PK-DB: pharmacokinetics database for individualized and stratified computational modeling.

A multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://pk-db.com), an open database for pharmacokinetics information from clinical trials. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status, genetic variants); (ii) applied interventions (e.g. dosing, substance, route of application); (iii) pharmacokinetic parameters (e.g. clearance, half-life, area under the curve) and (iv) measured pharmacokinetic time-courses. Key features are the representation of experimental errors, the normalization of measurement units, annotation of information to biological ontologies, calculation of pharmacokinetic parameters from concentration-time profiles, a workflow for collaborative data curation, strong validation rules on the data, computational access via a REST API as well as human access via a web interface. PK-DB enables meta-analysis based on data from multiple studies and data integration with computational models. A special focus lies on meta-data relevant for individualized and stratified computational modeling with methods like physiologically based pharmacokinetic (PBPK), pharmacokinetic/pharmacodynamic (PK/PD), or population pharmacokinetic (pop PK) modeling.

The Application of Point of Care Ultrasound to Screen for Pulmonary Hypertension: A Narrative Review.

BACKGROUND: Pulmonary Hypertension (PH) is a condition with several cardiopulmonary etiologies that has the potential of progressing to right heart failure without proper intervention. After a history, physical exam, and investigations, cases of suspected PH typically undergo imaging via a transthoracic echocardiogram (TTE). This is a resource-intensive procedure that is less accessible in remote communities. However, point of care ultrasound (POCUS), a portable ultrasound administered at the bedside, has potential to aid in the diagnostic process of PH. METHODS: The MEDLINE, Embase, and CENTRAL databases were searched to screen the intersection of POCUS and PH. Studies involved adult patients, and only English articles were accepted. Reviews, case reports, unfinished research, and conference abstracts were excluded. Our aim was to identify primary studies that correlated POCUS scan results and additional clinical findings related to PH. RESULTS: Nine studies were included after our search. In these studies, POCUS was effective in identifying dilatation of inferior vena cava (IVC); internal jugular vein (IJV); and hepatic, portal, and intrarenal veins in patients with PH. The presence of pericardial effusion, pleural effusion, or b-lines on POCUS are also associated with PH. CONCLUSIONS: This review suggests important potential for the use of POCUS in the initial screening of PH. IVC and basic cardiopulmonary POCUS exams are key for PH screening in patients with dyspnea. Right-heart dilatation can be visualized, and peripheral veins may be scanned based on clinical suspicion. POCUS offers screening as an extension of a physical exam, with direct visualization of cardiac morphology. However, more studies are required to develop a statistically validated POCUS exam for PH diagnosis. More studies should also be conducted at the primary-care level to evaluate the value of screening using POCUS for PH in less-differentiated patients.

Prophylactic Anticoagulation to Prevent Left Ventricular Thrombus Following Acute Myocardial Infarction: A Systematic Review and Meta-Analysis.

Clinical practice guidelines from the American Heart Association recommend consideration of prophylactic anticoagulation to prevent left ventricular thrombus (LVT) formation in patients with anterior ST-elevation myocardial infarction. These guidelines were given a low certainty of evidence (class IIb, level C), relying primarily on case studies and expert consensus to inform practice. Our objective was to compare the safety and efficacy of prophylactic anticoagulation, in addition to dual antiplatelet therapy, in the current era of timely primary percutaneous coronary intervention. Electronic databases, including EMBASE, MEDLINE, and Cochrane Library, were systematically searched from January 2012 through June 2022. A total of 7,378 publications were screened, and 5 publications were eventually included in this review: 1 randomized control trial and 4 retrospective studies involving 1,461 patients. Data were pooled using a fixed-effects model and reported as odds ratios (ORs) with 95% confidence intervals (CIs). The primary outcome of interest was the rate of LVT formation, and the secondary outcomes were the rate of major bleeding and systemic embolism. Pooled analysis showed a significantly lower rate of LVT formation (OR 0.28, 95% CI 0.11 to 0.73, p <0.01) and significantly higher rates of bleeding (OR 2.85, 95% CI 1.13 to 7.24, p = 0.03) in the triple therapy group compared with dual antiplatelet therapy. No significant difference was observed in the rate of systemic embolism between the groups (OR 0.37, 95% CI 0.12 to 1.13, p = 0.08). In this meta-analysis, there is no conclusive evidence to either support or oppose the use of triple therapy for LVT prevention in patients with anterior ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Appropriately powered randomized controlled trials are warranted to further evaluate the benefits of LVT prevention against the risks of major bleeding in this population.

Lessons Learned from POCUS Instruction in Undergraduate Medicine During the COVID-19 Pandemic.

Point of care Ultrasound (POCUS) has been adopted into clinical practice across many fields of medicine. Undergraduate medical education programs have recognized the need to incorporate POCUS training into their curricula, traditionally done in small groups with in-person sessions. This method is resource intensive and requires sufficient equipment and expertise. These requirements are often cited as barriers for implementation. During the Coronavirus Disease 2019 (COVID-19) pandemic, POCUS education was required to adapt to physical distancing regulations, giving rise to novel teaching methods for POCUS. This article outlines the implementation of a POCUS teaching session before and during the pandemic. It describes how these innovations can scale POCUS teaching and overcome barriers moving forward. A flipped classroom model was implemented for all learners. Learners were given an introductory POCUS module before the scheduled in-person or virtual teaching session. Sixty-nine learners participated in conventional in-person teaching, while twenty-two learners participated in virtual teaching following the pandemic-related restrictions. Learners completed a written test before and following the teaching. In-person learners were assessed using an objective structured assessment of ultrasound skills (OSAUS) pre- and post-learning sessions. A follow-up survey was conducted three years after the teaching sessions were completed. Both in-person and virtual groups demonstrated statistically significant improvement in knowledge scores (p <0.0001). Both groups had similar post-test learning scores (74.2 ± 13.6% vs. 71.8 ± 14.5 %, respectively). On follow-up questionnaires, respondents indicate that they found our online and in-person modes of teaching helpful during their residency. POCUS education continues to face a variety of barriers, including limitations in infrastructure and expertise. This study describes an adapted POCUS teaching model that is scalable, uses minimal infrastructure and retains the interactivity of conventional small-group POCUS teaching. This program can serve as a blueprint for other institutions offering POCUS teaching, especially when conventional teaching methods are limited.

The Potential of Natural Products in the Treatment of Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks receptors for targeted therapy. Consequently, chemotherapy is currently the mainstay of systemic treatment options. However, the enrichment of cancer stem cells (CSC, a subpopulation with stem-cell characteristics and tumor-initiating propensity) promotes chemo-resistance and tumorigenesis, resulting in cancer recurrence and relapse. Furthermore, toxic side effects of chemotherapeutics reduce patient wellbeing. Natural products specifically compounds derived from plants, have the potential to treat TNBC and target CSCs by inhibiting CSC signaling pathways. Literature evidence from six promising compounds was reviewed, including sulforaphane, curcumin, genistein, resveratrol, lycopene, and epigallocatechin-3-gallate. These compounds have been shown to promote cell cycle arrest and apoptosis in TNBC cells. They also could inhibit the epithelial-mesenchymal transition (EMT) that plays an important role in metastasis. In addition, those natural compounds have been found to inhibit pathways important for CSCs, such as NF-κB, PI3K/Akt/mTOR, Notch 1, Wnt/ß- catenin, and YAP. Clinical trials conducted on these compounds have shown varying degrees of effectiveness. Epidemiological case-control studies for the compounds commonly consumed in certain human populations have also been summarized. While in vivo and in vitro data are promising, further basic and clinical investigations are required. Likely, natural products in combination with other drugs may hold great potential to improve TNBC treatment efficacy and patient outcomes.