Nevin Manimala

Emerg Med Australas. 2023 Dec 15. doi: 10.1111/1742-6723.14360. Online ahead of print.

ABSTRACT

OBJECTIVE: Moderate risk patients with chest pain and no previously diagnosed coronary artery disease (CAD) who present to ED require further risk stratification. We hypothesise that management of these patients by ED physicians can decrease length of stay (LOS), without increasing patient harm.

METHODS: A prospective pilot study with comparison to a pre-intervention control group was performed on patients presenting with chest pain to an ED in Perth, Australia between May and October 2021, following the introduction of a streamlined guideline consisting of ED led decision making and early follow up. Patients had no documented CAD and were at moderate risk of major adverse cardiac events (MACE). Electronic data was used for comparison. Primary outcomes were total LOS and LOS following troponin.

RESULTS: One hundred eighty-six patients were included. Median total LOS was reduced by 62 min, but this change was not statistically significant (482 [360-795] vs 420 [360-525] min, P = 0.06). However, a significant 60 min decrease in LOS was found following the final troponin (240 (120-571) vs 180 (135-270) min, P = 0.02). There was no difference in the rate of MACE (0% vs 2%, P = 0.50), with no myocardial infarction or death.

CONCLUSIONS: Our study suggests that patients with no pre-existing CAD can be safely managed by emergency physicians streamlining their ED management and decreasing LOS. This pathway could be used in other centres following confirmation of the results by a larger study.

PMID:38100118 | DOI:10.1111/1742-6723.14360

JAMA Netw Open. 2023 Dec 1;6(12):e2347894. doi: 10.1001/jamanetworkopen.2023.47894.

ABSTRACT

IMPORTANCE: Physician turnover interrupts care delivery and creates health care system financial burden.

OBJECTIVE: To describe the prevalence of burnout, professional fulfillment, and intention to leave (ITL) among physicians at academic-affiliated health care systems and identify institutional and individual factors associated with ITL.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study administered a survey to 37 511 attending-level medical specialists at 15 academic medical institutions participating in the Healthcare Professional Well-Being Academic Consortium. Data were collected from October 2019 to July 2021. Statistical analysis was performed from May 2022 to March 2023.

EXPOSURES: Hypothesized institutional and individual determinants of occupational well-being.

MAIN OUTCOMES AND MEASURES: The main outcome was ITL, defined as having at least a moderate intention (a score of 2 on a 0-4 scale) to leave one’s institution within the next 2 years. Additional outcomes included burnout and professional fulfillment, defined using published Professional Fulfillment Index cut points.

RESULTS: Of 18 719 academic physician survey respondents (8381 [44.8%] male; 2388 [12.8%] Asian, 10 599 [56.6%] White, 1039 [5.6%] other race, 4693 [25.1%] unknown race; 294 [1.6%] Hispanic or Latina/Latino/Latinx), 6903 of 18 217 (37.9%) met criteria for burnout and 7301 of 18 571 (39.3%) for professional fulfillment; 5177 of 15 890 (32.6%) reported moderate or greater ITL. Burnout, professional fulfillment, and ITL varied across specialties. After adjusting for demographics, each 1-point increase (range 0-10) in burnout was directly associated with ITL (odds ratio [OR], 1.52 [95% CI, 1.49-1.55])c, and each 1-point increase in professional fulfillment was inversely associated with ITL (OR, 0.64 [95% CI, 0.63-0.65]). After adjusting for demographics, burnout, and professional fulfillment, each 1-point increase (range 0-10) in supportive leadership behaviors (OR, 0.83 [95% CI, 0.82-0.84]), peer support (OR, 0.93 [95% CI, 0.91-0.95]), personal-organizational values alignment (OR, 0.81 [95% CI, 0.80-0.82]), perceived gratitude (OR, 0.95 [95% CI, 0.92-0.97]), COVID-19 organizational support (OR, 0.88 [95% CI, 0.85-0.91]), and electronic health record helpfulness (OR, 0.95 [95% CI, 0.93-0.97]) were inversely associated with ITL, whereas each 1-point increase (range 0-10) in depression (OR, 1.08 [95% CI, 1.05-1.10]) and negative impact of work on personal relationships (OR, 1.09 [1.07-1.11]) were directly associated with ITL.

CONCLUSIONS AND RELEVANCE: In this cross-sectional study of academic physicians, 32.6% indicated moderate or higher ITL within 2 years. Burnout, lack of professional fulfillment, and other well-being factors were associated with ITL, suggesting the need for a comprehensive approach to reduce physician turnover.

PMID:38100103 | DOI:10.1001/jamanetworkopen.2023.47894

Epilepsia. 2023 Dec 15. doi: 10.1111/epi.17865. Online ahead of print.

ABSTRACT

Psychological stress is the most commonly self-reported precursor of epileptic seizures. However, retrospective and prospective studies remain inconclusive in this regard. Here, we explored whether seizures would be preceded by significant changes in reported stressors or resource utilization. This study is based on high-frequency time series through daily online completion of personalized questionnaires of 9-24 items in epilepsy outpatients and compared responses 1-14 days before seizures with interictal time series. Fourteen patients (79% women, age from 23 to 64 years) completed daily questionnaires over a period of 87 – 898 days (median: 277 days = 9.2 months). A total of 4560 fully completed daily questionnaires were analyzed, 685 of which included reported seizure events. Statistically significant changes in preictal compared to interictal dynamics were found in 11/14 patients (79%) across 41 items (22% of all 187 items). In 7/14 patients (50%) seizures were preceded by a significant mean increase of stressors and/or a significant mean decrease of resource utilization. This exploratory analysis of long-term prospective individual patient data of specific stressors and personal coping strategies generates the hypothesis that medium-term changes in psychological well-being may precede the occurrence of epileptic seizures in some patients.

PMID:38100099 | DOI:10.1111/epi.17865

J Ocul Pharmacol Ther. 2023 Dec 13. doi: 10.1089/jop.2023.0098. Online ahead of print.

ABSTRACT

Purpose: Diabetes mellitus has been associated with increased dry eye disease (DED) and exacerbates DED’s pathology. This preliminary short-term study aimed to evaluate the effects of 3% Diquafosol Sodium ophthalmic solution (DQS) on ocular surface inflammation and corneal nerve density in diabetic dry eye (DDE) patients. Methods: In this perspective, participants used 1 drop of 3% DQS (Diquas; Santen Pharmaceutical Co., Ltd., Osaka, Japan) 6 times daily for 8 weeks. Non-invasive tear breakup time (NITBUT), tear film lipid layer (TFLL), conjunctival hyperemia [redness score (RS)], corneoconjunctival staining (CFS), corneal sensitivity (CS), Meibomian gland quality (MGQ) and Meibomian gland expressibility (MGEx), corneal nerve fiber density (CNFD), and Standard Patient Evaluation Eye Dryness (SPEED) questionnaire were assessed at baseline, at weeks 4, and up to 8 weeks. Matrix metalloproteinase-9 (MMP-9) of tear samples was measured at baseline and weeks 8. Results: The mean age was 61.27 ± 11.68 years. At baseline NITBUT = 5.89 ± 2.81 s, tear meniscus height = 0.17 ± 0.05 mm, TFLL = 2.74 ± 0.51, CFS = 4.35 ± 0.68, CS = 53.83 ± 9.63 mm, MMP-9 = 49.10 ± 10.42 ng/mL, RS = 1.65 ± 0.44, MGEx = 1.85 ± 0.72, MGQ = 2.65 ± 0.50, CNFD = 20.36 ± 8.20 no./mm², and SPEED = 12.62 ± 3.91. At week 4, significant improvements were found in all parameters except RS (1.59 ± 0.46, P = 0.172) and CNFD (21.46 ± 8.41, P = 0.163). Finally, at week 8, all parameters had significant improvements. Conclusion: Preliminary short-term findings suggest that treatment of DDE patients with DQS was found to be safe and efficacious in improving dry eye parameters. In addition, inflammatory marker and corneal nerve density were significantly improved. This study was registered with ClinicalTrials.gov (NCT05193331).

PMID:38100078 | DOI:10.1089/jop.2023.0098

J Gen Intern Med. 2023 Dec 15. doi: 10.1007/s11606-023-08348-4. Online ahead of print.

ABSTRACT

BACKGROUND: Home INR testing (patient self-testing) is feasible and effective for warfarin patients but little is known about real-world differences in outcomes for patients using PST versus laboratory-based INR monitoring.

OBJECTIVE: To compare the safety/efficacy of patient self-testing of real-world warfarin therapy versus office/lab-based monitoring of therapy.

DESIGN/SETTING/PARTICIPANTS/EXPOSURE: A retrospective claims-based analysis of warfarin patients enrolled in the MarketScan® Commercial Claims and Encounters and Medicare databases between January 1, 2013, and March 30, 2020. Stratification was based on INR testing method: patient self-testing versus testing at physicians’ offices/local laboratory. The probability of adverse events in each cohort was determined after adjusting for demographic and baseline clinical characteristics using a repeated measures analysis.

MAIN MEASURES: Rates of all adverse events: deep venous thrombosis, pulmonary embolism, bleeding, and stroke. A secondary outcome of interest was emergency department visits.

KEY RESULTS: A total of 37,837 patients were included in the analysis: 1592 patients in the patient self-testing group and 36,245 in the office-based therapy group. After adjusting for demographic and baseline clinical characteristics, patients in the office-based group had statistically significantly higher rates of all adverse events (incidence rate ratio [IRR]=2.07, 95% CI [1.82, 2.36]), and specific adverse events including thromboembolism (IRR=4.38, 95% CI [3.29, 5.84]), major bleed (IRR=1.45, 95% CI [1.28, 1.64]), and stroke (IRR=1.30, 95% CI [1.05, 1.61]) than patients in the patient self-testing group. Office-based patients also had a statistically significant higher rate of emergency department visits than patient self-testing patients (IRR = 1.65, 95% CI [1.47, 1.84]).

CONCLUSIONS/RELEVANCE: This analysis of real-world claims data shows lower rates of stroke, thromboembolism, and major bleeding, as well as fewer emergency department visits, with patient self-testing compared to office-based/lab INR monitoring. Our finding that PST is safe and effective among current users suggests that more patients may benefit from its use.

PMID:38100006 | DOI:10.1007/s11606-023-08348-4

Res Child Adolesc Psychopathol. 2023 Dec 15. doi: 10.1007/s10802-023-01154-w. Online ahead of print.

ABSTRACT

Externalizing psychopathology is highly prevalent in children and adolescents. Yet, current understanding of the externalizing psychopathology spectrum is predominantly founded on cross-sectional and conventional longitudinal designs. Compared to these designs, intensive longitudinal data have greater ecological validity and provide insight into within-person fluctuations and short-term developmental dynamics. In this Special Issue, we bring together a selection of 10 innovative and original empirical articles to demonstrate the benefits of intensive longitudinal data for understanding the development of the externalizing psychopathology spectrum during childhood and adolescence, as well as one thoughtful commentary from leaders in the externalizing psychopathology field. In this Introduction to the Special Issue, we describe the articles included in this Special Issue in relation to study designs, timescales, samples, and statistical modeling techniques. We conclude by considering the implications of intensive longitudinal data for informing and enhancing our understanding of externalizing psychopathology with child and adolescent samples, as well as critical future research directions.

PMID:38099999 | DOI:10.1007/s10802-023-01154-w

Invest New Drugs. 2023 Dec 15. doi: 10.1007/s10637-023-01405-z. Online ahead of print.

ABSTRACT

AIM: Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects.

METHODS: In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing.

RESULTS: Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUC_last) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in C_max (P-value = 0.45) or AUC_last (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated.

CONCLUSION: The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased C_max in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.

PMID:38099989 | DOI:10.1007/s10637-023-01405-z

Eur Radiol. 2023 Dec 15. doi: 10.1007/s00330-023-10406-8. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of this proof-of-principle study combining data analysis and computer simulation was to evaluate the robustness of apparent diffusion coefficient (ADC) values for lymph node classification in prostate cancer under conditions comparable to clinical practice.

MATERIALS AND METHODS: To assess differences in ADC and inter-rater variability, ADC values of 359 lymph nodes in 101 patients undergoing simultaneous prostate-specific membrane antigen (PSMA)-PET/MRI were retrospectively measured by two blinded readers and compared in a node-by-node analysis with respect to lymph node status. In addition, a phantom and 13 patients with 86 lymph nodes were prospectively measured on two different MRI scanners to analyze inter-scanner agreement. To estimate the diagnostic quality of the ADC in real-world application, a computer simulation was used to emulate the blurring caused by scanner and reader variability. To account for intra-individual correlation, the statistical analyses and simulations were based on linear mixed models.

RESULTS: The mean ADC of lymph nodes showing PSMA signals in PET was markedly lower (0.77 × 10^-3 mm²/s) compared to inconspicuous nodes (1.46 × 10^-3 mm²/s, p < 0.001). High inter-reader agreement was observed for ADC measurements (ICC 0.93, 95%CI [0.92, 0.95]). Good inter-scanner agreement was observed in the phantom study and confirmed in vivo (ICC 0.89, 95%CI [0.84, 0.93]). With a median AUC of 0.95 (95%CI [0.92, 0.97]), the simulation study confirmed the diagnostic potential of ADC for lymph node classification in prostate cancer.

CONCLUSION: Our model-based simulation approach implicates a high potential of ADC for lymph node classification in prostate cancer, even when inter-rater and inter-scanner variability are considered.

CLINICAL RELEVANCE STATEMENT: The ADC value shows a high diagnostic potential for lymph node classification in prostate cancer. The robustness to scanner and reader variability implicates that this easy to measure and widely available method could be readily integrated into clinical routine.

KEY POINTS: • The diagnostic value of the apparent diffusion coefficient (ADC) for lymph node classification in prostate cancer is unclear in the light of inter-rater and inter-scanner variability. • Metastatic and inconspicuous lymph nodes differ significantly in ADC, resulting in a high diagnostic potential that is robust to inter-scanner and inter-rater variability. • ADC has a high potential for lymph node classification in prostate cancer that is maintained under conditions comparable to clinical practice.

PMID:38099965 | DOI:10.1007/s00330-023-10406-8

Arch Gynecol Obstet. 2023 Dec 15. doi: 10.1007/s00404-023-07309-w. Online ahead of print.

ABSTRACT

PURPOSE: We have previously published a retrospective matched-case control study comparing the effect of recombinant LH (r-hLH) versus highly purified human menopausal gonadotropin (hMG) supplementation on the follicle-stimulating hormone (FSH) during controlled ovarian hyperstimulation (COH) in the GnRH-antagonist protocol. The result from that study showed that the cumulative live birth rate (CLBR) was significantly higher in the r-hLH group (53% vs. 64%, p = 0.02). In this study, we aim to do a cost analysis between these two groups based on our previous study.

METHODS: The analysis consisted of 425 IVF and ICSI cycles in our previous study. There were 259 cycles in the r-hFSH + hMG group and 166 cycles in the r-hFSH + r-hLH group. The total cost related to the treatment of each patient was recorded. Probabilistic sensitivity analysis (PSA) and a cost-effectiveness acceptability curve (CEAC) were performed and created.

RESULTS: The total treatment cost per patient was significantly higher in the r-hFSH + r-hLH group than in the r-hFSH + hMG group ($4550 ± 798.86 vs. $4290 ± 734.6, p = 0.003). However, the mean cost per live birth in the r-hFSH + hMG group was higher at $8052, vs. $7059 in the r-hFSH + r-hLH group. The CEAC showed that treatment with hFSH + r-hLH proved to be more cost-effective than treatment with r-hFSH + hMG. Willingness-to-pay was evident when considering a hypothetical threshold of $18,513, with the r-hFSH + r-hLH group exhibiting a 99% probability of being considered cost-effective.

CONCLUSION: The cost analysis showed that recombinant LH is more cost-effective than hMG supplementation on r-hFSH during COH in the GnRH-antagonist protocol.

PMID:38099955 | DOI:10.1007/s00404-023-07309-w

J Math Biol. 2023 Dec 15;88(1):10. doi: 10.1007/s00285-023-02027-y.

ABSTRACT

Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the approximate Bayesian computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended fourier amplitude sensitivity test. Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored.

PMID:38099947 | DOI:10.1007/s00285-023-02027-y