Correction: Luedemann et al. Prostate Cancer-Associated miRNAs in Saliva: First Steps to an Easily Accessible and Reliable Screening Tool. Biomolecules 2022, 12, 1366.

The authors wish to make the following corrections to their paper [...].

Splitting Vertices in 2-Layer Graph Drawings.

Bipartite graphs model the relationships between two disjoint sets of entities in several applications and are naturally drawn as 2-layer graph drawings. In such drawings, the two sets of entities (vertices) are placed on two parallel lines (layers), and their relationships (edges) are represented by segments connecting vertices. Methods for constructing 2-layer drawings often try to minimize the number of edge crossings. We use vertex splitting to reduce the number of crossings, by replacing selected vertices on one layer by two (or more) copies and suitably distributing their incident edges among these copies. We study several optimization problems related to vertex splitting, either minimizing the number of crossings or removing all crossings with fewest splits. While we prove that some variants are ${\mathsf {NP}}$NP-complete, we obtain polynomial-time algorithms for others. We run our algorithms on a benchmark set of bipartite graphs representing the relationships between human anatomical structures and cell types.

Prostate Cancer-Associated miRNAs in Saliva: First Steps to an Easily Accessible and Reliable Screening Tool.

BACKGROUND: Common diagnostic tools for prostate cancer-prostate-specific antigen and transrectal biopsy-show only low predictive value and poor sensitivity. This study examines circulating miRNA in saliva to explore the possibility of a non-invasive and easy-to-execute diagnostic tool for prostate cancer screenings. METHODS: 16 miRNAs were extracted from salivary exosomes and analyzed via the delta-CT method. The presented method enables an application of the test in any health institution and even outpatient sector. Recruited participants were suspected to suffer from prostate cancer due to elevated PSA serum levels. Of these participants, 43 were diagnosed with prostate cancer, while 31 suffered from benign diseases and served as control group. RESULTS: hsa-mir-331-3p and hsa-mir-200b were significantly reduced in prostate cancer patients compared to the control group. ROC curve analysis revealed a reliable differentiation strength (AUC > 0.6) for both miRNAs with positive predictive values of 71% indicating prostate cancer. Differentiation of both groups based on PSA serum measurements was insufficient. The other 14 examined miRNAs showed no significant group differences. CONCLUSIONS: The presented method and miRNA are promising non-invasive tools to augment the current prostate cancer screening, thereby improving screening sensitivity and reducing numbers of false positive cancer suspects admitted to further invasive diagnostic and therapeutic steps.

Small RNAs as biomarkers to differentiate benign and malign prostate diseases: An alternative for transrectal punch biopsy of the prostate?

Prostate cancer (PCa) is the most common cancer and the third most frequent cause of male cancer death in Germany. MicroRNAs (miRNA) appear to be involved in the development and progression of PCa. A diagnostic differentiation from benign prostate hyperplasia (BPH) is often only possible through transrectal punch biopsy. This procedure is described as painful and carries risks. It was investigated whether urinary miRNAs can be used as biomarkers to differentiate the prostate diseases above. Therefore urine samples from urological patients with BPH (25) or PCa (28) were analysed using Next-Generation Sequencing to detect the expression profile of total and exosomal miRNA/piRNA. 79 miRNAs and 5 piwi-interacting RNAs (piRNAs) were significantly differentially expressed (adjusted p-value < 0.05 and log2-Fc > 1 or < -1). Of these, 6 miRNAs and 2 piRNAs could be statistically validated (AUC on test cohort > = 0.7). In addition, machine-learning algorithms were used to identify a panel of 22 additional miRNAs, whose interaction makes it possible to differentiate the groups as well. There are promising individual candidates for potential use as biomarkers in prostate cancer. The innovative approach of applying machine learning methods to this kind of data could lead to further small RNAs coming into scientific focus, which have so far been neglected.

Nanoscale Metal-Organic Layer Isolates Phthalocyanines for Efficient Mitochondria-Targeted Photodynamic Therapy.

Zinc-phthalocyanine (ZnPc) photosensitizers (PSs) have shown great potential in photodynamic therapy (PDT) owing to their strong absorption at long wavelengths (650-750 nm), high triplet quantum yields, and biocompatibility. However, the clinical utility of ZnPc PSs is limited by their poor solubility and tendency to aggregate in aqueous environments. Here we report the design of a new nanoscale metal-organic layer (nMOL) assembly, ZnOPPc@nMOL, with ZnOPPc [ZnOPPc = zinc(II)-2,3,9,10,16,17,23,24-octa(4-carboxyphenyl)phthalocyanine] PSs supported on the secondary building units (SBUs) of a Hf12 nMOL for PDT. Upon irradiation, SBU-bound ZnOPPc PSs absorb 700 nm light and efficiently sensitize the formation of singlet oxygen by preventing aggregation-induced self-quenching of ZnOPPc excited states. With intrinsic mitochondria-targeting capability, ZnOPPc@nMOL showed exceptional PDT efficacy with >99% tumor growth inhibition and 40-60% cure rates on two mouse models of colon cancer.

Nanoscale Metal-Organic Framework Co-delivers TLR-7 Agonists and Anti-CD47 Antibodies to Modulate Macrophages and Orchestrate Cancer Immunotherapy.

Nanoscale metal-organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy-radiodynamic therapy (RT-RDT). Herein, we report surface modification of a Hf-DBP nMOF for the co-delivery of a hydrophobic small-molecule toll-like receptor 7 agonist, imiquimod (IMD), and a hydrophilic macromolecule, anti-CD47 antibody (αCD47), for macrophage modulation and reversal of immunosuppression in tumors. IMD repolarizes immunosuppressive M2 macrophages to immunostimulatory M1 macrophages, while αCD47 blocks CD47 tumor cell surface marker to promote phagocytosis. Upon X-ray irradiation, IMD@Hf-DBP/αCD47 effectively modulates the immunosuppressive tumor microenvironment and activates innate immunity to orchestrate adaptive immunity when synergized with an anti-PD-L1 immune checkpoint inhibitor, leading to complete eradication of both primary and distant tumors on a bilateral colorectal tumor model. nMOFs thus provide a unique platform to co-deliver multiple immunoadjuvants for macrophage therapy to induce systematic immune responses and superb antitumor efficacy.

Nanoscale Metal-Organic Frameworks Stabilize Bacteriochlorins for Type I and Type II Photodynamic Therapy.

Herein we report the design of a bacteriochlorin-based nanoscale metal-organic framework, Zr-TBB, for highly effective photodynamic therapy via both type I and type II mechanisms. The framework of Zr-TBB stabilizes 5,10,15,20-tetra(p-benzoato)bacteriochlorin (TBB) ligands toward oxygen and light via geometrical constraint. Upon 740 nm light irradiation, Zr-TBB efficiently generates various reactive oxygen species, including singlet oxygen, superoxide anion, hydrogen peroxide, and hydroxyl radicals, to afford superb antitumor efficacy on mouse models of breast and colon cancers, with cure rates of 40% and 60%, respectively.

Disease X: accelerating the development of medical countermeasures for the next pandemic.

WHO has listed several priority diseases with epidemic potential for which there are no, or insufficient, medical countermeasures. In response, the Bill & Melinda Gates Foundation (with support from PricewaterhouseCoopers) coordinated subject matter experts to create a preparedness plan for Disease X. Disease X is caused by Pathogen X, an infectious agent that is not currently known to cause human disease, but an aetiologic agent of a future outbreak with epidemic or pandemic potential. We have identified crucial areas for acceleration in medical countermeasure product development and international coordination. We have also reviewed novel platforms and process improvements related to manufacturing, which could revolutionise the response to the next pandemic. Finally, we created several coordination and engagement guides. These guides range from the rational design of an intervention target product profile, to the key facets of vaccine and therapeutic development, to accelerated manufacturing and regulatory mechanisms. In this Personal View, we provide a high-level summary of the outcomes of the medical countermeasure development workstream, intended for a broad audience including academia, medical countermeasure developers, and multilateral coordinating bodies. We hope that they might find this piece useful in prioritising strategic investments and efforts to accelerate medical countermeasure development. We observed that in-depth analyses of clinical trial design, chemistry, manufacturing and control activities, and accelerated regulatory pathways are necessary for shortening the timelines for the product development of medical countermeasures. We intend to cover these topics in future publications.

High Detection Rate for Non-Muscle-Invasive Bladder Cancer Using an Approved DNA Methylation Signature Test.

INTRODUCTION: Cystoscopy and transurethral resection are the current reference standard tests to diagnose and histologically confirm non-muscle-invasive bladder cancer (NMIBC). In other tumor entities (ie, colon carcinoma, cervical cancer), DNA methylation markers have been approved as diagnostic tests with high diagnostic power. In our case-control study, we used an approved molecular cervical cancer diagnostics test that includes 6 DNA methylation markers (GynTect) for the detection of bladder cancer. PATIENTS AND METHODS: We included samples from 40 patients with bladder cancer and 34 control subjects. In a pilot study, we analyzed DNA methylation in 38 tumor tissues and 4 healthy ureters using methylation-specific polymerase chain reaction. Subsequently, we determined the sensitivity and specificity of the GynTect for the detection of bladder cancer in urine sediments from 40 patients with bladder cancer and 30 control subjects with benign prostatic hyperplasia or urolithiasis. RESULTS: The markers showed very different methylation rates in the NMIBC tissues, ranging from 2.6% to 78.9%. No methylation of any of the markers was detectable in the healthy ureters. Using the urine sediments from the patients with cancer and control subjects, we found surprisingly high sensitivity and specificity for the GynTect assay (60% and 96.7%, respectively). The application of different algorithms for evaluation of the markers included in GynTect resulted in a sensitivity of ≤ 90% and specificity of ≤ 100%. CONCLUSION: The GynTect assay, originally designed for cervical cancer diagnostics, showed unexpectedly high diagnostic accuracy for bladder cancer detection. The inclusion of additional methylation markers might allow for the development of a suitable diagnostic marker set based on the GynTect test for NMIBC diagnostics.

Titanium Hydroxide Secondary Building Units in Metal-Organic Frameworks Catalyze Hydrogen Evolution under Visible Light.

Herein we report the design of two new titanium metal-organic frameworks (MOFs), Ti3-BPDC-Ir and Ti3-BPDC-Ru, by doping [Ir(ppy)2(dcbpy)]Cl or [Ru(bpy)2(dcbpy)]Cl2 (bpy = 2,2'-bipyridine, ppy = 2-phenylpyridine, dcbpy = 2,2'-bipyridine-5,5'-dicarboxylate) into the Ti3-BPDC framework (BPDC = biphenyl-4,4'-dicarboxylate). Hierarchical assembly of photosensitizing ligands and Ti3(OH)2 secondary building units (SBUs) facilitates multielectron transfer to drive photocatalytic hydrogen evolution (HER) under visible light with turnover numbers of 6632 and 786 for Ti3-BPDC-Ir and Ti3-BPDC-Ru, respectively. Photophysical and electrochemical studies establish the photocatalytic HER via reductive quenching of the excited photosensitizers followed by electron transfer from the reduced photosensitizers to Ti3(OH)2 SBUs and explain the catalytic difference between the two MOFs. Density functional theory calculations reveal key steps of HER via protonation of TiIII-OH to generate the TiIII species with a vacant coordination site followed by proton-coupled electron transfer to afford the key TiIV-H intermediate.

Metal-Organic Framework Stabilizes a Low-Coordinate Iridium Complex for Catalytic Methane Borylation.

Catalytic borylation has recently been suggested as a potential strategy to convert abundant methane to fine chemicals. However, synthetic utility of methane borylation necessitates significant improvement of catalytic activities over original phenanthroline- and diphosphine-Ir complexes. Herein, we report the use of metal-organic frameworks (MOFs) to stabilize low-coordinate Ir complexes for highly active methane borylation to afford the monoborylated product. The mono(phosphine)-Ir based MOF, Zr-P1-Ir, significantly outperformed other Ir catalysts in methane borylation to afford CH3Bpin with a turnover number of 127 at 110 °C. Density functional theory calculations indicated a significant reduction of activation barrier for the rate limiting oxidative addition of methane to the four-coordinate (P1)IrIII(Bpin)3 catalyst to form the six-coordinate (P1)IrV(Bpin)3(CH3)(H) intermediate, thus avoiding the formation of sterically encumbered seven-coordinate IrV intermediates as found in other Ir catalysts based on chelating phenanthroline, bipyridine, and diphosphine ligands. MOF thus stabilizes the homogeneously inaccessible, low-coordinate (P1)Ir(boryl)3 catalyst to provide a unique strategy to significantly lower the activation barrier for methane borylation. This MOF-based catalyst design holds promise in addressing challenging catalytic reactions involving highly inert substrates.

Management of exposed pacemaker caused by burns.

Annual implants of cardiovascular implantable devices (CIEDs) are increasing, thus increasing the risk of device exposure. This case presents CIED management issues following traumatic thermal injury. A 59-year-old female presented to intensive care with 42% total body surface area burn involving tissue over her pacemaker generator. Electrophysiologists interrogated and reprogrammed the pacer and observed the patient over 72 hours without pacing. Serratia bacteremia developed and cardiology recommended device removal. The pacemaker generator and leads were removed by cardiothoracic and burn surgery. Postoperatively, asystole required emergency transvenous pacing wire placement. During bacteremia treatment, cardiology planned to pace with an active-fixation screw-in lead with long-term plans to place a single right ventricular chamber leadless pacemaker because of the extensive burns. The patient developed fungemia and the family opted for comfort care. This case report discusses the management of a CIED exposed after a traumatic thermal burn, including device extraction.

Electronic consults for improving specialty care access for veterans.

OBJECTIVES: We adopted e-consults within an active referral management (ARM) process for our Veterans Health Administration (VHA) outpatient cardiology clinic to reduce clinic wait times. STUDY DESIGN: Prospective multiphase cohort study. METHODS: Our ARM process consisted of reviewing all incoming consult requests for our outpatient clinic and triaging the requests to either an e-consult or a clinic visit. The primary outcome was wait time for an appointment in our clinic. RESULTS: Median wait time prior to the ARM process was 24 days. After implementation of the ARM process, wait times decreased to 13 days (46% reduction). Approximately 60% of incoming consults could be triaged into e-consults, predominantly by managing stable diseases or minor symptoms. CONCLUSIONS: E-consults and ARM of clinical referrals were effective at reducing wait times for our outpatient VHA cardiology clinic. The majority of clinical referrals could be handled through an e-consult and did not require an in-person clinic visit.

Cobalt-bridged secondary building units in a titanium metal-organic framework catalyze cascade reduction of N-heteroarenes.

We report here a novel Ti3-BPDC metal-organic framework (MOF) constructed from biphenyl-4,4'-dicarboxylate (BPDC) linkers and Ti3(OH)2 secondary building units (SBUs) with permanent porosity and large 1D channels. Ti-OH groups from neighboring SBUs point toward each other with an O-O distance of 2 Å, and upon deprotonation, act as the first bidentate SBU-based ligands to support CoII-hydride species for effective cascade reduction of N-heteroarenes (such as pyridines and quinolines) via sequential dearomative hydroboration and hydrogenation, affording piperidine and 1,2,3,4-tetrahydroquinoline derivatives with excellent activity (turnover number ∼ 1980) and chemoselectivity.

Hypoglycemia Emergencies: Factors Associated with Prehospital Care, Transportation Status, Emergency Department Disposition, and Cost.

Objectives: The objectives of this study were to evaluate demographic/clinical characteristics and treatment/transportation decisions by emergency medical services (EMS) for patients with hypoglycemia and link EMS activations to patient disposition, outcomes, and costs to the emergency medical system. This evaluation was to identify potential areas where improvements in prehospital healthcare could be made. Methods: This was a retrospective analysis of the National Emergency Medical Services Information System (NEMSIS) registry and three national surveys: Nationwide Emergency Department Sample (NEDS), National Hospital Ambulatory Medical Care Survey (NHAMCS), and Medical Expenditure Panel Survey (MEPS) from 2013, to examine care of hypoglycemia from the prehospital and the emergency department (ED) perspectives. Results: The study estimated 270,945 hypoglycemia EMS incidents from the NEMSIS registry. Treatments were consistent with national guidelines (i.e., oral glucose, intravenous [IV] dextrose, or glucagon), and patients were more likely to be transported to the ED if the incident was in a rural setting or they had other chief concerns related to the pulmonary or cardiovascular system. Use of IV dextrose decreased the likelihood of transportation. Approximately 43% of patients were not transported from the scene. Data from the NEDS survey estimated 258,831 ED admissions for hypoglycemia, and 41% arrived by ambulance. The median ambulance expenditure was $664 ± 98. From the ED, 74% were released. The average ED charge that did not lead to hospital admission was $3106 ± 86. Increased odds of overnight admission included infection and acute renal failure. Conclusions: EMS activations for hypoglycemia are sizeable and yet a considerable proportion of patients are not transported to or are discharged from the ED. Seemingly, these events resolved and were not medically complex. It is possible that implementation and appropriate use of EMS treat-and-release protocols along with utilizing programs to educate patients on hypoglycemia risk factors and emergency preparedness could partially reduce the burden of hypoglycemia to the healthcare system.

Human adenovirus type 17 from species D transduces endothelial cells and human CD46 is involved in cell entry.

More than 70 human adenoviruses with type-dependent pathogenicity have been identified but biological information about the majority of these virus types is scarce. Here we employed multiple sequence alignments and structural information to predict receptor usage for the development of an adenoviral vector with novel biological features. We report the generation of a cloned adenovirus based on human adenovirus type 17 (HAdV17) with high sequence homology to the well characterized human adenovirus type 37 (HAdV37) that causes epidemic keratoconjunctivitis (EKC). Our study revealed that human CD46 (CD46) is involved in cell entry of HAdV17. Moreover, we found that HAdV17 infects endothelial cells (EC) in vitro including primary cells at higher efficiencies compared to the commonly used human adenovirus type 5 (HAdV5). Using a human CD46 transgenic mouse model, we observed that HAdV17 displays a broad tropism in vivo after systemic injection and that it transduces ECs in this mouse model. We conclude that the HAdV17-based vector may provide a novel platform for gene therapy.

Iatrogenic Ventricular Fibrillation after Direct-Current Cardioversion of Preexcited Atrial Fibrillation Caused by Inadvertent T-Wave Synchronization.

Direct-current cardioversion is an important means of managing arrhythmias. During treatment, carefully synchronizing energy delivery to the QRS complex is necessary to avoid ventricular fibrillation caused by a shock during the vulnerable period of ventricular repolarization, that is, a shock on the T wave. The presence of an accessory pathway and ventricular preexcitation can lead to difficulty in distinguishing the QRS complex from the T wave because of bizarre, wide, irregular QRS complexes and prominent repolarization. We present the cases of 2 patients who had iatrogenic ventricular fibrillation from inappropriate T-wave synchronization during direct-current cardioversion of preexcited atrial fibrillation. Our experience shows that rapidly recognizing the iatrogenic cause of VF and immediate treatment with unsynchronized defibrillation can prevent adverse clinical outcomes.