Long-term impact of type 2 diabetes onset on dementia incidence rate among New Zealanders with impaired glucose tolerance: A tapered-matched landmark analysis over 25 years.

INTRODUCTION: We aimed to investigate the association between the onset of type 2 diabetes (T2D) and dementia incidence rates (IR) in the population with impaired glucose tolerance (IGT) identified in primary care in New Zealand (NZ) over 25 years. METHODS: Tapered matching and landmark analysis (accounting for immortal bias) were used to control for potential effects of known confounders. The association between T2D onset and 5- and 10-year IR of dementia was estimated by weighted Cox models. RESULTS: The onset of T2D was significantly associated with the 10-year IR of dementia, especially in the socioeconomically deprived, those of non-NZ European ethnicity, those currently smoking, and patients with higher metabolic measures. DISCUSSION: Our findings suggest that the onset of T2D is a significant risk factor for dementia in individuals with IGT. Dementia screening and structured diabetes prevention are vital in the population with IGT, particularly those from deprived or ethnic minority backgrounds. HIGHLIGHTS: Increased dementia incidence rate links with T2D onset in people with IGT. Significant incidence varied by ethnicity, socioeconomic status, and health factors. Results emphasize the diabetes manage and socioeconomic factors on dementia risk. Secondary analysis highlights the key role of vascular health in dementia prevention.

All-cause, premature, and cardiovascular death attributable to socioeconomic and ethnic disparities among New Zealanders with type 1 diabetes 1994-2019: a multi-linked population-based cohort study.

BACKGROUND: New Zealand (NZ) research into type 1 diabetes mellitus (T1DM) mortality can inform policy and future research. In this study we aimed to quantify the magnitude to which ethnicity and socioeconomic disparities influenced mortality at the population level among people with Type 1 diabetes (T1DM) in Auckland, New Zealand (NZ). METHODS: The cohort data were derived from the primary care diabetes audit program the Diabetes Care Support Service (DCSS), and linked with national primary care, pharmaceutical claims, hospitalisation, and death registration databases. People with T1DM enrolled in DCSS between 1994-2018 were included. All-cause, premature, and cardiovascular mortalities were estimated by Poisson regression models with adjustment for population-level confounders. The mortality rates ratio (MRR) was standardized against the DCSS type 2 diabetes population. Mortality rates were compared by ethnic group (NZ European (NZE) and non-NZE) and socioeconomic deprivation quintile. The population attributable fraction (PAF) was estimated for ethnic and socioeconomic disparities by Cox regression adjusting for demographic, lifestyle, and clinical covariates. The adjusted slope index inequality (SII) and relative index of inequality (RII) were used to measure the socioeconomic disparity in mortalities. RESULTS: Overall, 2395 people with T1DM (median age 34.6 years; 45% female; 69% NZE) were enrolled, among whom the all-cause, premature and CVD mortalities were 6.69 (95% confidence interval: 5.93-7.53), 3.30 (2.77-3.90) and 1.77 (1.39-2.23) per 1,000 person-years over 25 years. The overall MRR was 0.39 (0.34-0.45), 0.65 (0.52-0.80), and 0.31 (0.24-0.41) for all-cause, premature and CVD mortality, respectively. PAF attributable to ethnicity disparity was not significantly different for mortality. The adjusted PAF indicated that 25.74 (0.84-44.39)% of all-cause mortality, 25.88 (0.69-44.69)% of premature mortality, 55.89 (1.20-80.31)% of CVD mortality could be attributed to socioeconomic inequality. The SII was 8.04 (6.30-9.78), 4.81 (3.60-6.02), 2.70 (1.82-3.59) per 1,000 person-years and RII was 2.20 (1.94-2.46), 2.46 (2.09-2.82), and 2.53 (2.03-3.03) for all-cause, premature and CVD mortality, respectively. CONCLUSIONS: Our results suggest that socioeconomic disparities were responsible for a substantial proportion of all-cause, premature and CVD mortality in people with T1DM in Auckland, NZ. Reducing socioeconomic barriers to management and self-management would likely improve clinical outcomes.

The incidence of transfusion-related acute lung injury using active surveillance: A systematic review and meta-analysis.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-related mortality. A concern with passive surveillance to detect transfusion reactions is underreporting. Our aim was to obtain evidence-based estimates of TRALI incidence using meta-analysis of active surveillance studies and to compare these estimates with passive surveillance. STUDY DESIGN AND METHODS: We performed a systematic review and meta-analysis of studies reporting TRALI rates. A search of Medline and Embase by a research librarian identified studies published between January 1, 1991 and January 20, 2023. Prospective and retrospective observational studies reporting TRALI by blood component (red blood cells [RBCs], platelets, or plasma) were identified and all inpatient and outpatient settings were eligible. Adult and pediatric, as well as general and specific clinical populations, were included. Platelets and plasma must have used at least one modern TRALI donor risk mitigation strategy. A random effects model estimated TRALI incidence by blood component for active and passive surveillance studies and heterogeneity was examined using meta-regression. RESULTS: Eighty studies were included with approximately 176-million blood components transfused. RBCs had the highest number of studies (n = 66) included, followed by platelets (n = 35) and plasma (n = 34). Pooled TRALI estimates for active surveillance studies were 0.17/10,000 (95% confidence intervals [CI]: 0.03-0.43; I2 = 79%) for RBCs, 0.31/10,000 (95% CI: 0.22-0.42; I2 = <1%) for platelets, and 3.19/10,000 (95% CI: 0.09-10.66; I2 = 86%) for plasma. Studies using passive surveillance ranged from 0.02 to 0.10/10,000 among the various blood components. DISCUSSION: In summary, these estimates may improve a quantitative understanding of TRALI risk, which is important for clinical decision-making weighing the risks and benefits of transfusion.

Health Inequality in Eight Adverse Outcomes Over a 25-Year Period in a Multi-Ethnic Population in New Zealand Population with Impaired Glucose Tolerance and/or Impaired Fasting Glucose: An Age-Period-Cohort Analysis.

Purpose: We aimed to examine socioeconomic inequality (SI) in cause-specific outcomes among adults with impaired glucose tolerance (IGT) and/or Impaired fasting glucose (IFG) in New Zealand (NZ) over 25 years. Patients and Methods: A population-based open cohort was derived from Diabetes Care Support Service in NZ with national databases linkage. Patients aged ≥18 years with IGT and/or IFG were enrolled between 01/01/1994 and 31/07/2018 and followed up until death or 31/12/2018. Incident outcomes (all-cause, premature, cardiovascular, and cancer death; cardiovascular, myocardial infarction, stroke, heart failure, and end-stage kidney disease hospitalization) by demographic, anthropometric, socioeconomic status, clinical measurements, enrol-time-periods, and IGT/IFG were evaluated. Adjusted incidence rate ratios, absolute risk difference, and SI measurements (slope and relative index of inequality) were estimated using Age-Period-Cohort models. Results: 29,894 patients (58.5 (SD 14.3) years mean age; 52.2% female) were enrolled with 5.6 (IQR: 4.4-7.4) years of median follow-up. Mortality rates decreased, whereas hospitalization (except myocardial infarction) rates increased. SI was significant for each outcome. Higher mortality and hospitalization rates and worsened SI were common in men, older, the most deprived, and Maori patients, as well as patients with obesity, current smoking, with both IFG and IGT, and greater metabolic derangement (higher systolic blood pressure, lipids, and HbA1c, and lower level of mean arterial pressure). Conclusion: Enhanced management strategies are necessary for people with IGT and/or IFG to address persisting SI, especially for men, older people, current smokers, NZ European and Maori patients, patients with obesity, or with any abnormal metabolic measurements.

Association Between Onset of Type 2 Diabetes and Risk of Atrial Fibrillation in New Zealanders With Impaired Glucose Tolerance Over 25 Years.

Background The association between the onset of type 2 diabetes (T2D) and atrial fibrillation (AF) risk in individuals with impaired glucose tolerance (IGT) remains unclear. This study aimed to investigate the relationship between the incident onset of T2D and 5- and 10-year (after the landmark period) risks of AF in people with IGT identified in South and West Auckland primary care settings between 1994 and 2019. Methods and Results We compared AF risk in patients with IGT with and without newly diagnosed T2D within a 1- to 5-year exposure window. Tapered matching and landmark analysis (to address immortal bias) were used to control for confounding variables. The cohorts incorporated 785 patients who had T2D newly diagnosed within 5 years from enrollment (landmark date) and 15 079 patients without a T2D diagnosis. Patients progressing to T2D exhibited significantly higher 5-year (after the landmark period) AF risk (hazard ratio [HR], 1.34 [95% CI, 1.10-1.63]) and 10-year (after the landmark period) AF risk (HR, 1.28 [95% CI, 1.02-1.62]) compared with those without incident T2D. The association was more pronounced among men, older patients, socioeconomically deprived individuals, current smokers, those with higher metabolic measures, and lower renal function. New Zealand European ethnicity was associated with a lower 5- and 10-year risk of AF. Conclusions This study found a mediating effect of T2D on the risk of AF in a population with IGT in New Zealand. The development of risk scores and future replication studies can help identify and guide management of individuals with IGT at the highest risk of AF following incident T2D.

Meta-analysis of bacterial growth characteristics in platelet components: Refining the inputs of a simulation analysis comparing the relative safety of testing strategies.

BACKGROUND: The relative safety of bacterial risk control strategies for platelets that include culture with or without rapid testing has been compared using simulation analysis. A wide range of bacterial lag and doubling times were included. However, published data on growth rates are available and these data have not been synthesized. We conducted a systematic review and meta-analysis to estimate growth rates and used these estimates to refine a comparative safety analysis of bacterial risk control strategies in the FDA guidance STUDY DESIGN AND METHODS: Data were extracted from published studies on bacterial growth rates in platelet components during storage. These data were used to estimate the practical range of growth rates. This refined the inputs for a simulation model comparing the safety of the testing strategies. RESULTS: In total, 108 growth curves for 11 different aerobic organisms were obtained. Doubling times ranged from 0.8 to 12 h, but the lower 90% range was approximately 1-5 h. The revised comparative safety simulation using the narrower 1-5-h range showed similar rankings to the prior simulation, with 48-h large-volume delayed sampling with 7-day expiration (48C-7) demonstrating the lowest-ranking relative performance at the 103 and 105 colony forming unit (CFU)/mL exposure thresholds. DISCUSSION: This was a two-step study. First, meta-analysis of published data on aerobic bacterial growth rates in stored platelets showed the vast majority of doubling times were 1-5 h. Next, an updated comparative safety simulation yielded similar results to a prior study, with 48C-7 showing the least favorable relative safety performance.

Effect of onset of type 2 diabetes on risks of cardiovascular disease and heart failure among new Zealanders with impaired glucose tolerance over 25 years: tapered-matched landmark analysis.

BACKGROUND: This study aimed to examine the association between the incident onset of T2DM and 5- and 10-year risks of CVD and HF in people with IGT identified in primary care in South and West Auckland, New Zealand (NZ) between 1994 and 2019. METHODS: We compared CVD and HF risks in patients with IGT and with/without T2D newly diagnosed within the exposure window (1-5 years). Tapered matching and landmark analysis (to account for immortal bias) were used to control for potential effects of known confounders. RESULTS: Among 26,794 patients enrolled with IGT, 845 had T2D newly diagnosed within 5 years from enrolment (landmark date) and 15,452 did not have T2D diagnosed. Patients progressing to T2D (vs. those not progressing) had a similar 5-year risk for CVD (hazard ratio 1.19; 95% CI 0.61-2.32) but significantly higher 10-year risk of CVD (2.45(1.40-4.29)), 5-year risk of HF (1.94(1.20-3.12)) and 10-year risk of HF (2.84(1.83-4.39). The association between the onset of T2D and risk of 10-year risk of CVD, 5-year and 10-year risk of HF was more likely among men, the socioeconomically deprived, those currently smoking, patients with higher metabolic measures and/or those with lower renal function. Patients of NZ European ethnicity had a lower 10-year risk of CVD. CONCLUSIONS: The study suggests that the diagnosis of T2D mediates the risk of CVD and HF in people with IGT. The development of risk scores to identify and better manage individuals with IGT at high risk of T2D is warranted.

Adverse Clinical Outcomes Attributable to Socioeconomic and Ethnic Disparities Among People with Type 2 Diabetes in New Zealand Between 1994-2018: A Multiple Linked Cohort Study.

Purpose: The study aimed to examine the separate population-level contributions of the ethnic and socioeconomic disparities among people with type 2 diabetes mellitus (T2DM) and residence in New Zealand (NZ). Patients and Methods: A prospective cohort enrolled T2DM patients from 01/01/1994 into the Diabetes Care Support Service, a primary care audit program in Auckland, NZ. The cohort was linked to national registry databases (socioeconomic status, pharmaceutical claim, hospitalization, and death registration). Each cohort member was followed up till death or the study end time (31/12/2019), whichever came first. Incident clinical events (stroke, myocardial infarction (MI), heart failure (HF), end-stage renal disease (ESRD), and premature mortality (PM)) were used as outcomes. The attributable fractions (AFs) were estimated for the whole population and for specific population with NZ Europeans (NZE) and/or least deprived population as reference, both unadjusted and with adjustment for covariables by Cox Regression models. Results: Among 36,267 patients, adjusted population AFs indicated 6.6(-30.8-33.3)% of PM, 17.1(5.8-27.0)% of MI, 35.3(22.6-46.0)% of stroke, 14.3(3.2-24.2)% of HF, and 15.9(6.7-24.2)% of ESRD could be attributed to deprivation; while 14.3(3.3-25.4)% of PM, -3.3(-8.3-1.5)% of MI, -0.5(-6.7-5.3)% of stroke, 4.7(0.3-8.8)% of HF, 13.3(9.9-16.6)% of ESRD could be attributed to ethnicity. Deprivation contributed a significant AF to stroke, while ethnicity was important for ESRD. Gradient of AF for deprivation indicated NZE and Asians were most affected by deprivation across outcomes. Conversely, Maori, with the highest AFs for ethnicity of PM and ESRD, were unaffected by deprivation. At same deprivations, the AFs of MI and stroke were greatest among NZE compared with other ethnic groups; the AF of ESRD was greatest among Maori and Pasifika. Conclusion: Both socioeconomic deprivation and ethnicity are strongly associated with outcomes in patients with T2DM in NZ, although the extent of the deprivation gradient is greatest among NZE and Asians, and least among Maori.

The Fading of Protective Roots: A Multivariate Analysis of the Risk of Hypertension among Hispanics by Nativity.

OBJECTIVE: To examine the effects of Hispanic nativity on the risk and severity of hypertension relative to US-born non-Hispanic whites. METHODS: The analytic sample (n = 34,007) was comprised of cross-sectional data drawn from twenty years of the National Health and Nutrition Examination Survey, 1999-2018. RESULTS: Foreign-born Hispanics aged 65 years and older had a greater risk of severe hypertension compared to non-Hispanic Whites. When examined by length of residency in the US, elderly foreign-born Hispanics with less than 10 years of residency were at greater risk of hypertension and severe hypertension, while those with 20 or more years of residency had similar risks compared to non-Hispanic Whites. CONCLUSION: The "Hispanic Paradox" of better health despite lower socioeconomic status, was not observed in foreign-born or US-born Hispanics aged 65 years and older. Among elderly immigrants, those with fewer years of residency had the greatest hypertensive risk.

Precision quality control: a dynamic model for risk-based analysis of analytical quality.

OBJECTIVES: There is continuing pressure to improve the cost effectiveness of quality control (QC) for clinical laboratory testing. Risk-based approaches are promising but recent research has uncovered problems in some common methods. There is a need for improvements in risk-based methods for quality control. METHODS: We provide an overview of a dynamic model for assay behavior. We demonstrate the practical application of the model using simulation and compare the performance of simple Shewhart QC monitoring against Westgard rules. We also demonstrate the utility of trade-off curves for analysis of QC performance. RESULTS: Westgard rules outperform simple Shewhart control over a narrow range of the trade-off curve of false-positive and false negative risk. The risk trade-off can be visualized in terms of risk, risk vs. cost, or in terms of cost. Risk trade-off curves can be "smoothed" by log transformation. CONCLUSIONS: Dynamic risk-models may provide advantages relative to static models for risk-based QC analysis.

Risk Analysis for Quality Control Part 3: Practical Application of the Precision Quality Control Model.

BACKGROUND: We developed a theoretical framework (Precision Quality Control [PQC]) to minimize the cost of quality, but it is not known whether the method can be applied in practice. METHODS: We used data for 2 analytes, cadmium and carbohydrate-deficient transferrin (CDT), and applied the PQC framework to find the optimal control limits. These analytes were selected because they differed with respect to sigma values that are major determinants of control limits. We explored different ways to visualize the results: (a) risk trade-off (false-positive risk vs false-negative risk), (b) cost-risk trade-off (false-positive cost vs false-negative risk), and (c) cost minimization. RESULTS: We were able to use the PQC limit to produce 3 different visualizations to suggest control limits. The risk-based analysis was the simplest to apply, but the most difficult to interpret. The cost vs risk method was easy to apply but was still difficult to interpret. The cost minimization method was easy to interpret but required users to declare a willingness to pay that may be difficult to estimate. CONCLUSIONS: The PQC method can be used to find control limits that minimize the cost of quality.

Risk Analysis for Quality Control Part 1: The Impact of Transition Assumptions in the Parvin Model.

BACKGROUND: Setting quality control (QC) limits involves balancing the risk of false-positive results and false-negative results. Recent approaches to QC have focused on the assessment of false-negative results. The Parvin model is the most-used model for risk analysis. The Parvin model assumes that the system makes a transition from an in-control to an out-of-control (OOC) state but makes no further transitions after moving to the OOC state. The implications of this assumption are unclear. METHODS: We used simulation experiments to compare the performance of QC systems based on no OOC transitions allowed (NOOCTA) vs systems where OOC transitions were allowed (OOCTA). RESULTS: The NOOCTA assumption leads to paradoxical tradeoff curves between false-positive results and false-negative results. Predictions of a false-negative result based on NOOCTA were about 10 times lower than models based on OOCTA. CONCLUSIONS: The most common models for QC risk analysis underestimate false-negative results. There is a need to develop better risk-based methods for QC analysis.

Impact of assay stability on the false negative and false positive rates in quality control.

BACKGROUND: The dynamic Precision QC (PQC) model can be used to evaluate the performance of quality control (QC) monitoring systems. The model depends on inputs that describe the intrinsic shift behavior (i.e., stability) of an assay. The output of the model is a trade-off curve that shows the relationship between false negative (FN) and false positive (FP) risk events. The relationship between the inputs and outputs of this model has not yet been explored. METHODS: We used Monte Carlo simulation to generate trade-off curves using the PQC. We varied the input parameters that determine assay stability (shift probability and shift size distribution) and studied the impact of these inputs on the output (i.e., the trade-off curve relating FN risk to FP risk). RESULTS: FN risk is sensitive to the shift probability and the width of the control limits. FN risk is sensitive to the shape of the shift size distribution when the standard deviation (SD) of the shift size distribution is relatively narrow (i.e., SD < 2) but is less sensitive to the width of the shift size distribution when the SD is relatively large (i.e., SD > 2). CONCLUSIONS: Practical use of the PQC model may require the estimation of the shift probability and shift size distribution.

The epidemiology of transfusion-related acute lung injury: A scoping review and analysis.

BACKGROUND: The purpose of this scoping review was to identify available sources of evidence on the epidemiology of transfusion-related acute lung injury (TRALI) and whether meta-analysis on the incidence of TRALI is feasible. TRALI is a serious complication and the second leading cause of death related to blood transfusion. Estimates of the incidence of TRALI would provide a useful benchmark for research to reduce TRALI. STUDY DESIGN AND METHODS: We searched the Medline, EMBASE, and PubMed databases for publications related to the incidence of TRALI and hemovigilance. We included all studies irrespective of language or country. Both full-text articles and conference abstracts were included. Participants of the studies must all have received a blood transfusion. Reviews and case studies were excluded. RESULTS: We identified 427 articles or abstracts to include for review. More than half were abstracts, and the majority were published after 2010. Reported TRALI definitions varied, but only 27.2% of studies reported any definition for TRALI. TRALI rates were reported using different denominators, such as per blood unit (54.1%), patient (34.4%), and transfusion episode (14.8%). Study populations and contexts were mostly general (75.6% and 80.3%, respectively). There was also variation in study design with most being observational (90.6%) and only 13.1% of all studies used modern donor restriction policies. DISCUSSION: There was substantial variation in reporting in studies on TRALI incidence. Meta-analysis of TRALI rates may be feasible in specific circumstances where reporting is clear. Future studies should clearly report key items, such as a TRALI definition.

Bacterial culture time to detection in platelet components: An evidence synthesis and estimation of detection failures.

BACKGROUND: Non-pathogen reduction platelet bacterial risk control strategies in the US FDA guidance include at least one culture. Almost all of these strategies have a culture hold time of ≥12 h. Studies have reported time to detection (TTD) of bacterial cultures inoculated with bacteria from contaminated platelets, but these data and estimates of risk associated with detection failures have not been synthesized. METHODS: We performed a literature search to identify studies reporting TTD for samples obtained from spiked platelet components. Using extracted data, regression analysis was used to estimate TTD for culture bottles at different inoculum sizes. Detection failures were defined as events in which contaminated components are transfused to a patient. We then used published data on time of transfusion (ToT) to estimate the risk of detection failures in practice. RESULTS: The search identified 1427 studies, of which 16 were included for analysis. TTD data were available for 16 different organisms, including 14 in aerobic cultures and 11 in anaerobic cultures. For inocula of 1 colony forming unit (CFU), the average TTD for aerobic organisms was 19.2 h while it was 24.9 h in anaerobic organisms, but there was substantial overall variation. A hold time of 12 versus 24 h had minimal effect for most organisms. CONCLUSION: TTD variation occurs between bacterial species and within a particular species. Under typical inventory management, the relative contribution of culture detection failures is much smaller than the residual risk from sampling failures. Increasing the hold period beyond 12 h has limited value.

Ethnic differences in 25-year risk of incident chronic kidney disease among people with type 2 diabetes in New Zealand.

INTRODUCTION: Insights into ethnic differences in the natural history of chronic kidney disease (CKD) among people with type 2 diabetes mellitus (T2DM) might inform clinical strategies to address disparities in hospitalization and mortality. Risks of CKD II-V stages over a 25-year period between New Zealand Europeans (NZEs), Maori and Pasifika, and with T2DM in Auckland, New Zealand (NZ) were compared. RESEARCH DESIGN AND METHODS: As a primary care audit program in Auckland, the Diabetes Care Support Service was linked with national registration databases. People with existing CKD II-V were ruled out. To balance potential confounders, we applied a tapered matching method . 'Quasi-trial'-matched cohorts were set up separately between Maori and NZE and between Pasifika and NZE. Ethnic population differences in risk of any and each stage of CKD over 1994-2018 were examined by weighted Cox regression model. RESULTS: The HRs for developing any CKD, CKD stages II-V for Maori (n=2215) versus NZE (n=2028) were 1.18 (95% CI 0.99 to 1.41), 1.10 (95% CI 0.91 to 1.32), 1.70 (95% CI 1.19 to 2.43), 3.93 (95% CI 2.16 to 7.14), and 3.74 (95% CI 1.74 to 8.05), respectively. Compared with NZE (n=2474), the HRs for developing any CKD, CKD stages II-V for Pasifika (n=3101) were 1.31 (95% CI 1.09 to 1.57), 1.26 (95% CI 1.05 to 1.52), 1.71 (95% CI 1.14 to 2.57), 3.75 (95% CI 1.40 to 10.05), and 4.96 (95% CI 1.56 to 15.75), respectively. CONCLUSIONS: Among people with T2DM in NZ, significant ethnic differences exist in the risk of progressing to each stage of CKD (stage V in particular). Mechanism studies underlying these differences, as well as the need for identification of biomarkers to predict the early onset renal lesion, are warranted.

Molecular Dynamics and Free Energy Calculations of Dicyclohexano-18-crown-6 Diastereoisomers with Sm2+, Eu2+, Dy2+, Yb2+, Cf2+, and Three Halide Salts in Tetrahydrofuran and Acetonitrile Using the AMOEBA Force Field.

With the continual development of lanthanides (Ln) in current technological devices, an efficient separation process is needed that can recover greater amounts of these rare elements. Dicyclohexano-18-crown-6 (DCH18C6) is a crown ether that may be a promising candidate for Ln separation, but additional research is required. As such, molecular dynamics (MD) simulations have been performed on four divalent lanthanide halide salts (Sm2+, Eu2+, Dy2+, and Yb2+) and one divalent actinide halide salt (Cf2+) bound to three diastereoisomers of DCH18C6. Dy2+, Yb2+, Cf2+, DCH18C6, and tetrahydrofuran (THF) solvent were parameterized for the AMOEBA polarizable force field for the first time, whereas existing parameters for Sm2+ and Eu2+ were utilized from our previous efforts. A coordination number (CN) of six for Ln2+/An2+-O solvated in THF indicated that the cations interacted almost entirely with the oxygens of the polyether ring. A CN of one for Ln2+/An2+-N solvated in acetonitrile for systems containing iodide suggested that the N atom of acetonitrile was competitive with I- for cation interactions. Fluctuation between five and six CNs for Dy2+ and Yb2+ suggested that although the cations remained in the polyether ring, the size of the ring may not be an ideal fit as these cations possess comparatively smaller ionic radii. Gibbs binding free energies of Sm2+ in all DCH18C6 diastereoisomers solvated in THF were calculated. The binding free energy of the cis-syn-cis diastereoisomer was the most favorable, followed by cis-anti-cis, and then trans-anti-trans. Finally, two major types of conformation were observed for each diastereoisomer that were related to the electrostatic interactions and charge density of the cations.

An Efficient Approach to Large-Scale Ab Initio Conformational Energy Profiles of Small Molecules.

Accurate conformational energetics of molecules are of great significance to understand maby chemical properties. They are also fundamental for high-quality parameterization of force fields. Traditionally, accurate conformational profiles are obtained with density functional theory (DFT) methods. However, obtaining a reliable energy profile can be time-consuming when the molecular sizes are relatively large or when there are many molecules of interest. Furthermore, incorporation of data-driven deep learning methods into force field development has great requirements for high-quality geometry and energy data. To this end, we compared several possible alternatives to the traditional DFT methods for conformational scans, including the semi-empirical method GFN2-xTB and the neural network potential ANI-2x. It was found that a sequential protocol of geometry optimization with the semi-empirical method and single-point energy calculation with high-level DFT methods can provide satisfactory conformational energy profiles hundreds of times faster in terms of optimization.

A Case of Heyde's Syndrome With Subvalvular Aortic Stenosis.

Heyde's syndrome is a constellation of severe aortic stenosis, gastrointestinal arteriovenous malformations (AVMs), and an acquired von Willebrand type 2A coagulopathy resulting in moderate-to-severe gastrointestinal bleeding. Additional cardiac lesions have been observed to cause Heyde's syndrome including aortic regurgitation, mitral regurgitation, aortic/mitral valve prosthetic dysfunction, ventricular septal defects, hypertrophic cardiomyopathy, left ventricular assist devices, and extracorporeal life support devices. Repairing the cardiac lesion or removing the device decreases the incidence of gastrointestinal bleeding by normalizing the acquired von Willebrand coagulopathy and decreasing the amount of gastrointestinal AVMs likely to bleed. We describe a case of a 67-year-old woman found to have Heyde's syndrome arising from a subvalvular aortic membrane resulting in severe subaortic stenosis with no other significant cardiac lesion. She underwent successful resection of the membrane with septal myectomy, relieving the severe subaortic stenosis and resolving her anemia. Years later, she re-presented with severe gastrointestinal bleeding from gastrointestinal malformations. Early recognition of these cardiac lesions with gastrointestinal bleeds may help decrease the morbidity and mortality that Heyde's syndrome portends and provide evidence for early intervention.