Riboflavin-Vancomycin Conjugate Enables Simultaneous Antibiotic Photo-Release and Photodynamic Killing against Resistant Gram-Positive Pathogens.

Decades of antibiotic misuse have led to alarming levels of antimicrobial resistance, and the development of alternative diagnostic and therapeutic strategies to delineate and treat infections is a global priority. In particular, the nosocomial, multidrug-resistant "ESKAPE" pathogens such as Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp (VRE) urgently require alternative treatments. Here, we developed light-activated molecules based on the conjugation of the FDA-approved photosensitizer riboflavin to the Gram-positive specific ligand vancomycin to enable targeted antimicrobial photodynamic therapy. The riboflavin-vancomycin conjugate proved to be a potent and versatile antibacterial agent, enabling the rapid, light-mediated, killing of MRSA and VRE with no significant off-target effects. The attachment of riboflavin on vancomycin also led to an increase in antibiotic activity against S. aureus and VRE. Simultaneously, we evidenced for the first time that the flavin subunit undergoes an efficient photoinduced bond cleavage reaction to release vancomycin, thereby acting as a photoremovable protecting group with potential applications in drug delivery.

FluoroPi Device With SmartProbes: A Frugal Point-of-Care System for Fluorescent Detection of Bacteria From a Pre-Clinical Model of Microbial Keratitis.

Purpose: Rapid and accurate diagnosis of microbial keratitis (MK) could greatly improve patient outcomes. Here, we present the development of a rapid, accessible multicolour fluorescence imaging device (FluoroPi) and evaluate its performance in combination with fluorescent optical reporters (SmartProbes) to distinguish bacterial Gram status. Furthermore, we show feasibility by imaging samples obtained by corneal scrape and minimally invasive corneal impression membrane (CIM) from ex vivo porcine corneal MK models. Methods: FluoroPi was built using a Raspberry Pi single-board computer and camera, light-emitting-diodes (LEDs), and filters for white-light and fluorescent imaging, with excitation and detection of bacterial optical SmartProbes: Gram-negative, NBD-PMX (exmax 488 nm); Gram positive, Merocy-Van (exmax 590 nm). We evaluated FluoroPi with bacteria (Pseudomonas aeruginosa and Staphylococcus aureus) isolated from ex vivo porcine corneal models of MK by scrape (needle) and CIM with the SmartProbes. Results: FluoroPi provides <1 µm resolution and was able to readily distinguish bacteria isolated from ex vivo models of MK from tissue debris when combined with SmartProbes, retrieved by both scrape and CIM. Single bacteria could be resolved within the field of view, with limits of detection demonstrated as 103 to 104 CFU/mL. Sample preparation prior to imaging was minimal (wash-free), and imaging and postprocessing with FluoroPi were straightforward, confirming ease of use. Conclusions: FluoroPi coupled with SmartProbes provides effective, low-cost bacterial imaging, delineating Gram-negative and Gram-positive bacteria directly sampled from a preclinical model of MK. Translational Relevance: This study provides a crucial stepping stone toward clinical translation of a rapid, minimally invasive diagnostic approach for MK.

Environmentally sensitive photosensitizers enable targeted photodynamic ablation of Gram-positive antibiotic resistant bacteria.

Bacterial infections remain among the biggest challenges to human health, leading to high antibiotic usage, morbidity, hospitalizations, and accounting for approximately 8 million deaths worldwide every year. The overuse of antibiotics and paucity of antimicrobial innovation has led to antimicrobial resistant pathogens that threaten to reverse key advances of modern medicine. Photodynamic therapeutics can kill bacteria but there are few agents that can ablate pathogens with minimal off-target effects. Methods: We describe nitrobenzoselenadiazoles as some of the first environmentally sensitive organic photosensitizers, and their adaptation to produce theranostics with optical detection and light-controlled antimicrobial activity. We combined nitrobenzoselenadiazoles with bacteria-targeting moieties (i.e., glucose-6-phosphate, amoxicillin, vancomycin) producing environmentally sensitive photodynamic agents. Results: The labelled vancomycin conjugate was able to both visualize and eradicate multidrug resistant Gram-positive ESKAPE pathogens at nanomolar concentrations, including clinical isolates and those that form biofilms. Conclusion: Nitrobenzoselenadiazole conjugates are easily synthesized and display strong environment dependent ROS production. Due to their small size and non-invasive character, they unobtrusively label antimicrobial targeting moieties. We envisage that the simplicity and modularity of this chemical strategy will accelerate the rational design of new antimicrobial therapies for refractory bacterial infections.

Natural history of incomplete atypical femoral fractures in patients after a prolonged and variable course of bisphosphonate therapy-a long-term radiological follow-up.

Understanding the natural history of lateral femoral stress fractures helps to guide their management. Improvement in their radiographic characteristics is rare. Progression was generally sequential, most developing an incomplete fracture line before fracture displacement. Stopping bisphosphonates decreased the fracture rate, a feasible management option for lesions without incomplete fracture lines. INTRODUCTION: Retrospective study evaluating the natural history of lateral femoral stress fractures (FSF) by serial radiography over a variable period of time in a cohort of patients treated for some time with bisphosphonates for osteoporosis, whilst also identifying the fracture response in cases where bisphosphonates were discontinued. METHODS: The radiographs of 76 consecutive patients (92 femurs) with 161 FSF were reviewed to document their change over time. Femurs were classified into the following: A-normal, B-focal cortical thickening, C-dreaded black line and D-displaced fracture. Bisphosphonate history was recorded. RESULTS: 66.5% FSF showed group stability between the first and last radiographs: group B (79.1%), group C (45.7%). 28.6% progressed, mostly following an ordered sequence starting from group A, progressing to B, then C, before culminating in D. Progression rate was as follows: A-100% (11/11), B-18.3% (21/115), C-40% (14/35). Regression in FSF was uncommon-5.6% (8/161). 34.8% (32/92) sustained displaced fractures. Kaplan-Meier analysis showed statistically significant difference between the groups; median survival (95% CI): A-4189 (-), B-3383.0 (-), C-1807 (0.0-3788.6) and progression to displaced fracture when bisphosphonate had been stopped for at least 6 months. The group without recent bisphosphonates had a lower group progression rate (17.1%, 12/70). Nevertheless, 10.9% (5/46) progressed to displaced fracture. This group also had the highest proportion of stable (77.1%, 54/70) and regressive lesions (5.7%, 4/70). CONCLUSIONS: In FSF, there is natural progression from normal bone, to focal cortical thickening, to dreaded black line and eventually to displaced fracture. Most lesions persist, remaining static or progressing, especially if a dreaded black line is present and bisphosphonates are continued. Regression is uncommon and more frequent when bisphosphonates are discontinued. Despite stopping bisphosphonates, there remains a 10.9% risk of progression to displaced fracture.

Tuberous sclerosis and its rare association with macrodactyly and fibrous hamartomas.

Tuberous sclerosis complex is a genetic disease that results in abnormal cellular proliferation and hamartoma growths in multiple organ systems. However, macrodactyly and subcutaneous fibrous harmatomas are very uncommon associations with this disease. We see these rare manifestations in our case report of a 16-year-old female with tuberous sclerosis complex and discuss the imaging findings and pathogenetics of these manifestations. Through this, our report aims to expand the known clinical spectrum of features seen in tuberous sclerosis and aid in its diagnosis.

Insufficiency fractures related to low-dose adefovir dipivoxil treatment for chronic hepatitis B.

We present a case of a 53-year-old woman who developed multifocal insufficiency fractures associated with adefovir dipivoxil (ADV) induced osteomalacia, including recurring metatarsal insufficiency fractures and a subtrochanteric femoral insufficiency fracture requiring surgical fixation. She had received low-dose ADV treatment for 59 months for chronic hepatitis B viral infection at the time of presentation with subtrochanteric fracture. Imaging evidence of multifocal insufficiency fractures and metabolic disease on background of hypophosphatemia is attributed to hypophosphatemic osteomalacia from adefovir-induced renal proximal tubular dysfunction. Radiologists and clinicians should be aware of the possibility of insufficiency fractures in patients receiving ADV therapy to avoid delayed diagnosis and progression of high-risk proximal femoral fractures.

Fasciotomy and surgical tenotomy for recalcitrant lateral elbow tendinopathy: early clinical experience with a novel device for minimally invasive percutaneous microresection.

BACKGROUND: The optimal choice for intervention for recalcitrant lateral elbow tendinopathy remains unclear as various treatment modalities have documented comparable results in the literature. PURPOSE: To explore the safety, tolerability, and early efficacy of a new minimally invasive mode of treatment that delivers focused, calibrated ultrasonic energy, effectively microresecting the pathological tendon and removing only pathological tissue. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seven male and 13 female patients aged 33 to 65 years averaging 12.5 months (range, 4-48) of failed nonoperative therapy underwent the ultrasonic microresection procedure in an outpatient clinic setting. The procedure involved a sterile, ultrasound-guided percutaneous microresection with a proprietary device (TX1) performed through a stab incision under local anesthesia. The duration of the procedure and complications of the device or procedure were assessed. Outcome parameters included patient satisfaction; visual analog scale (VAS) pain scores; Disabilities of the Arm, Shoulder and Hand (DASH) scores at 1, 3, 6, and 12 months; and ultrasound assessment at 3 and 6 months. RESULTS: The median duration for the sterile confirmatory ultrasound examination (phase 1) was 88.5 seconds (range, 39-211; SD, ±47.6), the median duration of the procedure proper (phase 2) was 10.1 minutes (range, 4.1-19.4; SD, ±3.7), and the median energy time (duration the TX1 device was activated) was 32.5 seconds (range, 18-58; SD, ±11.0). No complications were encountered. A significant improvement in VAS score (from 5.5 to 3.3; P < .001) occurred by 1 week, and significant improvements in both DASH-Compulsory (from 21.7 to 11.3; P = .001) and DASH-Work (from 25.0 to 6.3; P = .012) scores occurred by 1 month. The VAS scores further improved at 3, 6, and 12 months (from 2.0 to 1.0 to 0.50; P = .003 and .023). The DASH-Compulsory score improved significantly from 3 to 6 months (from 8.6 to 4.6; P = .003), and both the DASH-Compulsory and DASH-Work scores were sustained by 12 months. Sonographically reduced tendon thickness (19 patients), resolved or reduced hypervascularity (17 patients), and reduced hypoechoic area (18 patients) occurred by 6 months. Nineteen of the 20 patients (95%) expressed satisfaction with the procedure, with 9 patients being very satisfied with their overall experience at 6 months after the procedure, 10 patients somewhat satisfied, and 1 patient neutral. CONCLUSION: Ultrasonic microresection of diseased tissue with the TX1 device provides a focally directed, safe, specific, minimally invasive, and well-tolerated treatment for recalcitrant lateral elbow tendinopathy in an office-based or ambulatory surgical setting with good evidence of some level of efficacy in 19 of 20 patients (95%) that is sustained for at least 1 year.

Uterine artery embolisation for symptomatic fibroids in a tertiary hospital in Singapore.

INTRODUCTION: Transcatheter uterine artery embolisation (UAE) for the treatment of symptomatic uterine enlargement due to fibroids has been performed in several overseas centres with promising results. We report our experience with UAE in Singapore General Hospital. MATERIALS AND METHODS: Twenty women with symptomatic uterine fibroids who declined surgery were treated by transcatheter UAE. The uterine arteries were selectively catheterised and embolised with polyvinyl alcohol particles. Post-procedure analgesia was administered via a patient-controlled analgesia pump. The patients were followed up at regular intervals clinically and with transabdominal ultrasonography. RESULTS: Transcatheter UAE was performed on all patients with no major complications. Nineteen patients had both uterine arteries embolised while 1 patient had only the right uterine artery embolised on account of hypoplasia of the left uterine artery. The mean hospital stay was 3.5 days (range, 2 to 9). At a mean follow-up of 56 weeks (range, 6 to 168), all patients reported improvements in their presenting symptoms. Objective improvement in terms of reduction of uterine and fibroid sizes was determined on ultrasonography. The median size of the uterine volume decreased from 308 to 187 mL while the median diameter of the largest fibroid reduced from 6.2 to 4.6 cm. The median haemoglobin level increased to 12.7 g/dL from the pre-procedural median of 9.9 g/dL. One patient, who initially responded with a decrease in uterine and dominant fibroid size, became symptomatic (menorrhagia) at 6 months post-embolisation. She underwent a repeat procedure with complete resolution of symptoms. A second patient had recurrence of symptoms at 12 months, but was subsequently lost to follow-up. CONCLUSION: Mid-term results of UAE for the treatment of symptomatic fibroids in our hospital indicate this to be a safe and effective therapeutic option.