Facile fabrication of degradable, serrated polyethylene diacrylate microneedles using stereolithography.

Microneedles have the potential for minimally invasive drug delivery. However, they are constrained by absence of rapid, scalable fabrication methods to produce intricate arrays and serrations for enhanced adhesion. 3D printing techniques like stereolithography (SLA) are fast, scalable modalities but SLAs require non-degradable and stiff resins. This work attempts to overcome this limitation by utilizing a poly (ethylene glycol diacrylate) (PEGDA, F3) resin and demonstrating its compatibility with a commercial SLA printer. FESEM images showed high printing efficiency of customized bioinks (F3) similar to commercial resins using SLA 3D printer. Mechanical endurance tests of whole MNA showed that MNs array printed from F3 resin (485 ± 5.73 N) required considerably less force than commercial F1 resin (880 ± 32.4 N). Penetration performance of F1 and F3 was found to be 10.8 ± 2.06 N and 0.705 ± 0.03 N. In-vitro degradation study in PBS showed that MNs fabricated from F3 resin exhibited degradation after 7 days, which was not observed with the commercial F1 resin provided by the manufacturer. The histology of porcine skin exhibited formation of triangular pores with pore length of 548 µm and efficient penetration into the deeper dermal layer. In conclusion, PEGDA can be used as for fabricating degradable, serrated solid MNs over commercial resin.

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.

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.

Serum miR-215-5p, miR-192-5p and miR-378a-5p as novel diagnostic biomarkers for periampullary adenocarcinoma.

OBJECTIVE: MicroRNAs (miRNAs) are present in human serum in a stable form. Circulating miRNAs are increasingly recognized as promising biomarkers for early cancer detection. The aim of this study was to identify serum miRNAs as biomarkers for periampullary adenocarcinoma (PAC). PATIENTS AND METHODS: 68 patients with PAC and 50 healthy controls (HCs) subjects were recruited in this study. The expression levels of 11 selected miRNAs were determined in serum samples using the SYBR-green quantitative reverse transcription polymerase chain reaction (qRT-PCR) method. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic potential of serum miRNAs. RESULTS: The expression levels of three miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) were significantly upregulated in the serum samples derived from the PAC patients compared with those from the HC (p < 0.001). The ROC analysis showed that all three significantly altered miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) could potentially discriminate patients with PAC from HC with AUC value of 0.771 (95% CI: 0.684-0.843), 0.877 (95% CI: 0.799-0.927) and 0.768 (95% CI: 0.674-0.853) respectively. Further comparisons showed that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) can strongly discriminate early-stage PAC patients from HC with an AUC value of 0.802 (95% CI: 0.719-0.886), 0.870 (95% CI: 0.793-0.974) and 0.793 (95% CI: 0.706-0.880) respectively, may aid in early detection of PAC. CONCLUSIONS: Taken together, our findings demonstrated that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) may serve as noninvasive biomarkers for the early detection of PAC.

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.

Current status of mannose receptor-targeted drug delivery for improved anti-HIV therapy.

In the pursuit of achieving better therapeutic outcomes in the treatment of HIV, innovative drug delivery strategies have been extensively explored. Mannose receptors, which are primarily found on macrophages and dendritic cells, offer promising targets for drug delivery due to their involvement in HIV pathogenesis. This review article comprehensively evaluates recent drug delivery system advancements targeting the mannose receptor. We have systematically described recent developments in creating and utilizing drug delivery platforms, including nanoparticles, liposomes, micelles, noisomes, dendrimers, and other nanocarrier systems targeted at the mannose receptor. These strategies aim to enhance drug delivery specificity, bioavailability, and therapeutic efficacy while decreasing off-target effects and systemic toxicity. Furthermore, the article delves into how mannose receptors and HIV interact, highlighting the potential for exploiting this interaction to enhance drug delivery to infected cells. The review covers essential topics, such as the rational design of nanocarriers for mannose receptor recognition, the impact of physicochemical properties on drug delivery performance, and how targeted delivery affects the pharmacokinetics and pharmacodynamics of anti-HIV agents. The challenges of these novel strategies, including immunogenicity, stability, and scalability, and future research directions in this rapidly growing area are discussed. The knowledge synthesis presented in this review underscores the potential of mannose receptor-based targeted drug delivery as a promising avenue for advancing HIV treatment. By leveraging the unique properties of mannose receptors, researchers can design drug delivery systems that cater to individual needs, overcome existing limitations, and create more effective and patient-friendly treatments in the ongoing fight against HIV/AIDS.

Clinical Significance of MUC4 and Associated Proteins in Pancreatic and Periampullary Cancers.

OBJECTIVE: This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. MATERIALS AND METHODS: Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. RESULT: MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. CONCLUSIONS: Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.

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.

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.

Ectopic overexpression of Eleusine coracana CAX3 confers tolerance to metal and ion stress in yeast and Arabidopsis.

Ionic and metal toxicity in plants is still a global problem for the environment, agricultural productivity and ultimately poses human health threats when these metal ions accumulate in edible organs of plants. Metal and ion transport from cytosol to the vacuole is considered an important component of metal and ion tolerance and a plant's potential utility in phytoremediation. Finger millet (Eleusine coracana) is an orphan crop but has prominent nutritional value in comparison to other cereals. Previous transcriptomic studies suggested that one of the calcium/proton exchanger (EcCAX3) is strongly upregulated during different developmental stages of spikes development in plant. This finding led us to speculate that high calcium accumulation in the grain might be because of CAX3 function. Moreover, phylogenetic analysis shows that EcCAX3 is more closely related to foxtail millet, sorghum and rice CAX3 protein. To decipher the functional role of EcCAX3, we have adopted complementation of yeast triple mutant K677 (Δpmc1Δvcx1Δcnb1), which has defective calcium transport machinery. Furthermore, metal tolerance assay shows that EcCAX3 expression conferred tolerance to different metal stresses in yeast. The gain-of-function study suggests that EcCAX3 overexpressing Arabidopsis plants shows better tolerance to higher concentration of different metal ions as compared to wild type Col-0 plants. EcCAX3-overexpression transgenic lines exhibits abundance of metal transporters and cation exchanger transporter transcripts under metal stress conditions. Furthermore, EcCAX3-overexpression lines have higher accumulation of macro- and micro-elements under different metal stress. Overall, this finding highlights the functional role of EcCAX3 in the regulation of metal and ion homeostasis and this could be potentially utilized to engineer metal fortification and generation of stress tolerant crops in near future.

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.

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.

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.

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.

Effect of Peri-operative Blood Transfusion on Neurological Outcome Following Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Study.

BACKGROUND: Anemia is a common complication of aneurysmal subarachnoid hemorrhage and is associated with unfavorable outcomes. Whether the physiological benefits of transfusion for anemia surpass the risk of blood transfusion remains to be determined. OBJECTIVES: The primary outcome was to evaluate the impact of peri-operative blood transfusion on the long-term neurological outcome, assessed by Glasgow Outcome Scale Extended at 3 months. The secondary outcomes included the impact of transfusion on the short-term neurological outcome, assessed by Modified Rankin Score at discharge/7 days, and on the incidence of vasospasm, infarction, re-exploration, tracheostomy, and length of hospital stay. MATERIAL AND METHODS: This prospective observational study was conducted on 185 patients with aneurysmal subarachnoid hemorrhage undergoing clipping of the aneurysmal neck. In our study, blood transfusion was administered to keep the target Hb around 10 g/dL. RESULTS: Unfavorable long-term outcome was found in 27/97 (28%) of patients who received a blood transfusion as compared to 13/74 (18%) of patients who did not receive a transfusion (P = 0.116). Patients receiving transfusion had more chances of an unfavorable outcome at discharge/7 days as compared to those not transfused [44/103 (43%) versus 22/80 (27%)], P = 0.025. There were increased chances of vasospasm, infarction, re-exploration, tracheostomy, and increased length of hospital stay in patients receiving transfusion (P < 0.05). CONCLUSIONS: The use of blood transfusion in patients with aneurysmal subarachnoid hemorrhage was associated with increased neurological complications and hence an unfavorable short-term outcome. However, when used judiciously as per the clinical requirements, blood transfusion did not have a significant effect on long-term neurological outcome.

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.

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.

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.