Antibacterial Properties of Rose Bengal Conjugated to Hyaluronic Acid.

Dental diseases, including conditions affecting oral structures, have become more common due to unhealthy lifestyle choices. Traditional antibiotic treatments face challenges related to the development of antibiotic resistance in bacteria. Photodynamic antibacterial chemotherapy is emerging as a promising alternative using photosensitizers to generate reactive oxygen species upon exposure to light. This article examines the photosensitizer Rose Bengal (RB) immobilized in hyaluronic acid (HA) for prolonged antibacterial action. The RB-HA conjugate demonstrated a molar ratio of approximately three RB residues to each of the ten units of HA. RB-HA exhibited a high singlet oxygen quantum yield (ΔΦ = 0.90), suggesting its efficacy in photodynamic treatment. A photostability analysis revealed slower photobleaching of RB-HA, which is essential for prolonged application. Under visible light and ultrasonic treatment, RB-HA exhibited effective antibacterial activity against Gram-positive S. aureus and Gram-negative E. coli bacteria for at least 80 days. The gradual release of RB ensured sustained bactericidal concentration. The study establishes RB-HA as a promising candidate for antimicrobial photodynamic and sonodynamic therapy in dental and other medical fields, providing enhanced stability and prolonged antibacterial efficacy.

Evaluation of the implementation of evidence-based pediatric asthma exacerbation treatments in a regional consortium of emergency medical Services Agencies.

OBJECTIVE: Asthma exacerbations are a frequent reason for pediatric emergency medical services (EMS) encounters. The objective of this study was to examine the implementation of evidence-based treatments for pediatric asthma in a regional consortium of EMS agencies. METHODS: This retrospective study applied the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) implementation framework to data from an EMS agency consortium in the Cincinnati, Ohio region. The study analyzed one year before an oral systemic corticosteroid (OCS) option was added to the agencies' protocol, and five years after the protocol change. We constructed logistic regression models for the primary outcome of Reach, defined as the proportion of pediatric asthma patients who received a systemic corticosteroid. We modeled Maintenance (Reach measured monthly over time) using time series models. RESULTS: A total of 713 patients were included, 133 pre- and 580 post-protocol change. In terms of Reach, 3% (n = 4) of eligible patients received a systemic corticosteroid pre-OCS versus 20% (n = 116) post-OCS. Multivariable modeling of Reach revealed the study period, EMS transport time, months since implementation of OCS, and number of bronchodilators administered by EMS as significant covariates for the administration of a systemic corticosteroid. For Maintenance, it took approximately two years to reach maximal administration of systemic corticosteroids. CONCLUSIONS: Indicators of asthma severity and time since the protocol change were significantly associated with EMS administration of systemic corticosteroids to pediatric asthma patients. The two-year time for maximal Reach suggests further work is required to understand how to best implement evidence-based pediatric asthma treatments in EMS.

Prehospital Pediatric Asthma Care during COVID-19: Changes to EMS Treatment Protocols and Downstream Clinical Effects.

INTRODUCTION: During the COVID-19 pandemic, many emergency medical services (EMS) agencies modified treatment guidelines for clinical care and standard operating procedures. For the prehospital care of pediatric asthma exacerbations, modifications included changes to bronchodilator administration, systemic corticosteroid administration, and introduction of alternative medications. Since timely administration of bronchodilators and systemic corticosteroids has been shown to improve pediatric asthma clinical outcomes, we investigated the association of COVID-19 protocol modifications in the prehospital management of pediatric asthma on hospital admission rates and emergency department (ED) length-of-stay. METHODS: This is a multicenter, retrospective, observational cohort study comparing prehospital pediatric asthma patients treated by EMS clinicians from four EMS systems before and after implementation of COVID-19 interim EMS protocol modifications. We included children ages 2-18 years who were treated and transported by ground EMS for respiratory-related prehospital primary complaints, and who also had asthma-related ED discharge diagnoses. Patient data and outcomes were compared from 12 months prior to and 12 months after the implementation of interim COVID-19 prehospital protocol modifications using univariate and multivariable statistics. RESULTS: A total of 430 patients met inclusion criteria with a median age of 8 years. There was a slight male predominance (57.9%) and the majority of patients were African American (78.4%). There were twice as many patients treated prior to the COVID-19 protocol modifications (N = 287) compared to after (N = 143). There was a significant decrease in EMS bronchodilator administration from 76% to 59.4% of patients after COVID-19 protocol guidelines were implemented (p < 0.0001). Mixed effects models for hospital admission (to both pediatric inpatient units and pediatric intensive care units) as well as ED length-of-stay did not show any significant effect after the COVID-19 protocol change period (p = 0.18 and p = 0.55, respectively). CONCLUSIONS: Despite a decrease in prehospital bronchodilator administration after COVID-19 changes to prehospital pediatric asthma management protocols, hospital admission rates and ED length-of-stay did not significantly increase. However, this finding is tempered by the marked decrease in study patients treated after COVID-19 prehospital protocol modifications. Given the potential for future waves of COVID-19 variants, further studies with larger patient populations are warranted.

EMS Administration of Systemic Corticosteroids to Pediatric Asthma Patients: An Analysis by Severity and Transport Interval.

INTRODUCTION: Pediatric asthma exacerbations are a common cause of emergency medical services (EMS) encounters. Bronchodilators and systemic corticosteroids are mainstays of asthma exacerbation therapy, yet data on the efficacy of EMS administration of systemic corticosteroids are mixed. This study's objective was to assess the association between EMS administration of systemic corticosteroids to pediatric asthma patients on hospital admission rates based on asthma exacerbation severity and EMS transport intervals. METHODS: This is a sub-analysis of the Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial (EASI AS ODT). EASI AS ODT is a non-randomized, stepped wedge, observational study examining outcomes one year before and one year after seven EMS agencies incorporated an oral systemic corticosteroid option into their protocols for the treatment of pediatric asthma exacerbations. We included EMS encounters for patients ages 2-18 years confirmed by manual chart review to have asthma exacerbations. We compared hospital admission rates across asthma exacerbation severities and EMS transport intervals using univariate analyses. We geocoded patients and created maps to visualize the general trends of patient characteristics. RESULTS: A total of 841 pediatric asthma patients met inclusion criteria. While most patients were administered inhaled bronchodilators by EMS (82.3%), only 21% received systemic corticosteroids, and only 19% received both inhaled bronchodilators and systemic corticosteroids. Overall, there was no significant difference in hospitalization rates between patients who did and did not receive systemic corticosteroids from EMS (33% vs. 32%, p = 0.78). However, although not statistically significant, for patients who received systemic corticosteroids from EMS, there was an 11% decrease in hospitalizations for mild exacerbation patients and a 16% decrease in hospitalizations for patients with EMS transport intervals greater than 40 min. CONCLUSION: In this study, systemic corticosteroids were not associated with a decrease in hospitalizations of pediatric patients with asthma overall. However, while limited by small sample size and lack of statistical significance, our results suggest there may be a benefit in certain subgroups, particularly patients with mild exacerbations and those with transport intervals longer than 40 min. Given the heterogeneity of EMS agencies, EMS agencies should consider local operational and pediatric patient characteristics when developing standard operating protocols for pediatric asthma.

The Success of Resident-Associated Lumbar Punctures at a Large, Single-Center Children's Hospital.

OBJECTIVES: The frequency of lumbar punctures (LPs) has declined across US children's hospitals over the past decade, potentially decreasing procedural learning opportunities for pediatric resident trainees. Our study sought to determine whether the proportion of successful LPs performed by our pediatric residents has significantly changed over time. METHODS: This study is a single-center retrospective study to evaluate our pediatric resident LP success. We evaluated our primary outcome, proportion of overall LP success over time, using linear regression. We similarly used linear regression for proportion of successful resident-associated LPs over time. We calculated the median number of LPs of all pediatric residents during the study period. RESULTS: We analyzed 3143 LPs from April 2012 to December 2019. Both the overall number of LPs performed and the proportion of LPs that were successful have not significantly changed over an 8-year period ( P > 0.05, P > 0.05). Similarly, the number of our resident-associated LPs and the proportion of successful resident-associated LPs have not changed over the study period ( P > 0.05, P > 0.05). Our pediatric residents performed a median of 3 LPs (interquartile range: 2-4) in the pediatric emergency department (PED) over residency. CONCLUSIONS: Despite national trends showing decreased LP rates at pediatric hospitals, we demonstrated stable proportions of LPs and success by our pediatric residents. Pediatric residents perform a relatively low number of LPs in the PED setting alone. Future research is needed to demonstrate whether these overall low numbers in the PED translate to procedural competency after residency graduation.

Molecular genotyping of 15 B. anthracis strains isolated in Eastern Siberia and Far East.

Bacillus anthracis is a pathogenic bacterium, which causes anthrax disease. The ability of this bacterium to form spores, which can be preserved in soil for decades and cause outbreaks later on, makes this pathogen a serious problem for veterinary and health services of many countries. Siberia is one of the most anthrax-influenced regions of Russia. In this research we report on the results of genotyping based on whole genome SNP analysis of 15 strains, isolated on the territory of Eastern Siberia and the Far East in 1956-2018. In this research, we sequenced 15 genomes of B. anthracis strains isolated from infected humans and animals, and from soil samples from the territory of Eastern Siberia and the Far East in the period from 1956 to 2018. We used genomic sequences obtained in this study and 219 B. anthracis genomes available in the international GenBank database to perform a comparative analysis. As a result we detected 6400 chromosomal SNPs which allowed to differentiate the studied strains. We built phylogenetic reconstruction of the global B. anthracis population based on the detected SNPs using the Maximum Likelihood Method and described genetic diversity of the strains isolated on the territory of Eastern Siberia and the Far East. Strains, isolated on this territory from 1956 to 2018 belong to 5 different genetic groups: "Ames", "STI", "Tsiankovskii", "Siberia" and "Asia". The greatest diversity of the strains is registered for two regions of the southern part of Eastern Siberia - Tyva and Buryatia. This research expands current understanding of genetic diversity of B. anthracis strains circulating on the territory of Russia.

Comparison of children receiving emergent sepsis care by mode of arrival.

OBJECTIVE: To determine if differences in patient characteristics, treatments, and outcomes exist between children with sepsis who arrive by emergency medical services (EMS) versus their own mode of transport (self-transport). METHODS: Retrospective cohort study of patients who presented to the Emergency Department (ED) of two large children's hospitals and treated for sepsis from November 2013 to June 2017. Presentation, ED treatment, and outcomes, primarily time to first bolus and first parental antibiotic, were compared between those transported via EMS versus patients who were self-transported. RESULTS: Of the 1813 children treated in the ED for sepsis, 1452 were self-transported and 361 were transported via EMS. The EMS group were more frequently male, of black race, and publicly insured than the self-transport group. The EMS group was more likely to have a critical triage category, receive initial care in the resuscitation suite (51.9 vs. 22%), have hypotension at ED presentation (14.4 vs. 5.4%), lactate >2.0 mmol/L (60.6 vs. 40.8%), vasoactive agents initiated in the ED (8.9 vs. 4.9%), and to be intubated in the ED (14.4 vs. 2.8%). The median time to first IV fluid bolus was faster in the EMS group (36 vs. 57 min). Using Cox LASSO to adjust for potential covariates, time to fluids remained faster for the EMS group (HR 1.26, 95% CI 1.12, 1.42). Time to antibiotics, ICU LOS, 3- or 30-day mortality rates did not differ, yet median hospital LOS was significantly longer in those transported by EMS versus self-transported (6.5 vs. 5.3 days). CONCLUSIONS: Children with sepsis transported by EMS are a sicker population of children than those self-transported on arrival and had longer hospital stays. EMS transport was associated with earlier in-hospital fluid resuscitation but no difference in time to first antibiotic. Improved prehospital recognition and care is needed to promote adherence to both prehospital and hospital-based sepsis resuscitation benchmarks.

Phylogenetic analysis of Bacillus anthracis strains from Western Siberia reveals a new genetic cluster in the global population of the species.

BACKGROUND: Anthrax is a zoonotic disease caused by the gram-positive bacterium Bacillus anthracis. The most anthrax-endemic regions of Russia are Siberia and North Caucasus. Previously, genotyping of Russian B.anthracis isolates was carried out using canSNP and MLVA data; these methods yield lower resolution results compared to whole genome SNP analysis (wgSNP). In this research, we have used wgSNP method for genotyping of 10 B.anthracis isolates, obtained during 1961-2016 in Russia on territory of Western Siberia. RESULTS: We have analyzed 185 B.anthracis genomes available in GenBank database and genomes of 10 isolates obtained in this study to determine the place of Russian isolates in the global phylogeny of B.anthracis. For the studied genomes we have detected 7203 SNPs, which were used for building a phylogenetic reconstruction with Maximum Likelihood Method. Results of the phylogenetic analysis indicate that Russian strains belong to three different genetic groups. Three strains belong to genetic group "Ames", two strains - to "STI" group. Five strains belong to the main genetic line B, and four of them form a subcluster, described for the first time, which we have named "Siberia". CONCLUSIONS: In this study, the data on genetic diversity of B.anthracis strains on the territory of Western Siberia is presented for the first time. As a result of complex phylogenetic analysis, the place of these isolates was determined in the global phylogenetic structure of the B.anthracis population. We describe a new cluster in the main genetic line B for the first time.

Reaction Monitoring Using SABRE-Hyperpolarized Benchtop (1 T) NMR Spectroscopy.

The conversion of [IrCl(COD)(IMes)] (COD = cis, cis-1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene) in the presence of an excess of para-hydrogen ( p-H2) and a substrate (4-aminopyridine (4-AP) or 4-methylpyridine (4-MP)) into [Ir(H)2(IMes)(substrate)3]Cl is monitored by 1H NMR spectroscopy using a benchtop (1 T) spectrometer in conjunction with the p-H2-based hyperpolarization technique signal amplification by reversible exchange (SABRE). A series of single-shot 1H NMR measurements are used to monitor the chemical changes that take place in solution through the lifetime of the hyperpolarized response. Non-hyperpolarized high-field 1H NMR control measurements were also undertaken to confirm that the observed time-dependent changes relate directly to the underlying chemical evolution. The formation of [Ir(H)2(IMes)(substrate)3]Cl is further linked to the hydrogen isotope exchange (HIE) reaction, which leads to the incorporation of deuterium into the ortho positions of 4-AP, where the source of deuterium is the solvent, methanol- d4. Comparable reaction monitoring results are achieved at both high-field (9.4 T) and low-field (1 T). It is notable that the low sensitivity of the benchtop (1 T) NMR enables the use of protio solvents, which when used here allows the effects of catalyst formation and substrate deuteration to be separated. Collectively, these methods illustrate how low-cost low-field NMR measurements provide unique insight into a complex catalytic process through a combination of hyperpolarization and relaxation data.

Genotyping and phylogenetic location of one clinical isolate of Bacillus anthracis isolated from a human in Russia.

BACKGROUND: Anthrax is a zoonotic disease caused by the Gram-positive bacterium Bacillus anthracis. In Russia, there are more than 35 thousand anthrax stationary unfavourable sites. At the same time, there is very little published information about the isolates of B. anthracis from the territory of Russia. In this study, we report the use of whole genome sequencing (WGS) and bioinformatics analysis to characterize B. anthracis 81/1 strain isolated in Russia in 1969 from a person during an outbreak of the disease in the Stavropol region. RESULTS: We used 232 B. anthracis genomes, which are currently available in the GenBank database, to determine the place of the Russian isolate in the global phylogeny of B. anthracis. The studied strain was characterized by PCR-based genetic methods, such as Multiple-Locus Variable-Number Tandem Repeat Analysis (MLVA), canonical single nucleotide polymorphisms (canSNP), as well as the method of full-genomic analysis of nucleotide polymorphisms (wgSNP). The results indicate that the Russian B. anthracis 81/1 strain belongs to Trans-Eurasion (TEA) group, the most representative in the world. CONCLUSIONS: In this study, the full genomic sequence of virulent B. anthracis strain from Russia was characterized for the first time. As a result of complex phylogenetic analysis, the place of this isolate was determined in the global phylogenetic structure of the B. anthracis population, expanding our knowledge of anthrax phylogeography in Russia.

Characterization of Children with Septic Shock Cared for by Emergency Medical Services.

Objective: To inform the future development of a pediatric prehospital sepsis tool, we sought to 1) describe the characteristics, emergent care, and outcomes for children with septic shock who are transported by emergency medicine services (EMS) and compare them to those self-transported; and 2) determine the EMS capture rate of common sepsis screening parameters and the concordance between the parameters documented in the EMS record and in the emergency department (ED) record. Methods: This is a retrospective cohort study of children ages 0 through 21 years who presented to a pediatric ED with septic shock between 11/2013 and 06/2016. Data, collected by electronic and manual chart review of EMS and ED records, included demographics, initial vital signs in both EMS and ED records, ED triage level, site of initial ED care, ED disposition, ED therapeutic interventions, outcomes, and times associated with processes. Potential screening parameters were dichotomized as normal vs. abnormal based on age-dependent normative data. Results: Of the children with septic shock treated in our ED, 19.3% arrived via EMS. These children as compared to those self-transported were more likely (i.e., p < 0.05) to be male, have public insurance, receive initial care in the ED resuscitation suite, be hypotensive on arrival, receive their first ED fluid bolus sooner (33 vs. 58 minutes), receive vasoactive agents, be mechanically ventilated in the first 24 hours, and have slightly longer length of hospital stays. Both groups had similar times to antibiotics. While poor outcomes were rare, the 3- and 30-day mortalities were similar for both groups. EMS capture rates were highest for heart rate and respiratory rate and lowest for temperature, glucose, and blood pressure. Interrater reliability was highest for heart rate. Conclusions: Children presenting to the ED with septic shock transported by EMS represent a critically ill subset of modest proportions. Realization of a sepsis screening tool for this vulnerable population will require both creation of a tool containing a limited subset of objective parameters along with processes to ensure capture.

SABRE hyperpolarization enables high-sensitivity 1H and 13C benchtop NMR spectroscopy.

Benchtop NMR spectrometers operating with low magnetic fields of 1-2 T at sub-ppm resolution show great promise as analytical platforms that can be used outside the traditional laboratory environment for industrial process monitoring. One current limitation that reduces the uptake of benchtop NMR is associated with the detection fields' reduced sensitivity. Here we demonstrate how para-hydrogen (p-H2) based signal amplification by reversible exchange (SABRE), a simple to achieve hyperpolarization technique, enhances agent detectability within the environment of a benchtop (1 T) NMR spectrometer so that informative 1H and 13C NMR spectra can be readily recorded for low-concentration analytes. SABRE-derived 1H NMR signal enhancements of up to 17 000-fold, corresponding to 1H polarization levels of P = 5.9%, were achieved for 26 mM pyridine in d4-methanol in a matter of seconds. Comparable enhancement levels can be achieved in both deuterated and protio solvents but now the SABRE-enhanced analyte signals dominate due to the comparatively weak thermally-polarized solvent response. The SABRE approach also enables the acquisition of 13C NMR spectra of analytes at natural isotopic abundance in a single scan as evidenced by hyperpolarized 13C NMR spectra of tens of millimolar concentrations of 4-methylpyridine. Now the associated signal enhancement factors are up to 45 500 fold (P = 4.0%) and achieved in just 15 s. Integration of an automated SABRE polarization system with the benchtop NMR spectrometer framework produces renewable and reproducible NMR signal enhancements that can be exploited for the collection of multi-dimensional NMR spectra, exemplified here by a SABRE-enhanced 2D COSY NMR spectrum.

Detection of the synthetic cathinone N,N-dimethylpentylone in seized samples from prisons.

Drug use is prevalent in prisons with drugs associated with depressant effects found to be more prevalent than stimulants. Synthetic cathinones (SCats; often sold as "bath salts", "ecstasy", "molly", and "monkey dust") are the second largest category of new psychoactive substances (NPS) currently monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and are commonly used as substitutes for regulated stimulants, such as amphetamine, cocaine, and MDMA. N,N-dimethylpentylone (also known as dimethylpentylone, dipentylone, and bk-DMBDP) was detected for the first time in the Scottish prisons in seven powder samples seized between January and July 2023. Samples were analyzed using gas chromatography-mass spectrometry (GC-MS), ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-QToF-MS), and nuclear magnetic resonance imaging (NMR). Dimethylpentylone was detected alongside other drugs in four samples, including the novel benzodiazepine desalkylgidazepam (bromonordiazepam) and the synthetic cannabinoid receptor agonists (SCRAs) MDMB-INACA and MDMB-4en-PINACA.

Emergency Department Pediatric Mental and Behavioral Health Patients Transported by Emergency Medical Services and Police: Trends and Interventions.

OBJECTIVE: We aimed to understand transport utilization trends, demographics, emergency department (ED) interventions, and outcomes of pediatric mental and behavioral health (MBH) patients transported by emergency medical services (EMS), police, or self-transported. METHODS: This retrospective cohort study utilized electronic health record data from patients aged 5 to 18 years presenting with acute MBH conditions at 2 affiliated pediatric EDs from January 2012 to December 2020. Data included demographics, ED interventions for aggression/agitation, Brief Rating of Aggression by Children and Adolescents (BRACHA) scores, and ED dispositions. Descriptive statistics and comparative analyses were conducted using chi-square, Wilcoxon rank sum tests, and multivariable logistic regression. Linear regression analyzed trends. RESULTS: Of 440,302 ED encounters, 70,557 (16%) were for acute MBH concerns, with 14.6% transported by EMS and 5.9% by police. The proportion of MBH visits increased from 9.9% in 2012 to 19.8% in 2020 (95% (confidence interval) CI [0.7, 1.7], P = 0.0009), with a concurrent 0.4% annual increase in those transported by EMS (95% CI [0.2, 0.6], P = 0.006). MBH patients transported by EMS and police had significantly higher odds of requiring restraint in the ED and were more likely to have higher BRACHA scores and to be admitted compared to self-transported patients (all comparisons, P < 0.001). CONCLUSIONS: Pediatric MBH ED visits and EMS utilization are increasing. MBH patients transported by EMS and police may represent a more aggressive ED population. Given the rising encounters within this high-risk population, our EDs, EMS, and police need support and resources for safe pediatric MBH patient management.

Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial (EASI-AS-ODT).

BACKGROUND: In the emergency department (ED), prompt administration of systemic corticosteroids for pediatric asthma exacerbations decreases hospital admission rates. However, there is sparse evidence for whether earlier administration of systemic corticosteroids by emergency medical services (EMS) clinicians, prior to ED arrival, further improves pediatric asthma outcomes. METHODS: Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial is a multicenter, observational, nonrandomized stepped-wedge design study with seven participating EMS agencies who adopted an oral systemic corticosteroid (OCS) into their protocols for pediatric asthma treatment. Using univariate analyses and multivariable mixed-effects models, we compared hospital admission rates for pediatric asthma patients ages 2-18 years before and after the introduction of a prehospital OCS and for those who did and did not receive a systemic corticosteroid from EMS. RESULTS: A total of 834 patients were included, 21% of whom received a systemic corticosteroid from EMS. EMS administration of systemic corticosteroids increased after the introduction of an OCS from 14.7% to 28.1% (p < 0.001). However, there was no significant difference between hospital admission rates and ED length of stay before and after the introduction of OCS or between patients who did and did not receive a systemic corticosteroid from EMS. Mixed-effects models revealed that age 14-18 years (coefficient -0.83, p = 0.002), EMS administration of magnesium (coefficient 1.22, p = 0.04), and initial EMS respiratory severity score (coefficient 0.40, p < 0.001) were significantly associated with hospital admission. CONCLUSIONS: In this multicenter study, the addition of an OCS into EMS agency protocols for pediatric asthma exacerbations significantly increased systemic corticosteroid administration but did not significantly decrease hospital admission rates. As overall EMS systemic corticosteroid administration rates were low, further work is required to understand optimal implementation of EMS protocol changes to better assess potential benefits to patients.

Synthesis and biological evaluation of theranostic Trastuzumab-SN38 conjugate for Near-IR fluorescence imaging and targeted therapy of HER2+ breast cancer.

Here, we report on the design, synthesis, and biological evaluation of a new theranostic antibody drug conjugate (ADC), Cy5-Ab-SS-SN38, that consists of the HER2-specific antibody trastuzumab (Ab) connected to the near infrared (NIR) pentamethine cyanine dye Cy5 and SN38, which is a bioactive metabolite of the anticancer drug irinotecan. SN38 is bound to an antibody through a glutathione-responsive self-immolative disulfide carbamate linker. For the first time, we explored this linker in ADC and found that it to reduce the drug release rate, which is important for safe drug delivery. The developed ADC exhibited specific accumulation and nanomolar anti-breast cancer activity on HER2-positive (HER2+) cell lines but no effect on HER2-. Animals treated with this ADC exhibited good tolerance. In vivo studies have shown that the ADC had good targeting ability for HER2+ tumors with much higher anticancer potency than trastuzumab itself or a mixture of trastuzumab with SN38. Side-by-side HER2+/HER2-xenograft at the 10 mg/kg dose exhibited specific accumulation and reduction of HER2+ tumor but not accumulation or growth inhibition of HER2-counterpart. The self-immolative disulfide linker implemented in this study was proven to be successful, broadening its utilization with other antibodies for targeted anticancer therapy in general. We believe that the theranostic ADCs comprising the glutathione-responsive self-immolative disulfide carbamate linker are applicable for the treatment and fluorescent monitoring of malignancies and anticancer drug delivery.

Effect of Solubilizing Group on the Antibacterial Activity of Heptamethine Cyanine Photosensitizers.

Antibiotic resistance of pathogenic bacteria dictates the development of novel treatment modalities such as antimicrobial photodynamic therapy (APDT) utilizing organic dyes termed photosensitizers that exhibit a high cytotoxicity upon light irradiation. Most of the clinically approved photosensitizers are porphyrins that are poorly excitable in the therapeutic near-IR spectral range. In contrast, cyanine dyes function well in the near-IR region, but their phototoxicity, in general, is very low. The introduction of iodine atoms in the cyanine molecules was recently demonstrated to greatly increase their phototoxicity. Herein, we synthesized a series of the new iodinated heptamethine cyanine dyes (ICy7) containing various solubilizing moieties, i.e., negatively charged carboxylic (ICy7COOH) and sulfonic (ICy7SO3H) groups, positively charged triphenylphosphonium (ICy7PPh3), triethylammonium (ICy7NEt3) and amino (ICy7NH2) groups, and neutral amide (ICy7CONHPr) group. The effect of these substituents on the photodynamic eradication of Gram-positive (S. aureus) and Gram-negative (E. coli and P. aeruginosa) pathogens was studied. Cyanine dyes containing the amide and triphenylphosphonium groups were found to be the most efficient for eradication of the investigated bacteria. These dyes are effective at low concentrations of 0.05 µM (33 J/cm2) for S. aureus, 50 µM (200 J/cm2) for E. coli, and 5 µM (100 J/cm2) for P. aeruginosa and considered, therefore, promising photosensitizers for APDT applications. The innovation of the new photosensitizers consisted of a combination of the heavy-atom effect that increases singlet oxygen generation with the solubilizing group's effect improving cell uptake, and with effective near-IR excitation. Such a combination helped to noticeably increase the APDT efficacy and should pave the way for the development of more advanced photosensitizers for clinical use.

Examination of disparities in prehospital encounters for pediatric asthma exacerbations.

Introduction: There are disparities in multiple aspects of pediatric asthma care; however, prehospital care disparities are largely undescribed. This study's objective was to examine racial and geographic disparities in emergency medical services (EMS) medication administration to pediatric patients with asthma. Methods: This is a substudy of the Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial, which includes data from pediatric asthma patients ages 2-18 years. We examined rates of EMS administration of systemic corticosteroids and inhaled bronchodilators by patient race. We geocoded EMS scene addresses, characterized the locations' neighborhood-based conditions and resources relevant to children using the Child Opportunity Index (COI) 2.0, and analyzed associations between EMS scene address COI with medications administered by EMS. Results: A total of 765 patients had available racial data and 825 had scene addresses that were geocoded to a COI. EMS administered at least 1 bronchodilator to 84.7% (n = 492) of non-White patients and 83.2% of White patients (n = 153), P = 0.6. EMS administered a systemic corticosteroid to 19.4% (n = 113) of non-White patients and 20.1% (n = 37) of White patients, P = 0.8. There was a significant difference in bronchodilator administration between COI categories of low/very low versus moderate/high/very high (85.0%, n = 485 vs. 75.9%, n = 192, respectively, P = 0.003). Conclusions: There were no racial differences in EMS administration of medications to pediatric asthma patients. However, there were significantly higher rates of EMS bronchodilator administration for encounters in low/very low COIs. That latter finding may reflect inequities in asthma exacerbation severity for patients living in disadvantaged areas.

The metabolism of the synthetic cannabinoids ADB-BUTINACA and ADB-4en-PINACA and their detection in forensic toxicology casework and infused papers seized in prisons.

Early warning systems detect new psychoactive substances (NPS), while dedicated monitoring programs and routine drug and toxicology testing identify fluctuations in prevalence. We report the increasing prevalence of the synthetic cannabinoid receptor agonist (SCRA) ADB-BUTINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-butyl-1H-indazole-3-carbox-amide). ADB-BUTINACA was first detected in a seizure in Sweden in 2019, and we report its detection in 13 routine Swedish forensic toxicology cases soon after. In January 2021, ADB-BUTINACA was detected in SCRA-infused papers seized in Scottish prisons and has rapidly increased in prevalence, being detected in 60.4% of the SCRA-infused papers tested between January and July 2021. In this work, ADB-BUTINACA was incubated with human hepatocytes (HHeps), and 21 metabolites were identified in vitro, 14 being detected in authentic case samples. The parent drug and metabolites B9 (mono-hydroxylation on the n-butyl tail) and B16 (mono-hydroxylation on the indazole ring) are recommended biomarkers in blood, while metabolites B4 (dihydrodiol formation on the indazole core), B9, and B16 are suitable biomarkers in urine. ADB-4en-PINACA (N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[pent-4-en-1-yl]-1H-indazole-3-carboxamide) was detected in Scottish prisons in December 2020, but, unlike ADB-BUTINACA, prevalence has remained low. ADB-4en-PINACA was incubated with HHeps, and 11 metabolites were identified. Metabolites E3 (dihydrodiol formed in the tail moiety) and E7 (hydroxylation on the linked/head group) are the most abundant metabolites in vitro and are suggested as urinary biomarkers. The in vitro potencies of ADB-BUTINACA (EC50 , 11.5 nM and ADB-4en-PINACA (EC50 , 11.6 nM) are similar to that of MDMB-4en-PINACA (EC50 , 4.3 nM). A third tert-leucinamide SCRA, ADB-HEXINACA was also detected in prison samples and warrants further investigation.