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.

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.

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.

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.

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.

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.

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.

Direct Heterocycle C-H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation.

One of the major challenges in developing catalytic methods for C-C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C-H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo) halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr-H substrate classes undergoing C-H activation without the need for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ-generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle and the palladacycle effects C-H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale.

Sequential Intracardiac Activation Time Mapping of Arrhythmias Without Fiducial Time References.

Sequential local activation time (LAT) mapping of intracardiac electrograms' activations requires a stable reference signal to align recording phases. OBJECTIVE: This work's purpose is to develop an LAT mapping approach that does not rely on a time-alignment reference (TAR). METHODS: To create an LAT map in absence of TAR (TARLess), the coordinates and LATs of recording electrodes are collected sequentially; a bank of candidate functions (CFs) is constructed that contains constant binary level CFs and non-linear functions of recording points' coordinates. Finally, a subset of CFs is linearly combined to create an activation time function with output matching electrodes' LATs. Synthetic and clinical data were deployed to validate TARLess. A simple two-dimensional computer model was used to create 30 different wavefront collision scenarios in a region with spatial conduction heterogeneities. Furthermore, sequential recordings were collected from seven atrial fibrillation patients during stimulation from one or two sites, after sinus rhythm was achieved post catheter ablation. RESULTS: We showed that TARLess maps are similar to the one that uses TAR; for the 20 clinical maps, the mean absolute difference between measured LAT with the TAR and TARLess approach was 5.2 ±2.0 milliseconds. CONCLUSION: We developed a novel method to create an LAT map of sequential recordings without using any TAR and showed that it can create accurate maps even during the collision of multiple wavefronts. SIGNIFICANCE: TARLess mapping does not require a reference catheter which could lead to reduction in ablation procedure duration, cost, and potential complications.

Triphenylphosphine─Closed-Shell Metal Cation Interactions.

The interactions between group 1 and 11 monocations and group 2 dications with triphenylphosphine were studied by using a combination of correlated molecular orbital theory and density functional theory. Two binding modes were found: the front side (phosphorus lone pair) and back side (phenyl rings). Group 1 and 2 cations prefer binding to the π system rather than to the lone pair of the phosphorus atom, and their ligand binding energies (LBEs) correlate with the atomic ionic radii as well as the hardness of the atomic ion. Group 11 monocations prefer binding to the lone pair of the phosphorus atom, and their LBEs are correlated with the hardness of the cation but exhibit a different trend than for the groups 1 and 2 cations. The LBEs of the cations with C2H4, C6H6, and C6H5PH2 are also reported to aid in the analysis of the cation-π interactions and the influence of the PH2 substituent on the energy of this interaction. The LBEs for binding to C2H4 and C6H6 are the most complete and reliable set of values for these species.

Inter-hospital variation in data collection, radiotherapy treatment, and survival in patients with head and neck cancer: A multisite study.

BACKGROUND AND PURPOSE: Inter-hospital inequalities in head and neck cancer (HNC) survival may exist due to variation in radiotherapy treatment-related factors. This study investigated inter-hospital variation in data collection, primary radiotherapy treatment, and survival in HNC patients from an Australian setting. MATERIALS AND METHODS: Data collected in oncology information systems (OIS) from seven Australian hospitals was extracted for 3,182 adults treated with curative radiotherapy, with or without surgery or chemotherapy, for primary, non-metastatic squamous cell carcinoma of the head and neck (2000-2017). Death data was sourced from the National Death Index using record linkage. Multivariable Cox regression was used to assess the association between survival and hospital. RESULTS: Inter-hospital variation in data collection, primary radiotherapy dose, and five-year HNC-related death was detected. Completion of eleven fields ranged from 66%-98%. Primary radiotherapy treated Tis-T1N0 glottic and any stage oral cavity and oropharynx cancers received significantly different time-corrected biologically equivalent dose in two gray fractions (EQD2T) by hospital, with observed deviation from Australian radiotherapy guidelines. Increased EQD2T dose was associated with a reduced risk of five-year HNC-related death in all patients and those treated with primary radiotherapy. Hospital, tumour site, and T and N classification were also identified as independent prognostic factors for five-year HNC-related death in all patients treated with radiotherapy. CONCLUSION: Unexplained variation exists in HNC-related death in patients treated at Australian hospitals. Available routinely collected data in OIS are insufficient to explain variation in survival. Innovative data collection, extraction, and classification practices are needed to inform clinical practice.

Right atrial collision time (RACT): A novel marker of propensity for typical atrial flutter.

INTRODUCTION: The risk of typical atrial flutter (AFL) is increased proportionately to right atrial (RA) size or right atrial scarring that results in reduced conduction velocity. These characteristics result in propagation of a flutter wave by ensuring the macro re-entrant wave front does not meet its refractory tail. The time taken to traverse the circuit would take account of both of these characteristics and may provide a novel marker of propensity to develop AFL. Our goal was to investigate right atrial collision time (RACT) as a marker of existing typical AFL. METHODS: This single-centre, prospective study recruited consecutive typical AFL ablation patients that were in sinus rhythm. Controls were consecutive electrophysiology study patients >18 years of age. While pacing the coronary sinus (CS) ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral right atrial wall. This RACT is a measure of conduction velocity and distance from CS to a collision point on the lateral right atrial wall. RESULTS: Ninety-eight patients were included in the analysis, 41 with atrial flutter and 57 controls. Patients with atrial flutter were older, 64.7 ± 9.7 versus 52.4 ± 16.8 years (<.001), and more often male (34/41 vs. 31/57 [.003]). The AFL group mean RACT (132.6 ± 17.3 ms) was significantly longer than that of controls (99.1 ± 11.6 ms) (p < .001). A RACT cut-off of 115.5 ms had a sensitivity and specificity of 92.7% and 93.0%, respectively for diagnosis of atrial flutter. A ROC curve indicated an AUC of 0.96 (95% CI: 0.93-1.0, p < .01). CONCLUSION: RACT is a novel and promising marker of propensity for typical AFL. This data will inform larger prospective studies.

Pre- and postsynaptic modulation of hippocampal inhibitory synaptic transmission by pregnenolone sulphate.

Neurosteroids are important endogenous modulators of GABAA receptor-mediated neurotransmission within the CNS and play a vital role in maintaining normal healthy brain function. Research has mainly focussed on neurosteroids such as allopregnanolone and tetrahydro-deoxycorticosterone (THDOC) which are allosteric potentiators of GABAA receptors, whilst the sulphated steroids, including pregnenolone sulphate (PS), which inhibit GABAA receptor function, have been relatively neglected. Importantly, a full description of PS effects on inhibitory synaptic transmission, at concentrations that are expected to inhibit postsynaptic GABAA receptors, is lacking. Here, we address this deficit by recording inhibitory postsynaptic currents (IPSCs) from rat hippocampal neurons both in culture and in acute brain slices and explore the impact of PS at micromolar concentrations. We reveal that PS inhibits postsynaptic GABAA receptors, evident from reductions in IPSC amplitude and decay time. Concurrently, PS also causes an increase in synaptic GABA release which we discover is due to the activation of presynaptic TRPM3 receptors located close to presynaptic GABA release sites. Pharmacological blockade of TRPM3 receptors uncovers a PS-evoked reduction in IPSC frequency. This second presynaptic effect is caused by PS activation of inwardly-rectifying Kir2.3 channels on interneurons, which act to depress synaptic GABA release. Overall, we provide a comprehensive characterisation of pre- and postsynaptic modulation by PS of inhibitory synaptic transmission onto hippocampal neurons which elucidates the diverse mechanisms by which this understudied neurosteroid can modulate brain function.

Is cortical inhibition in primary motor cortex related to executive control?

Recent research using paired-pulse transcranial magnetic stimulation (TMS) has shown that the speed with which people can stop an action is linked to GABAergic inhibitory activity in the motor system. Specifically, a significant proportion of the variance in stop signal reaction time (SSRT; a widely used measure of inhibitory control) is accounted for by short-interval cortical inhibition (SICI). It is still unclear whether this relationship reflects a broader link between GABAergic processes and executive functions, or a specific link between GABAergic processes and motor stopping ability. The current study sought to replicate the correlation between SSRT and SICI while investigating whether this association generalises to other measures of inhibitory control and working memory, and to long-interval cortical inhibition (LICI). Participants completed a battery of inhibition (Stop-Signal, Stroop, Flanker) and working memory (n-back, Digit Span, and Operation Span) tasks. We replicated the correlation between SICI and SSRT but found no other correlations between behavioural measures of executive control and the two cortical measures of inhibition. These findings indicate that the relationship between SSRT and SICI is specific to a particular property of response inhibition and likely reflects the function of local inhibitory networks mediated by GABAA.

The Utility of Oncology Information Systems for Prognostic Modelling in Head and Neck Cancer.

Cancer centres rely on electronic information in oncology information systems (OIS) to guide patient care. We investigated the completeness and accuracy of routinely collected head and neck cancer (HNC) data sourced from an OIS for suitability in prognostic modelling and other research. Three hundred and fifty-three adults diagnosed from 2000 to 2017 with head and neck squamous cell carcinoma, treated with radiotherapy, were eligible. Thirteen clinically relevant variables in HNC prognosis were extracted from a single-centre OIS and compared to that compiled separately in a research dataset. These two datasets were compared for agreement using Cohen's kappa coefficient for categorical variables, and intraclass correlation coefficients for continuous variables. Research data was 96% complete compared to 84% for OIS data. Agreement was perfect for gender (κ = 1.000), high for age (κ = 0.993), site (κ = 0.992), T (κ = 0.851) and N (κ = 0.812) stage, radiotherapy dose (κ = 0.889), fractions (κ = 0.856), and duration (κ = 0.818), and chemotherapy treatment (κ = 0.871), substantial for overall stage (κ = 0.791) and vital status (κ = 0.689), moderate for grade (κ = 0.547), and poor for performance status (κ = 0.110). Thirty-one other variables were poorly captured and could not be statistically compared. Documentation of clinical information within the OIS for HNC patients is routine practice; however, OIS data was less correct and complete than data collected for research purposes. Substandard collection of routine data may hinder advancements in patient care. Improved data entry, integration with clinical activities and workflows, system usability, data dictionaries, and training are necessary for OIS data to generate robust research. Data mining from clinical documents may supplement structured data collection.

Machine Learning and Nomogram Prognostic Modeling for 2-Year Head and Neck Cancer-Specific Survival Using Electronic Health Record Data: A Multisite Study.

PURPOSE: There is limited knowledge of the prediction of 2-year cancer-specific survival (CSS) in the head and neck cancer (HNC) population. The aim of this study is to develop and validate machine learning models and a nomogram for the prediction of 2-year CSS in patients with HNC using real-world data collected by major teaching and tertiary referral hospitals in New South Wales (NSW), Australia. MATERIALS AND METHODS: Data collected in oncology information systems at multiple NSW Cancer Centres were extracted for 2,953 eligible adults diagnosed between 2000 and 2017 with squamous cell carcinoma of the head and neck. Death data were sourced from the National Death Index using record linkage. Machine learning and Cox regression/nomogram models were developed and internally validated in Python and R, respectively. RESULTS: Machine learning models demonstrated highest performance (C-index) in the larynx and nasopharynx cohorts (0.82), followed by the oropharynx (0.79) and the hypopharynx and oral cavity cohorts (0.73). In the whole HNC population, C-indexes of 0.79 and 0.70 and Brier scores of 0.10 and 0.27 were reported for the machine learning and nomogram model, respectively. Cox regression analysis identified age, T and N classification, and time-corrected biologic equivalent dose in two gray fractions as independent prognostic factors for 2-year CSS. N classification was the most important feature used for prediction in the machine learning model followed by age. CONCLUSION: Machine learning and nomogram analysis predicted 2-year CSS with high performance using routinely collected and complete clinical information extracted from oncology information systems. These models function as visual decision-making tools to guide radiotherapy treatment decisions and provide insight into the prediction of survival outcomes in patients with HNC.