Cell-Free DNA Analysis of Fetal Aneuploidies in Early Pregnancy Loss.

Background: Products of conception samples are often collected and analyzed to try to determine the cause of an early pregnancy loss. However, sample collection may not always be possible, and maternal cell contamination and culture failure can affect the analysis. Cell-free DNA-based analysis of a blood sample could be used as an alternative method in early pregnancy loss cases to detect if aneuploidies were present in the fetus. Methods: In this prospective study, blood samples from early pregnancy loss patients were analyzed for the presence of fetal aneuploidies using a modified version of a noninvasive prenatal testing assay for cell-free DNA analysis. Results from cell-free DNA analysis were compared against the gold standard, microarray analysis of products of conception samples. This study was registered with ClinicalTrials.gov, identifier: NCT04935138. Results: Of the 76 patient samples included in the final study cohort, 11 were excluded from performance calculations. The 65 patient samples included in the final analysis included 49 with an abnormal microarray result and 16 with a normal microarray result. Based on results from these 65 samples, the study found that genome-wide cell-free DNA analysis had a sensitivity of 73.5% with a specificity of 100% for the detection of fetal aneuploidies in early pregnancy loss cases. Conclusions: This prospective study provides further support for the utility of cell-free DNA analysis in detecting fetal aneuploidies in early pregnancy loss cases. This approach could allow for a noninvasive method of investigating the etiology of miscarriages to be made available clinically.

Chlamydia and Gonorrhea Testing in Pregnancy: Time to Improve Adherence and Update Recommendations.

OBJECTIVE: The aim of the study is to evaluate adherence to national recommendations for Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhea) testing during pregnancy including tests for cure/clearance and for persistence/potential reinfection at time of delivery. MATERIALS AND METHOD: We evaluated results of chlamydia and gonorrhea nucleic acid amplification tests (NAAT) performed by major national reference laboratory from January 2010 through July 2022. RESULTS: Of 3,519,781 uniquely identified pregnant individuals, we identified 4,077,212 pregnancies. Among pregnancies that had chlamydia or gonorrhea testing, 3.7% (149,422/4,055,016) and 0.4% (15,858/ 4,063,948) were initially positive, respectively. Initial tests occurred in the first trimester for approximately 88%. Of those initially chlamydia test positive, 71% were retested; 15.8% in <4 weeks and 37.3% >8 weeks (similarly for gonorrhea). Among patients initially test positive in early/mid pregnancy, more than one-third had no evidence of late pregnancy retesting. Individuals who were initially test negative and subsequently retested positive were approximately 50% likely to have the last available result be positive. Among all whom initially tested positive and were retested, 6.8% and 4.0%, were positive for chlamydia and gonorrhea, respectively on their last test before estimated delivery. There was no subsequent negative test before estimated delivery for 35.1% and 36.9% chlamydia or gonorrhea infected patients, respectively. CONCLUSIONS: Adherence to current recommendations is suboptimal and may not be adequate to reduce disease burden. Professional societies and practice plans should work to encourage better adherence to existing guidelines to protect the health of women and their newborns. We propose recommendations that may be helpful in reducing disease burden.

Phosphine versus Carbene Metal Interactions: Bond Energies.

A variety of different ground-state structures of carbene and phosphine groups 1 and 2 cationic, group 11 cationic, and group 10 neutral complexes were studied using density functional theory (DFT) and correlated molecular orbital theory (CCSD(T)) methods. Geometries of complexes with phosphines were studied and compared to available experimental data. Among the three analyzed phosphine ligands, PH3, PMe3, and PPh3, PH3 was found to have noticeably smaller ligand binding energies (LBEs, ΔH298 K). PPh3 has the greatest LBEs with group 2 dications. The difference in LBEs for PMe3 and PPh3 in complexes with group 1 monocations and transition-metal (TM) complexes was significantly less pronounced. The stability and reactivity of phosphine complexes were analyzed and compared with those of previously studied N-heterocyclic carbenes (NHC). PH3 has smaller LBEs compared to NHC carbenes. The lower LBEs correlate with the hardness for M(11)+ complexes and correlate with both the hardness and ionic radii for the M(1)+ and M(2)2+ complexes. The presence of additional PH3 substituents on the metal center makes the LBE smaller compared to their unsubstituted or less substituted analogs. The presence of NH3 in a structure causes a smaller effect on binding, and, except for carbene-PtNH3, an increase in LBE was observed. Composite-correlated molecular orbital theory (G3MP2) was used to predict the LBE of various Lewis acidic ligands with PH3 and NHCs to contrast their binding behavior. Binding either phosphine or carbene to metal diamine complexes caused ligand exchange and transfer of NH3 to an outer coordination sphere.

A Novel Approach to Measuring an Old Construct: Aligning the Conceptualisation and Operationalisation of Cognitive Flexibility.

A successful adjustment to dynamic changes in one's environment requires contingent adaptive behaviour. Such behaviour is underpinned by cognitive flexibility, which conceptually is part of fluid intelligence. We argue, however, that conventional approaches to measuring fluid intelligence are insufficient in capturing cognitive flexibility. We address the discrepancy between conceptualisation and operationalisation by introducing two newly developed tasks that aim at capturing within-person processes of dealing with novelty. In an exploratory proof-of-concept study, the two flexibility tasks were administered to 307 university students, together with a battery of conventional measures of fluid intelligence. Participants also provided information about their Grade Point Averages obtained in high school and in their first year at university. We tested (1) whether an experimental manipulation of a requirement for cognitive inhibition resulted in systematic differences in difficulty, (2) whether these complexity differences reflect psychometrically differentiable effects, and (3) whether these newly developed flexibility tasks show incremental value in predicting success in the transition from high school to university over conventional operationalisations of fluid intelligence. Our findings support the notion that cognitive flexibility, when conceptualised and operationalised as individual differences in within-person processes of dealing with novelty, more appropriately reflects the dynamics of individuals' behaviour when attempting to cope with changing demands.

Forty Years Searching for Neurosteroid Binding Sites on GABAA Receptors.

Brain inhibition is a vital process for controlling and sculpting the excitability of the central nervous system in healthy individuals. This level of control is provided over several timescales and involves the neurotransmitter GABA acting at inhibitory synapses to: rapidly inhibit neurons by activating the GABAA receptor; over a slower timescale, to tonically activate extrasynaptic GABAA receptors to provide a low level of background inhibition; and finally, to activate G-protein coupled GABAB receptors to control transmitter release by inhibiting presynaptic Ca2+ channels whilst providing postsynaptic inhibition via K+ channel activation. From this plethora of roles for GABA and its receptors, the GABAA receptor isoform is of major interest due to its dynamic functional plasticity, which in part, is due to being targeted by modulatory brain neurosteroids derived from sex and stress hormones. This family of neurosteroids can, depending on their structure, potentiate, activate and also inhibit the activity of GABAA receptors to affect brain inhibition. This review tracks the methods that have been deployed in probing GABAA receptors, and charts the sterling efforts made by several groups to locate the key neurosteroid binding sites that affect these important receptors. Increasing our knowledge of these binding sites will greatly facilitate our understanding of the physiological roles of neurosteroids and will help to advance their use as novel therapeutics to combat debilitating brain diseases.

Confidence judgments interfere with perceptual decision making.

Determining one's confidence in a decision is a vital part of decision-making. Traditionally, psychological experiments have assessed a person's confidence by eliciting confidence judgments. The notion that such judgments can be elicited without impacting the accuracy of the decision has recently been challenged by several studies which have shown reactivity effects-either an increase or decrease in decision accuracy when confidence judgments are elicited. Evidence for the direction of reactivity effects has, however, been decidedly mixed. Here, we report three studies designed to specifically make reactivity effects more prominent by eliciting confidence judgment contemporaneously with perceptual decisions. We show that confidence judgments elicited contemporaneously produce an impairment in decision accuracy, this suggests that confidence judgments may rely on a partially distinct set of cues/evidence than the primary perceptual decision and, additionally, challenges the continued use of confidence ratings as an unobtrusive measure of metacognition.

Maternal red blood cell alloimmunization prevalence in the United States.

ABSTRACT: Hemolytic disease of fetus and newborn (HDFN) is a life-threatening disease mediated by maternal alloimmunization to red blood cell (RBC) antigens. Studies of maternal alloimmunization prevalence in the United States lack national data. This study describes prevalence and trends in alloimmunization in pregnancy in the United States. RBC antibodies (abs) were identified in a large, nationwide, commercial laboratory database from 2010 through 2021. The cohort comprised pregnancies for which the year of laboratory collection and patient's state of residence were available. Data were normalized based on US Centers for Disease Control and Prevention estimates of live births and weighted by year and US Census Division. Cochrane-Armitage tests assessed temporal trends of alloimmunization. Of 9 876 196 pregnancies, 147 262 (1.5%) screened positive for RBC abs, corresponding to an estimated prevalence of 1518 of 100 000 pregnancies. Of identified RBC abs, anti-D comprised 64.1% pregnancies (586/100 000). Prevalence of other high-risk RBC abs for HDFN included anti-K (68/100 000) and anti-c (29/100 000). Incidence of all 3 high-risk abs increased from 2010 to 2021 (all P < .001). Among almost 10 million pregnancies in the United States, comprising an estimated 14.4% of all pregnancies, 1.5% screened positive for RBC abs. Almost three-quarters (679/100 000 [74.3%]) of RBC abs identified were high risk for HDFN. Although prevalence of anti-D is difficult to interpret without the ability to distinguish alloimmunization from passive immunity, it remains problematic in HDFN, ranking second only to anti-K in critical titers. Given the sequelae of HDFN, new initiatives are required to reduce the incidence of alloimmunization in patients of reproductive potential.

Real-World Analysis of the Clinical and Economic Impact of the 21-Gene Recurrence Score (RS) in Invasive Lobular Early-Stage Breast Carcinoma in Ireland.

Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (17.5%) patients aged ≤50 at diagnosis, RS was ≤15 in 16 (55%), 16-20 in 6 (21%), 21-25 in 5 (17%), >25 in 1 (3.5%), and unknown in 1 (3.5%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of €921,543.84 in treatment costs, and net savings of €387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.

Identifying risk factors for developing obesity: a record linkage longitudinal study in metropolitan Sydney using the 45 and Up Study.

BACKGROUND: Primary care clinicians have key responsibilities in obesity prevention and weight management. AIMS: We aimed to identify risk factors for developing obesity among people aged ≥45 years. METHODS: We conducted a record linkage longitudinal study of residents of metropolitan Sydney, Australia using data from the: (1) 45 and Up Study at baseline (2005-2009) and first follow-up (2012-2015); (2) Medicare claims; (3) Pharmaceutical Benefits Scheme; and (4) deaths registry. We examined risk factors for developing obesity (body mass index [BMI]: 30-40) at follow-up, separately for people within the: (1) healthy weight range (BMI 18.5-<25) and (2) overweight range (BMI 25-<30) at baseline. Covariates included demographics, modifiable behaviours, health status, allied health use, and medication use. Crude and adjusted relative risks were estimated using Poisson regression modelling. RESULTS: At follow-up, 1.1% (180/16,205) of those in the healthy weight range group, and 12.7% (1,939/15,266) of those in the overweight range group developed obesity. In both groups, the following were associated with developing obesity: current smoking at baseline, physical functioning limitations, and allied health service use through team care planning, while any alcohol consumption and adequate physical activity were found to be associated with a lower risk of developing obesity. In the healthy weight group, high psychological distress and the use of antiepileptics were associated with developing obesity. In the overweight group, female sex and full-time work were associated with developing obesity, while older age was found to be associated with a lower risk of developing obesity. CONCLUSIONS: These findings may inform the targeting of preventive interventions for obesity in clinical practice and broader public health programs.

Early intervention to prevent weight gain requires a targeted multidisciplinary team-based approach to improve diet, increase physical activity, and change behaviour. However, the capacity to provide this within primary care is limited and there is little funding for consultations with allied health professionals. There is a need to identify priority at-risk groups to help primary care clinicians target interventions to those in most need. We have identified, using a longitudinal study of residents of metropolitan Sydney, key characteristics of older adults who are at risk of gaining weight and developing obesity, including risk behaviours (smoking and physical inactivity), and chronic conditions or their treatment (physical function, psychological distress, and use of anti-epileptic medications). These findings may help alert clinicians to the need for preventive interventions in selected cases, as well as informing the targeting of public health programs.

Impact of multimorbidity and complex multimorbidity on healthcare utilisation in older Australian adults aged 45 years or more: a large population-based cross-sectional data linkage study.

OBJECTIVES: As life expectancy increases, older people are living longer with multimorbidity (MM, co-occurrence of ≥2 chronic health conditions) and complex multimorbidity (CMM, ≥3 chronic conditions affecting ≥3 different body systems). We assessed the impacts of MM and CMM on healthcare service use in Australia, as little was known about this. DESIGN: Population-based cross-sectional data linkage study. SETTING: New South Wales, Australia. PARTICIPANTS: 248 496 people aged ≥45 years who completed the Sax Institute's 45 and Up Study baseline questionnaire. PRIMARY OUTCOME: High average annual healthcare service use (≥2 hospital admissions, ≥11 general practice visits and ≥2 emergency department (ED) visits) during the 3-year baseline period (year before, year of and year after recruitment). METHODS: Baseline questionnaire data were linked with hospital, Medicare claims and ED datasets. Poisson regression models were used to estimate adjusted and unadjusted prevalence ratios for high service use with 95% CIs. Using a count of chronic conditions (disease count) as an alternative morbidity metric was requested during peer review. RESULTS: Prevalence of MM and CMM was 43.8% and 15.5%, respectively, and prevalence increased with age. Across three healthcare settings, MM was associated with a 2.02-fold to 2.26-fold, and CMM was associated with a 1.83-fold to 2.08-fold, increased risk of high service use. The association was higher in the youngest group (45-59 years) versus the oldest group (≥75 years), which was confirmed when disease count was used as the morbidity metric in sensitivity analysis.When comparing impact using three categories with no overlap (no MM/CMM, MM with no CMM, and CMM), CMM had greater impact than MM across all settings. CONCLUSION: Increased healthcare service use among older adults with MM and CMM impacts on the demand for primary care and hospital services. Which of MM or CMM has greater impact on risk of high healthcare service use depends on the analytic method used. Ageing populations living longer with increasing burdens of MM and CMM will require increased Medicare funding and provision of integrated care across the healthcare system to meet their complex needs.