The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta-analysis.

OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.

Geometric microcanonical theory of two-dimensional truncated Euler flows.

This paper presents a geometric microcanonical ensemble perspective on two-dimensional truncated Euler flows, which contain a finite number of (Fourier) modes and conserve energy and enstrophy. We explicitly perform phase space volume integrals over shells of constant energy and enstrophy. Two applications are considered. In the first part, we determine the average energy spectrum for highly condensed flow configurations and show that the result is consistent with Kraichnan's canonical ensemble description, despite the fact that no thermodynamic limit is invoked. In the second part, we compute the probability density for the largest-scale mode of a free-slip flow in a square, which displays reversals. We test the results against numerical simulations of a minimal model and find excellent agreement with the microcanonical theory, unlike the canonical theory, which fails to describe the bimodal statistics. This article is part of the theme issue 'Mathematical problems in physical fluid dynamics (part 2)'.

The effect of unilateral tubal block diagnosed by hysterosalpingogram on clinical pregnancy rate in intrauterine insemination cycles: systematic review and meta-analysis.

BACKGROUND: Fallopian tube occlusion is a common cause of infertility, but the effect of unilateral tubal block (UTB) on pregnancy rates (PR) after controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) remains controversial. OBJECTIVE: To evaluate PR after COH-IUI among infertile women with proximal and distal UTB diagnosed by hysterosalpingogram (HSG), compared against women with bilateral patent tubes experiencing unexplained infertility. SEARCH STRATEGY: We searched EMBASE, MEDLINE, Google Scholar, Cochrane Library, and PUBMED from inception to 14 January 2018. SELECTION CRITERIA: Studies that report PR/cycle or cumulative PR among women with UTB and controls were included. DATA COLLECTION AND ANALYSIS: Two authors independently selected and extracted study characteristics and data. Methodological quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. MAIN RESULTS: Among 2965 patients and 5749 IUI cycles across ten studies, no significant difference in PR/cycle (odds ratio, OR = 0.88; 95% confidence interval, 95% CI = 0.69-1.12) and cumulative PR (OR = 0.80, 95% CI = 0.62-1.04) was observed. Patients with proximal UTB demonstrated similar PR/cycle (OR = 1.06, 95% CI = 0.68-1.66) and cumulative PR (OR = 1.10, 95% CI = 0.75-1.62), compared with controls, whereas patients with distal UTB had significantly lower cumulative PR (OR = 0.49, 95% CI = 0.25-0.97, P = 0.04). Patients with proximal block also demonstrated significantly improved cumulative PR, compared with patients with distal block (OR=2.41, 95% CI = 1.37-4.25, P = 0.002). CONCLUSION: Infertile patients with proximal UTB diagnosed by HSG can expect similar pregnancy rates after COH-IUI, compared with those with bilateral tubal patency and unexplained infertility, whereas patients with distal UTB have lower odds of pregnancy. These differences may reflect inherent diagnostic limitations of HSG or differences in underlying pathologies. TWEETABLE ABSTRACT: Meta-analysis evaluates pregnancy outcomes after COH-IUI in women with unilateral tubal block diagnosed by HSG.

Pattern and predictors of medical care received by hepatitis B carriers during pregnancy and after delivery.

OBJECTIVE: The objective of the study is to evaluate the pattern and predictors of medical care received by hepatitis B virus (HBV) carriers during pregnancy and after delivery in Hong Kong. STUDY DESIGN: The study is a retrospective analysis. METHODS: Pregnant HBV carriers and their infants were followed up for 9-12 months after delivery. Face-to-face interviews were conducted to investigate what medical care they received for HBV before, during and after pregnancy. RESULTS: Data were available for 412 HBV carriers. A total of 375 (91.0%) women were known HBV carriers before pregnancy. Routine antenatal screening picked out the remaining 37 (9.0%) HBV carriers; these women were younger, more likely to be smokers and had a lower level of education (P < 0.05) than known HBV carriers. In total, 356 of 412 (86.4%) HBV carriers did not receive any medical care for HBV during pregnancy. Known HBV carrier status, history of medical check-up and the use of antiviral treatment before pregnancy were significant predictors for HBV medical care during pregnancy (P < 0.05). The results show that 217 of 412 (52.6%) HBV carriers did not receive medical care for HBV after delivery. HBV medical care before pregnancy, use of antiviral treatment before pregnancy and a higher level of education were significant predictors for postpartum HBV medical care (P < 0.05). Multivariate analysis showed that HBV medical care before pregnancy (odds ratio [OR], 7.73; 95% confidence interval [CI], 3.21-18.65; P < 0.001) and the use of antiviral treatment (OR, 5.02; 95% CI, 1.41-17.81; P = 0.013) were associated with medical care during pregnancy. Medical care before pregnancy was also associated with postpartum HBV medical care (OR, 5.05; 95% CI, 3.29-7.51; P < 0.001). CONCLUSIONS: A significant proportion of HBV carriers did not receive HBV-related medical check-ups during and after pregnancy in Hong Kong despite the majority being aware of their carrier status. Medical care before pregnancy predicted antenatal and postpartum HBV medical care.

The role of the endometrial receptivity array (ERA) in patients who have failed euploid embryo transfers.

PURPOSE: Endometrial receptivity issues represent a potential source of implantation failure. The aim of this study was to document our experience with the endometrial receptivity array (ERA) among patients with a history of euploid blastocyst implantation failure. We investigated whether the contribution of the endometrial factor could be identified with the ERA test and if actionable results can lead to improved outcomes. METHODS: A retrospective review was performed for 88 patients who underwent ERA testing between 2014 and 2017. Reproductive outcomes were compared for patients undergoing frozen embryo transfer (FET) using a standard progesterone protocol versus those with non-receptive results by ERA and subsequent FET according to a personalized embryo transfer (pET) protocol. RESULTS: Of patients with at least one previously failed euploid FET, 22.5% had a displaced WOI diagnosed by ERA and qualified for pET. After pET, we found that implantation and ongoing pregnancy rates were higher (73.7 vs. 54.2% and 63.2 vs. 41.7%, respectively) compared to patients without pET, although differences were not statistically significant. CONCLUSIONS: Our experience demonstrates that a significant proportion of patients with a history of implantation failure of a euploid embryo have a displaced WOI as detected by the ERA. For these patients, pET using a modified progesterone protocol may improve the outcomes of subsequent euploid FET. Larger randomized studies are required to validate these results.

The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong.

INTRODUCTION: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. METHODS: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. RESULTS: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. CONCLUSION: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Comparative evaluation of performance measures for shading correction in time-lapse fluorescence microscopy.

Time-lapse fluorescence microscopy is a valuable technology in cell biology, but it suffers from the inherent problem of intensity inhomogeneity due to uneven illumination or camera nonlinearity, known as shading artefacts. This will lead to inaccurate estimates of single-cell features such as average and total intensity. Numerous shading correction methods have been proposed to remove this effect. In order to compare the performance of different methods, many quantitative performance measures have been developed. However, there is little discussion about which performance measure should be generally applied for evaluation on real data, where the ground truth is absent. In this paper, the state-of-the-art shading correction methods and performance evaluation methods are reviewed. We implement 10 popular shading correction methods on two artificial datasets and four real ones. In order to make an objective comparison between those methods, we employ a number of quantitative performance measures. Extensive validation demonstrates that the coefficient of joint variation (CJV) is the most applicable measure in time-lapse fluorescence images. Based on this measure, we have proposed a novel shading correction method that performs better compared to well-established methods for a range of real data tested.

Is congenital pulmonary airway malformation really a rare disease? Result of a prospective registry with universal antenatal screening program.

BACKGROUND: Congenital pulmonary airway malformation (CPAM) is an increasingly recognized disease with potential mortality. Owing to limited published studies, the true incidence is yet to be determined. We carried out this prospective study with the aim to estimate its true incidence on a population basis. METHODS: An antenatal ultrasonography program was implemented since 2009. Fetuses with suspected intra-thoracic lesions were monitored by regular follow-ups. Antenatal course, postnatal outcomes, and other demographics were compared to those of patients with CPAM in the previous decades (1989-2008). The incidence of CPAM was calculated in different periods. RESULTS: 66 CPAM patients were identified between 2009 and 2014 with 62 patients being detected by antenatal scan. In contrast, 45 patients were identified between 1989 and 2008 with 27 patients being detected antenatally. The incidence rate during the past and recent period was estimated as ~1 in 27,400 and ~1 in 7200 live births, respectively (p = 0.024). CONCLUSION: With increasing awareness of clinicians and the universal use of latest ultrasound technology, it is likely that more CPAM cases will be detected in the future. Here, we presented our best estimated incidence rate of CPAM, yet only a larger scale study can reveal its true incidence.

Effect of non-invasive prenatal testing as a contingent approach on the indications for invasive prenatal diagnosis and prenatal detection rate of Down's syndrome.

INTRODUCTION: In Hong Kong, universal combined first-trimester screening for Down's syndrome was started as a 'free service' in July 2010. Non-invasive prenatal testing was available as a self-financed item in August 2011. This study aimed to determine whether the introduction of non-invasive prenatal testing as a contingent approach influenced the indications for invasive prenatal diagnosis and the consequent prenatal detection of Down's syndrome. METHODS: This historical cohort study was conducted at the Prenatal Diagnosis Clinic of Queen Elizabeth Hospital in Hong Kong. We compared the indications for invasive prenatal diagnosis and prenatal detection of Down's syndrome in singleton pregnancies 1 year before and 2 years following the availability of non-invasive prenatal testing as a contingent test after a positive aneuploidy test. All pregnant women who attended our hospital for counselling about universal Down's syndrome screening between August 2010 and July 2013 were recruited. RESULTS: A total of 16 098 women were counselled. After the introduction of non-invasive prenatal testing, the invasive prenatal diagnosis rate for a positive aneuploidy screening reduced from 77.7% in 2010-11 to 68.8% in 2012-13. The new combined conventional plus non-invasive prenatal testing strategy was associated with a lower false-positive rate (6.9% in 2010-11 vs 5.2% in 2011-12 and 4.9% in 2012-13). There was no significant increase in invasive prenatal diagnosis for structural anomalies over the years. There was no significant trend in the overall prenatal detection rate of Down's syndrome (100% 1 year before vs 89.1% 2 years after introduction of non-invasive prenatal testing). Four (2.6%) of 156 women who underwent non-invasive prenatal testing for a screen-positive result had a high-risk result for trisomy 21, which was subsequently confirmed by invasive prenatal diagnosis. There were no false-negative cases. CONCLUSION: The introduction of non-invasive prenatal testing as a contingent approach reduced the invasive prenatal diagnosis rate for a positive aneuploidy screening without affecting the invasive prenatal diagnosis rate for structural anomalies or the overall detection rate of fetal Down's syndrome.

Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes.

Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified.

Preoperative lifestyle modifications combined with a structured exercise protocol on patient outcomes following total knee replacement surgery: A systematic review.

BACKGROUND: Medical guidelines recommend structured prehabilitation protocols consisting of lifestyle modifications and exercise to enhance post-operative outcomes for patients undergoing a total knee replacement (TKR). However, current research showing effectiveness is limited and has primarily focused on outcomes of exercise-based prehabilitation. OBJECTIVES: To investigate whether a structured prehabilitation protocol consisting of exercise and lifestyle modifications improves physical function and patient-reported outcomes following TKR surgery compared with usual care. DESIGN: Systematic review. METHODS: Five databases were searched to identify randomised controlled trials comparing structured prehabilitation programs consisting of lifestyle modifications and exercise, with usual care, for those undergoing a TKR. Methodological quality of included studies was assessed via the RoB 2.0 tool and results synthesis via a Grading of Recommendation Assessment, Development and Evaluation approach was performed to determine the certainty evidence for each outcome. RESULTS/FINDINGS: Four studies were included in this review. Despite a positive trend supporting the inclusion of a structured prehabilitation protocol, additional improvements in post-operative pain, physical function and self-reported function were only seen in one study. Reductions in hospital length of stay were also seen in one study. No additional improvements in post-operative quality of life following prehabilitation were reported. CONCLUSION: Limited evidence supporting prehabilitation reported in our review is likely attributed to the intervention type, intensity, and delivery model of included studies. However, there remains to be strong evidence supporting the use of a structured prehabilitation protocol consisting of lifestyle modifications and exercise to improve post-operative outcome.

Periplasmic stress contributes to a tradeoff between protein secretion and cell growth in E. Coli Nissile.

Maximizing protein secretion is an important target in the design of engineered living systems. In this paper, we characterize a tradeoff between cell growth and per cell protein secretion in the curli biofilm secretion system of E Coli Nissile 1917. Initial characterization using 24-hour continuous growth and protein production monitoring confirms decreased growth rates at high induction leading to a local maximum in total protein production at intermediate induction. Propidium iodide staining at the endpoint indicates that cellular death is a dominant cause of growth reduction. Assaying variants with combinatorial constructs of inner and outer membrane secretion tags, we find that diminished growth at high production is specific to secretory variants associated with accumulation of protein containing the outer membrane transport tag in the periplasmic space. RNA sequencing experiments indicate upregulation of known periplasmic stress response genes in the highly secreting variant, further implicating periplasmic stress in the growth-secretion tradeoff. Overall, these results motivate additional strategies for optimizing total protein production and longevity of secretory engineered living systems.

Automated and semi-automated cell tracking: addressing portability challenges.

Cell tracking is a key task in the high-throughput quantitative study of important biological processes, such as immune system regulation and neurogenesis. Variability in cell density and dynamics in different videos, hampers portability of existing trackers across videos. We address these potability challenges in order to develop a portable cell tracking algorithm. Our algorithm can handle noise in cell segmentation as well as divisions and deaths of cells. We also propose a parameter-free variation of our tracker. In the tracker, we employ a novel method for recovering the distribution of cell displacements. Further, we present a mathematically justified procedure for determining the gating distance in relation to tracking performance. For the range of real videos tested, our tracker correctly recovers on average 96% of cell moves, and outperforms an advanced probabilistic tracker when the cell detection quality is high. The scalability of our tracker was tested on synthetic videos with up to 200 cells per frame. For more challenging tracking conditions, we propose a novel semi-automated framework that can increase the ratio of correctly recovered tracks by 12%, through selective manual inspection of only 10% of all frames in a video.

Cultural differences in child delivery: comparisons between Jewish and Arab women in Israel.

OBJECTIVE: To compare Jewish and Arab women characteristics regarding pregnancy follow-up, compliance to a health regime and behavioural expressions during labour, delivery and the post-partum period. DESIGN: The participants answered a 45-item questionnaire designed for the current research. SETTING: The first three post-partum days in the delivery ward at one of the biggest hospitals in Israel. PARTICIPANTS: A total of 126 Jewish and Arab-Muslim parturients. RESULTS: Significant differences were found (P < 0.01) concerning pregnancy follow-up attendance and participation in a prenatal course, which were lower among Arab women. Several differences were found regarding delivery room attendance, type and number of companions, and behavioural expressions of pain, which were demonstrated more among Arab women. Epidural anaesthesia was highly prevalent among Jewish women, in comparison with the Arab women. While all Arab women decided to breastfeed their babies, only 71% of Jewish women expressed a wish to breastfeed. No significant differences were found between weight gains during pregnancy, reasons for delivery room attendance, number of pregnancy weeks prior to delivery and newborn weight. CONCLUSIONS: Cultural differences exist between Jewish and Arab women attending delivery rooms in Israel. Understanding these cultural differences may assist caregivers in providing culturally sensitive treatment that is suited to the parturients' needs.