Heat and Cardiovascular Mortality: An Epidemiological Perspective.

As global temperatures rise, extreme heat events are projected to become more frequent and intense. Extreme heat causes a wide range of health effects, including an overall increase in morbidity and mortality. It is important to note that while there is sufficient epidemiological evidence for heat-related increases in all-cause mortality, evidence on the association between heat and cause-specific deaths such as cardiovascular disease (CVD) mortality (and its more specific causes) is limited, with inconsistent findings. Existing systematic reviews and meta-analyses of epidemiological studies on heat and CVD mortality have summarized the available evidence. However, the target audience of such reviews is mainly limited to the specific field of environmental epidemiology. This overarching perspective aims to provide health professionals with a comprehensive overview of recent epidemiological evidence of how extreme heat is associated with CVD mortality. The rationale behind this broad perspective is that a better understanding of the effect of extreme heat on CVD mortality will help CVD health professionals optimize their plans to adapt to the changes brought about by climate change and heat events. To policymakers, this perspective would help formulate targeted mitigation, strengthen early warning systems, and develop better adaptation strategies. Despite the heterogeneity in evidence worldwide, due in part to different climatic conditions and population dynamics, there is a clear link between heat and CVD mortality. The risk has often been found to be higher in vulnerable subgroups, including older people, people with preexisting conditions, and the socioeconomically deprived. This perspective also highlights the lack of evidence from low- and middle-income countries and focuses on cause-specific CVD deaths. In addition, the perspective highlights the temporal changes in heat-related CVD deaths as well as the interactive effect of heat with other environmental factors and the potential biological pathways. Importantly, these various aspects of epidemiological studies have never been fully investigated and, therefore, the true extent of the impact of heat on CVD deaths remains largely unknown. Furthermore, this perspective also highlights the research gaps in epidemiological studies and the potential solutions to generate more robust evidence on the future consequences of heat on CVD deaths.

Cyanobacterial Proteomics: Diversity and Dynamics.

Cyanobacteria (oxygenic photoautrophs) comprise a diverse group holding significance both environmentally and for biotechnological applications. The utilization of proteomic techniques has significantly influenced investigations concerning cyanobacteria. Application of proteomics allows for large-scale analysis of protein expression and function within cyanobacterial systems. The cyanobacterial proteome exhibits tremendous functional, spatial, and temporal diversity regulated by multiple factors that continuously modify protein abundance, post-translational modifications, interactions, localization, and activity to meet the dynamic needs of these tiny blue greens. Modern mass spectrometry-based proteomics techniques enable system-wide examination of proteome complexity through global identification and high-throughput quantification of proteins. These powerful approaches have revolutionized our understanding of proteome dynamics and promise to provide novel insights into integrated cellular behavior at an unprecedented scale. In this Review, we present modern methods and cutting-edge technologies employed for unraveling the spatiotemporal diversity and dynamics of cyanobacterial proteomics with a specific focus on the methods used to analyze post-translational modifications (PTMs) and examples of dynamic changes in the cyanobacterial proteome investigated by proteomic approaches.

CaLAP1 and CaLAP2 orchestrate anthocyanin biosynthesis in the seed coat of Cicer arietinum.

MAIN CONCLUSION: Our findings shed light on the regulation of anthocyanin and proanthocyanidin biosynthesis in chickpea seed coats. Expression of R2R3-MYB transcription factors CaLAP1 and CaLAP2 enhanced the anthocyanins and proanthocyanidins content in chickpea. The seed coat color is a major economic trait in leguminous crop chickpea (Cicer arietinum). Anthocyanins and proanthocyanidins (PAs) are two classes of flavonoids that mainly contribute to the flower, seed coat and color of Desi chickpea cultivars. Throughout the land plant lineage, the accumulation of anthocyanins and PAs is regulated by MYB and bHLH transcription factors (TFs), which form an MBW (MYB, bHLH, and WD40) complex. Here, we report two R2R3-MYB TFs in chickpea belonging to the anthocyanin-specific subgroup-6, CaLAP1 (Legume Anthocyanin Production 1), and CaLAP2 (Legume Anthocyanin Production 2), which are mainly expressed in the flowers and developmental stages of the seeds. CaLAP1 and CaLAP2 interact with TT8-like CabHLH1 and WD40, forming the MBW complex, and bind to the promoter sequences of anthocyanin- and PA biosynthetic genes CaCHS6, CaDFR2, CaANS, and CaANR, leading to anthocyanins and PA accumulation in the seed coat of chickpea. Moreover, these CaLAPs partially complement the anthocyanin-deficient phenotype in the Arabidopsis thaliana sextuple mutant seedlings. Overexpression of CaLAPs in chickpea resulted in significantly higher expression of anthocyanin and PA biosynthetic genes leading to a darker seed coat color with higher accumulation of anthocyanin and PA. Our findings show that CaLAPs positively modulate anthocyanin and PA content in seed coats, which might influence plant development and resistance to various biotic and abiotic stresses.

Contaminant Organism Growth in Febrile Infants at Low Risk for Invasive Bacterial Infection.

In this multicenter, cross-sectional, secondary analysis of 4042 low-risk febrile infants, nearly 10% had a contaminated culture obtained during their evaluation (4.9% of blood cultures, 5.0% of urine cultures, and 1.8% of cerebrospinal fluid cultures). Our findings have important implications for improving sterile technique and reducing unnecessary cultures.

A Lipophilic Salt Form to Enhance the Lipid Solubility and Certain Biopharmaceutical Properties of Lapatinib.

Lapatinib (LTP) commercially available as lapatinib ditosylate (LTP-DTS) salt is the only drug approved for the treatment of HER-positive metastatic breast cancer. A low and pH-dependent solubility results in poor and variable oral bioavailability, thus driving significant interest in molecular modification and formulation strategies of the drug. Furthermore, due to very high crystallinity, LTP and LTP-DTS have low solubility in lipid excipients, making it difficult to be delivered by lipid-based carrier systems. Thus, the present work reports a new salt form of LTP with a docusate counterion to enhance the pharmaceutical properties of the drug (LTP-DOC). NMR spectra showed a downfield shift of the methylene singlet proton from 3.83 and 4.41 ppm, indicating a lowering of electron density on the adjacent nitrogen atom and confirming the formation of amine-sulfonyl salt through the specified basic nitrogen center located adjacent to the furan ring. PXRD diffractograms of LTP-DOC indicated a reduced crystallinity of the prepared salt. The dissolution, equilibrium solubility, lipid excipient solubility, partitioning coefficient, distribution coefficient, tabletability, and in vitro cytotoxicity of the lipophilic salt of LTP were investigated. The equilibrium solubility data showed that LTP-DOC possesses a pH-independent solubility profile in the pH range of 3.5 to 7.4 with a 3.14 times higher permeability coefficient than commercial ditosylate salt. Furthermore, the prepared LTP-DOC salts showed twice higher log P than the free base and 8 times higher than LTP-DTS. The prepared LTP-DOC was found to have 4- to 9-fold higher solubility in lipid excipients like Capmul MCM C8 and Maisine CC compared to the ditosylate salt. The LTP-DOC salt was tabletable and showed approximately 1.2 times lower dissolution than commercial ditosylate salt, indicating extended-release behavior. A cytotoxicity study of LTP-DOC salt showed an approximately 2.5 times lower IC50 value than the LTP-free base and 1.7 times lower than commercial ditosylate salt with an approximately 3 times higher selectivity index. The investigations strongly indicate a high translational potential of the prepared salt form in maintaining solubility-lipophilicity interplay, enhancing the drug's bioavailability, and developing lipidic formulations.

Excess Mortality Risk Due to Heat Stress in Different Climatic Zones of India.

India is at a high risk of heat stress-induced health impacts and economic losses owing to its tropical climate, high population density, and inadequate adaptive planning. The health impacts of heat stress across climate zones in India have not been adequately explored. Here, we examine and report the vulnerability to heat stress in India using 42 years (1979-2020) of meteorological data from ERA-5 and developed climate-zone-specific percentile-based human comfort class thresholds. We found that the heat stress is usually 1-4 °C higher on heatwave (HW) days than on nonheatwave (NHW) days. However, the stress on NHW days remains considerable and cannot be neglected. We then showed the association of a newly formulated India heat index (IHI) with daily all-cause mortality in three cities - Delhi (semiarid), Varanasi (humid subtropical), and Chennai (tropical wet and dry), using a semiparametric quasi-Poisson regression model, adjusted for nonlinear confounding effects of time and PM2.5. The all-cause mortality risk was enhanced by 8.1% (95% confidence interval, CI: 6.0-10.3), 5.9% (4.6-7.2), and 8.0% (1.7-14.2) during "sweltering" days in Varanasi, Delhi, and Chennai, respectively, relative to "comfortable" days. Across four age groups, the impact was more severe in Varanasi (ranging from a 3.2 to 7.5% increase in mortality risk for a unit rise in IHI) than in Delhi (2.6-4.2% higher risk) and Chennai (0.9-5.7% higher risk). We observed a 3-6 days lag effect of heat stress on mortality in these cities. Our results reveal heterogeneity in heat stress impact across diverse climate zones in India and call for developing an early warning system keeping in mind these regional variations.

Urinalysis in Suspected Child Abuse Evaluation in the Emergency Department.

BACKGROUND: Intra-abdominal injury (IAI) is the second leading cause of mortality in abused children. It is challenging to identify in young patients due to their limited verbal skills, delayed symptoms, less muscular abdominal wall, and limited bruising. METHODS: We conducted a retrospective cohort study of children aged 0 to 12 months who were evaluated in the emergency department for suspected child abuse with a skeletal survey and urinalysis between January 1, 2015, and December 31, 2017. Our primary objective was to identify the proportion of IAI cases identified by urinalysis alone (>10 RBC/HPF) and not by examination findings or other laboratory results. A secondary objective was to quantify potential delay in disposition while waiting for urinalysis results, calculated as the length of time between receiving skeletal survey and laboratory results and receiving urinalysis results. RESULTS: Six hundred thirteen subjects met our inclusion criteria; two subjects had hematuria, one of whom had a urinary tract infection. The other was determined to have blood from a catheterized urine specimen. One subject was found to have an IAI. We further found that urinalysis was delayed for 78% of subjects and took a median of 93 [interquartile range, 46-153] minutes longer than imaging and/or laboratories. CONCLUSIONS: No subjects were diagnosed with abdominal trauma based on urinalysis during evaluation in the emergency department who would not have been identified by other standard testing. In addition, patients' disposition was delayed while waiting for urinalysis.

Development of a Small-Footprint 50 MHz Linear Array: Fabrication and Micro-Ultrasound Imaging Demonstration.

Compact high-frequency arrays are of interest for clinical and preclinical applications in which a small-footprint or endoscopic device is needed to reach the target anatomy. However, the fabrication of compact arrays entails the connection of several dozens of small elements to the imaging system through a combination of flexible printed circuit boards at the array end and micro-coaxial cabling to the imaging system. The methods currently used, such as wire bonding, conductive adhesives, or a dry connection to a flexible circuit, considerably increase the array footprint. Here, we propose an interconnection method that uses vacuum-deposited metals, laser patterning, and electroplating to achieve a right-angle, compact, reliable connection between array elements and flexible-circuit traces. The array elements are thickened at the edges using patterned copper traces, which increases their cross-sectional area and facilitates the connection. We fabricated a 2.3 mm by 1.7 mm, 64-element linear array with elements at a 36 µm pitch connected to a 4 cm long flexible circuit, where the interconnect adds only 100 µm to each side of the array. Pulse-echo measurements yielded an average center frequency of 55 MHz and a -6 dB bandwidth of 41%. We measured an imaging resolution of 35 µm in the axial direction and 114 µm in the lateral direction and demonstrated the ex vivo imaging of porcine esophageal tissue and the in vivo imaging of avian embryonic vasculature.

Natural food flavours: a healthier alternative for bakery industry-a review.

Human beings always remained attracted towards vivid food flavours and aroma. Ever since the food industry came into existence, several brands and industries worldwide have been busy creating storms in the food markets through flavours, aromas, textures and substances to intrigue the consumers' minds. The ingredients that go into the preparation of these food items include a list of various preservatives, taste enhancers, stabilizers, colours and to make it look attractive and delicious but may not be healthy. Most of the flavours that are used by food brands are often chemical based and are synthesized completely in the laboratory. The use of artificial/synthetic flavourings in the form of chemical food additives and taste enhancers lead to long term health issues which include potential risks of neurological problems, cytotoxicity, genotoxicity, different types of hypersensitivities and even cancers. Food and Drug Administration (FDA, USA) conduct frequent studies to limit the use of artificial flavouring and additives which are totally chemical based and mimic natural food flavours and extract. Benzaldehyde-an organic chemical closely resembles the flavour of roasted almonds and ethyl vanillin which is 3 times potent than natural vanilla extract used is various confectionery items. Also several ester derivatives are used for mimicking natural fruit flavours like strawberry, guava and cherry. These chemicals pose a considerable threat to human health, knowingly or unknowingly. Antagonistically, natural food flavours, though not as popular as artificial ones prove to be healthier and carry the same aroma and taste as artificial flavouring agents. This review paper sheds light on the pervasiveness of natural and artificial food flavouring agents in the market, their benefits and drawbacks and how they have been in a constant race for dominating the bakery industry.

Bardet-Biedl Syndrome with Choledochal Cyst: Rare Association with a Novel Variant.

Bardet-Biedl syndrome is an autosomal-recessive ciliopathic disorder affecting multiple organ systems. Characteristic features include progressive retinal dystrophy, obesity, polydactyly hypogonadism, mental retardation, and renal disorders. Other manifestations include congenital heart diseases, hepatic fibrosis, ataxia, and diabetes. Approximately 30% of patients with Biedl-Bardet syndrome (BBS) have hepatobiliary disorders such as periportal fibrosis, nonalcoholic fatty liver disease, and cystic dilation of the bile ducts. The association of BBS with choledochal cysts (CDC) is extremely rare. Here, we report a case of a 14-year-old boy with a novel variant of BBS and associated type IV CDC. The patient was managed surgically with CDC excision and Roux-en-Y hepaticojejunostomy.

Ellagic Acid Reverses Alterations in the Expression of AMPA Receptor and Its Scaffolding Proteins in the Cerebral Cortex and Memory Decline in STZ-sporadic Alzheimer' s Disease Mouse Model.

RATIONALE: Alzheimer's disease (AD), an age-dependent devastating neuropsychiatric disorder, is a leading cause of learning, memory and intellectual disabilities. Current therapeutic approaches for the amelioration of the anomalies of AD are not effective. OBJECTIVE: In the present study, the molecular mechanisms underlying sporadic AD (sAD), the memory related behavioral analysis and neuroprotective effects of Ellagic acid (EA) were investigated. METHOD: sAD mouse model was developed by intracerebroventricular (ICV) injection of Streptozotocin (STZ). The efficacy of EA, a naturally occurring polyphenol, in amelioration of anomalies associated with sAD was assessed. EA was administered once daily for 28 days at a dose of 75 mg/kg body weight followed by neurobehavioral, biochemical, molecular and neuronal count analysis to delineate the mode of action of EA. RESULT: The ICV injection of STZ in mice significantly increased the expression of AD biomarkers in addition to enhanced oxidative stress. A decline in the discrimination index in Novel Object Recognition Test was observed indicating the compromise of recognition memory in AD. Studies on the expression of genes involved in synaptic plasticity reveal the dysregulation of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) of the glutamate and its scaffolding proteins in the postsynaptic density and thereby synaptic plasticity in AD. ICV-STZ led to significant upregulation of apoptotic markers which led to decrease in neuronal density of the cerebral cortex. EA significantly reversed the above and improved anomalies of sAD. CONCLUSION: EA was observed to profoundly modulate the genes involved in AD pathophysiology, restored antioxidant enzymes activity, reduced lipid peroxidation and neuronal loss in the sAD brain. Further, EA was observed to effectively modulate the genes involved in apoptosis and synaptic plasticity. Therefore, EA possesses promising anti-AD properties, which may improve AD-associated anomalies by modulating synaptic plasticity via AMPAR signaling.

Burden of Tuberculosis among tribal populations of India: A systematic review and meta-analysis.

ABSTRACT: Tuberculosis (TB) continues to impose a significant burden on tribal populations in India, a high-risk group for the disease. Despite its preventable and curable nature, TB remains a formidable health challenge for these communities. However, a critical knowledge gap exists regarding the population-based prevalence of TB among tribal populations in India. The current systematic review and meta-analysis were carried out to provide a single, population-based estimate. A comprehensive search was conducted on PubMed, Embase, Scopus, and Web of Science databases using the keywords 'tuberculosis', 'TB', and 'tribal' or 'tribes'. This search encompassed articles published between 1 January 2000 and 1 March 2023. The included articles underwent a quality assessment screening to ensure their reliability and relevance. Subsequently, a pooled estimate of TB prevalence among tribal populations was quantified using a random-effects model. To investigate potential sources of heterogeneity in the prevalence estimates, subgroup analyses were performed. We identified 14 studies that encompassed a substantial population of 267,377 individuals from various regions in India belonging to tribal communities. The application of a random-effects model yielded a pooled prevalence estimate of 894.4 per 100,000 population, with a 95% confidence interval ranging from 523.5 to 1361.9. The assessment of heterogeneity using the Cochrane Q test indicated significant variability among the included studies (I2 = 99.17%; P < 0.001). Notably, the prevalence of TB among tribal populations was found to be higher than the national prevalence. The scientific evidence available for the prevalence of TB among tribal populations is restricted to a few tribes only. Conducting further research to estimate the prevalence among other tribes all over the country is the need of the hour and should be addressed accordingly.

Pediatric Facial Fracture in Garhwal Himalayan Region of Uttarakhand State: A Retrospective Study.

Background: Pediatric facial fractures are fairly uncommon injuries and comprise less than 15% of all facial fractures in the literature. Objectives: To analyze the pattern of pediatric facial fractures and compare the results with similar studies performed in India and the rest of the world. Materials and Methods: A total of 231 patients were admitted for the treatment of maxillofacial fractures. Data on etiology, anatomical location, mode of treatment, duration of stay, and X-ray advice were recorded. Results: Pediatric trauma comprised 27% of the total population. The most common cause of injury was road traffic accident (RTA), that is, 28 (43.8%) patients. Conclusion: The incidence of pediatric facial trauma is high in the hilly Garhwal-Himalayan region of Uttarakhand state in India as compared to other states of India.

Voltage-dependent anion channel 3 (VDAC3) mediates P. syringae induced ABA-SA signaling crosstalk in Arabidopsis thaliana.

Pathogen severely affects plant mitochondrial processes including respiration, however, the roles and mechanism of mitochondrial protein during the immune response remain largely unexplored. The interplay of plant hormone signaling during defense is an outcome of plant pathogen interaction. We recently discovered that the Arabidopsis calcineurin B-like interacting protein kinase 9 (AtCIPK9) interacts with the voltage-dependent anion channel 3 (AtVDAC3) and inhibits MV-induced oxidative damage. Here we report the characterization of AtVDAC3 in an antagonistic interaction pathway between abscisic acid (ABA) and salicylic acid (SA) signaling in Pseudomonas syringae -Arabidopsis interaction. In this study, we observed that mutants of AtVDAC3 were highly susceptible to Pseudomonas syringae infection as compared to the wild type (WT) Arabidopsis plants. Transcripts of VDAC3 and CIPK9 were inducible upon ABA application. Following pathogen exposure, expression analyses of ABA and SA biosynthesis genes indicated that the function of VDAC3 is required for isochorisimate synthase 1 (ICS1) expression but not for Nine-cis-epoxycaotenoid dioxygenase 3 (NCED3) expression. Despite the fact that vdac3 mutants had increased NCED3 expression in response to pathogen challenge, transcripts of ABA sensitive genes such as AtRD22 and AtRAB18 were downregulated even after exogenous ABA application. VDAC3 is required for ABA responsive genes expression upon exogenous ABA application. We also found that Pseudomonas syringae-induced SA signaling is downregulated in vdac3 mutants since overexpression of VDAC3 resulted in hyperaccumulation of Pathogenesis related gene1 (PR1) transcript. Interestingly, ABA application prior to P. syringae inoculation resulted in the upregulation of ABA responsive genes like Responsive to ABA18 (RAB18) and Responsive to dehydration 22 (RD22). Intriguingly, in the absence of AtVDAC3, Pst challenge can dramatically increase ABA-induced RD22 and RAB18 expression. Altogether our results reveal a novel Pathogen-SA-ABA interaction pathway in plants. Our findings show that ABA plays a significant role in modifying plant-pathogen interactions, owing to cross-talk with the biotic stress signaling pathways of ABA and SA.

Mixed Solvency Concept to Replace Harmful Organic Solvent: Recent Trends and Future Challenges in Formulation Development.

Organic solvents are hazardous and should be replaced with less harmful alternatives. When developing a new formulation for a medicine with low aqueous solubility, improving its solubility might be a significant difficulty. According to the mixed solvency concept, a novel concept of solubilization, the solubility of poorly soluble drugs can be increased by dissolving them in a concentrated solution comprising various substances. Methods commonly used to improve solubility include complexation, pH modification, salt formation, hydrotropy, cosolvency, and micelle solubilization. By reducing the concentration of specific solubilizers, this method can be used to reduce the toxicity of solubilizers in various formulations of poorly soluble medicines. This review aims to provide scientists with a fresh concept for enhancing medication solubility. The benefits and drawbacks of currently available green solvents have been analyzed as potential replacements for traditional solvents. Some examples of these solvents are bio-based solvents like ethanol, methanol, and cyrene; d-limonene; deep eutectic solvents such as ionic liquids and natural deep eutectic solvents; supercritical fluids; subcritical water; surfactant-based solutions like hydrotopes and supramolecular solvents; and deep eutectic solvents like cyrene.

Comparison of the Efficacy of Sterile Silicone Studs Versus Lidocaine for the Attenuation of the Hemodynamic Response to Skull Pin Insertion: A Randomized Controlled Trial.

BACKGROUND: Skull pin insertion causes hypertension and tachycardia that adversely affects cerebral hemodynamics. We compared the efficacy of sterile silicone studs (SS) and pin site infiltration with lidocaine in attenuation of the sympathetic response to skull pin insertion. METHODS: Adult patients (N = 120) undergoing supratentorial craniotomy under general anesthesia were randomized to receive either medical-grade sterile SS or 2 mL of 2% plain lidocaine infiltration at each pin site. Hemodynamic (heart rate and mean arterial pressure) response to skull pin insertion at baseline and at 0, 1, 2, 3, and 5 minutes after skull pin insertion was compared. Requirement of rescue analgesia (fentanyl), complications such as pin-site bleeding, and surgeon satisfaction score were assessed. RESULTS: Heart rate in the lidocaine group was significantly greater at 0, 1, 2, 3, and 5 minutes after pin insertion compared with the SS group (P < 0.05). Mean arterial pressure was also significantly higher in the lidocaine group at 0, 1, 2, and 3 minutes after pin insertion (P = 0.001, P = 0.01, P = 0.034, and P = 0.042) compared with the SS group. The number of patients requiring fentanyl [17/60 (28.3%) vs. 40/60 (66%), P = 0.001] was lower in the SS group. The incidence of pin site bleeding was also lower in the SS group, and surgeon satisfaction score was greater. CONCLUSIONS: Sterile SS appear to be more effective than lidocaine infiltration in attenuating the hemodynamic response to skull pin insertion with minimal adverse effects. Further multicenter studies are necessary to conclusively establish the safety and efficacy of sterile SS.

Elevated levels of peripheral Th17 cells and Th17-related cytokines in patients with periampullary adenocarcinoma.

AIM: Periampullary adenocarcinoma (PAC) is a malignant tumor originating at the ampulla of Vater, distal common bile duct, head of the pancreas, ampulla and duodenum. The levels of circulating Th17 cells and Th17-related cytokines in patients with PAC remain unreported. Therefore, the aim of this study was to determine the levels of circulating Th17 cells and Th17-related cytokines in patients with PAC. MATERIALS AND METHODS: Flow cytometry was used to measure Th17 cell proportions in PBMCs from 60 PAC patients and 30 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-17A and IL-23 levels in serum samples, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed IL-17A mRNA expression and Th17-related transcription factors (RORγt and STAT3) in tissue samples. RESULTS: The findings showed a substantial increase in Th17 cell percentages, elevated concentrations of IL-17A and IL-23, and higher mRNA expression levels of IL-17A, RORγt, and STAT3 in patients with PAC when compared to healthy controls (HCs). CONCLUSION: Th17 cells play an important role in the pathogenesis of PAC and may represent potential therapeutic targets.

Optimization of an in vitro Pseudomonas aeruginosa Biofilm Model to Examine Antibiotic Pharmacodynamics at the Air-Liquid Interface.

Pseudomonas aeruginosa is an important cause of lower respiratory tract infections, such as ventilator-associated bacterial pneumonia (VABP). Using inhaled antibiotics to treat VABP can achieve high drug concentrations at the infection site while minimizing systemic toxicities. Despite the theoretical advantages, clinical trials have failed to show a benefit for inhaled antibiotic therapy in treating VABP. A potential reason for this discordance is the presence of biofilm-embedded bacteria in lower respiratory tract infections. Drug selection and dosing are often based on data from bacteria grown planktonically. In the present study, an in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model was optimized to evaluate the activity of simulated epithelial lining fluid exposures of inhaled and intravenous doses of polymyxin B and tobramycin against two P. aeruginosa strains. Antibiotic activity was also determined against the P. aeruginosa strains grown planktonically. Our study revealed that inhaled antibiotic exposures were more active than their intravenous counterparts across biofilm and planktonic populations. Inhaled exposures of polymyxin B and tobramycin exhibited comparable activity against planktonic P. aeruginosa. Although inhaled polymyxin B exposures were initially more active against P. aeruginosa biofilms (through 6 h), tobramycin was more active by the end of the experiment (48 h). Together, these data slightly favor the use of inhaled tobramycin for VABP caused by biofilm-forming P. aeruginosa that are not resistant to either antibiotic. The optimized in vitro air-liquid interface pharmacokinetic/pharmacodynamic biofilm model may be beneficial for the development of novel anti-biofilm agents or to optimize antibiotic dosing for infections such as VABP.

Adaptation of a Clinical High-Frequency Transrectal Ultrasound System for Prostate Photoacoustic Imaging: Implementation and Pre-clinical Demonstration.

OBJECTIVE: High-frequency, high-resolution transrectal micro-ultrasound (micro-US: ≥15 MHz) imaging of the prostate is emerging as a beneficial tool for scoring disease risk and accurately targeting biopsies. Adding photoacoustic (PA) imaging to visualize abnormal vascularization and accumulation of contrast agents in tumors has potential for guiding focal therapies. In this work, we describe a new imaging platform that combines a transrectal micro-US system with transurethral light delivery for PA imaging. METHODS: A clinical transrectal micro-US system was adapted to acquire PA images synchronous to a tunable laser pulse. A transurethral side-firing optical fiber was developed for light delivery. A polyvinyl chloride (PVC)-plastisol phantom was developed and characterized to image PA contrast agents in wall-less channels. After resolution measurement in water, PA imaging was demonstrated in phantom channels with dyes and biodegradable nanoparticle contrast agents called porphysomes. In vivo imaging of a tumor model was performed, with porphysomes administered intravenously. RESULTS: Photoacoustic imaging data were acquired at 5 Hz, and image reconstruction was performed offline. PA image resolution at a 14-mm depth was 74 and 261 µm in the axial and lateral directions, respectively. The speed of sound in PVC-plastisol was 1383 m/s, and the attenuation was 4 dB/mm at 20 MHz. PA signal from porphysomes was spectrally unmixed from blood signals in the tumor, and a signal increase was observed 3 h after porphysome injection. CONCLUSION: A combined transrectal micro-US and PA imaging system was developed and characterized, and in vivo imaging demonstrated. High-resolution PA imaging may provide valuable additional information for diagnostic and therapeutic applications in the prostate.