rate. Results of the random forest model demonstrate that phytoplankton taxonomic data outperform chlorophyll a in terms of predictive importance.

Predicting outcome in clinically isolated syndrome using machine learning.

We aim to determine if machine learning techniques, such as support vector machines (SVMs), can predict the occurrence of a second clinical attack, which leads to the diagnosis of clinically-definite Multiple Sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS), on the basis of single patient's lesion features and clinical/demographic characteristics. Seventy-four patients at onset of CIS were scanned and clinically reviewed after one and three years. CDMS was used as the gold standard against which SVM classification accuracy was tested. Radiological features related to lesional characteristics on conventional MRI were defined a priori and used in combination with clinical/demographic features in an SVM. Forward recursive feature elimination with 100 bootstraps and a leave-one-out cross-validation was used to find the most predictive feature combinations. 30 % and 44 % of patients developed CDMS within one and three years, respectively. The SVMs correctly predicted the presence (or the absence) of CDMS in 71.4 % of patients (sensitivity/specificity: 77 %/66 %) at 1 year, and in 68 % (60 %/76 %) at 3 years on average over all bootstraps. Combinations of features consistently gave a higher accuracy in predicting outcome than any single feature. Machine-learning-based classifications can be used to provide an "individualised" prediction of conversion to MS from subjects' baseline scans and clinical characteristics, with potential to be incorporated into routine clinical practice.

Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects.

Anophthalmia/microphthalmia (A/M) is a genetically heterogeneous birth defect for which the etiology is unknown in more than 50% of patients. We used exome sequencing with the ACE Exome(TM) (Personalis, Inc; 18 cases) and UCSF Genomics Core (21 cases) to sequence 28 patients with A/M and four patients with varied developmental eye defects. In the 28 patients with A/M, we identified de novo mutations in three patients (OTX2, p.(Gln91His), RARB, p.Arg387Cys and GDF6, p.Ala249Glu) and inherited mutations in STRA6 in two patients. In patients with developmental eye defects, a female with cataracts and cardiomyopathy had a de novo COL4A1 mutation, p.(Gly773Arg), expanding the phenotype associated with COL4A1 to include cardiomyopathy. A male with a chorioretinal defect, microcephaly, seizures and sensorineural deafness had two PNPT1 mutations, p.(Ala507Ser) and c.401-1G>A, and we describe eye defects associated with this gene for the first time. Exome sequencing was efficient for identifying mutations in pathogenic genes for which there is no clinical testing available and for identifying cases that expand phenotypic spectra, such as the PNPT1 and COL4A1-associated disorders described here.

Beaver-mediated methane emission: The effects of population growth in Eurasia and the Americas.

Globally, greenhouse gas budgets are dominated by natural sources, and aquatic ecosystems are a prominent source of methane (CH(4)) to the atmosphere. Beaver (Castor canadensis and Castor fiber) populations have experienced human-driven change, and CH(4) emissions associated with their habitat remain uncertain. This study reports the effect of near extinction and recovery of beavers globally on aquatic CH4 emissions and habitat. Resurgence of native beaver populations and their introduction in other regions accounts for emission of 0.18-0.80 Tg CH(4) year(-1) (year 2000). This flux is approximately 200 times larger than emissions from the same systems (ponds and flowing waters that became ponds) circa 1900. Beaver population recovery was estimated to have led to the creation of 9500-42 000 km(2) of ponded water, and increased riparian interface length of >200 000 km. Continued range expansion and population growth in South America and Europe could further increase CH(4) emissions.

Gene-based association identifies SPATA13-AS1 as a pharmacogenomic predictor of inhaled short-acting beta-agonist response in multiple population groups.

Inhaled short-acting beta-agonist (SABA) medication is commonly used in asthma patients to rapidly reverse airway obstruction and improve acute symptoms. We performed a genome-wide association study of SABA medication response using gene-based association tests. A linear mixed model approach was first used for single-nucleotide polymorphism associations, and the results were later combined using GATES to generate gene-based associations. Our results identified SPATA13-AS1 as being significantly associated with SABA bronchodilator response in 328 healthy African Americans. In replication, this gene was associated with SABA response among the two separate groups of African Americans with asthma (n=1073, P=0.011 and n=1968, P=0.014), 149 healthy African Americans (P=0.003) and 556 European Americans with asthma (P=0.041). SPATA13-AS1 was also associated with longitudinal SABA medication usage in the two separate groups of African Americans with asthma (n=658, P=0.047 and n=1968, P=0.025). Future studies are needed to delineate the precise mechanism by which SPATA13-AS1 may influence SABA response.

[NiTiBOND an optimized self-crimping stapes prosthesis for treatment of otosclerosis]. / NiTiBOND, eine optimierte Steigbügelprothese zur chirurgischen Behandlung der Otosklerose.

BACKGROUND: Compared to traditional stapes prostheses, self-crimping prostheses have been shown to result in similar, if not better, closure of the air bone gap in patients undergoing stapedotomy for otosclerosis. To achieve self-crimping, nitinol, a shape memory alloy, has been used for several years but concerns have been raised regarding possible damage to the incus and its muco-periosteum. We investigate these concerns with regard to the newer NiTiBOND stapes prosthesis in an observational multi-centre study. MATERIAL AND METHODS: In a multicentre, prospective observational study, 76 patients undergoing stapedotomy with the NiTiBond prosthesis across 4 centres were compared to 75 -retrospectively selected control SMart patients. Complications, intra-operative user-friendliness and audiological results at 3 months were documented. RESULTS: Audiological improvement and the rate of complications were similar in both groups. Non inferiority was shown at all frequencies and in the pure-tone average. The NiTiBOND prosthesis was described as very user-friendly. CONCLUSIONS: By eliminating manual crimping, stapedotomy using the NiTiBOND prosthesis can be facilitated and standardized. Furthermore, intraoperative handling characteristics of the prosthesis are very good which may further reduce operative risk. Importantly, we show that these benefits are not to the detriment of audiological outcome. Larger and longer-term studies are required to further evaluate results.

A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation.

Wnt signaling, which encompasses multiple biochemical pathways that regulate neural development downstream of extracellular Wnt glycoprotein ligands, has been suggested to contribute to major psychiatric disorders including autism spectrum disorders (ASD). We used next-generation sequencing and Sequenom genotyping technologies to resequence 10 Wnt signaling pathway genes in 198 ASD patients and 240 matched controls. Results for single-nucleotide polymorphisms (SNPs) of interest were confirmed in a second set of 91 ASD and 144 control samples. We found a significantly increased burden of extremely rare missense variants predicted to be deleterious by PolyPhen-2, distributed across seven genes in the ASD sample (3.5% in ASD vs 0.8% in controls; Fisher's exact test, odds ratio (OR)=4.37, P=0.04). We also found a missense variant in WNT1 (S88R) that was overrepresented in the ASD sample (8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048; OR=8.2 and P=0.053 after correction for population stratification). Functional analysis revealed that WNT1-S88R is more active than wild-type WNT1 in assays for the Wnt/ß-catenin signaling pathway. Our findings of a higher burden in ASD of rare missense variants distributed across 7 of 10 Wnt signaling pathway genes tested, and of a functional variant at the WNT1 locus associated with ASD, support that dysfunction of this pathway contributes to ASD susceptibility. Given recent findings of common molecular mechanisms in ASD, schizophrenia and affective disorders, these loci merit scrutiny in other psychiatric conditions as well.

Anti-inflammatory and anti-allergic activities of Pentaherb formula, Moutan Cortex (Danpi) and gallic acid.

Pentaherb formula (PHF) has been proven to improve the quality of life of children with atopic dermatitis without side effects. The aim of this study was to elucidate the potential anti-inflammatory and anti-allergic activities of PHF, Moutan Cortex (Danpi/DP) and gallic acid (GA) using human basophils (KU812 cells), which are crucial effector cells in allergic inflammation. PHF, DP and GA could significantly suppress the expression of allergic inflammatory cytokine IL-33-upregulated intercellular adhesion molecule (ICAM)-1, and the release of chemokines CCL2, CCL5, CXCL8 and inflammatory cytokine IL-6 from KU812 cells (all p < 0.05). With the combined use of dexamethasone (0.01 µg/mL) and GA (10 µg/mL), the suppression of ICAM-1 expression and CCL5 and IL-6 release of IL-33-activated KU812 cells were significantly greater than the use of GA alone (all p < 0.05). The suppression of the IL-33-induced activation of intracellular signalling molecules p38 mitogen activated protein kinase, nuclear factor-kB and c-Jun amino-terminal kinase in GA-treated KU812 cells could be the underlying mechanism for the suppression on ICAM-1, chemokines and cytokines. The combined use of dexamethasone with the natural products PHF or DP or GA might therefore enhance the development of a novel therapeutic modality for allergic inflammatory diseases with high potency and fewer side effects.

Beta-adrenergic receptor polymorphisms and cardiac graft function in potential organ donors.

Prior studies have demonstrated associations between beta-adrenergic receptor (ßAR) polymorphisms and left ventricular dysfunction-an important cause of allograft nonutilization for transplantation. We hypothesized that ßAR polymorphisms predispose donor hearts to LV dysfunction after brain death. A total of 1043 organ donors managed from 2001-2006 were initially studied. The following ßAR single nucleotide polymorphisms were genotyped: ß1AR 1165C/G (Arg389Gly), ß1AR 145A/G (Ser49Gly), ß2AR 46G/A (Gly16Arg) and ß2AR 79C/G (Gln27Glu). In multivariable regression analyses, the ß2AR46 SNP was significantly associated with LV systolic dysfunction, with each minor allele additively decreasing the odds for LV ejection fraction <50%. The ß1AR1165 and ß2AR46 SNPs were associated with higher dopamine requirement during the donor management period: donors with the GG and AA genotypes had ORs of 2.64 (95% CI 1.52-4.57) and 2.70 (1.07-2.74) respectively for requiring >10 µg/kg/min of dopamine compared to those with the CC and GG genotypes. However, no significant associations were found between ßAR SNPs and cardiac dysfunction in 364 donors managed from 2007-2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association. ßAR polymorphisms may be associated with cardiac dysfunction after brain death, but these relationships require further study in independent donor cohorts.

A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.