Continuous glucose monitoring for glycaemic control and cardiovascular risk reduction in patients with type 2 diabetes not on insulin therapy: A clinical trial.

AIM: To evaluate the impact of the Dexcom G6 continuous glucose monitoring (CGM) device on glycaemic control and cardiometabolic risk in patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk who are not on insulin therapy. MATERIALS AND METHODS: Adults with T2DM with glycated haemoglobin (HbA1c) >7% and body mass index (BMI) ≥30 kg/m2 not using insulin were enrolled in a two-phase cross-over study. In phase 1, CGM data were blinded, and participants performed standard glucose self-monitoring. In phase 2, the CGM data were unblinded, and CGM, demographic and cardiovascular risk factor data were collected through 90 days of follow-up and compared using paired tests. RESULTS: Forty-seven participants were included (44% women; 34% Black; mean age 63 years; BMI 37 kg/m2; HbA1c 8.4%; 10-year predicted atherosclerotic cardiovascular disease risk 24.0%). CGM use was associated with a reduction in average glucose (184.0 to 147.2 mg/dl, p < .001), an increase in time in range (57.8 to 82.8%, p < .001) and a trend towards lower glucose variability (26.2 to 23.8%). There were significant reductions in HbA1c, BMI, triglycerides, blood pressure, total cholesterol, diabetes distress and 10-year predicted risk for atherosclerotic cardiovascular disease (p < .05 for all) and an increase in prescriptions for sodium-glucose cotransporter 2 inhibitors (36.2 to 83.0%) and glucagon-like peptide-1 receptor agonists (42.5 to 87.2%, p < .001 for both). CONCLUSIONS: Dexcom G6 CGM was associated with improved glycaemic control and cardiometabolic risk in patients with T2DM who were not on insulin. CGM can be a safe and effective tool to improve diabetes management in patients at high risk for adverse cardiovascular outcomes.

Symptomatic Patient With Two Separate Accessory Navicular Bones.

We present the case of a symptomatic patient with two separate accessory navicular bones, a novel finding that does not fall within current classification standards. Furthermore, there is a paucity of current literature with regard to the management of symptomatic cases. Accessory navicular bones, sometimes referred to as os naviculare, are ossicles that can occur in multiple configurations and are considered developmental anomalies. The accessory navicular is an accessory bone found on the medial side of the navicular bone of the foot. While often asymptomatic, they can occasionally lead to clinically significant pain and/or deformity that can cause patients to seek out treatment and sometimes surgical correction. Diagnosis relies on clinical suspicion and imaging studies. A nine-year-old female patient presented initially with complaints of sharp pain over the medial side of her left foot, after which X-rays were obtained that demonstrated an accessory navicular bone. Upon diagnosis, conservative measures were implemented, including placing the patient in a short-leg cast with limited activity. After a failed trial of conservative measures, the patient underwent surgical excision of the accessory navicular bone, with imaging and intraoperative findings of two separate accessory navicular bones, a unique finding in patients with accessory navicular bones. During the six-week follow-up, the patient improved with no new complaints or concerns and was informed she could begin weight-bearing as tolerated with two crutches; she was then weaned from the crutches and returned to normal activity. In the current case, we followed the same route of treatment used to treat a single accessory navicular bone, utilizing first non-surgical interventions and then ultimately surgical excision after continual pain despite conservative measures. This case highlights the promising outcome for a patient with two separate accessory navicular bones when following the guidelines for the treatment of a single accessory navicular bone.

Pediatric Medial Condyle of Humerus Fracture Dislocation: A Case Report.

We present the case of a six-year-old male patient, status post fall with elbow dislocation, successfully reduced. At the time of injury, he had normal appearing x-rays, signs of a mildly discrete chip, and possible epicondyle ossification, but no definitive fracture. A medial condyle fracture with dislocation was missed at the original time of injury. The patient returned several years later with mild elbow stiffness and intermittent pain. CT scan at this time demonstrated nonunion of the medial condyle. The patient underwent subsequent open reduction and internal fixation (ORIF) and is currently doing well clinically. Although rare, a medial condyle dislocation fracture needs surgical intervention to reduce morbidity, and therefore, should be in the differential when working up a pediatric fracture.

An 8-year retrospective review of emergency laparotomy outcomes in a Queensland rural hospital.

OBJECTIVE: Emergency laparotomy (EL) is a major operation performed in critically unwell patients. The National Emergency Laparotomy Audit (NELA), undertaken in the UK since 2013 has shown progressive improvement in clinical outcomes, specifically reduced mortality, and length of stay (LOS) through the implementation of perioperative key performance indicators (KPIs) (ANZ J Surg. 2021;91:2575, Br J Surg. 2015;102:57, Br J Surg. 2017;104:463, JAMA Surg. 2019;154:e190145). The objective is to generate a rural hospital EL audit (MELA) to evaluate local outcomes and clinical standards of practice with regional, national, and international benchmarks. METHODS: A review of medical records between January 2014 and December 2021 of patients who undergo an EL. Data collected include patient demographics, clinical information, compliance to KPIs and the primary outcomes of 30-day mortality and LOS. DESIGN: This is a descriptive quantitative study. The inclusion and exclusion criteria were similar to those defined in NELA and ANZELA-QI. SETTING AND PARTICIPANTS: The general surgeons at the rural hospital provide emergency surgery services for the North-West Queensland community. MAIN OUTCOME MEASURES: To review local clinical outcomes of 30-day mortality, LOS, and adherence to perioperative KPIs. RESULTS: Overall, 84 patients met inclusion criteria. The median age (IQR) was 61 (48.8-70.3) years. The 30-day mortality was 3.6% and mean LOS was 12.8 (±13.4) days which was secondary to the low-risk patients within the data set. Compliance to KPIs (≥80%) was achieved in five of eight standards assessed. CONCLUSION: Local outcomes appear to be comparable to national and international benchmarks and a similar rural setting. The audited cohort outperformed the national standard in adherence to perioperative KPIs.

Strong and ductile titanium-oxygen-iron alloys by additive manufacturing.

Titanium alloys are advanced lightweight materials, indispensable for many critical applications1,2. The mainstay of the titanium industry is the α-ß titanium alloys, which are formulated through alloying additions that stabilize the α and ß phases3-5. Our work focuses on harnessing two of the most powerful stabilizing elements and strengtheners for α-ß titanium alloys, oxygen and iron1-5, which are readily abundant. However, the embrittling effect of oxygen6,7, described colloquially as 'the kryptonite to titanium'8, and the microsegregation of iron9 have hindered their combination for the development of strong and ductile α-ß titanium-oxygen-iron alloys. Here we integrate alloy design with additive manufacturing (AM) process design to demonstrate a series of titanium-oxygen-iron compositions that exhibit outstanding tensile properties. We explain the atomic-scale origins of these properties using various characterization techniques. The abundance of oxygen and iron and the process simplicity for net-shape or near-net-shape manufacturing by AM make these α-ß titanium-oxygen-iron alloys attractive for a diverse range of applications. Furthermore, they offer promise for industrial-scale use of off-grade sponge titanium or sponge titanium-oxygen-iron10,11, an industrial waste product at present. The economic and environmental potential to reduce the carbon footprint of the energy-intensive sponge titanium production12 is substantial.

Airway emergency after dental extraction.

Life-threatening airway emergencies and uncontrolled haemorrhage following dental extractions is rarely encountered. Inappropriate handling of dental luxators may lead to unexpected traumatic events resulting from penetrating or blunt trauma to the surrounding soft tissues and vascular damage. Bleeding during or after surgery usually resolves spontaneously or with local haemostatic interventions. Pseudoaneurysms are rare occurrences secondary to blunt or penetrating trauma usually produced by arterial injury leading to extravasation of blood. The rapidly enlarging haematoma with risk of spontaneous pseudoaneurysm rupture is an airway and surgical emergency necessitating urgent intervention. The following case highlights the importance of appreciating the potential complications associated with extractions in the maxilla, significant anatomical relationships and recognizing the clinical signs of a threatened airway.

Food insecurity and atherosclerotic cardiovascular disease risk in adults with diabetes.

OBJECTIVES: Adults with diabetes are at an increased risk of atherosclerotic cardiovascular disease (ASCVD), and food insecurity may be a major and underappreciated risk compounder in this population. We sought to analyze the prevalence of food insecurity and its association with ASCVD in adults with diabetes. METHODS: A total of 6424 participants with diabetes were included from the 2019 and 2020 National Health Interview Survey. Food insecurity was determined with a 10-question U.S. Adult Food Security Survey Module, and classified as high, marginal, low, and very low. ASCVD was defined as a self-reported history of coronary artery disease, myocardial infarction, or stroke. RESULTS: Of the 6424 included participants (weighted: n = 21 690 217), 5 405 543 (24.4%) reported a history of ASCVD and 2 946 061 (13.3%) were identified as food insecure (low or very low food security). Adults with food insecurity were more likely to have ASCVD than adults who were food secure (28.9% vs 23.7%; P = 0.008). In the multivariate analyses adjusted for traditional cardiovascular risk factors, all levels of food insecurity were associated with ASCVD compared with food-secure adults (marginal security: odds ratio [OR]: 1.60; 95% confidence interval [CI], 1.18-2.18]; P = 0.003; low security: OR: 2.09; 95% CI, 1.58-2.74]; P < 0.001; very low security: OR: 1.69; 95% CI, 1.22-2.34]; P = 0.001). The association persisted when adjusted for income, location, education, and insurance status. In adults with diabetes and ASCVD, income was a negative factor for food insecurity (OR: 0.71; 95% CI, 0.62-0.80; P < 0.001), but female sex and smoking were positive factors (OR: 1.90; 95% CI, 1.29-2.80; P = 0.001; and OR: 1.97; 95% CI, 1.23-3.18; P = 0.005; respectively). At younger ages, the prevalence of food insecurity increased, especially in adults with ASCVD. CONCLUSIONS: We showed that 13% of U.S. adults with diabetes are food insecure, which was associated with ASCVD independent of traditional and socioeconomic risk factors. Our findings emphasize the importance of recognizing food insecurity as a driver of ASCVD in adults with diabetes, and encourage future efforts at reducing this disparity.

Coronary Artery Calcium Scoring for Risk Assessment in Patients With Severe Hypercholesterolemia.

The American College of Cardiology and the American Heart Association guidelines recommend treatment of patients with severe hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C] ≥190 mg/100 ml) with a high-intensity statin. However, atherosclerotic cardiovascular disease (ASCVD) risk, even among those with severe hypercholesterolemia, is heterogeneous, and coronary artery calcium (CAC) scoring may be used to clarify risk. We sought to evaluate CAC in patients with severe hypercholesterolemia and measure its impact on real-world statin prescriptions. We identified patients with at least 1 LDL-C ≥190 mg100 ml who had a CAC scoring in the Community Benefit of No-Charge Calcium Score Screening Program (CLARIFY) study (NCT04075162) between 2014 and 2020. We explored the CAC distribution, factors associated with CAC >0, and ASCVD risk (myocardial infarction, stroke, revascularization, death). A total of 1,904 patients (1.257 women, aged 57.8 ± 9.3 years) with severe hypercholesterolemia were included. LDL-C ranged from 190 to 524 mg100 ml (mean 215.5 ± 27 mg100 ml). A total of 864 patients (45.4%) had CAC = 0 and 1,561 (82%) had CAC <100. In patients with LDL-C ≥250 mg100 ml, 67 (36.6%) had CAC = 0. Age, male gender, smoking, diabetes, systolic blood pressure, and obesity (ps ≤0.001) were associated with CAC >0. In patients with LDL-C ≥190 mg100 ml, CAC was associated with a higher risk for ASCVD events (CAC ≥100 vs CAC <100, hazard ratio 3.57 [1.81 to 7.04], p <0.001). A higher CAC category was associated with increased statin use after CAC scoring (p <0.001). In patients with severe hypercholesterolemia, 45% had CAC = 0, which was associated with a significantly lower ASCVD risk. CAC was associated with statin prescription and cholesterol lowering. In conclusion, CAC scoring may be used to clarify ASCVD risk in this heterogeneous population with severe hypercholesterolemia.

Relation of coronary calcium scoring with cardiovascular events in patients with diabetes: The CLARIFY Registry.

INTRODUCTION: Coronary artery calcium (CAC) scoring is not routinely performed in patients with diabetes based on an existing class I indication for statin therapy in these patients. However, CAC scoring may improve risk classification and prediction of atherosclerotic cardiovascular disease (ASCVD) events beyond risk scores in asymptomatic individuals with prediabetes and diabetes, warranting CAC assessment in this population. The routine availability through provision of no-charge CAC as an alternative to routine probabilistic risk scores may improve utilization of preventive therapies especially in traditionally underserved populations. METHODS: Prospective observational study in a large health system offering no-charge CAC scoring for primary prevention risk prediction with available glycosylated hemoglobin (HbA1c) measurements between June 2015 and March 2019 were divided according to no diabetes (HbA1c <5.7 %), prediabetes (HbA1c 5.7 %-6.4 %), or diabetes (HbA1c ≥ 6.5 % or charted history) and followed for major adverse cardiovascular events [myocardial infarction, stroke, death (MACE) or coronary revascularization]. Patient characteristics, health history, laboratory data, and statin prescription rates were measured at baseline and at one year after CAC scoring. RESULTS: A total of 12,194 subjects with available HbA1c underwent CAC scoring during the study period (6462 diabetes, 2062 prediabetes, and 3670 without diabetes). At a median follow-up of 1.2 years, there were 458 MACE events (71 patients without diabetes, 66 patients with prediabetes, and 321 patients with diabetes). Among patients with diabetes or prediabetes, increased CAC was associated with MACE (HR 1.38 [1.26-1.51], p < 0.001) and MACE or revascularization (HR 1.70 [1.57-1.85], p < 0.001). In patients with diabetes, CAC category was associated with greater statin initiation (89.6 % for CAC≥400 vs 60.1 % for CAC = 0, p < 0.001) and high intensity statin initiation (42.2 % for CAC≥400 vs 16.8 % for CAC = 0, p < 0.001) at one year post CAC scoring. Patients with diabetes had greater reductions in systolic blood pressure, LDL-C, total cholesterol, and triglycerides from baseline with a CAC ≥400 compared to a lower CAC category (p = 0.007). CONCLUSIONS: CAC burden is associated with ASCVD risk in patients with diabetes. CAC scoring increases statin prescriptions and reduces ASCVD risk in patients with diabetes, potentially warranting routine CAC assessment in this population.

Abiotrophia defectiva bacterial endocarditis complicated by an infective intracranial mycotic aneurysm - The need for aggressive odontogenic source control.

Abiotrophia defectiva or nutritionally variant streptococci (NVS) was first described in 1961 as a rare cause of infectious endocarditis (IE). It is distinct to the Streptococcus genus, pleomorphic, and demonstrates variable Gram-staining characteristics due to poor growth in culture media requiring extended incubation or 16S rRNA sequencing in culture negative situations.1 NVS has also been implicated in the pathogenesis of culture-negative endocarditis. In comparison with other causes of endocarditis, it has the ability to secrete exopolysaccharide and adheres to fibronectin in the extracellular matrix of endovascular structures.2 NVS is associated with significant morbidity and mortality, higher rates of multisystem complications ranging from pancreatic abscess, intracranial aneurysms, osteomyelitis, and valvular destruction, despite sensitivity to antibiotics.

Routine Use of the "Penumbra" Thrombectomy Device in Myocardial Infarction: A Real-World Experience-ROPUST Study.

Objectives: Evaluation of the safety and efficacy of the Penumbra device as an adjunct to percutaneous coronary intervention (PCI) in patients with myocardial infarction (MI) and a large thrombus burden that requires thrombectomy. Background: For patients with acute MI, PCI is the primary reperfusion method. Large thrombus burden has always been a limitation of successful reperfusion. However, the use of current aspiration devices has been associated with an increased incidence of stroke. Methods: We performed a retrospective chart review at the University Hospitals Medical Center in Cleveland. Our study included data from patients who underwent PCI for ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI) assisted by the Penumbra Cat RX device (a wide-lumen thrombus aspiration catheter) between May 2019 and February 2021. The primary outcome was the final thrombolysis in myocardial infarction (TIMI) flow. The secondary endpoints were a composite of adverse cardiac events at 6 months. About 50% of the patients did undergo transfemoral PCI as per preference of individual operators. The Penumbra thrombectomy device can be used both by radial and femoral approach and does not need any different guide catheter use. Results: TIMI flow 3 was achieved in 111 patients (90.2%). The secondary endpoint occurred in 11 patients (8.9%, 3 MI, 8 heart failure hospitalizations). There were no stroke events or device-related complications. The door-to-balloon time was not affected by usage of the Penumbra device. Failure in the restoration of TIMI 3 flow was associated with the use of balloon angioplasty prior to the application of the Penumbra device, leading to distal embolization. Conclusions: The Penumbra Cat RX provides safe and effective thrombus removal with better clinical outcomes, even in high-risk patients with acute coronary syndrome.

Machine Learning Estimation of Low-Density Lipoprotein Cholesterol in Women With and Without HIV.

INTRODUCTION: Low-density lipoprotein cholesterol (LDL-C) is typically estimated from total cholesterol, high-density lipoprotein cholesterol, and triglycerides. The Friedewald, Martin-Hopkins, and National Institutes of Health equations are widely used but may estimate LDL-C inaccurately in certain patient populations, such as those with HIV. We sought to investigate the utility of machine learning for LDL-C estimation in a large cohort of women with and without HIV. METHODS: We identified 7397 direct LDL-C measurements (5219 from HIV-infected individuals, 2127 from uninfected controls, and 51 from seroconvertors) from 2414 participants (age 39.4 ± 9.3 years) in the Women's Interagency HIV Study and estimated LDL-C using the Friedewald, Martin-Hopkins, and National Institutes of Health equations. We also optimized 5 machine learning methods [linear regression, random forest, gradient boosting, support vector machine (SVM), and neural network] using 80% of the data (training set). We compared the performance of each method using root mean square error, mean absolute error, and coefficient of determination (R2) in the holdout (20%) set. RESULTS: SVM outperformed all 3 existing equations and other machine learning methods, achieving the lowest root mean square error and mean absolute error, and the highest R2 (11.79 and 7.98 mg/dL, 0.87, respectively, compared with those obtained using the Friedewald equation: 12.45 and 9.14 mg/dL, 0.87). SVM performance remained superior in subgroups with and without HIV, with nonfasting measurements, in LDL <70 mg/dL and triglycerides > 400 mg/dL. CONCLUSIONS: In this proof-of-concept study, SVM is a robust method that predicts directly measured LDL-C more accurately than clinically used methods in women with and without HIV. Further studies should explore the utility in broader populations.

Diaphragmatic pacemaker-induced ventricular tachycardia leading to cardiac arrest: a case report.

BACKGROUND: Diaphragmatic pacemakers are used to assist respiration in ventilator-dependent patients. Electromagnetic interference with intrinsic cardiac electrical activity is a theoretical risk but has never been reported in the literature. This case highlights a serious complication of cardiac arrest as a result of diaphragmatic pacing. CASE SUMMARY: We report a quadriplegic patient with recent diaphragmatic pacemaker implantation who presented with ventricular tachycardia leading to cardiac arrest. Extensive workup was negative for other aetiologies for ventricular arrhythmias. Reduction of the left-sided diaphragmatic pacemaker voltage resulted in cessation of ventricular ectopy. DISCUSSION: Diaphragmatic pacing at high voltages can cause unwanted transmission of impulses to the cardiac myocytes as a rare complication. This should be noted as a possible complication of intramuscular diaphragmatic pacing, and efforts should be taken to circumvent this risk in the future.

Cytarabine-induced pericarditis confirmed using cardiac MRI: A case report.

Pericarditis is a rare but debilitating complication of cytarabine therapy. While echocardiography can aid with the diagnosis, cardiac MRI has superior accuracy in establishing the diagnosis. In this case, we describe a 65-year-old patient receiving cytarabine as part of induction chemotherapy for acute myeloid leukemia who developed acute pericarditis. Her cardiac MRI revealed pericardial edema on T2-weighted STIR imaging and pericardial late gadolinium enhancement which confirmed the diagnosis.

Soluble Tumor Necrosis Factor Receptor 1 is Associated With Cardiovascular Risk in Persons With Coronary Artery Calcium Score of Zero.

BACKGROUND: A coronary artery calcium (CAC) score of zero confers a low but nonzero risk of atherosclerotic cardiovascular events (CVD) in asymptomatic patient populations, and additional risk stratification is needed to guide preventive interventions. Soluble tumor necrosis factor receptors (sTNFR-1 and sTNFR-2) are shed in the context of TNF-alpha signaling and systemic inflammation, which play a role in atherosclerosis and plaque instability. We hypothesized that serum sTNFR-1 concentrations may aid in cardiovascular risk stratification among asymptomatic patients with a CAC score of zero. METHODS: We included all participants with CAC=0 and baseline sTNFR-1 measurements from the prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA). The primary outcome was a composite CVD event (myocardial infarction, stroke, coronary revascularization, cardiovascular death). RESULTS: The study included 1471 participants (mean age 57.6 years, 64% female), with measured baseline sTNFR-1 ranging from 603 pg/mL to 5544 pg/mL (mean 1294 pg/mL ±378.8 pg/mL). Over a median follow-up of 8.5 years, 37 participants (2.5%) experienced a CVD event. In multivariable analyses adjusted for Framingham Score, doubling of sTNFR-1 was associated with a 3-fold increase in the hazards of CVD (HR 3.0, 95% CI: 1.48-6.09, P = 0.002), which remained significant after adjusting for traditional CVD risk factors individually (HR 2.29; 95% CI: 1.04-5.06, P=0.04). Doubling of sTNFR-1 was also associated with progression of CAC >100, adjusted for age (OR 2.84, 95% CI: 1.33-6.03, P=0.007). CONCLUSIONS: sTNFR-1 concentrations are associated with more CVD events in participants with a CAC score of zero. Utilizing sTNFR-1 measurements may improve cardiovascular risk stratification and guide primary prevention in otherwise low-risk individuals.

Direct Planimetry of Left Ventricular Outflow Tract Area by Simultaneous Biplane Imaging: Challenging the Need for a Circular Assumption of the Left Ventricular Outflow Tract in the Assessment of Aortic Stenosis.

BACKGROUND: Evaluation of aortic stenosis (AS) requires calculation of aortic valve area (AVA), which relies on the assumption of a circular-shaped left ventricular outflow tract (LVOT). However, the LVOT is often elliptical, and the circular assumption underestimates the true LVOT area (LVOTA). Biplane imaging using transthoracic echocardiography allows direct planimetry of LVOTA. The aim of this study was to assess the feasibility of obtaining LVOTA using this technique and its impact on the discordance between AVA and gradient criteria in AS grading. METHODS: We prospectively studied 134 patients (median age, 80 years; interquartile range, 73-87 years; 39% women) with AS, including 82 (61%) with severe AS and 52 (39%) with mild or moderate AS. LVOTA was traced using direct planimetry (LVOTAbiplane) and compared with LVOTA calculated using the circular assumption (LVOTAcirc). In a subset of patients who underwent cardiac computed tomography, direct planimetry of LVOTA was used as a reference standard. RESULTS: LVOTAbiplane was significantly larger than LVOTAcirc (4.20 cm2 [interquartile range, 3.66-4.90 cm2] vs 3.73 cm2 [interquartile range, 3.14-4.15 cm2], P < .001). Among 30 patients who underwent cardiac computed tomography, LVOTAbiplane had better agreement with LVOTA by direct planimetry than LVOTAcirc (mean bias, -0.45 ± 0.63 vs -1.02 ± 0.63 cm2; P < .0001). Of 82 patients with severe AS (AVA ≤ 1 cm2 using LVOTAcirc), 40 (49%) had discordant mean gradient (<40 mm Hg). By using LVOTAbiplane, patients with discordant AVA and mean gradient decreased from 49% to 27% (P = .004), and 29% of patients with severe AS were reclassified with moderate AS, with the highest percentage of reclassification in the group with low-gradient AS with preserved left ventricular ejection fraction. CONCLUSIONS: Direct planimetry using biplane imaging avoids the inherent underestimation of LVOTA using the circular assumption. LVOTA obtained by biplane planimetry can lead to better concordance between AVA and mean gradient and classification of AS severity.

Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment.

In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts as a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) affect their diffusion and penetration. To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment. Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and quantify their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates significantly higher diffusive transport of phage than negative control through in vitro tumor ECM. Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and spatial ordering impact diffusive transport. The P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited ∼40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to functionalized control particles. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy.

One-Pot Synthesis of Layered Disodium Zirconium Phosphate: Crystal Structure and Application in the Remediation of Heavy-Metal-Contaminated Wastewater.

Inorganic ion exchangers offer advantages whenever operation at high temperatures or in oxidizing environments is required. A novel two-dimensional disodium zirconium phosphate, Zr(NaPO4)2·H2O, was reported and investigated as an ion exchanger for heavy metals. The material was synthesized by a novel minimalistic solventless approach, and its solid-state structure was determined from powder X-ray diffraction data. Zr(NaPO4)2·H2O crystallizes in the space group P21/c with cell parameters a = 8.7584(1) Å, b = 5.3543(1) Å, c = 18.1684(3) Å, ß = 109.053 (1)°, and Z = 4. Its layered structure is similar to that of α-zirconium phosphate, Zr(HPO4)2·H2O. However, unlike α-zirconium phosphate which is limited in practical applications by its narrow interlayer spacing (d = 7.6 Å), the disodium zirconium phosphate has a larger spacing of 8.6 Å between planes. The material with inherent structural advantages displays excellent sorption for heavy metals such as Pb2+, Cu2+, Cd2+, and Tl+, maintaining its high selectivity with distribution coefficients, Kd, of 104-105 mL/g even in the presence of a large excess of Na+, K+, Mg2+, and Ca2+, which are commonly present in underground water. In particular, the maximum sorption capacity for the highly toxic Tl+ is a record high, 5.07 mmol/g (1036 mg/g). The fast reaction kinetics indicate that the exchangeable positions in Zr(NaPO4)2·H2O are readily accessible, in contrast to Zr(HPO4)2·H2O. The ease of preparation, benign nature, and advantageous ion-exchange properties make Zr(NaPO4)2·H2O a highly promising sorbent for the treatment of water polluted with heavy metals.

Mucus-penetrating phage-displayed peptides for improved transport across a mucus-like model.

The objective of this work is to use phage display libraries as a screening tool to identify peptides that facilitate transport across the mucus barrier. Mucus is a complex selective barrier to particles and molecules, limiting penetration to the epithelial surface of mucosal tissues. In mucus-associated diseases such as cystic fibrosis (CF), mucus has increased viscoelasticity and a higher concentration of covalent and non-covalent physical entanglements compared to healthy tissues, which greatly hinders permeability and transport of drugs and particles across the mucosae for therapeutic delivery. Treatment of CF lung diseases and associated infections must overcome this abnormal mucosal barrier. Critical bottlenecks hindering effective drug penetration remain and while recent studies have shown hydrophilic, net-neutral charge polymers can improve the transport of nanoparticles and minimize interactions with mucus, there is a dearth of alternative carriers available. We hypothesized that the screening of a phage peptide library against a CF mucus model would lead to the identification of phage-displayed peptide sequences able to improve transport in mucus. These combinatorial libraries possess a large diversity of peptide-based formulations (108-109) to achieve unprecedented screening for potential mucus-penetrating peptides. Here, phage clones displaying discovered peptides were shown to have up to 2.6-fold enhanced diffusivity in the CF mucus model. In addition, we demonstrate reduced binding affinities to mucin compared to wild-type control. These findings suggest that phage display libraries can be used as a strategy to improve transmucosal delivery.

Mechanochemistry-Based Synthesis of Highly Crystalline γ-Zirconium Phosphate for Selective Ion Exchange.

Highly crystalline γ-zirconium phosphate has been synthesized by a novel minimalistic approach and investigated as a selective ion exchanger for cesium, ammonium and potassium. In contrast to current solution-based preparations, the mechanochemistry-based synthesis provides easy access to γ-zirconium phosphate with short synthesis times and low crystallization temperature. The addition of NaF as a mineralizer increases the crystallinity of γ-zirconium phosphate, which forms micrometer-sized uniformly shaped rectangular platelets. The crystalline material has extremely high selectivity to cesium even in the presence of 1000- or 500-fold excess Na+ or Ca2+, respectively. The removal efficiency was >98% in the pH range of 2-5.5. As an ion exchanger for purification of dialysate, crystalline γ-zirconium phosphate shows higher uptake of ammonium and potassium ions than the amorphous gel compound currently used in sorbent cartridges. This sustainable protocol opens up opportunities for many practical applications of γ-zirconium phosphate.