A Methodological Approach for Motor Selection in Dental Impression Material Dispensers Using Experimental and Image Analysis Techniques.

This study presents a methodology to prevent the overdesign of electric dispensers for dental impression materials by analyzing the necessary load and determining the appropriate pressurization speed and drive motor capacity. We derived an equation to calculate the required torque and rotational speed of the motor based on the extrusion load and the speed of the impression material. A specialized load measurement system was developed to measure the load necessary to extrude the impression material. Through experiments and image processing, we measured the radius of curvature of the trajectory of the impression material and correlated it with the pressurization speed. Techniques such as position coordinate plotting, curve fitting, and circle fitting were employed to determine the pressurization speed that aligns with the manufacturer's recommended curvature radius. These findings led to a substantial decrease in the necessary motor torque and rotational speed compared with the current standards. This research provides a systematic approach to sizing drive motors using extrusion load and pressurization speed, aiming to reduce overdesign, power consumption, and the weight and size of the motor and battery, thereby contributing to the development of more efficient and compact dental impression material dispensers.

Regioselective Hydroxylation of Unsymmetrical Ketones Using Cu, H2O2, and Imine Directing Groups via Formation of an Electrophilic Cupric Hydroperoxide Core.

Herein, we describe the regioselective functionalization of unsymmetrical ketones using imine directing groups, Cu, and H2O2. The C-H hydroxylation of the substrate-ligands derived from 2-substituted benzophenones occurred exclusively at the γ-position of the unsubstituted ring due to the formation of only one imine stereoisomer. Conversely, the imines derived from 4-substituted benzophenones produced E/Z mixtures that upon reacting with Cu and H2O2 led to two γ-C-H hydroxylation products. Contrary to our initial hypothesis, the ratio of the hydroxylation products did not depend on the ratio of the E/Z isomers but on the electrophilicity of the reactive [LCuOOH]1+. A detailed mechanistic analysis suggests a fast isomerization of the imine substrate-ligand binding the CuOOH core before the rate-determining electrophilic aromatic hydroxylation. Varying the benzophenone substituents and/or introducing electron-donating and electron-withdrawing groups on the 4-position of pyridine of the directing group allowed for fine-tuning of the electrophilicity of the mononuclear [LCuOOH]1+ to reach remarkable regioselectivities (up to 91:9 favoring the hydroxylation of the electron-rich arene ring). Lastly, we performed the C-H hydroxylation of alkyl aryl ketones, and like in the unsymmetrical benzophenones, the regioselectivity of the transformations (sp3 vs sp2) could be controlled by varying the electronics of the substrate and/or the directing group.

Breastfeeding and impact on childhood hospital admissions: a nationwide birth cohort in South Korea.

Benefits of breastfeeding for both the mother and the child are well established, but a comprehensive and robust study to investigate the protective effect of breastfeeding and attenuated time effect stratified by cause of morbidity are lacking. This study is based on the nationwide birth cohort in Korea that includes data on all infants born from 2009 to 2015. Of 1,608,540 children, the median follow-up period was 8.41 years (interquartile range, 6.76-10.06). When compared to children with fully formula feeding, the hospital admission rate was 12% lower in those with partially breastfeeding and 15% lower in those with exclusive breastfeeding. The apparent protective effect of breastfeeding was reduced with increasing age. Our study provides potential evidence of the beneficial association of breastfeeding on subsequent hospital admissions. The protective effect declined over time as the children grew older. Encouraging any breastfeeding for at least the first 6 months among infants is an important public health strategy to improve overall child health.

Hydrogel-Based Biosensors for Effective Therapeutics.

Nanotechnology and polymer engineering are navigating toward new developments to control and overcome complex problems. In the last few decades, polymer engineering has received researchers' attention and similarly, polymeric network-engineered structures have been vastly studied. Prior to therapeutic application, early and rapid detection analyses are critical. Therefore, developing hydrogel-based sensors to manage the acute expression of diseases and malignancies to devise therapeutic approaches demands advanced nanoengineering. However, nano-therapeutics have emerged as an alternative approach to tackling strenuous diseases. Similarly, sensing applications for multiple kinds of analytes in water-based environments and other media are gaining wide interest. It has also been observed that these functional roles can be used as alternative approaches to the detection of a wide range of biomolecules and pathogenic proteins. Moreover, hydrogels have emerged as a three-dimensional (3D) polymeric network that consists of hydrophilic natural or synthetic polymers with multidimensional dynamics. The resemblance of hydrogels to tissue structure makes them more unique to study inquisitively. Preceding studies have shown a vast spectrum of synthetic and natural polymer applications in the field of biotechnology and molecular diagnostics. This review explores recent studies on synthetic and natural polymers engineered hydrogel-based biosensors and their applications in multipurpose diagnostics and therapeutics. We review the latest studies on hydrogel-engineered biosensors, exclusively DNA-based and DNA hydrogel-fabricated biosensors.

Global, regional, and national burden of allergic disorders and their risk factors in 204 countries and territories, from 1990 to 2019: A systematic analysis for the Global Burden of Disease Study 2019.

BACKGROUND: Asthma and atopic dermatitis (AD) are chronic allergic conditions, along with allergic rhinitis and food allergy and cause high morbidity and mortality both in children and adults. This study aims to evaluate the global, regional, national, and temporal trends of the burden of asthma and AD from 1990 to 2019 and analyze their associations with geographic, demographic, social, and clinical factors. METHODS: Using data from the Global Burden of Diseases (GBD), Injuries, and Risk Factors Study 2019, we assessed the age-standardized prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of both asthma and AD from 1990 to 2019, stratified by geographic region, age, sex, and socio-demographic index (SDI). DALYs were calculated as the sum of years lived with disability and years of life lost to premature mortality. Additionally, the disease burden of asthma attributable to high body mass index, occupational asthmagens, and smoking was described. RESULTS: In 2019, there were a total of 262 million [95% uncertainty interval (UI): 224-309 million] cases of asthma and 171 million [95% UI: 165-178 million] total cases of AD globally; age-standardized prevalence rates were 3416 [95% UI: 2899-4066] and 2277 [95% UI: 2192-2369] per 100,000 population for asthma and AD, respectively, a 24.1% [95% UI: -27.2 to -20.8] decrease for asthma and a 4.3% [95% UI: 3.8-4.8] decrease for AD compared to baseline in 1990. Both asthma and AD had similar trends according to age, with age-specific prevalence rates peaking at age 5-9 years and rising again in adulthood. The prevalence and incidence of asthma and AD were both higher for individuals with higher SDI; however, mortality and DALYs rates of individuals with asthma had a reverse trend, with higher mortality and DALYs rates in those in the lower SDI quintiles. Of the three risk factors, high body mass index contributed to the highest DALYs and deaths due to asthma, accounting for a total of 3.65 million [95% UI: 2.14-5.60 million] asthma DALYs and 75,377 [95% UI: 40,615-122,841] asthma deaths. CONCLUSIONS: Asthma and AD continue to cause significant morbidity worldwide, having increased in total prevalence and incidence cases worldwide, but having decreased in age-standardized prevalence rates from 1990 to 2019. Although both are more frequent at younger ages and more prevalent in high-SDI countries, each condition has distinct temporal and regional characteristics. Understanding the temporospatial trends in the disease burden of asthma and AD could guide future policies and interventions to better manage these diseases worldwide and achieve equity in prevention, diagnosis, and treatment.

Chromenopyrazole-Peptide Conjugates as Small-Molecule Based Inhibitors Disrupting the Protein-RNA Interaction of LIN28-let-7.

Targeting the protein-RNA interaction of LIN28 and let-7 is a promising strategy for the development of novel anticancer therapeutics. However, a limited number of small-molecule inhibitors disrupting the LIN28-let-7 interaction with potent efficacy are available. Herein, we developed a novel LIN28-inhibiting strategy by targeting selective hotspot amino acids at the LIN28-let-7 binding interface with small-molecule-based bifunctional conjugates. Starting from reported small-molecule LIN28 inhibitors, we identified a feasible linker-attachment position after performing a structure-activity relationship exploration based on the LIN28-targeting chromenopyrazoles. In parallel, a virtual alanine scan identified hotspot residues at the protein-RNA binding interface, based on which we designed a set of peptides to enhance the interaction with the identified hotspot residues. Conjugation of the tailor-designed peptides with linker-attached chromenopyrazoles yielded a series of bifunctional small-molecule-peptide conjugates, represented by compound 83 (PH-223), as a new LIN28-targeting chemical modality. Our result demonstrated an unexplored rational design approach using bifunctional conjugates to target protein-RNA interactions.

Rational design and evaluation of 2-((pyrrol-2-yl)methylene)thiophen-4-ones as RNase L inhibitors.

Ribonuclease L (RNase L) plays a crucial role in an antiviral pathway of interferon-induced innate immunity by degrading RNAs to prevent viral replication. Modulating RNase L activity thus mediates the innate immune responses and inflammation. Although a few small molecule-based RNase L modulators have been reported, only limited molecules have been mechanistically investigated. This study explored the strategy of RNase L targeting by using a structure-based rational design approach and evaluated the RNase L-binding and inhibitory activities of the yielded 2-((pyrrol-2-yl)methylene)thiophen-4-ones, which exhibited improved inhibitory effect as determined by in vitro FRET and gel-based RNA cleavage assay. A further structural optimization study yielded selected thiophenones that showed >30-fold more potent inhibitory activity than that of sunitinib, the approved kinase inhibitor with reported RNase L inhibitory activity. The binding mode with RNase L for the resulting thiophenones was analyzed by using docking analysis. Furthermore, the obtained 2-((pyrrol-2-yl)methylene)thiophen-4-ones exhibited efficient inhibition of RNA degradation in cellular rRNA cleavage assay. The newly designed thiophenones are the most potent synthetic RNase L inhibitors reported to date and the results revealed in our study lay the foundation for the development of future RNase L-modulating small molecules with new scaffold and improved potency.

The impact of urinary incontinence on multiple health outcomes: an umbrella review of meta-analysis of observational studies.

BACKGROUND AND AIM: We aimed to capture the breadth of health outcomes that have been associated with the presence of Urinary Incontinence (UI) and systematically assess the quality, strength, and credibility of these associations through an umbrella review and integrated meta-analyses. METHODS: We assessed meta-analyses of observational studies based on random-effect summary effect sizes and their p-values, 95% prediction intervals, heterogeneity, small-study effects, and excess significance. We graded the evidence from convincing (Class I) to weak (Class IV). RESULTS AND DISCUSSION: From 3172 articles returned in search of the literature, 9 systematic reviews were included with a total of 41 outcomes. Overall, 37 out of the 41 outcomes reported nominally significant summary results (p < 0.05), with 22 associations surviving the application of a more stringent p-value (p < 10-6). UI was associated with worse scores than controls in female sexual function (Class II), while it was also associated with a higher prevalence of depression (odds ratio [OR] = 1.815; 95% confidence interval [CI]: 1.551-2.124), and anxiety (OR = 1.498; 95% CI: 1.273-1.762) (Class IV). UI was associated with poorer quality of life (QoL), higher rate of mortality (hazard ratio = 2.392; 95% CI: 2.053-2.787) an increase in falls, frailty, pressure ulcers, diabetes, arthritis, and fecal incontinence (Class IV). CONCLUSIONS: UI is associated with female sexual dysfunction, with highly suggestive evidence. However, the evidence of other adverse outcomes including depression, anxiety, poorer QoL, higher mortality, falls, pressure ulcers, diabetes, arthritis, fecal incontinence, and frailty is only weak. A multidimensional approach should be taken in managing UI in the clinical setting.

The association between socioeconomic status and use of potentially inappropriate medications in older adults.

BACKGROUND: Potentially inappropriate medication (PIM) use is an important public health problem, particularly among older adults who may need multiple pharmacologic therapies for various chronic conditions. As socioeconomic status (SES) affects the quality of healthcare that individuals receive, SES may be associated with the use of PIM in older adults. This study aimed to determine whether low SES is associated with increased use of PIM. METHODS: We studied 4927 participants (aged 66-90 years) who were on at least one medication at visit five (2011-2013) of the Atherosclerosis Risk in Communities Study. We created a cumulative SES score categorized as high (7-9), middle (3-6), and low (0-2) based on education, income, and area deprivation index. We use multivariable logistic regression to examine the associations between SES and use of two or more PIM for older adults, defined by the 2019 Beers Criteria. RESULTS: A total of 31.0% and 6.9% of the participants used one or more PIM and two or more PIM, respectively. After adjusting for demographic characteristics and insurance type, low cumulative SES score was associated with significantly greater use of two or more PIM (odds ratio [OR] = 1.83 [95% confidence interval (CI) 1.18-2.86]), as was middle cumulative SES score (OR = 1.40 [95% CI 1.06-1.83]), compared to high cumulative SES score. The results remained significant after further adjusting for comorbidities and medication burden for low cumulative SES score (OR = 1.66 [95%CI 1.02-2.71]). CONCLUSIONS: We found that lower SES was associated with greater use of PIM among older adults independent of their medication burden and comorbidities, suggesting socioeconomic disparities in quality of medication management. Focused efforts targeting older adults with low SES to reduce PIM use may be needed to prevent adverse drug events.

Do worsening lung ultrasound scans identify severe COVID-19 trajectories?

Background: While point-of-care ultrasound (POCUS) has been used to track worsening COVID-19 disease it is unclear if there are dynamic differences between severity trajectories. Methods: We studied 12-lung zone protocol scans from 244 participants [with repeat scans obtained in 3 days (N = 114), 7 days (N = 53), and weekly (N = 9)] ≥ 18 years of age hospitalized for COVID-19 pneumonia. Differences in mean lung ultrasound (LUS) scores and percent of lung fields with A-lines over time were compared between peak severity levels (as defined by the WHO clinical progression scale) using linear mixed-effects models. Results: Mean LUS scores were elevated by 0.19 (p = 0.035) and A-lines were present in 14.7% fewer lung fields (p = 0.02) among those with ICU-level or fatal peak illness compared to less severe hospitalized illness, regardless of duration of illness. There were no differences between severity groups in the trajectories of mean LUS score 0.19 (p = 0.66) or percent A-lines (p = 0.40). Discussion: Our results do not support the use of serial LUS scans to monitor COVID-19 disease progression among hospitalized adults.

Point-of-Care Lung Ultrasound Predicts Severe Disease and Death Due to COVID-19: A Prospective Cohort Study.

The clinical utility of point-of-care lung ultrasound (LUS) among hospitalized patients with COVID-19 is unclear. DESIGN: Prospective cohort study. SETTING: A large tertiary care center in Maryland, between April 2020 and September 2021. PATIENTS: Hospitalized adults (≥ 18 yr old) with positive severe acute respiratory syndrome coronavirus 2 reverse transcriptase-polymerase chain reaction results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28 days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean LUS Score (mLUSS) (ranging from 0 to 3) across lung zones was determined. The primary outcome was time to ICU-level care, defined as high-flow oxygen, noninvasive, or invasive mechanical ventilation, within 28 days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study; the median age was 61 years and 114 participants (43.2%) were female. The median mLUSS was 1.0 (interquartile range, 0.5-1.3). Following enrollment, 27 participants (10.0%) went on to require ICU-level care, and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (adjusted hazard ratio [aHR], 3.61; 95% CI, 1.27-10.2) and 28-day mortality (aHR, 3.10; 95% CI, 1.29-7.50). Pleural line abnormalities were independently associated with disease progression to death (aHR, 20.93; CI, 3.33-131.30). CONCLUSIONS: Participants with a mLUSS greater than or equal to 1 or pleural line changes on LUS had an increased likelihood of subsequent requirement of high-flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.

Small-molecule screening of ribonuclease L binders for RNA degradation.

Small molecules targeting the ubiquitous latent ribonuclease (RNase L), which has limited sequence specificity toward single-stranded RNA substrates, hold great potential to be developed as broad-spectrum antiviral drugs by modulating the RNase L-mediated innate immune responses. The recent development of proximity-inducing bifunctional molecules, as described in the strategy of ribonuclease targeting chimeras, demonstrated that small-molecule RNase L activators can function as the essential RNase L-recruiting component to design bifunctional molecules for targeted RNA degradation. However, only a single screening study on small-molecule RNase L activators with poor potency has been reported to date. Herein, we established a FRET assay and conducted a screening of 240,000 small molecules to identify new RNase L activators with improved potency. The extremely low hit rate of less than 0.03% demonstrated the challenging nature of RNase L activation by small molecules available from current screening collections. A few hit compounds induced enhanced thermal stability of RNase L upon binding, although validation assays did not lead to the identification of compounds with significantly improved RNase L activating potency. The sulfonamide compound 17 induced a thermal shift of ~ 0.9 °C upon binding to RNase L, induced significant apoptosis in cancer cells, and showed single-digit micromolar inhibitory activity against cancer cell proliferation. This study paves the way for future structural optimization for the development of small-molecule RNase L binders.

The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review.

YKL-40, a chitinase-3-like protein 1 (CHI3L1) or human cartilage glycoprotein 39 (HC gp-39), is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells and vascular smooth muscle cells. Its biological function is not well elucidated, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases. Although having important biological roles in autoimmunity, there were only attempts to elucidate relationships of YKL-40 with a single or couple of diseases in the literature. Therefore, in order to analyze the relationship between YKL-40 and the overall diseases, we reviewed 51 articles that discussed the association of YKL-40 with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease and inflammatory bowel disease. Several studies showed that YKL-40 could be assumed as a marker for disease diagnosis, prognosis, disease activity and severity. It is also shown to be involved in response to disease treatment. However, other studies showed controversial results particularly in the case of Behçet disease activity. Therefore, further studies are needed to elucidate the exact role of YKL-40 in autoimmunity and to investigate its potential in therapeutics.

Environmental risk factors, protective factors, and biomarkers for postpartum depressive symptoms: an umbrella review.

We performed an umbrella review on environmental risk/protective factors and biomarkers for postpartum depressive symptoms to establish a hierarchy of evidence. We systematically searched PubMed, Embase, and the Cochrane Database of Systematic Reviews from inception until 12 January 2021. We included systematic reviews providing meta-analyses related to our research objectives. Methodological quality was assessed by AMSTAR 2, and the certainty of evidence was evaluated by GRADE. This review was registered in PROSPERO (CRD42021230784). We identified 30 articles, which included 45 environmental risk/protective factors (154,594 cases, 7,302,273 population) and 9 biomarkers (2018 cases, 16,757 population). The credibility of evidence was convincing (class I) for antenatal anxiety (OR 2.49, 1.91-3.25) and psychological violence (OR 1.93, 1.54-2.42); and highly suggestive (class II) for intimate partner violence experience (OR 2.86, 2.12-3.87), intimate partner violence during pregnancy (RR 2.81, 2.11-3.74), smoking during pregnancy (OR 2.39, 1.78-3.2), history of premenstrual syndrome (OR 2.2, 1.81-2.68), any type of violence experience (OR 2.04, 1.72-2.41), primiparity compared to multiparity (RR 1.76, 1.59-1.96), and unintended pregnancy (OR 1.53, 1.35-1.75).

Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries.

Autism spectrum disorder (ASD) substantially contributes to the burden of mental disorders. Improved awareness and changes in diagnostic criteria of ASD may have influenced the diagnostic rates of ASD. However, while data on trends in diagnostic rates in some individual countries have been published, updated estimates of diagnostic rate trends and ASD-related disability at the global level are lacking. Here, we used the Global Burden of Diseases, Injuries, and Risk Factors Study data to address this gap, focusing on changes in prevalence, incidence, and disability-adjusted life years (DALYs) of ASD across the world. From 1990 to 2019, overall age-standardized estimates remained stable globally. Both prevalence and DALYs increased in countries with high socio-demographic index (SDI). However, the age-standardized incidence decreased in some low SDI countries, indicating a need to improve awareness. The male/female ratio decreased between 1990 and 2019, possibly accounted for by increasing clinical attention to ASD in females. Our results suggest that ASD detection in low SDI countries is suboptimal, and that ASD prevention/treatment in countries with high SDI should be improved, considering the increasing prevalence of the disorder. Additionally, growing attention is being paid to ASD diagnosis in females, who might have been left behind by ASD epidemiologic and clinical research previously. ASD burden estimates are underestimated as GBD does not account for mortality in ASD.

PTSD and Depression 8 Years After the 2004 Tsunami in Sri Lanka.

OBJECTIVES: To evaluate prevalence and risk factors of posttraumatic stress disorder (PTSD) and depression among directly exposed (DE) and indirectly or nonexposed (INE) populations in Sri Lanka 8 y after the Indian Ocean Tsunami in 2004. METHODS: Population-based structured survey study was conducted among Sri Lankan adults living in 5 coastal districts, Hamboantha, Matara, Galle, Kalutara, and Colombo in 2012-2013. A total of 430 individuals, 325 in DE, 105 in INE, participated in the survey. DE and INE groups were compared for demographics and outcomes. Bivariate and multiple logistic regressions with backward selection were used to identify risk factors for partial PTSD and depression. RESULTS: The prevalence of PTSD, partial PTSD and depression were 2.8%, 10.5%, and 18.8% in DE group, respectively. In multivariable analyses tsunami exposure, female gender, subjective physical health before the tsunami, previous trauma, and depression were significantly associated with partial PTSD. Female gender, high frequency of religious activity, previous trauma, social support, and PTSD were significantly associated with depression. CONCLUSIONS: The psychological impacts of the tsunami did wane over time, but still present at lower rate even in 8 y. It is important to address these lingering sequelae and expand access to at risk individuals.

Synthesis and evaluation of RNase L-binding 2-aminothiophenes as anticancer agents.

Aminothiophene is a scaffold that is widely present in drugs and biologically active small molecules as chemical probes. In this study, 43 compounds sharing a 2-aminothiophenone-3-carboxylate (ATPC) scaffold, known to activate the ribonuclease L (RNase L), were synthesized and selected ATPCs showed enhancement of thermal stability of RNase L upon binding. Screening of antiproliferation activities against human cancer cell lines revealed that ATPCs represented by compounds 4l and 50 showed potent single-digit micromolar antiproliferation activity against human cancer cell lines. Compounds 4l and 50 exhibited time- and dose-dependent proliferation inhibition, induced cellular apoptosis measured by cleaved PARP and via flow cytometry, inhibited cell migration, and inhibited cell colony formation. Combining the results reported in this work, ATPCs were evaluated as potential anticancer agents mediated by RNase L-binding and apoptosis induction. The work contributes to the study on the polypharmacological properties of aminothiophene-containing small molecules.

Improving Antibacterial Activity of a HtrA Protease Inhibitor JO146 against Helicobacter pylori: A Novel Approach Using Microfluidics-Engineered PLGA Nanoparticles.

Nanoparticle drug delivery systems have emerged as a promising strategy for overcoming limitations of antimicrobial drugs such as stability, bioavailability, and insufficient exposure to the hard-to-reach bacterial drug targets. Although size is a vital colloidal feature of nanoparticles that governs biological interactions, the absence of well-defined size control technology has hampered the investigation of optimal nanoparticle size for targeting bacterial cells. Previously, we identified a lead antichlamydial compound JO146 against the high temperature requirement A (HtrA) protease, a promising antibacterial target involved in protein quality control and virulence. Here, we reveal that JO146 was active against Helicobacter pylori with a minimum bactericidal concentration of 18.8-75.2 µg/mL. Microfluidic technology using a design of experiments approach was utilized to formulate JO146-loaded poly(lactic-co-glycolic) acid nanoparticles and explore the effect of the nanoparticle size on drug delivery. JO146-loaded nanoparticles of three different sizes (90, 150, and 220 nm) were formulated with uniform particle size distribution and drug encapsulation efficiency of up to 25%. In in vitro microdilution inhibition assays, 90 nm nanoparticles improved the minimum bactericidal concentration of JO146 two-fold against H. pylori compared to the free drug alone, highlighting that controlled engineering of nanoparticle size is important in drug delivery optimization.