Precision public health is a relatively new field that integrates components of precision medicine, such as human genomics research, with public health concepts to help improve population health. Despite interest in advancing precision public health initiatives using human genomics research, current and future opportunities in this emerging field remain largely undescribed. To that end, we provide examples of promising opportunities and current applications of genomics research within precision public health and outline future directions within five major domains of public health: biostatistics, environmental health, epidemiology, health policy and health services, and social and behavioral science. To further extend applications of genomics within precision public health research, three key cross-cutting challenges will need to be addressed: developing policies that implement precision public health initiatives at multiple levels, improving data integration and developing more rigorous methodologies, and incorporating initiatives that address health equity. Realizing the potential to better integrate human genomics within precision public health will require transdisciplinary efforts that leverage the strengths of both precision medicine and public health.
Lynch syndrome is the most common inherited cancer syndrome that increases the risk of developing colorectal and endometrial cancer. Universal screening guidelines were first recommended by the Centers for Disease Control and Prevention (CDC) in 2009 and are updated annually by multiple societies. Therefore, one would expect genetic testing rates to increase over time. But testing remains underutilized among those with colorectal or endometrial cancer, even though early detection can improve prognosis and survival rates. In this study, we aimed to understand differences in genetic testing uptake among those with colorectal cancer or endometrial cancer from 2005, 2010, 2015, using data from the National Health Interview Survey (NHIS). We examined genetic testing uptake across cancer-type, age (≤50 or ≥51), sex, race, insurance, and education using a χ2 statistical analysis. Despite an upward genetic testing trend in 2010, we found no significant differences in genetic testing uptake over time. In 2010, non-White individuals experienced the highest increase from 2005 in comparison with White individuals. However, genetic testing rates declined for both groups by 2015. Our findings show that genetic testing for colorectal cancer and endometrial cancer did not increase over a 10-year period in spite of guidelines that recommend testing.
PURPOSE. To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. METHODS. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. RESULTS. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal tmax. Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed. CONCLUSIONS. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.
Coadministration of κ-opioid receptor agonists (κ-agonists) with cocaine prevents alterations in dialysate dopamine (DA) concentration in the nucleus accumbens (Acb) that occur during abstinence from repeated cocaine treatment. Quantitative microdialysis was used to determine the mechanism producing these effects. Rats were injected with cocaine (20 mg/kg, i.p.), or saline, and the selective κ-agonist U-69593 (0.32 mg/kg, s.c.), or vehicle, once daily for 5 d. Extracellular DA concentration (DAext) and extraction fraction (Ed), an indirect measure of DA uptake, were determined 3 d later. Repeated cocaine treatment increased Ed, whereas repeated U-69593 treatment decreased Ed, relative to controls. Coadministration of both drugs yielded intermediate Ed values not different from controls. In vitro DA uptake assays confirmed that repeated U-69593 treatment produces a doserelated, region-specific decrease in DA uptake and showed that acute U-69593 administration increases DA uptake in a norbinaltorphimine reversible manner. Repeated U-69593 also led to a decrease in [125I]RTI-55 binding to the DA transporter (DAT), but did not decrease total DAT protein. These results demonstrate that κ-opioid receptor activation modulates DA uptake in the Acb in a manner opposite to that of cocaine: Repeated U-69593 administration decreases the basal rate of DA uptake, and acute U-69593 administration transiently increases DA uptake. κ-agonist treatment also alters DAT function. The action of κ-agonists on DA uptake or DAT binding, or both, may be the mechanism(s) mediating the previously reported "cocaine-antagonist" effect of κ-opioid receptor agonists.
Diabetes mellitus is a major public health issue that considerably impacts mortality, morbidity, and healthcare costs worldwide. The COVID-19 pandemic has created havoc in diabetes management, too, like other spectrums of life. A descriptive, cross-sectional study was adopted to determine the effect of Social Support, Self-Care Behaviour and Self-Efficacy in Type 2 Diabetes Mellitus (T2D) during this COVID-19 pandemic. Two hundred T2D patients who satisfied the inclusion criteria were chosen using a convenient sampling procedure. The tool consists of four sections, including socio-demographic characteristics, Multidimensional Scale of Perceived Social Support (MSPSS), revised Summary of Diabetes Self-Care Activities (SDSCA) Scale and modified Diabetes Management Self-Efficacy Scale (DMS). Descriptive and inferential statistics were used to analyze the obtained data. The mean and SD of diabetic management self-efficacy is 5.74 (1.95) and 4.37 (1.4), respectively, for patients with HbA1c < 6.5% and HbA1c ≥ 6.5%. The self-care activities of the patients who had good glycemic control were 4.31 (2.06) compared to 3.50 (1.73) who did not. The social support received by the patients was 6.13 (2.13) vs. 5.31 (1.67) among patients with glycemic control vs. no control. The results show that social support (p = 0.04), self-efficacy (p =0.01) and self-care activities (p = 0.001) were significantly related to the level of glycemic control of the T2D patients. A significant relationship was also identified between gender (p = 0.036), age (p = 0.001) and education status (p = 0.000) with HbA1c control of the participants. This study demonstrates a significant relationship between social support, self-care behaviours, self-efficacy and glycemic management in T2D patients. During this COVID-19 pandemic, interventions to enhance the self-care activities like exercise and social support to boost their self-efficacy; for better diabetes management, reducing diabetes complications or prolonging their onset are the need of the hour.
Anoctamin 1 (ANO1)/TMEM16A is a Cl<sup>−</sup> channel activated by intracellular Ca<sup>2+</sup> mediating numerous physiological functions. However, little is known of the ANO1 activation mechanism by Ca<sup>2+</sup>. Here, we demonstrate that two helices, “reference” and “Ca<sup>2+</sup> sensor” helices in the third intracellular loop face each other with opposite charges. The two helices interact directly in a Ca<sup>2+</sup>-dependent manner. Positively and negatively charged residues in the two helices are essential for Ca<sup>2+</sup>-dependent activation because neutralization of these charges change the Ca<sup>2+</sup> sensitivity. We now predict that the Ca<sup>2+</sup> sensor helix attaches to the reference helix in the resting state, and as intracellular Ca<sup>2+</sup> rises, Ca<sup>2+</sup> acts on the sensor helix, which repels it from the reference helix. This Ca<sup>2+</sup>-dependent push-pull conformational change would be a key electromechanical movement for gating the ANO1 channel. Because chemical activation of ANO1 is viewed as an alternative means of rescuing cystic fibrosis, understanding its gating mechanism would be useful in developing novel treatments for cystic fibrosis.
We provide causal evidence that regulation induced product shocks significantly impact aggregate demand and firm performance in pharmaceutical markets. Event study results suggest an average loss between $569 million and $882 million. Affected products lose, on average, $186 million over their remaining effective patent life. This leaves a loss of between $383 million and $696 million attributable to declines in future innovation. Our findings complement research that shows drugs receiving expedited review are more likely to suffer from regulation induced product shocks. Thus, it appears we may be trading off quicker access to drugs today for less innovation tomorrow. Results remain robust to variation across types of relabeling, market sizes, and levels of competition.
by
Michael S Blaiss;
Jonathan A Bernstein;
Adam Kessler;
Jesse M Pines;
Carlos A Camargo Jr;
Paula Fulgham;
Ryan Haumschild;
Kristin Rupp;
Timothy Tyler;
Joseph Moellman
Since 1955, the only available H1 antihistamines for intravenous administration have been first-generation formulations and, of those, only intravenously administered (IV) diphenhydramine is still approved in the USA. Orally administered cetirizine hydrochloride, a second-generation H1 antihistamine, has been safely used over-the-counter for many years. In 2019, IV cetirizine was approved for the treatment of acute urticaria. In light of this approval, this narrative review discusses the changing landscape of IV antihistamines for the treatment of histamine-mediated conditions. Specifically, IV antihistamines will be discussed as a treatment option for acute urticaria and angioedema, as premedication to prevent infusion reactions related to anticancer agents and other biologics, and as an adjunct treatment for anaphylaxis and other allergic reactions. Before the development of IV cetirizine, randomized controlled trials of IV antihistamines for these indications were lacking. Three randomized controlled trials have been conducted with IV cetirizine versus IV diphenhydramine in the ambulatory care setting. A phase 3 trial of IV cetirizine 10 mg versus IV diphenhydramine 50 mg was conducted in 262 adults who presented to the urgent care/emergency department with acute urticaria requiring antihistamines. For the primary efficacy endpoint, defined as change from baseline in a 2-h patient-rated pruritus score, non-inferiority of IV cetirizine to IV diphenhydramine was demonstrated (score − 1.6 vs − 1.5, respectively; 95% CI − 0.1, 0.3). Compared with IV diphenhydramine, IV cetirizine demonstrated fewer adverse effects including less sedation, a significantly shorter length of stay in the treatment center, and fewer returns to the treatment center at 24 and 48 h. Similar findings were demonstrated in another phase 2 acute urticaria trial and in a phase 2 trial assessing IV cetirizine for pretreatment for infusion reactions in the oncology/immunology setting. IV cetirizine is associated with similar patient outcomes, fewer adverse effects, and increased treatment center efficiency than IV diphenhydramine.
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Raquel Carvalho Montenegro;
Alison Howarth;
Alessandro Ceroni;
Vita Fedele;
Batoul Farran;
Felipe Pantoja Mesquita;
Martin Frejno;
Benedict-Tilman Berger;
Stephanie Heinzlmeir;
Heba Z Sailem;
Roberta Tesch;
Daniel Ebner;
Stefan Knapp;
Rommel Burbano;
Bernhard Kuster;
Susanne Müller
Gastric cancer (GC) remains the third leading cause of cancer-related death despite several improvements in targeted therapy. There is therefore an urgent need to investigate new treatment strategies, including the identification of novel biomarkers for patient stratification. In this study, we evaluated the effect of FDA-approved kinase inhibitors on GC. Through a combination of cell growth, migration and invasion assays, we identified dasatinib as an efficient inhibitor of GC proliferation. Mass-spectrometry-based selectivity profiling and subsequent knockdown experiments identified members of the SRC family of kinases including SRC, FRK, LYN and YES, as well as other kinases such as DDR1, ABL2, SIK2, RIPK2, EPHA2, and EPHB2 as dasatinib targets. The expression levels of the identified kinases were investigated on RNA and protein level in 200 classified tumor samples from patients, who had undergone gastrectomy, but had received no treatment. Levels of FRK, DDR1 and SRC expression on both mRNA and protein level were significantly higher in metastatic patient samples regardless of the tumor stage, while expression levels of SIK2 correlated with tumor size. Collectively, our data suggest dasatinib for treatment of GC based on its unique property, inhibiting a small number of key kinases (SRC, FRK, DDR1 and SIK2), highly expressed in GC patients. Copyright: Montenegro et al.
Introduction: In 1988, an estimated 350,000 children were paralyzed by polio and 125 countries reported polio cases, the World Health Assembly passed a resolution to achieve polio eradication by 2000, and the Global Polio Eradication Initiative (GPEI) was established as a partnership focused on eradication. Today, following eradication efforts, polio cases have decreased >99% and eradication of all three types of wild polioviruses is approaching. However, since polio resources substantially support disease surveillance and other health programs, losing polio assets could reverse progress toward achieving Global Vaccine Action Plan goals. Areas covered: As the end of polio approaches and GPEI funds and capacity decrease, we document knowledge, experience, and lessons learned from 30 years of polio eradication. Expert commentary: Transitioning polio assets to measles and rubella (MR) elimination efforts would accelerate progress toward global vaccination coverage and equity. MR elimination feasibility and benefits have long been established. Focusing efforts on MR elimination after achieving polio eradication would make a permanent impact on reducing child mortality but should be done through a ‘diagonal approach’ of using measles disease transmission to identify areas possibly susceptible to other vaccine-preventable diseases and to strengthen the overall immunization and health systems to achieve disease-specific goals.