Tag: nevin manimala

J Chem Inf Model. 2023 May 25. doi: 10.1021/acs.jcim.3c00276. Online ahead of print.

ABSTRACT

Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge. We use an iteration of the database containing >120 million catalogue compounds to find fragment merges for four crystallographic screening campaigns and contrast the results with a traditional fingerprint-based similarity search. The two approaches identify complementary sets of merges that recapitulate the observed fragment-protein interactions but lie in different regions of chemical space. We further show our methodology is an effective route to achieving on-scale potency by retrospective analyses for two different targets; in analyses of public COVID Moonshot and Mycobacterium tuberculosis EthR inhibitors, potential inhibitors with micromolar IC₅₀ values were identified. This work demonstrates the use of the Fragment Network to increase the yield of fragment merges beyond that of a classical catalogue search.

PMID:37229647 | DOI:10.1021/acs.jcim.3c00276

Chaos. 2023 May 1;33(5):053117. doi: 10.1063/5.0152959.

ABSTRACT

We investigate epidemic spreading in a deterministic susceptible-infected-susceptible model on uncorrelated heterogeneous networks with higher-order interactions. We provide a recipe for the construction of one-dimensional reduced model (resilience function) of the N-dimensional susceptible-infected-susceptible dynamics in the presence of higher-order interactions. Utilizing this reduction process, we are able to capture the microscopic and macroscopic behavior of infectious networks. We find that the microscopic state of nodes (fraction of stable healthy individual of each node) inversely scales with their degree, and it becomes diminished due to the presence of higher-order interactions. In this case, we analytically obtain that the macroscopic state of the system (fraction of infectious or healthy population) undergoes abrupt transition. Additionally, we quantify the network’s resilience, i.e., how the topological changes affect the stable infected population. Finally, we provide an alternative framework of dimension reduction based on the spectral analysis of the network, which can identify the critical onset of the disease in the presence or absence of higher-order interactions. Both reduction methods can be extended for a large class of dynamical models.

PMID:37229635 | DOI:10.1063/5.0152959

Echocardiography. 2023 May 25. doi: 10.1111/echo.15624. Online ahead of print.

ABSTRACT

BACKGROUND: Data on intraoperative three-dimensionally derived right ventricular free-wall strain (3D-RV FWS) is sparse.

OBJECTIVES: We sought to evaluate the normal range of intraoperative 3D-RV FWS in patients scheduled for coronary artery bypass graft (CABG) surgery and compared to conventional echocardiographic parameters. Prospective observational study.

METHODS: A total of 150 patients with preserved left and right ventricular (RV) function and sinus rhythm, without significant heart valve disease or pulmonary hypertension undergoing isolated on-pump CABG surgery, with an uneventful, complication-free intraoperative course. 3D-RV FWS analysis and conventional echocardiographic assessment of RV function were performed intraoperatively in anesthetized and ventilated patients using transesophageal echocardiography (TEE). TomTec 4D RV-Function 2.0 software for assessment of 3D-RV FWS and three-dimensional right ventricular ejection fraction (3D-RV EF). Philips QLAB 10.8 was used to evaluate tissue velocity of the tricuspid annulus (RV S´), tricuspid annular systolic excursion (TAPSE), and RV fractional area change (FAC). All echocardiographic measurements were performed under stable hemodynamic conditions and predefined fluid management without any vasoactive support or pacing. The prospective observational study was performed in a single university hospital setting.

RESULTS: Assessment of 3D-RV FWS was feasible in 95% of patients. No included patient experienced any serious perioperative complication. In our group of patients, median values with interquartile range (IQR) for 3D-RV FWS and 3D-RV EF were -25.2 (IQR -29.9 to -21.8) and 46.3% (IQR 41.0%-50.1%), respectively. RV FAC, RV S´, and TAPSE accounted for 39.7% (IQR 34.5%-44.4%), 14.8 cm/s (IQR 11.8-19.0 cm/s), and 22 mm (IQR 20-25 mm). The normal range (2.5% to 97.5% percentile) for 3D-RV FWS was -37.1 to -12.8. There was no relevant correlation of 3D-RV FWS to postoperative outcome in this group of CABG patients.

CONCLUSION: We present distribution values for intraoperative 3D-RV FWS and conventional parameters of RV function assessment in a healthy on-pump CABG patient population without serious perioperative complications. We observed no correlations of these parameters with any of the outcome parameters considered. Therefore, we consider these values to be intraoperative TEE-assessed normal values, which can be expected in on-pump CABG patients.

PMID:37229579 | DOI:10.1111/echo.15624

Clin Orthop Relat Res. 2023 May 25. doi: 10.1097/CORR.0000000000002698. Online ahead of print.

ABSTRACT

BACKGROUND: The ability to predict survival accurately in patients with osseous metastatic disease of the extremities is vital for patient counseling and guiding surgical intervention. We, the Skeletal Oncology Research Group (SORG), previously developed a machine-learning algorithm (MLA) based on data from 1999 to 2016 to predict 90-day and 1-year survival of surgically treated patients with extremity bone metastasis. As treatment regimens for oncology patients continue to evolve, this SORG MLA-driven probability calculator requires temporal reassessment of its accuracy.

QUESTION/PURPOSE: Does the SORG-MLA accurately predict 90-day and 1-year survival in patients who receive surgical treatment for a metastatic long-bone lesion in a more recent cohort of patients treated between 2016 and 2020?

METHODS: Between 2017 and 2021, we identified 674 patients 18 years and older through the ICD codes for secondary malignant neoplasm of bone and bone marrow and CPT codes for completed pathologic fractures or prophylactic treatment of an impending fracture. We excluded 40% (268 of 674) of patients, including 18% (118) who did not receive surgery; 11% (72) who had metastases in places other than the long bones of the extremities; 3% (23) who received treatment other than intramedullary nailing, endoprosthetic reconstruction, or dynamic hip screw; 3% (23) who underwent revision surgery, 3% (17) in whom there was no tumor, and 2% (15) who were lost to follow-up within 1 year. Temporal validation was performed using data on 406 patients treated surgically for bony metastatic disease of the extremities from 2016 to 2020 at the same two institutions where the MLA was developed. Variables used to predict survival in the SORG algorithm included perioperative laboratory values, tumor characteristics, and general demographics. To assess the models’ discrimination, we computed the c-statistic, commonly referred to as the area under the receiver operating characteristic (AUC) curve for binary classification. This value ranged from 0.5 (representing chance-level performance) to 1.0 (indicating excellent discrimination) Generally, an AUC of 0.75 is considered high enough for use in clinical practice. To evaluate the agreement between predicted and observed outcomes, a calibration plot was used, and the calibration slope and intercept were calculated. Perfect calibration would result in a slope of 1 and intercept of 0. For overall performance, the Brier score and null-model Brier score were determined. The Brier score can range from 0 (representing perfect prediction) to 1 (indicating the poorest prediction). Proper interpretation of the Brier score necessitates a comparison with the null-model Brier score, which represents the score for an algorithm that predicts a probability equal to the population prevalence of the outcome for each patient. Finally, a decision curve analysis was conducted to compare the potential net benefit of the algorithm with other decision-support methods, such as treating all or none of the patients. Overall, 90-day and 1-year mortality were lower in the temporal validation cohort than in the development cohort (90 day: 23% versus 28%; p < 0.001, and 1 year: 51% versus 59%; p<0.001).

RESULTS: Overall survival of the patients in the validation cohort improved from 28% mortality at the 90-day timepoint in the cohort on which the model was trained to 23%, and 59% mortality at the 1-year timepoint to 51%. The AUC was 0.78 (95% CI 0.72 to 0.82) for 90-day survival and 0.75 (95% CI 0.70 to 0.79) for 1-year survival, indicating the model could distinguish the two outcomes reasonably. For the 90-day model, the calibration slope was 0.71 (95% CI 0.53 to 0.89), and the intercept was -0.66 (95% CI -0.94 to -0.39), suggesting the predicted risks were overly extreme, and that in general, the risk of the observed outcome was overestimated. For the 1-year model, the calibration slope was 0.73 (95% CI 0.56 to 0.91) and the intercept was -0.67 (95% CI -0.90 to -0.43). With respect to overall performance, the model’s Brier scores for the 90-day and 1-year models were 0.16 and 0.22. These scores were higher than the Brier scores of internal validation of the development study (0.13 and 0.14) models, indicating the models’ performance has declined over time.

CONCLUSION: The SORG MLA to predict survival after surgical treatment of extremity metastatic disease showed decreased performance on temporal validation. Moreover, in patients undergoing innovative immunotherapy, the possibility of mortality risk was overestimated in varying severity. Clinicians should be aware of this overestimation and discount the prediction of the SORG MLA according to their own experience with this patient population. Generally, these results show that temporal reassessment of these MLA-driven probability calculators is of paramount importance because the predictive performance may decline over time as treatment regimens evolve. The SORG-MLA is available as a freely accessible internet application at https://sorg-apps.shinyapps.io/extremitymetssurvival/.Level of Evidence Level III, prognostic study.

PMID:37229565 | DOI:10.1097/CORR.0000000000002698

J Vet Med Educ. 2023 May 25:e20230011. doi: 10.3138/jvme-2023-0011. Online ahead of print.

ABSTRACT

This work describes the implementation of online timed closed-book formative assessments across several modules of a first-year undergraduate veterinary program. This process does not require significant time investment since it can be implemented into existing programs of study. Students were surveyed on how they used these formative assessments for learning and overall, were overwhelmingly positive about the opportunity to practice and receive feedback on their performance. Quantitative statistics on preferences as well as qualitative thematic analysis of open free-text questions reveal clear preferences in how they choose to engage with the assessments for learning, as well as how they prefer assessments to be administered. Students were positive about the online nature of the exams and prefer formative assessments to be distributed across the teaching semesters without any time restrictions, allowing them to be completed as and when they choose. Immediate feedback in the form of model answers is the students’ preference, although some value signposting to relevant resources for further research. Furthermore, students report that they want more questions and tests to complement their learning, and overwhelming rely on guided and structured activities for learning and revision which will need to be balanced with opportunities to develop critical thinking and independent learning skills when studying in a professional course, given students are not likely to default into such behavior. This work models a process many curriculum designers have, and continue to undergo in higher education as online, hybrid, and blended approaches to teaching have received renewed interest.

PMID:37229550 | DOI:10.3138/jvme-2023-0011

J Vet Med Educ. 2023 May 25:e20220128. doi: 10.3138/jvme-2022-0128. Online ahead of print.

ABSTRACT

Carol Dweck’s mindset theory describes whether an individual believes that attributes, like intelligence or morality, can be honed (growth mindset) or are innate (fixed mindset). An educator’s mindset impacts their approach to teaching, students’ learning, participation in faculty development, and wellbeing. Mindset can affect faculty members’ openness to curricular change, making the study of veterinary educator mindset timely and salient, as competency-based education is spurring curricular change worldwide. The purpose of this study was to examine the mindsets of veterinary educators internationally. A survey, consisting of demographic questions and mindset items (based on previously published scales), was distributed electronically to veterinary educators internationally, at universities where English is the primary instruction medium. Mindset was evaluated for the following traits: intelligence, clinical reasoning, compassion, and morality. Scale validation, descriptive statistics, and associations to demographic variables were evaluated. Four hundred and forty-six complete surveys were received. Overall, the study population demonstrated predominantly growth mindsets for all traits, higher than population averages, with some variation by trait. There was a small effect on years teaching towards growth mindset. No other associations were found. Veterinary educators internationally who participated in this study demonstrated higher rates of growth mindset than the general population. In other fields, a growth mindset in educators has had implications for faculty wellbeing, teaching and assessment practices, participation in faculty development, and openness to curricular change. Further research is needed in veterinary education to evaluate the implications of these high rates of growth mindset.

PMID:37229549 | DOI:10.3138/jvme-2022-0128

Syst Biol. 2023 May 25:syad012. doi: 10.1093/sysbio/syad012. Online ahead of print.

ABSTRACT

Models based on the Ornstein-Uhlenbeck process have become standard for the comparative study of adaptation. Cooper et al. (2016) have cast doubt on this practice by claiming statistical problems with fitting Ornstein-Uhlenbeck models to comparative data. Specifically, they claim that statistical tests of Brownian motion may have too high Type I error rates and that such error rates are exacerbated by measurement error. In this note, we argue that these results have little relevance to the estimation of adaptation with Ornstein-Uhlenbeck models for three reasons. First, we point out that Cooper et al. (2016) did not consider the detection of distinct optima (e.g. for different environments), and therefore did not evaluate the standard test for adaptation. Second, we show that consideration of parameter estimates, and not just statistical significance, will usually lead to correct inferences about evolutionary dynamics. Third, we show that bias due to measurement error can be corrected for by standard methods. We conclude that Cooper et al. (2016) have not identified any statistical problems specific to Ornstein-Uhlenbeck models, and that their cautions against their use in comparative analyses are unfounded and misleading. [adaptation, Ornstein-Uhlenbeck model, phylogenetic comparative method.].

PMID:37229537 | DOI:10.1093/sysbio/syad012

Anal Chem. 2023 May 25. doi: 10.1021/acs.analchem.3c00918. Online ahead of print.

ABSTRACT

We report methods that improve the quantification of digital bead assays (DBA)─such as the digital enzyme-linked immunosorbent assay (ELISA)─that have found widespread use for high sensitivity measurement of proteins in clinical research and diagnostics. In digital ELISA, proteins are captured on beads, labeled with enzymes, individual beads are interrogated for activity from one or more enzymes, and the average number of enzymes per bead (AEB) is determined based on Poisson statistics. The widespread use of digital ELISA has revealed limitations to the original approaches to quantification that can lead to inaccurate AEB. Here, we have addressed the inaccuracy in AEB due to deviations from Poisson distribution in a digital ELISA for Aβ-40 by changing the AEB calculation from a fixed threshold between digital counting and average normalized intensity to a smooth, continuous combination of digital counting and intensity. We addressed issues with determining the average product fluorescence intensity from single enzymes on beads by allowing outlier, high intensity arrays to be removed from average intensities, and by permitting the use of a wider range of arrays. These approaches improved the accuracy of a digital ELISA for tau protein that was affected by aggregated detection antibodies. We increased the dynamic range of a digital ELISA for IL-17A from AEB ∼25 to ∼130 by combining long and short exposure images at the product emission wavelength to create virtual images. The methods reported will significantly improve the accuracy and robustness of DBA based on imaging─such as single molecule arrays (Simoa)─and flow detection.

PMID:37229528 | DOI:10.1021/acs.analchem.3c00918

Health Educ Res. 2023 May 25:cyad021. doi: 10.1093/her/cyad021. Online ahead of print.

ABSTRACT

Innovative approaches addressing the elevated human immunodeficiency virus (HIV) risk among men who have sex with men (MSM) or transgender women (TGW) migrants in South Africa are urgently needed. We sought to present the acceptability, feasibility and preliminary efficacy of ‘Externalize and Mobilize!’, a multi-session arts- and theatre-based HIV prevention group intervention for MSM and TGW migrants in South Africa. Fourteen participants-MSM (n = 7; 50%), genderqueer/nonbinary persons (n = 4; 29%) and TGW (n = 3; 21%)-in Cape Town were recruited and enrolled in the intervention and administered pre- and post-intervention assessments of HIV knowledge, HIV risk-reduction self-efficacy, stigma and resilience. The intervention, delivered over 4 days, was completed by all 14 participants. Scores on HIV knowledge and HIV risk-reduction self-efficacy were statistically significantly higher at post-intervention compared with pre-intervention. Additionally, participants responded affirmatively (i.e. ‘Agree’ or ‘Strongly agree’) on all items assessing intervention acceptability. Findings demonstrate the high acceptability, feasibility and preliminary efficacy of an arts- and theatre-based intervention for increasing HIV knowledge and HIV risk-reduction self-efficacy among MSM and TGW migrants in South Africa. This study provides further support for the use of creative and innovative interventions to address entrenched HIV disparities in South Africa.

PMID:37229526 | DOI:10.1093/her/cyad021

J Am Assoc Nurse Pract. 2023 May 25. doi: 10.1097/JXX.0000000000000885. Online ahead of print.

ABSTRACT

BACKGROUND: The increased lifespan of individuals having sickle cell disease (SCD) causes an overall increase in hospitalizations and more instances in which pain may not be well controlled.

LOCAL PROBLEM: The mainstay treatment for severe pain is opioids and the underlying cause. Laws affecting opioid prescribing, implicit bias, racial inequity, poor research funding, and lack of knowledge contribute to poor patient outcomes.

METHOD: Data were collected retrospectively using electronic medical record data from before and after the intervention.

INTERVENTION: The individualized pain management plan (IPMP) was initiated in collaboration with the patient, pain nurse practitioner (NP), and hematologist.

RESULT: The mean length of stay for the traditional pain management plan (TPMP) was 7.89 days compared with 5.66 days for the IPMP, with a mean difference of 2.23 days, t = 2.278, p = .024 (p < .05). There was a decrease in the admission of the individuals with the IPMP, with 25% readmitted within 30 days of discharge, versus 59.0% who were readmitted using the TPMP. Chi-square showed statistical significance (χ2 = 61.667, p = .000) in using nonpharmacological interventions with the IPMP group.

CONCLUSION: The IPMP with a patient-centered approach did improve patient outcomes for African American adults living with SCD.

PMID:37229519 | DOI:10.1097/JXX.0000000000000885