Next Generation Sequencing Detects Premeiotic Errors in Human Oocytes

Autosomal aneuploidy is the leading cause of embryonic and foetal death in humans. This arises mainly from errors in meiosis I or II of oogenesis. A largely ignored source of error stems from germinal mosaicism, which leads to premeiotic aneuploidy. Molecular cytogenetic studies employing metaphase fluorescence in situ hybridization and comparative genomic hybridisation suggest that premeiotic aneuploidy may affect 10–20% of oocytes overall. Such studies have been criticised on technical grounds. We report here an independent study carried out on unmanipulated oocytes that have been analysed using next generation sequencing (NGS). This study confirms that the incidence of premeiotic aneuploidy in an unselected series of oocytes exceeds 10%. A total of 140 oocytes donated by 42 women gave conclusive results; of these, 124 (88.5%) were euploid. Sixteen out of 140 (11.4%) provided evidence of premeiotic aneuploidy. Of the 140, 112 oocytes were immature (germinal vesicle or metaphase I), of which 10 were aneuploid (8.93%); the remaining 28 were intact metaphase II - first polar body complexes, and six of these were aneuploid (21.4%). Of the 16 aneuploid cells, half contained simple errors (one or two abnormal chromosomes) and half contained complex errors. We conclude that germinal mosaicism leading to premeiotic aneuploidy is a consistent finding affecting at least 10% of unselected oocytes from women undergoing egg collection for a variety of reasons. The importance of premeiotic aneuploidy lies in the fact that, for individual oocytes, it greatly increases the risk of an aneuploid mature oocyte irrespective of maternal age. As such, this may account for some cases of aneuploid conceptions in very young women.

Beyond Refeeding: The Effect of Including a Dietitian in Eating Disorder Treatment. A Systematic Review

Eating disorders are potentially life-threatening mental health disorders that require management by a multidisciplinary team including medical, psychological and dietetic specialties. This review systematically evaluated the available literature to determine the effect of including a dietitian in outpatient eating disorder (ED) treatment, and to contribute to the understanding of a dietitian’s role in ED treatment. Six databases and Google Scholar were searched for articles that compared treatment outcomes for individuals receiving specialist dietetic treatment with outcomes for those receiving any comparative treatment. Studies needed to be controlled trials where outcomes were measured by a validated instrument (PROSPERO CRD42021224126). The searches returned 16,327 articles, of which 11 articles reporting on 10 studies were included. Two studies found that dietetic intervention significantly improved ED psychopathology, and three found that it did not. Three studies reported that dietetic input improved other psychopathological markers, and three reported that it did not. One consistent finding was that dietetic input improved body mass index/weight and nutritional intake, although only two and three studies reported on each outcome, respectively. A variety of instruments were used to measure each outcome type, making direct comparisons between studies difficult. Furthermore, there was no consistent definition of the dietetic components included, with many containing psychological components. Most studies included were also published over 20 years ago and are now out of date. Further research is needed to develop consistent dietetic guidelines and outcome measures; this would help to clearly define the role of each member of the multidisciplinary team, and particularly the role of dietitians, in ED treatment.

The association of loneliness with health and social care utilisation in older adults in the general population: A systematic review

Background and Objectives Loneliness is proposed to be linked with increased service use. This review examined the association of loneliness and health and social care utilisation (HSCU) in older adults from the general population. Research Design and Methods Four databases were screened for studies that examined the association of loneliness (predictor) with HSCU (outcome) in older adults (defined as majority of sample 60 or older). Study quality was assessed with the NIH scale for observational cohorts and cross-sectional studies. Results We identified 32 studies, of which 9 prospective studies were evaluated as being good or good-fair quality. Two good-fair quality studies found loneliness at baseline was associated with subsequent admission to a residential care home. There was emerging evidence that loneliness was associated with emergency department use (n=1), and CVD-specific hospitalisation (n=1). Once adjusted for confounders the highest quality studies found no association of baseline loneliness with physician utilisation, outpatient service utilisation, skilled nursing facility use, and planned or unplanned hospital admissions. The remaining, studies were cross-sectional, or of fair to poor quality, and inadequate to reliably determine whether loneliness was associated with a subsequent change in HSCU. Discussion and implications There was heterogeneity in study design, measurement, and study quality. This generated an inconsistent evidence base where we cannot determine clear inferences about the relationship between loneliness and HSCU. Only one consistent finding was observed between two good-fair quality studies regarding care home admission. To determine clinical implications and make reliable inferences additional good quality longitudinal research is needed.

The Impact of Hazard Statement Design Elements in Procedures: Counterintuitive Findings and Implications for Standards

Objective The objective of these studies was to identify hazard statement (HS) design elements in procedures that affected whether both workers and lab participants performed the associated hazard mitigation. Background Many of the incidents in high-risk industries are the result of issues with procedures (e.g., standard operating procedures; SOPs) workers use to support their performance. HSs in these procedures are meant to communicate potential work hazards and methods of mitigating those hazards. However, there is little empirical research regarding whether current hazard design guidelines for consumer products translate to procedures. Method Two experimental studies—(1) a laboratory study and (2) a high-fidelity simulation—manipulated the HS design elements present in procedures participants used while performing tasks. Participants’ adherence to the mitigation of the hazard was compared for the HS designs. Results The guidelines for HSs from consumer products did not translate to procedures. Specifically, the presence of an alert icon, a box around the statement, and highlighting the statement did not improve adherence to HSs. Indeed, the only consistent finding was for the Icon, with its presence reliably predicting nonadherence in both studies. Additionally, the total number of design elements did not have a positive effect on adherence. Conclusion These findings indicate that more fundamental procedure HSs research is needed to identify effective designs as well as to understand the potential attentional mechanisms associated with these findings. Application The findings from these studies indicate that current regulations and guidelines should be revisited regarding hazard presentation in procedures.

The Aftermath of Anti-Dumping: Are Temporary Trade Barriers Really Temporary?

A consistent finding in the literature is that anti-dumping (AD) acts as a significant barrier to bilateral trade, in particular, during the time such measures are in force. Adding to a relatively scarce empirical literature, however, we identify adverse impacts of AD which survive well beyond its revocation. More specifically, while we cannot rule out a slight post-revocation recovery, we find empirical evidence that once affected bilateral trade does not fully recover on average following revocation. We use panel data at the Harmonized System four-digit (HS4) level of aggregation to produce these results and show that they are robust to the duration of AD cases, the time of their imposition and revocation, differentiation by economic sector and the nature of imposing countries. Several explanations for our observed empirical results seem plausible, and we provide a theoretical framework which suggests our results could be driven by market exit or underinvestment of targeted firms.

Atypical presentation of giant cell arteritis associated with SIADH: a rare association

We present here an interesting case of a 67-year-old man with 3 weeks history of lethargy, loss of appetite, generalised weakness and weight loss. Following thorough investigations, occult malignancy was ruled out. Hyponatraemia was a consistent finding which needed further classification. Additional workup including cerebral imaging and neurophysiological studies excluded cerebral vascular events and myopathies. Vasculitis screening was undertaken, and the diagnostic dilemma was revealed by the temporal arteries Doppler ultrasound which showed classical ‘halo sign’. Diagnosis of temporal arteritis was made and linked with syndrome of inappropriate antidiuretic hormone secretion, which appears to be a rare association with few instances on record. Patient was treated with high dose of prednisolone with marked improvement of clinical features.

Optimisation of Plug and Abandonment Process Utilising Nuclear Technology for through Tubing Cement Evaluation

One of the major factors in the well plug and abandonment (P&A) process is to provide a proper isolation in aging wells which requires effective placement of the cement plug in the most suitable location in the well. Identifying cement placement is usually achieved by running cement evaluation logging to define the quality of cement and top of cement depth behind and in between the casing annuli. However, this comes with significant costs due to tubulars or casings removal requirement prior to logging run in order to conduct a proper evaluation. This is necessary since acoustic and ultrasonic based cement evaluation technologies will not be able to determine cement quality behind several casing layers if the job is done through tubing. The cost involved is substantial especially in offshore operation in which the daily operating rate is significantly higher compared to an onshore operation. A new approach to cement evaluation has been tested during the well P&A campaign in one of the aging oil fields in offshore, Peninsular Malaysia. A nuclear based technology comprised of Gamma-Gamma, Neutron-Neutron and Neutron-Gamma measurements were utilized to evaluate cement integrity behind production casing and between production casing as well as intermediate casing while logging run was deployed through tubing in memory mode. Log data was compared with acoustic and ultrasonic based cement evaluation technology that was deployed after the tubing was pulled out in one of the wells. Results had shown a consistent finding with the conventional ultrasonic based cement evaluation data. Based on the logging results, cement placement design and depth was finalized and the cement plug was successfully tested as outlined in the well P&A guideline. Findings from this logging run had provided useful insight to the operator to validate the nuclear based thru tubing cement evaluation technology for wells P&A application. Huge cost saving could be captured through this application as a result of eliminating total rig days via offline cement evaluation logging and based on the results obtained planning for the exact well P&A design requirement prior to the rig arrival. This paper will outline the method, tools used to acquire the cement evaluation data and its operational advantages. Acquired data will be presented and discussed along with the methodology used to determine cement volume and top of cement depth behind and in between the casings.

Is Pupil Activity Associated With the Strength of Memory Signal for Words in a Continuous Recognition Memory Paradigm?

Research on pupillometry provides an increasing evidence for associations between pupil activity and memory processing. The most consistent finding is related to an increase in pupil size for old items compared with novel items, suggesting that pupil activity is associated with the strength of memory signal. However, the time course of these changes is not completely known, specifically, when items are presented in a running recognition task maximizing interference by requiring the recognition of the most recent items from a sequence of old/new items. The sample comprised 42 healthy participants who performed a visual word recognition task under varying conditions of retention interval. Recognition responses were evaluated using behavioral variables for discrimination accuracy, reaction time, and confidence in recognition decisions. Pupil activity was recorded continuously during the entire experiment. The results suggest a decrease in recognition performance with increasing study-test retention interval. Pupil size decreased across retention intervals, while pupil old/new effects were found only for words recognized at the shortest retention interval. Pupillary responses consisted of a pronounced early pupil constriction at retrieval under longer study-test lags corresponding to weaker memory signals. However, the pupil size was also sensitive to the subjective feeling of familiarity as shown by pupil dilation to false alarms (new items judged as old). These results suggest that the pupil size is related not only to the strength of memory signal but also to subjective familiarity decisions in a continuous recognition memory paradigm.

The Ability of CBFβ-SMMHC to Increase RUNX1 Binding Affinity to Target DNA Correlates with Its Leukemogenic Potential

Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. We recently showed that RUNX1 is indispensable for Cbfb-MYH11-induced leukemogenesis in a mouse model. We found that RUNX1 interacted with CBFβ-SMMHC, the fusion protein encoded by CBFB-MYH11, to directly regulate critical genes for leukemogenesis (Zhen et al., Blood, 2020). However, our current understanding of the interaction between CBFβ-SMMHC and RUNX1 does not provide adequate explanation on how the RUNX1-CBFβ-SMMHC complex forms and how the complex interacts with DNA for leukemogenesis as CBFβ-SMMHC without the RUNX1 high-affinity-binding-domain (CBFβ-SMMHC-ΔHABD) is also able to induce leukemia while CBFβ-SMMHC with mutations in the C-terminal multimerization domain (CBFβ-SMMHC-mDE) is not able to induce leukemia in mice. To address this question, we used RHD domain of RUNX1, CBFβ, CBFβ-SMMHC, CBFβ-SMMHC-ΔHABD and CBFβ-SMMHC-mDE proteins, which were purified from E. coli overexpressing these proteins, to explore how the HABD and DE domains affect the interactions between CBFβ-SMMHC, RHD and RUNX1-target DNA Bio-Layer Interferometry (BLI) and negative staining. As expected, deletion of the HABD domain significantly reduced CBFβ-SMMHC's binding affinity to RHD by BLI assay. Interestingly, differences in binding affinity between RHD and different versions of CBFβ-SMMHC did not correlate with their leukemogenic capability. On the other hand, the binding affinity between RHD and its target oligo was more significantly enhanced by CBFβ-SMMHC and CBFβ-SMMHC-ΔHABD that can induce leukemia than CBFβ-SMMHC-DE, which cannot. We also found that both CBFβ-SMMHC and CBFβ-SMMHC-ΔHABD, but not CBFβ-SMMHC-mDE, could form a filament structure by negative staining, suggesting the filament formation ability is important for leukemogenesis by CBFβ-SMMHC. In addition, RHD reduces filament formation by CBFβ-SMMHC, which was overcome when target oligo was added. In contrast, RHD could not inhibit filament formation by CBFβ-SMMHC-ΔHABD, suggesting that HABD interaction is required for RHD to disrupt filament formation by CBFβ-SMMHC. Overall, we found that leukemogenic capability of CBFβ-SMMHC correlates with its ability to enhance binding between RHD and its target DNA and to form multimerized filaments. The results also suggest that HABD and DE domains of CBFβ-SMMHC are required for the formation of the RUNX1-CBFβ-SMMHC complex with higher binding affinity to target DNA. Disclosures No relevant conflicts of interest to declare.

Fixel-Based Analysis and Free Water Corrected DTI Evaluation of HIV-Associated Neurocognitive Disorders

Background: White matter (WM) damage is a consistent finding in HIV-infected (HIV+) individuals. Previous studies have evaluated WM fiber tract-specific brain regions in HIV-associated neurocognitive disorders (HAND) using diffusion tensor imaging (DTI). However, DTI might lack an accurate biological interpretation, and the technique suffers from several limitations. Fixel-based analysis (FBA) and free water corrected DTI (fwcDTI) have recently emerged as useful techniques to quantify abnormalities in WM. Here, we sought to evaluate FBA and fwcDTI metrics between HIV+ and healthy controls (HIV−) individuals. Using machine learning classifiers, we compared the specificity of both FBA and fwcDTI metrics in their ability to distinguish between individuals with and without cognitive impairment in HIV+ individuals.Methods: Forty-two HIV+ and 52 HIV– participants underwent MRI exam, clinical, and neuropsychological assessments. FBA metrics included fiber density (FD), fiber bundle cross section (FC), and fiber density and cross section (FDC). We also obtained fwcDTI metrics such as fractional anisotropy (FAT) and mean diffusivity (MDT). Tract-based spatial statistics (TBSS) was performed on FAT and MDT. We evaluated the correlations between MRI metrics with cognitive performance and blood markers, such as neurofilament light chain (NfL), and Tau protein. Four different binary classifiers were used to show the specificity of the MRI metrics for classifying cognitive impairment in HIV+ individuals.Results: Whole-brain FBA showed significant reductions (up to 15%) in various fiber bundles, specifically the cerebral peduncle, posterior limb of internal capsule, middle cerebellar peduncle, and superior corona radiata. TBSS of fwcDTI metrics revealed decreased FAT in HIV+ individuals compared to HIV– individuals in areas consistent with those observed in FBA, but these were not significant. Machine learning classifiers were consistently better able to distinguish between cognitively normal patients and those with cognitive impairment when using fixel-based metrics as input features as compared to fwcDTI metrics.Conclusion: Our findings lend support that FBA may serve as a potential in vivo biomarker for evaluating and monitoring axonal degeneration in HIV+ patients at risk for neurocognitive impairment.