Dynamic diagnosis of metamaterials through laser-induced vibrational signatures.

Mechanical metamaterials at the microscale exhibit exotic static properties owing to their engineered building blocks1-4, but their dynamic properties have remained substantially less explored. Their design principles can target frequency-dependent properties5-7 and resilience under high-strain-rate deformation8,9, making them versatile materials for applications in lightweight impact resistance10-12, acoustic waveguiding7,13 or vibration damping14,15. However, accessing dynamic properties at small scales has remained a challenge owing to low-throughput and destructive characterization8,16,17 or lack of existing testing protocols. Here we demonstrate a high-throughput, non-contact framework that uses MHz-wave-propagation signatures within a metamaterial to non-destructively extract dynamic linear properties, omnidirectional elastic information, damping properties and defect quantification. Using rod-like tessellations of microscopic metamaterials, we report up to 94% direction-dependent and rate-dependent dynamic stiffening at strain rates approaching 102 s-1, as well as damping properties three times higher than their constituent materials. We also show that frequency shifts in the vibrational response allow for characterization of invisible defects within the metamaterials and that selective probing allows for the construction of experimental elastic surfaces, which were previously only possible computationally. Our work provides a route for accelerated data-driven discovery of materials and microdevices for dynamic applications such as protective structures, medical ultrasound or vibration isolation.

Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid.

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13-0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity. SIGNIFICANCE STATEMENT: In this study, the role of farnesoid-X-receptor (FXR) in mustard vesicant-induced pulmonary toxicity was analyzed using nitrogen mustard (NM) as a model. This study's findings that administration of obeticholic acid, an FXR agonist, to rats reduces NM-induced pulmonary injury, oxidative stress, and fibrosis provide novel mechanistic insights into vesicant toxicity, which may be useful in the development of efficacious therapeutics.

Differential effects of healthcare worker burnout on psychotropic medication use and misuse by occupational level.

PURPOSE: Burnout has been well examined among physicians and other high-wage, high-autonomy healthcare positions. However, lower-wage healthcare workers with less workplace autonomy (e.g., medical assistants, nurses' aides) represent a substantial proportion of the workforce, but remain understudied. We aimed to examine the effects of burnout on psychotropic medication use and misuse and whether these effects differed by occupational level. METHODS: In March 2022, we collected data from a diverse sample of US healthcare workers (N = 200) and examined the cross-sectional relationship between burnout and changes in prescribed psychotropic medication (i.e., starting, stopping, and/or having a change in the dose/frequency) during the COVID-19 pandemic. We also separately examined the relationship between burnout and psychotropic medication misuse (i.e., without a prescription, in greater amounts, more often, longer than prescribed, and/or for a reason other than prescribed). We stratified models by occupational level (prescribers/healthcare administrators vs. other healthcare workers). RESULTS: Greater burnout was associated with higher odds of changes in prescribed psychotropic medication among prescribers/healthcare administrators (aOR = 1.23, 95% CI 1.01, 1.48), but not among other healthcare workers (aOR = 1.04, 95% CI 0.98, 1.10). Greater burnout was not associated with psychotropic medication misuse among prescribers/healthcare administrators (aOR = 0.96, 95% CI 0.82, 1.12) but was associated with increased odds of psychotropic medication misuse among other healthcare workers (aOR = 1.07, 95% CI 1.01, 1.14). CONCLUSIONS: Potential disparities in help-seeking and healthcare access might manifest in non-medical use of prescription drugs among some healthcare workers, which has implications for worker safety and well-being.

Unmet needs and harm reduction preferences of syringe services program participants: differences by co-use of illicit opioids and methamphetamine.

BACKGROUND: The current fourth wave of the United States opioid overdose epidemic is characterized by the co-use of opioids and stimulants, including illicit opioids and methamphetamine. The co-use of these two drugs, known as "goofballing," is associated with higher risk for several adverse outcomes, including more frequent injections, greater health risks, and higher morbidity. Considering these differences, this unique subpopulation of people who inject drugs (PWID) may also have unique unmet needs and harm reduction preferences. METHODS: We collected self-reported data from participants (N = 50) of a syringe services program (SSP), including basic needs and harm reduction preferences. Using bivariate analyses, we examined differences between SSP participants who do and do not co-use illicit opioids and methamphetamine. Co-use was defined as reporting the use of both drugs, which may or may not have been used simultaneously. RESULTS: In the overall sample, the mean level of need was highest for bus passes or other transportation, a person who can help you get the services you need, medication for opioid use disorder, and a job or job training. Additionally, all participants reported being either interested or very interested in fentanyl test strips, safe consumption sites, delivery of syringe service supplies, and delivery of naloxone. Those who endorsed co-use had a greater need for food, healthcare, substance use disorder treatment, a support person to help them access needed services, and bus passes or transportation. CONCLUSIONS: Unmet needs were prevalent, and the desire for more harm reduction services was high among these PWID. Results also suggest people who co-use illicit opioids and methamphetamine may have the greatest unmet needs and desire for additional harm reduction services.

Tunable Mechanical Response of Self-Assembled Nanoparticle Superlattices.

Self-assembled nanoparticle superlattices (NPSLs) are an emergent class of self-architected nanocomposite materials that possess promising properties arising from precise nanoparticle ordering. Their multiple coupled properties make them desirable as functional components in devices where mechanical robustness is critical. However, questions remain about NPSL mechanical properties and how shaping them affects their mechanical response. Here, we perform in situ nanomechanical experiments that evidence up to an 11-fold increase in stiffness (∼1.49 to 16.9 GPa) and a 5-fold increase in strength (∼88 to 426 MPa) because of surface stiffening/strengthening from shaping these nanomaterials via focused-ion-beam milling. To predict the mechanical properties of shaped NPSLs, we present discrete element method (DEM) simulations and an analytical core-shell model that capture the FIB-induced stiffening response. This work presents a route for tunable mechanical responses of self-architected NPSLs and provides two frameworks to predict their mechanical response and guide the design of future NPSL-containing devices.

Combined Intranasal Nanoemulsion and RIG-I Activating RNA Adjuvants Enhance Mucosal, Humoral, and Cellular Immunity to Influenza Virus.

Current influenza virus vaccines are focused on humoral immunity and are limited by the short duration of protection, narrow cross-strain efficacy, and suboptimal immunogenicity. Here, we combined two chemically and biologically distinct adjuvants, an oil-in-water nanoemulsion (NE) and RNA-based agonists of RIG-I, to determine whether the diverse mechanisms of these adjuvants could lead to improved immunogenicity and breadth of protection against the influenza virus. NE activates TLRs, stimulates immunogenic apoptosis, and enhances cellular antigen uptake, leading to a balanced TH1/TH2/TH17 response when administered intranasally. RIG-I agonists included RNAs derived from Sendai and influenza viral defective interfering RNAs (IVT DI, 3php, respectively) and RIG-I/TLR3 agonist, poly(I:C) (pIC), which induce IFN-Is and TH1-polarized responses. NE/RNA combined adjuvants potentially allow for costimulation of multiple innate immune receptor pathways, more closely mimicking patterns of activation occurring during natural viral infection. Mice intranasally immunized with inactivated A/Puerto Rico/8/1934 (H1N1) (PR/8) adjuvanted with NE/IVT DI or NE/3php (but not NE/pIC) showed synergistic enhancement of systemic PR/8-specific IgG with significantly greater avidity and virus neutralization activity than the individual adjuvants. Notably, NE/IVT DI induced protective neutralizing titers after a single immunization. Hemagglutinin stem-specific antibodies were also improved, allowing recognition of heterologous and heterosubtypic hemagglutinins. All NE/RNAs elicited substantial PR/8-specific sIgA. Finally, a unique cellular response with enhanced TH1/TH17 immunity was induced with the NE/RNAs. These results demonstrate that the enhanced immunogenicity of the adjuvant combinations was synergistic and not simply additive, highlighting the potential value of a combined adjuvant approach for improving the efficacy of vaccination against the influenza virus.

Effectiveness of percutaneous vacuum-assisted excision (VAE) of breast lesions of uncertain malignant potential (B3 lesions) as an alternative to open surgical biopsy.

OBJECTIVES: Traditionally B3 breast lesions are treated surgically, but overtreatment is a concern, as the majority have a final benign diagnosis. A national screening program introduced vacuum-assisted excision (VAE) for managing B3 lesions in late 2016. This retrospective study aimed to assess the outcomes associated with this approach. METHODS: All B3 lesions diagnosed between 01/2017 and 12/2019 were identified at two centres. Information was obtained on the initial biopsy and final histology, and method of VAE image guidance, needle size and number of cores. Lesions were excluded if there was cancer elsewhere in the breast at the time of diagnosis; the lesion was not suitable for VAE due to position in the breast or had B3 pathology for which open biopsy was still required. The final decision to offer VAE was always made at a multidisciplinary meeting (MDM). Risk difference was used to test the significance at p ≤ .05. RESULTS: In total, 258 B3 lesions were diagnosed, 105 (40.7%) met the inclusion criteria and underwent VAE. VAE was performed under X-ray (89/105) or ultrasound guidance (16/105), taking an average of 18.5 cores with the 10-G needle or 10.8 cores with the 7-G needle. Nine cases (8.6%) were upgraded to a malignant diagnosis following VAE. Malignancy was found in 15.5% (9/58) of B3 lesions with epithelial atypia, but in none without atypia (0/47) (p = .004). No new lesions or malignancy has occurred at the site of the VAE with an average mammographic follow-up of 2.2 years. CONCLUSION: Upgrade to malignancy following VAE was uncommon (8.6%) and associated with atypia in the initial biopsy. VAE is an alternative approach to the management of B3 lesions, reducing open surgical procedures. KEY POINTS: • Upgrade to malignancy after a vacuum-assisted excision of a B3 breast lesion is uncommon with an 8.6% upgrade rate. • The risk of a malignant diagnosis after a vacuum-assisted excision was significantly higher for B3 lesions with atypia compared to those without (+15.5% difference, p = .004).

Steric Inhibition of 5' UTR Regulatory Elements Results in Upregulation of Human CFTR.

Cystic fibrosis (CF) is an autosomal recessive monogenic disease caused by mutations in the CFTR gene. Therapeutic approaches that are focused on correcting CFTR protein face the challenge of the heterogeneity in CFTR mutations and resulting defects. Thus, while several small molecules directed at CFTR show benefit in the clinic for subsets of CF patients, these drugs cannot treat all CF patients. Additionally, the clinical benefit from treatment with these modulators could be enhanced with novel therapies. To address this unmet need, we utilized an approach to increase CFTR protein levels through antisense oligonucleotide (ASO)-mediated steric inhibition of 5' UTR regulatory elements. We identified ASOs to upregulate CFTR protein expression and confirmed the regulatory role of the sites amenable to ASO-mediated upregulation. Two ASOs were investigated further, and both increased CFTR protein expression and function in cell lines and primary human bronchial epithelial cells with distinct CF genotypes. ASO treatment further increased CFTR function in almost all CF genotypes tested on top of treatment with the FDA approved drug Symdeko (ivacaftor and tezacaftor). Thus, we present a novel approach to CFTR therapeutic intervention, through ASO-mediated modulation of translation.

Photocontrolled Release of Doxorubicin Conjugated through a Thioacetal Photocage in Folate-Targeted Nanodelivery Systems.

Despite their proven ability for precise and targeted release, nanoplatform systems for photocontrolled delivery often face formidable synthetic challenges, in part due to the paucity of advanced linker strategies. Here, we report on a novel linker strategy using a thioacetal ortho-nitrobenzaldehyde (TNB) cage, demonstrating its application for delivery of doxorubicin (Dox) in two nanoscale systems. This photocleavable linker, TNB(OH), which presents two identical arms, each terminated with a hydroxyl functionality, was prepared in a single step from 6-nitroveratraldehyde. TNB(OH) was used to cross-link Dox to a folate receptor (FAR)-targeting poly(amidoamine) dendrimer conjugate G5(FA)n=5.4(Dox)m=5.1, and also used to prepare an upconversion nanocrystal (UCN) conjugate, UCN-PPIX@(Dox)(G5FA), a larger core/shell nanostructure. In this core/shell nanostructure, the UCN core emits UV and visible light luminescence upon near-infrared (NIR) excitation, allowing for the photocleavage of the TNB linker as well as the photostimulation of protoporphyrin IX (PPIX) coupled as a cytotoxic photosensitizer. Drug-release experiments performed in aqueous solutions with long-wavelength ultraviolet A (UVA) light showed that Dox release occurred rapidly from its TNB linked form or from its dendrimer conjugated form with comparable decay kinetics. Cellular toxicity studies in FAR-overexpressing KB carcinoma cells demonstrated that each nanoconjugate lacked intrinsic cytotoxicity until exposed to UVA or NIR (980 nm) (for the UCN nanoconjugate), which resulted in induction of potent cytotoxicity. In summary, this new TNB strategy offers synthetic convenience in drug conjugation chemistry with the ability for the temporal control of drug activation at the delivery site.

Evaluation of the Project P.A.T.H.S. (extension phase) based on the perspective of the program participants.

Subjective outcome evaluation data were collected from 236 schools (n=87,943 students) after students had participated in the Tier 1 Program in the second year of the Extension Phase of the Project P.A.T.H.S. in Hong Kong. Using schools as the units of analysis, results showed that the program and implementers were perceived in a positive manner and approximately four-fifths of the participants regarded the program as helpful to them. There were some significant grade differences in the subjective outcome evaluation findings with small effect size. Multiple regression analyses showed that whereas perceived qualities of the program positively predicted perceived effectiveness of the program, perceived qualities of implementers negatively predicted program effectiveness. The present study suggests that irrespective of cohorts at different times, junior secondary school students perceived the program to be beneficial to them. The theoretical and practical implications of the present findings are discussed.

Helping adolescents with greater psychosocial needs: the extension phase of the Project P.A.T.H.S. in Hong Kong.

Subjective outcome evaluation data were collected from 24,198 students of 236 schools after completion of the Tier 2 Program in the second year of the Extension Phase of the Project P.A.T.H.S. in Hong Kong. Using schools as units of analysis, results showed that the program, implementers, and effectiveness were perceived in a positive manner. Although subjective outcome evaluation findings differed across participant types, grades, and program types did not show significant differences on the outcome measures. Consistent with previous reports, perceived effectiveness of the program was significantly predicted by student perceptions about the program and program instructor. These findings provide support for the claim that the Tier 2 Program is effective in promoting positive development among adolescents with greater psychosocial needs in the extension phase of the Project P.A.T.H.S. in Hong Kong.

Evaluation of Project P.A.T.H.S. by the program implementers: findings based on the extension phase.

A total of 236 schools participated in the Project P.A.T.H.S. in the 2010/2011 school year. After completion of the Tier 1 Program, subjective outcome evaluation data were collected from 3275 program implementers. Based on the consolidated findings based on schools as units, results showed that participants had positive perceptions of the program, implementers, and benefits of the program. More than four-fifths of the implementers regarded the program as helpful to the program participants. Multiple regression analysis revealed that perceived qualities of the program and the program implementers predicted perceived effectiveness of the program. Grade differences were not significant. The present study provides additional support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. in Hong Kong.

Transforming potential program implementers in professional development: the Project P.A.T.H.S. in Hong Kong.

High quality pre-implementation professional training is the cornerstone for successful implementation of positive youth development programs. A qualitative evaluation study was conducted to understand the experiences of the potential program implementers of the Project P.A.T.H.S. in Hong Kong. The findings showed that participants highly valued the learning experiences acquired from the training program, particularly in the areas of knowledge acquisition and personal growth. Participants who benefited from these dimensions developed attitudes and skills that are desirable for the implementation of the Project P.A.T.H.S. Implications about the conditions that are conducive to the P.A.T.H.S. training program in promoting knowledge, skills acquisition, retention, application, and generalization are discussed.

Development of a credit-bearing service leadership subject for university students in Hong Kong.

Given that service industries contribute to 93% of Hong Kong's GDP, an important question that should be asked is whether the education system can promote the development of service leadership among young people in Hong Kong. Unfortunately, service leadership programs specifically designed for university students are lacking in Hong Kong. In this paper, the basic tenets of the Service Leadership and Management framework are presented. Based on the fundamental postulation that effective service leadership is a function of moral character, competence and care (E=MC(2)), a subject called "Service Leadership" has recently been developed at The Hong Kong Polytechnic University. This paper outlines the objectives, intended learning outcomes, syllabus, assessment, and references of the subject. The proposed evaluation strategies are also described.

Student classroom misbehavior: an exploratory study based on teachers' perceptions.

This study aimed to examine the conceptions of junior secondary school student misbehaviors in classroom, and to identify the most common, disruptive, and unacceptable student problem behaviors from teachers' perspective. Twelve individual interviews with teachers were conducted. A list of 17 student problem behaviors was generated. Results showed that the most common and disruptive problem behavior was talking out of turn, followed by nonattentiveness, daydreaming, and idleness. The most unacceptable problem behavior was disrespecting teachers in terms of disobedience and rudeness, followed by talking out of turn and verbal aggression. The findings revealed that teachers perceived student problem behaviors as those behaviors involving rule-breaking, violating the implicit norms or expectations, being inappropriate in the classroom settings and upsetting teaching and learning, which mainly required intervention from teachers.

Classroom misbehavior in the eyes of students: a qualitative study.

Using individual interviews, this study investigated perceptions of classroom misbehaviors among secondary school students in Hong Kong (N = 18). Nineteen categories of classroom misbehaviors were identified, with talking out of turn, disrespecting teacher, and doing something in private being most frequently mentioned. Findings revealed that students tended to perceive misbehaviors as those actions inappropriate in the classroom settings and even disrupting teachers' teaching and other students' learning. Among various misbehaviors, talking out of turn and disrespecting teacher were seen as the most disruptive and unacceptable. These misbehaviors were unacceptable because they disturbed teaching and learning, and violated the values of respect, conformity, and obedience in the teacher-student relationship within the classroom. The frequency and intensity of misbehaviors would escalate if students found it fun, no punishment for such misbehaviors, or teachers were not authoritative enough in controlling the situations. Implications for further research and classroom management are discussed.

Qualitative evaluation of project P.A.T.H.S.: an integration of findings based on program participants.

An integration of the qualitative evaluation findings collected in different cohorts of students who participated in Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) (n = 252 students in 29 focus groups) was carried out. With specific focus on how the informants described the program, results showed that the descriptions were mainly positive in nature, suggesting that the program was well received by the program participants. When the informants were invited to name three metaphors that could stand for the program, positive metaphors were commonly used. Beneficial effects of the program in different psychosocial domains were also voiced by the program participants. The qualitative findings integrated in this paper provide further support for the effectiveness of the Tier 1 Program of Project P.A.T.H.S. in promoting holistic development in Chinese adolescents in Hong Kong.

The project P.A.T.H.S. in Hong Kong--lessons learned and implications for positive youth development programs.

The Project P.A.T.H.S. is a positive youth development program which attempts to promote holistic development of junior secondary schools in Hong Kong. It is ground breaking in terms of the number of schools participating in the project and financial resources injected into the project. Based on the experiences gained from the implementation of the project and evaluation data collected from 2005 to 2011, several issues pertinent to the development of positive youth development programs in the Chinese culture are discussed. These issues include complexity of program development, importance of training, identification of factors governing program implementation, need for evaluation, and promotion of sustainability of the program in the long run.

Evaluation of the project P.A.T.H.S. based on students' weekly diaries: findings from eight datasets.

This paper aims to investigate the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. (positive adolescent training through holistic social programmes) based on eight datasets collected between 2005 and 2009. A total of 1,138 students who participated in the program were randomly invited (from the whole grade or in some classes) to write a piece of journal in the form of a weekly diary in order to reveal their perceptions and feelings regarding the program and the perceived benefits of the program. Based on an integration of findings from different databases, results showed that the respondents generally (1) had positive views on the program, (2) had positive views on the instructors, and (3) perceived that they had acquired competencies at the societal, school, familial, interpersonal, and personal levels after joining the program. Acknowledging the limitations of diaries, the present qualitative findings provide support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. in Hong Kong.