Biocompatible Tough Ionogels with Reversible Supramolecular Adhesion.

Cohesive and interfacial adhesion energies are difficult to balance to obtain reversible adhesives with both high mechanical strength and high adhesion strength, although various methods have been extensively investigated. Here, a biocompatible citric acid/L-(-)-carnitine (CAC)-based ionic liquid was developed as a solvent to prepare tough and high adhesion strength ionogels for reversible engineered and biological adhesives. The prepared ionogels exhibited good mechanical properties, including tensile strength (14.4 MPa), Young's modulus (48.1 MPa), toughness (115.2 MJ m-3), and high adhesion strength on the glass substrate (24.4 MPa). Furthermore, the ionogels can form mechanically matched tough adhesion at the interface of wet biological tissues (interfacial toughness about 191 J m-2) and can be detached by saline solution on demand, thus extending potential applications in various clinical scenarios such as wound adhesion and nondestructive transfer of organs.

Regulation of Hydrophobic Structures of Antibacterial Guanidinium-Based Amphiphilic Polymers for Subcutaneous Implant Applications.

Antimicrobial peptide mimics have been used to kill bacteria and construct antibacterial materials. Precise design and construction of chemical structure are essential for easy access to highly effective antimicrobial peptide mimics. Herein, cationic guanidinium-based polymers (PGXs) with varying hydrophobic structures were synthesized to explore the structure and antibacterial activity relationship of antimicrobial peptide mimics and to construct antibacterial implants. The effect of the hydrophobic chemical structure, including carbon chain length and configuration, on the antimicrobial activities against both Escherichia coli and Staphylococcus aureus was investigated. The antibacterial activities of PGXs improved with increasing alkyl chain length, and PGXs with a straight-chain hydrophobic structure exhibited better bactericidal activities than those with cyclic alkane and aromatic hydrocarbon. Furthermore, PGXs grafted with poly(dimethylsiloxane) (PDMS-PGXs) showed a similar bactericidal change tendency of PGXs in solution. Additionally, the PDMS-PGXs showed potent antibiofilm performance in vitro, which can inhibit bacterial infection in vivo as subcutaneous implants. This study may propose a basis for the precise design and construction of antibacterial materials and provide a promising way of designing biomedical devices and implants with bacterial infection-combating activities.

Effects and underlying mechanisms of L-arginine on spontaneous muscle contraction of rat colon.

Arginine (Arg), as a basic amino acid, has been reported to be involved in regulation of gut motility. However, the evidence is limited and the underlying mechanism is not fully understood. Our study was conducted to investigate the effects of L-Arg on spontaneous contraction of the longitudinal muscle strip (LMS) of the rat colon and the relevant mechanisms. An organ bath system was used to detect the contractile force of the LMS. Whole-cell voltage-clamp techniques were applied to observe alterations in the currents of large conductance Ca2+-activated K+ (KCa) channels, voltage-dependent potassium (KV) channels, and L-type Ca2+ channels (LTCCs) in smooth muscle cells (SMCs) of the colon. We found that L-Arg within the physiological concentration had no effect on contraction of LMS, while 1 mM L-Arg significantly increased both the amplitude and frequency of LMS contractility. And the increase in force was mucosa-dependent, whereas changes in frequency as well as in amplitude were inhibited by atropine. In addition, L-Arg (1 mM) activated the LTTCs and inhibited both KCa channels and KV channels on SMCs. Thus, L-Arg above the physiological concentration exerted an excitatory effect on colonic LM contraction, and stimulation by L-Arg was mediated by ACh. In addition, LTCCs, KCa channels, and KV channels on SMCs were involved in the action of L-Arg.

Physicians Prescribe More Opioid Than Needed to Treat Pain in Children After Outpatient Urological Procedures: An Observational Cohort Study.

BACKGROUND: The epidemic of nonmedical use of prescription opioids (NMUPOs) has been fueled in part by the availability of leftover, legitimately prescribed opioids. In children, outpatient urological procedures are among the most common surgeries performed, but data are lacking to guide appropriate postoperative opioid prescribing. The aim of this study was to compare the amount of prescribed opioid medication to the amount taken for acute pain after minor pediatric urological surgery and to determine the disposition of excess opioid. In addition, we explored whether distinct patient characteristics and procedure type influenced opioid prescribing and consumption. METHODS: Of the 139 families of pediatric patients enrolled, 115 were interviewed within 48 hours and/or 10-14 days of discharge to determine the amount of opioid prescribed and consumed, duration of treatment, and disposition of unconsumed opioid. RESULTS: The most common procedures performed were circumcision (n = 58) and orchiopexy (n = 40). Most patients (98%) were male, and 77% were <8 years of age. All opioid prescriptions were for oxycodone dosed every 4 hours as needed (PRN). Median number of doses prescribed was 30 (interquartile range [IQR], 23-31; n = 138) for both respondents who reported doses remaining (IQR, 29-31; n = 83) and those who did not (IQR, 22-32; n = 55). Among those reporting doses remaining, median number of doses consumed was 4.2 (IQR, 0-14). Multivariable linear regression showed no significant association between doses consumed and patient age, type of procedure, discharge pain score, or use of adjuvant analgesics. Median duration of opioid therapy was 2 days (IQR, 0-5; n = 83) with each additional day of opioid use corresponding to an average increase in consumption of 2.3 doses (95% confidence interval [CI], 1.8-2.8). An estimated 75% (95% CI, 69%-81%) of opioid dispensed was not consumed, and 86% (72/83) of patients took ≤18 doses. Forty-four of 65 (68%) families reported receiving no disposal instructions for leftover opioid, and only 7 families disposed of leftover medication. CONCLUSIONS: For minor pediatric urological surgeries in young boys, a 3-day supply (18 doses) of opioid was sufficient to adequately treat acute postoperative pain in most patients. Adjusting opioid dispensing to align with consumption and better educating patients and families on opioid disposal can be used to potentially decrease availability of leftover opioids in homes and communities.

Factors Associated With Colonoscopy Compliance Based on Health Belief Model in a Community-Based Colorectal Cancer Screening Program Shanghai, China.

Screening can help early detection of colorectal cancer (CRC) in the general population. However, colonoscopy compliance in screening program is low in China. The study aimed to identify factors associated with colonoscopy compliance based on Health Belief Model (HBM). An investigation was conducted in Huangpu District, Shanghai in 2015. High-risk individuals of CRC received an in-person interview with physicians to fill out a questionnaire. The questionnaires assessing predictors of colonoscopy compliance were collected, and status of colonoscopy participation was determined. Univariate and multiple logistic regression analyses were conducted. Among 2,568 high-risk population (20.68%), 531 subjects underwent colonoscopy. Participants with both risk assessment and fecal immunochemical test positive were most likely to undergo colonoscopy. Based on HBM, colonoscopy compliance was positively associated with higher perceived severity (odds ratio [OR] = 1.05, 95% confidence interval [CI] = [1.00, 1.10]). Higher perceived barriers (OR = 0.97, 95% CI = [0.94, 0.99]), without prior colonoscopy (OR = 0.35, 95% CI = [0.26, 0.47]), not knowing anyone who underwent colonoscopy before (OR = 0.74, 95% CI = [0.58, 0.96]), without health-care provider recommendation on colonoscopy (OR = 0.58, 95% CI = [0.44, 0.77]), and without psychosocial support from someone for colonoscopy (OR = 0.27, 95% CI = [0.21, 0.35]) were shown to be associated with colonoscopy noncompliance. The colonoscopy compliance was low in this CRC screening program in Shanghai, China. The influencing factors were positive results in primary screening, perceived severity, perceived barriers, personal or others' experiences in colonoscopy, health-care provider recommendation, and psychosocial supports. Effective education campaign and facilitated communication between health-care providers and high-risk population were suggested in the future interventions.

Opioid Prescribing for the Treatment of Acute Pain in Children on Hospital Discharge.

BACKGROUND: The epidemic of nonmedical use of prescription opioids has been fueled by the availability of legitimately prescribed unconsumed opioids. The aim of this study was to better understand the contribution of prescriptions written for pediatric patients to this problem by quantifying how much opioid is dispensed and consumed to manage pain after hospital discharge, and whether leftover opioid is appropriately disposed of. Our secondary aim was to explore the association of patient factors with opioid dispensing, consumption, and medication remaining on completion of therapy. METHODS: Using a scripted 10-minute interview, parents of 343 pediatric inpatients (98% postoperative) treated at a university children's hospital were questioned within 48 hours and 10 to 14 days after discharge to determine amount of opioid prescribed and consumed, duration of treatment, and disposition of unconsumed opioid. Multivariable linear regression was used to examine predictors of opioid prescribing, consumption, and doses remaining. RESULTS: Median number of opioid doses dispensed was 43 (interquartile range, 30-85 doses), and median duration of therapy was 4 days (interquartile range, 1-8 days). Children who underwent orthopedic or Nuss surgery consumed 25.42 (95% confidence interval, 19.16-31.68) more doses than those who underwent other types of surgery (P < .001), and number of doses consumed was positively associated with higher discharge pain scores (P = .032). Overall, 58% (95% confidence interval, 54%-63%) of doses dispensed were not consumed, and the strongest predictor of number of doses remaining was doses dispensed (P < .001). Nineteen percent of families were informed how to dispose of leftover opioid, but only 4% (8 of 211) did so. CONCLUSIONS: Pediatric providers frequently prescribed more opioid than needed to treat pain. This unconsumed opioid may contribute to the epidemic of nonmedical use of prescription opioids. Our findings underscore the need for further research to develop evidence-based opioid prescribing guidelines for physicians treating acute pain in children.

Size-fractioned ultrafine particles and black carbon associated with autonomic dysfunction in subjects with diabetes or impaired glucose tolerance in Shanghai, China.

BACKGROUND: Particles in smaller size fractions, such as ultrafine particles (UFPs) (with diameter less than 100 nm), has become of significant cardiovascular health concerns. However, the biological plausibility underlying potential relationship between UFPs and cardiovascular outcomes is less studied. METHODS: Fifty-three subjects living in Shanghai with type-2 diabetes (T2D) or impaired glucose tolerance (IGT) were followed for autonomic dysfunctions with three repeated measurements in 2010. Minute-to-minute concentrations of ambient particles in small size-fractions (5-560 nm), black carbon (BC), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) were monitored using a central monitoring laboratory equipped with real-time air monitors close to residential area of the subjects. Generalized linear mixed models, with adjustment for individual risk factors, were applied to assess the effects of air pollution on autonomic dysfunctions in subjects. RESULTS: Our study showed that significant reduction in the standard deviation of all NN intervals (SDNN) ranging from 3.4% to 8.1% were associated with interquartile range (IQR) increase of number concentration of particles (PNC) in size fractions<100 nm, and reduction from 1.3% to 4.6% with particles of diameter 100-200 nm, in subjects with diabetes or glucose tolerance. Increased exposure to traffic-related pollutants BC, NO2 and CO, and combustion pollutant SO2, were also significantly associated with HRV reductions. However, no effect was observed for particles in size fraction of 200-560 nm and O3. Diabetic risk factor and gender appeared to have significant interactions on autonomic dysfunction associated with UFPs and traffic pollution exposures in certain time-window. CONCLUSIONS: Our results suggest that underlying diabetes or impaired glucose tolerance may confer reduced autonomic function of heart due to traffic pollution exposure.

Poly(ionic liquid)-Flocculated Chlorella Loading Bactericidal and Antioxidant Hydrogel as a Biological Hydrogen Therapy for Diabetic Wound Dressing.

Infection and oxidative stress seriously hinder the healing of diabetic wounds, resulting in various serious health and clinical problems. Herein, a sustainable biological hydrogen (H2)-producing hyaluronic acid-based hydrogel patch (HAP-Chl) was constructed by loading an imidazolium-based poly(ionic liquid) (PIL) flocculated live Chlorella as a diabetic wound dressing. The PIL can flocculate Chlorella through electrostatic interactions between PIL and Chlorella to form Chlorella agglomerates, endowing the Chlorella in the central agglomerates with the ability to continuously produce H2 for 24 h under mild conditions. Combining the membrane disruption-related bactericidal mechanism of PIL and the antioxidant properties of the produced H2, HAP-Chl was determined to be antibacterial and antioxidant. In addition to exhibiting biocompatible and nontoxic activities, subsequent Staphylococcus aureus-infected chronic wound studies revealed that HAP-Chl is capable of promoting the healing of chronic wounds by effectively killing bacteria, reducing extensive ROS, relieving inflammation, and promoting the deposition of mature collagen and angiogenesis. This study provides a new strategy for constructing an in situ sustainable H2-producing hydrogel, enabling the formation of novel antibacterial and antioxidant material platforms with potential for wound dressing applications.

High-Toughness and High-Strength Solvent-Free Linear Poly(ionic liquid) Elastomers.

Solvent-free elastomers, unlike gels, do not suffer from solvent evaporation and leakage in practical applications. However, it is challenging to realize the preparation of high-toughness (with both high stress and strain) ionic elastomers. Herein, high-toughness linear poly(ionic liquid) (PIL) elastomers are constructed via supramolecular ionic networks formed by the polymerization of halometallate ionic liquid (IL) monomers, without any chemical crosslinking. The obtained linear PIL elastomers exhibit high strength (16.5 MPa), Young's modulus (157.49 MPa), toughness (130.31 MJ m-3 ), and high crack propagation insensitivity (fracture energy 243.37 kJ m-2 ), owing to the enhanced intermolecular noncovalent interactions of PIL chains. Furthermore, PIL elastomer-based strain, pressure, and touch sensors have shown high sensitivity. The linear noncovalent crosslinked network endows the PIL elastomers with self-healing and recyclable properties, and broad application prospects in the fields of flexible sensor devices, health monitoring, and human-machine interaction.

Chlorella-Loaded Antibacterial Microneedles for Microacupuncture Oxygen Therapy of Diabetic Bacterial Infected Wounds.

Hypoxia and infection are urgent clinical problems in chronic diabetic wounds. Herein, living Chlorella-loaded poly(ionic liquid)-based microneedles (PILMN-Chl) are constructed for microacupuncture oxygen and antibacterial therapy against methicillin-resistant Staphylococcus aureus (MRSA)-infected chronic diabetic wounds. The PILMN-Chl can stably and continuously produce oxygen for more than 30 h due to the photosynthesis of the loaded self-supported Chlorella. By combining the barrier penetration capabilities of microneedles, the continuous and sufficient oxygen supply of Chlorella, and the sterilization activities of PIL, the PILMN-Chl can accelerate chronic diabetic wounds in vivo by topical targeted sterilization and hypoxia relief in deep parts of wounds. Thus, the self-oxygen produced microneedles modality may provide a promising and facile therapeutic strategy for treating chronic, hypoxic, and infected diabetic wounds.

Antibacterial, anti-inflammatory and wet-adhesive poly(ionic liquid)-based oral patch for the treatment of oral ulcers with bacterial infection.

Oral aphthous ulcers are a common inflammatory efflorescence of oral mucosa, presenting as inflammation and oral mucosal damage and manifesting as pain. The moist and highly dynamic environment of the oral cavity makes the local treatment of oral aphthous ulcers challenging. Herein, a poly(ionic liquid)-based diclofenac sodium (DS)-loaded (PIL-DS) buccal tissue adhesive patch fabricated with intrinsically antimicrobial, highly wet environment adhesive properties and anti-inflammatory activities to treat oral aphthous ulcers was developed. The PIL-DS patch was prepared via polymerization of a catechol-containing ionic liquid, acrylic acid, and butyl acrylate, followed by anion exchange with DS-. The PIL-DS can adhere to wet tissues, including mucosa muscles and organs, and efficiently deliver the carried DS- at wound sites, exerting remarkable synergistic antimicrobial (bacteria and fungi) properties. Accordingly, the PIL-DS elicited dual therapeutic effects on oral aphthous ulcers with Staphylococcus aureus infection through antibacterial and anti-inflammatory activities, significantly accelerating oral aphthous ulcer healing as an oral mucosa patch. The results indicated that the PIL-DS patch, with inherently antimicrobial and wet adhesion properties, is promising for treating oral aphthous ulcers in clinical practice. STATEMENT OF SIGNIFICANCE: Oral aphthous ulcers are a common oral mucosal disease, which could lead to bacterial infection and inflammation in severe cases, especially for people with large ulcers or low immunity. However, moist oral mucosa and highly dynamic oral environment make it challenging to maintain therapeutic agents and physical barriers at the wound surface. Therefore, an innovative drug carrier with wet adhesion is urgently needed. Herein, a poly(ionic liquid)-based diclofenac sodium (DS)-loaded (PIL-DS) buccal tissue adhesive patch was developed to treat oral aphthous ulcers showing intrinsically antimicrobial and highly wet environment adhesive properties due to the presence of catechol-containing ionic liquid monomer. Additionally, the PIL-DS showed significantly therapeutic effects on oral aphthous ulcers with S. aureus infection through antibacterial and anti-inflammatory activities. We expect that our work can provide inspiration for the development of treatment for microbially infected oral ulcers.

Frailty and risk of adverse outcomes among community-dwelling older adults in China: a comparison of four different frailty scales.

Background: Data on which frailty scales are most suitable for estimating risk in Chinese community populations remain limited. Herein we examined and compared four commonly used frailty scales in predicting adverse outcomes in a large population-based cohort of Chinese older adults. Methods: A total of 5402 subjects (mean age 66.3 ± 9.6 years, 46.6% male) from the WHO Study on global AGEing and adult health (SAGE) in Shanghai were studied. Frailty was measured using a 35-item frailty index (FI), the frailty phenotype (FP), FRAIL, and Tilburg Frailty Indicator (TFI). Multivariate logistic regression models were performed to evaluate the independent association between frailty and outcomes including 4-year disability, hospitalization, and 4- and 7-year all-cause mortality. The accuracy for predicting these outcomes was determined by evaluating the area under the curve (AUC). The prevalence of frailty, sensitivity, and specificity were calculated using our proposed cut-off points and other different values. Results: Prevalence of frailty ranged from 4.2% (FRAIL) to 16.9% (FI). FI, FRAIL and TFI were comparably associated with 4-year hospitalization, and 4- and 7-year mortality (adjusted odds ratios [aORs] 1.44-1.69, 1.91-2.22 and 1.85-2.88, respectively). FRAIL conferred the greatest risk of 4-year disability, followed by FI and TFI (aOR 5.55, 3.50, and 1.91, respectively). FP only independently predicted 4- and 7-year mortality (aOR 1.57 and 2.21, respectively). AUC comparisons showed that FI, followed by TFI and FRAIL, exhibited acceptable predictive accuracy for 4-year disability, 4- and 7-year mortality (AUCs 0.76-0.78, 0.71-0.71, 0.65-0.72, respectively), whereas all scales poorly predicted 4-year hospitalization (AUCs 0.53-0.57). For each scale, while specificity estimates (85.3-97.3%) were high and similar across all outcomes, their sensitivity estimates (6.3-56.8%) were not sufficient yet. Prevalence of frailty, sensitivity, and specificity varied considerably when different cut-off points were used. Conclusion: Frailty defined using any of the four scales was associated with an increased risk of adverse outcomes. Although FI, FRAIL and TFI exhibited fair-to-moderate predictive accuracy and high specificity estimates, their sensitivity estimates were not sufficient yet. Overall, FI performed best in estimating risk, while TFI and FRAIL were additionally useful, the latter perhaps being more applicable to Chinese community-dwelling older adults.

Nitric oxide-releasing poly(ionic liquid)-based microneedle for subcutaneous fungal infection treatment.

Poor permeation of therapeutic agents and similar eukaryotic cell metabolic and physiological properties of fungi and human cells are two major challenges that lead to the failure of current therapy for fungi-induced skin and soft tissue infections. Herein, a nitric oxide (NO)-releasing poly(ionic liquid)-based microneedle (PILMN-NO) with the capacity of deep persistent NO toward subcutaneous fungal bed is presented as a synergistic antifungal treatment strategy to treat subcutaneous fungal infection. Upon the insertion of PILMN-NO into skin, the contact fungicidal activities induced by electrostatic and hydrophobic effects of poly(ionic liquid) and the released NO sterilization resulting from the peroxidation and nitrification effect of NO achieved enhanced antifungal efficacy against fungi (Candida albicans) both in vitro and in vivo. Simultaneously, PILMN-NO showed biofilm ablation ability and efficiently eliminated mature biofilms. In vivo fungal-induced subcutaneous abscess studies revealed that PILMN-NO could effectively sterilize fungi while suppressing the inflammatory reaction, facilitating collagen deposition and angiogenesis, and promoting wound healing. This work provides a new strategy to overcome the difficulties in deep skin fungal infection treatment and has potential for further exploitation of NO-releasing microbicidal therapy.

Attitudes and self-reported practices of orthopedic providers regarding prescription opioid use.

OBJECTIVE: Orthopedic surgeons are the third-highest opioid prescribers in the United States. Their prescribing practices can significantly affect the quantity of unconsumed opioids available to fuel the current opioid epidemic. The aim of this study was to identify prescribing patterns and knowledge gaps among orthopedic providers for targeted future interventions and investigation. DESIGN: An online survey describing six common orthopedic surgical scenarios was distributed electronically to determine opioid type and quantity prescribed at discharge, medication disposal instructions, and the use of prescription drug monitoring programs (PDMPs) in the prescription writing process. SETTING: Tertiary care academic hospitals. PARTICIPANTS: Orthopedic physicians and mid-level providers practicing at Johns Hopkins Medical Institutions and University of Maryland Medical System. Of 179 providers contacted, 127 (71 percent) completed the survey. MAIN OUTCOME MEASURES: Quantity of opioid prescribed, utilization of PDMPs, and provision of opioid disposal instructions. RESULTS: While statistically significant associations were identified between quantity of opioid prescribed and surgical procedure, for five of six scenarios 95 percent of respondents recommended prescribing >55 oxycodone 5 mg pill equivalents (PEs) at discharge. An inverse correlation between years of clinical practice and mean number of PEs prescribed was observed. Fewer than 40 percent of respondents modified prescribing when presented with clinically relevant changes in scenario (history of depression or drug abuse). Over 60 percent of respondents do not use PDMPs, and 79 percent do not provide opioid disposal instructions. CONCLUSIONS: Our findings support a need for targeted education to mitigate the role of orthopedic postoperative prescribing practices on the current opioid abuse epidemic.

Cancer incidence and mortality patterns in Luwan district of Shanghai during 2002-2011.

Cancer has become the leading cause of death and a major burden to public health in China. The current study analyzed the composition, incidence, mortality, and temporal trends for some major cancer types among permanent residents in Luwan district of Shanghai from 2002 to 2011, so as to provide data for cancer research. Data were collected from the database of cancer registration and management system in Shanghai. Number of new cases, number of deaths, incidence, and mortality of each cancer type were calculated. The incidence and mortality rates were standardized. Temporal trends in the incidence and mortality were assessed using average annual percent change. There were 12,843 new cancer cases and 8,331 deaths from cancer in Luwan from January 2002 to December 2011. Age-standardized incidence rates by Segi's standard were 229.46 and 205.05 per 100,000 population for males and females, respectively. For males, the most commonly diagnosed cancers were lung, colorectal, stomach, liver, prostate, bladder, pancreas, kidney, lymphoma, and esophageal cancers; for females, they were breast, colorectal, lung, stomach, thyroid, liver, ovary, pancreas, uterus, and brain cancers. The incidence rates for all cancers combined increased significantly for both males and females from 2002 to 2011 (p < 0.05 for both). Age-standardized mortality rates were 147.04 and 90.62 per 100,000 population for males and females, respectively. The mortality rates have stayed stable during the 10-year period for both males and females (p > 0.05 for both). Our results suggest that cancer incidence and mortality rates in Luwan district of Shanghai vary by age, sex, tumor type. The increasing trends in cancer incidence call for effective prevention and control measures in the district. The significance of cancer registration for disease surveillance and management needs to be further advocated.

Association between size-segregated particles in ambient air and acute respiratory inflammation.

The health effects of particulate matter (PM) in ambient air are well documented. However, whether PM size plays a critical role in these effects is unclear in the population studies. This study investigated the association between the ambient concentrations of PM with varies sizes (5.6-560nm) and a biomarker of acute respiratory inflammation, the fraction of exhaled nitric oxide (FENO), in a panel of 55 elderly people in Shanghai, China. Linear mixed-effect model was fitted to estimate the association between FENO and moving average concentrations of PM, adjusting for temperature, relative humidity, day of the week, and age. Results showed that among the measured particles size range, Aitken-mode (20-100nm) particles had the strongest positive association with increased FENO when using moving average concentration of PM up to 24h prior to visits. The estimates were robust to the adjustment for gender, condition of chronic disease and use of medication, and to the sensitive analysis using different times of visits. The authors concluded that the association between acute respiratory inflammation and PM concentration of fine particulates depended on particle size, and suggested Aitken-mode particles may be the most responsible for this adverse health association.