Nevin Manimala

Chem Biol Drug Des. 2021 Mar 3. doi: 10.1111/cbdd.13838. Online ahead of print.

ABSTRACT

Phosphatidylinositol-3-kinase (PI3K) is important for cell proliferation, differentiation, and apoptosis, and the diverse physiological roles of different PI3K isoforms have highlighted the significance of the development of PI3Kδ inhibitors. A large number of PI3Kδ inhibitors have been reported after the FDA approval of Idelalisib, but the clinical use of Idelalisib was limited because of its serious side effects. Therefore, great efforts have been made on the development of PI3Kδ inhibitors with higher selectivity and lower toxicity, but there is no new PI3Kδ inhibitor coming into the market so far. Even so, as the first listed PI3K inhibitor, Idelalisib could be used as an effective tool to investigate the selective inhibition mechanism of PI3Kδ. Thus, in this study, a modeling strategy integrated 3D-QSAR, pharmacophore model and molecular dynamics simulation was employed to reveal the key chemical characteristics of Idelalisib analogs and the binding pattern between the inhibitors and PI3Kδ. First, the CoMFA model with high statistical significance was built to reveal the general structure activity relationships. And then, a reliable pharmacophore model with a robust discrimination capability was constructed to expound the main chemical characteristics of the PI3Kδ inhibitors. Finally, molecular dynamics simulation was conducted to explore the binding modes and some key residues refer to δ-selective binding were highlighted with binding free energy calculation. In summary, these models and results would provide some effective help for the discovery or the rational design of novel PI3Kδ inhibitors.

PMID:33657663 | DOI:10.1111/cbdd.13838

Br J Dermatol. 2021 Mar 3. doi: 10.1111/bjd.19895. Online ahead of print.

ABSTRACT

BACKGROUND: A nomogram to predict SN-positivity (the Melanoma Institute Australia (MIA) nomogram) was recently developed and externally validated using two large single-institution databases. However, there remains a need to further validate the nomogram’s performance using population-based data.

OBJECTIVES: This study sought to address this using a European national patient cohort.

METHODS: Cutaneous melanoma patients who underwent SN biopsy in the Netherlands between 2000 and 2014 were included. Their data were obtained from the Dutch Pathology Registry (PALGA). The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. Negative predictive values (NPV) were calculated at various predicted probability cut-offs.

RESULTS: Of the 3049 patients who met the eligibility criteria, 23% (691) were SN-positive. Validation of the MIA nomogram (included parameters: Breslow thickness, ulceration, age, melanoma subtype and lymphovascular invasion) showed a good C-statistic of 0.69 (95% CI 0.66-0.71) with excellent calibration (R² 0.985, p=0.399). The NPV of 90.1%, found at a 10% predicted probability cut-off from having a positive SN biopsy, implied that by using the nomogram, a 16.3% reduction in the rate of performing a SN biopsy could be achieved with an error rate of 1.6%. Validation of the MIA nomogram considering mitotic rate as present/absent showed a C-statistic of 0.70 (95% CI 0.68-0.73).

CONCLUSIONS: This population-based validation study in European melanoma patients confirmed the value of the MIA nomogram in predicting SN-positivity. Its use will spare low-risk patients the inconvenience, cost and potential risks of SN biopsy while ensuring that high-risk patients are still identified.

PMID:33657653 | DOI:10.1111/bjd.19895

Int Endod J. 2021 Mar 3. doi: 10.1111/iej.13505. Online ahead of print.

ABSTRACT

AIM: To investigate the effects of a bioactive glass with a high proportion of phosphorus (BG-hP) on the repair and regeneration of dental pulps in rats under an inflammatory microenvironment.

METHODOLOGY: Human dental pulp cells (hDPCs) stimulated with 1 μg/mL lipopolysaccharide (LPS) were cocultured with 0.1 mg/mL BG-hP. Cell proliferation was detected by MTT assays. The expression of inflammation-related genes and odontogenic differentiation-related genes was determined by real-time PCR. Alizarin red staining was used to detect the formation of mineralized nodules. Coronal pulp tissues of rat molars were stimulated with 10 mg/mL LPS and then treated with BG-hP. The expression of inflammation-related genes in pulp tissue was determined by real-time PCR. Haematoxylin-eosin staining and Masson staining were performed to observe the inflammatory response and mineralized matrix formation, after subcutaneous implantation in nude mice, at 3 days and 4 weeks, respectively. Analysis of variance was performed to measure statistical significance (P < 0.05).

RESULTS: BG-hP significantly reduced expression of interleukin-6 (IL-6) and IL-8 and significantly upregulated the expression of IL-10, IL-4 and transforming growth factor-β1 of the LPS-stimulated hDPCs (P < 0.05). BG-hP significantly inhibited the initial cell number (P < 0.05), but the hDPCs stimulated by LPS and cocultured with BG-hP maintained the same proliferation rate as the untreated hDPCs. BG-hP significantly promoted the expression of dentine matrix protein-1 and dentine sialophosphoprotein and the mineralization capacity of the LPS-stimulated hDPCs (P < 0.05). Furthermore, BG-hP significantly downregulated the expression of Il-6 and reduced the inflammatory response of the LPS-stimulated pulp tissue 3 days after subcutaneous implantation (P < 0.05). Four weeks after subcutaneous implantation, BG-hP induced the formation of a continuous layer of dentine-like structure with dentinal tubules and polarizing odontoblast-like cells aligned along it in the LPS-stimulated pulp tissue.

CONCLUSION: The present preliminarily results demonstrated that the bioactive glass with a high proportion of phosphorus inhibited the inflammatory response and promoted the formation of a pulp-dentine complex in a rat experimental model. This study provides a foundation for the construction of materials with the dual functions of exerting anti-inflammatory effects and promoting tissue regeneration to meet the needs of dental pulp repair and regeneration.

PMID:33657647 | DOI:10.1111/iej.13505

Appl Clin Inform. 2021 Jan;12(1):141-152. doi: 10.1055/s-0040-1722615. Epub 2021 Mar 3.

ABSTRACT

OBJECTIVES: We characterize physician workflow in two distinctive emergency departments (ED). Physician practices mediated by electronic health records (EHR) are explored within the context of organizational complexity for the delivery of care.

METHODS: Two urban clinical sites, including an academic teaching ED, were selected. Fourteen physicians were recruited. Overall, 62 hours of direct clinical observations were conducted characterizing clinical activities (EHR use, team communication, and patient care). Data were analyzed using qualitative open-coding techniques and descriptive statistics. Timeline belts were used to represent temporal events.

RESULTS: At site 1, physicians, engaged in more team communication, followed by direct patient care. Although physicians spent 61% of their clinical time at workstations, only 25% was spent on the EHR, primarily for clinical documentation and review. Site 2 physicians engaged primarily in direct patient care spending 52% of their time at a workstation, and 31% dedicated to EHRs, focused on chart review. At site 1, physicians showed nonlinear complex workflow patterns with a greater frequency of multitasking and interruptions, resulting in workflow fragmentation. In comparison, at site 2, a less complex environment with a unique patient assignment system, resulting in a more linear workflow pattern.

CONCLUSION: The nature of the clinical practice and EHR-mediated workflow reflects the ED work practices. Physicians in more complex organizations may be less efficient because of the fragmented workflow. However, these effects can be mitigated by effort distribution through team communication, which affords inherent safety checks.

PMID:33657633 | DOI:10.1055/s-0040-1722615

Thromb Haemost. 2021 Mar 3. doi: 10.1055/s-0041-1723991. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Dural arteriovenous fistulae (DAVFs) can develop secondary to cerebral venous thrombosis (CVT). The incidence of DAVF has not yet been investigated prospectively.

METHODS: Between July 2012 and January 2018, combined static and dynamic 4D MR venography (4D-combo-MRV) was performed in 24 consecutive patients at diagnosis of CVT and after 6 months. 3 Tesla magnetic resonance imaging with time of flight and contrast-enhanced magnetization-prepared rapid acquisition with gradient echo were performed at baseline to evaluate the extent of thrombosis and affected vessel segments. Baseline and follow-up 4D-combo-MRV were assessed for signs of DAVF. Interrater reliability of DAVF detection and the extent of recanalization were analyzed with kappa statistics.

RESULTS: DAVFs were detected in 4/30 CVT patients (13.3%, 95% confidence interval [CI] 3.3-26.7). Two of 24 patients (8.3%, 95% CI: 0-20.8) had coincidental DAVF with CVT on admission. At follow-up, de novo formation of DAVF following CVT was seen in 2/24 patients (8.3%, 95% CI: 0-20.8). Both de novo DAVFs were low grade and benign fistulae (Cognard type 1, 2a), which had developed at previously thrombosed segments. Endovascular treatment was required in two high degree lesions (Cognard 2a + b) detected at baseline and in one de novo DAVF (Cognard 1) because of debilitating headache and tinnitus. Thrombus load, vessel recanalization, and frequency of cerebral lesions (hemorrhage, ischemia) were not associated with DAVF occurrence.

CONCLUSION: This exploratory study showed that de novo DAVF formation occurs more frequently than previously described. Although de novo DAVFs were benign, 75% of all detected DAVFs required endovascular treatment. Therefore, screening for DAVF by dynamic MRV, such as 4D-combo-MRV, seems worthwhile in CVT patients.

PMID:33657624 | DOI:10.1055/s-0041-1723991

Semin Thromb Hemost. 2021 Mar;47(2):129-138. doi: 10.1055/s-0041-1722861. Epub 2021 Feb 26.

ABSTRACT

Computational models of various facets of hemostasis and thrombosis have increased substantially in the last decade. These models have the potential to make predictions that can uncover new mechanisms within the complex dynamics of thrombus formation. However, these predictions are only as good as the data and assumptions they are built upon, and therefore model building requires intimate coupling with experiments. The objective of this article is to guide the reader through how a computational model is built and how it can inform and be refined by experiments. This is accomplished by answering six questions facing the model builder: (1) Why make a model? (2) What kind of model should be built? (3) How is the model built? (4) Is the model a “good” model? (5) Do we believe the model? (6) Is the model useful? These questions are answered in the context of a model of thrombus formation that has been successfully applied to understanding the interplay between blood flow, platelet deposition, and coagulation and in identifying potential modifiers of thrombin generation in hemophilia A.

PMID:33657623 | DOI:10.1055/s-0041-1722861

J Clin Rheumatol. 2021 Mar 5. doi: 10.1097/RHU.0000000000001726. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVE: The objective of this study was to identify patient and disease characteristics associated with the symptomatic severity of knee osteoarthritis (OA) at the time of initial knee OA diagnosis by an orthopedist.

METHODS: This medical records review included patients initially diagnosed with knee OA during 2016 to 2017 by a single orthopedic surgeon in a university-based tertiary care setting. All variables were assessed at first OA diagnosis. Main outcomes were subscales of the Knee Injury and Osteoarthritis Outcome Score-Pain, other Symptoms, knee-related quality of life, and function in daily living. Multivariable regression analyses examined the following predictors of main outcomes: sex, race, age, insurance type, body mass index, Charlson comorbidity index, and radiographic OA severity (Kellgren-Lawrence grade).

RESULTS: Of the 559 patients included in the study, most were African American (52.1%), female (71.7%), and had severe radiographic OA (Kellgren-Lawrence grade, 4; 68.7%). Female sex, African American racial/ethnic group, Medicaid insurance, younger age, and severe radiographic OA were independently statistically significantly associated with worse symptoms, pain, and function (p < 0.05 for all). Body mass index and Charlson comorbidity index were not statistically significant predictors of any outcome.

CONCLUSIONS: This study identified disparities in the perception of knee OA problems at initial orthopedist diagnosis based on sex, age, race, insurance, and radiographic OA severity. Because most of these variables are also associated with more rapid progression of OA, identifying their biopsychosocial underpinnings may help determine which interventions are most likely to redress these disparities and delay progression to end-stage knee OA.

PMID:33657591 | DOI:10.1097/RHU.0000000000001726

J Hypertens. 2021 Mar 1. doi: 10.1097/HJH.0000000000002833. Online ahead of print.

ABSTRACT

OBJECTIVE: Several online sources provide up-to-date open-access data on numbers, rates and proportions of COVID-19 deaths. Our article aims of comparing and interpreting between-country trends of mortality rate, case-fatality and all-cause excess mortality.

METHODS: We used data from open databases (Our World in Data mostly) for comparing mortality of eleven western countries (Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Spain, Sweden, UK, USA). Between-country trends in mortality rate and case-fatality (both including deaths for COVID-19 as numerator and therefore labelled as COVID-19 mortality metrics) and all-cause excess mortality (i.e. observed deaths during the epidemic compared with those expected based on mortality in the same periods of previous years) were compared.

RESULTS: Although Belgium ranks first in mortality from COVID-19 (possibly due to the broadest criterion for attributing a death to COVID-19), it does not rank first for all-cause excess mortality. Conversely, compared with Belgium, the UK, Italy and Spain have reported lower COVID-19 mortality (possibly due to the narrower definitions for a COVID-19 death) but higher all-cause excess mortality. Germany and Austria are the unique countries for which COVID-19 mortality, case-fatality and all-cause excess mortality consistently exhibited the lowest rates.

CONCLUSION: Between-country heterogeneity of COVID-19 mortality metrics could be largely explained by differences of criteria for attributing a death to COVID-19; in age/comorbidity structures; in policies for identifying asymptomatic people affected from SARS-CoV-2 infection. All-cause excess mortality is recommended as a more reliable metric for comparing countries.

PMID:33657587 | DOI:10.1097/HJH.0000000000002833

J Hypertens. 2021 Mar 1. doi: 10.1097/HJH.0000000000002835. Online ahead of print.

ABSTRACT

OBJECTIVE: Few studies investigated the role of different predictors of advanced liver fibrosis in unselected populations. Here, we estimate the prevalence of steatosis and fibrosis in the general United States population by means of transient elastography and evaluate the impact of blood pressure (BP) and diabetes on disease severity.

METHODS: This is a cross-sectional study of United States adults participating in the 2017-2018 cycle of the National Health and Nutrition Examination Survey. Participants underwent a transient elastography examination, and liver steatosis and fibrosis were estimated through the controlled attenuation parameter (CAP) score and liver stiffness measurement (LSM), respectively.

RESULTS: Four thousand, three hundred and seventy-one participants had reliable transient elastography and BP readings. Steatosis (CAP ≥ 248 dB/m), advanced fibrosis (LSM ≥ 9.6 kPa) and cirrhosis (LSM ≥ 13 kPa) were present in 56.9, 5.5 and 2.9% of participants, respectively. After controlling for potential confounders, risk of steatosis increased proportionally going from participants with optimal (reference) to those with normal [odds ratio (OR) 1.24, 95% confidence interval (CI) 0.83-1.86], high normal (OR 1.41, 95% CI 1.01-1.97) and elevated BP (OR 1.64, 95% CI 1.21-2.21), whereas no significant association was found between BP status and liver fibrosis. Conversely, presence of diabetes increased the risk of both steatosis (OR 2.15, 95% CI 1.49-3.11) and advanced fibrosis (OR 2.25, 95% CI 1.36-3.72).

CONCLUSION: Liver steatosis and fibrosis are highly prevalent in the multiethnic United States adult population, raising concerns for future incidence of cirrhosis and its complications. BP status was associated with a progressively higher risk of steatosis, whereas obesity and diabetes were consistently associated with both steatosis and fibrosis.

PMID:33657584 | DOI:10.1097/HJH.0000000000002835

Public Health Genomics. 2021 Mar 3:1-10. doi: 10.1159/000513723. Online ahead of print.

ABSTRACT

AIMS: The goal of this project was to better understand the motivating and discouraging factors toward genetic research and biobank programs in patients with bipolar disorder, particularly across gender and racial identities.

METHODS: A survey (n = 63) of adults diagnosed with bipolar disorder was conducted at the general psychiatric inpatient unit and outpatient clinic at the University of Mississippi Medical Center. Participants were asked to rate on a Likert scale their attitudes toward medical research generally, mental health research specifically, and willingness to participate in a bipolar DNA biobank. Last, they were asked to endorse motivating factors or concerns for their attitude toward participation.

RESULTS: Neither attitudes toward research nor willingness to participate in a bipolar biobank differed across gender, age, or education level, but Black/African American participants were statistically significantly less likely to endorse a willingness to participate in a biobank compared to White participants. As observed in previous work, Black/African American participants were significantly more likely to endorse concerns regarding violations of trust, privacy, or autonomy. However, while there were no significant differences in discouraging factors among individuals who indicated an opposition to participating in a biobank compared to those who indicated support, there was a significant decrease in support of motivating factors, including increasing knowledge, personal benefit, and duty to community, for those not interested in participating.

CONCLUSIONS: Black/African American participants with bipolar disorder were more likely to express concerns about DNA and biobank research. But while race was a contributing factor to support or opposition to biobanking for bipolar disorder research, more salient was insufficient positive motivation. These results highlight the need to emphasize contemporary safeguards on DNA research and biobanking as an ethical duty and to identify the need for community-based educational interventions to promote a greater understanding of the positive benefits to motivate increased research participation.

PMID:33657561 | DOI:10.1159/000513723