HBD-2 binds SARS-CoV-2 RBD and blocks viral entry: Strategy to combat COVID-19.

New approaches to complement vaccination are needed to combat the spread of SARS-CoV-2 and stop COVID-19-related deaths and medical complications. Human beta defensin 2 (hBD-2) is a naturally occurring epithelial cell-derived host defense peptide that has anti-viral properties. Our comprehensive in-silico studies demonstrate that hBD-2 binds the site on the CoV-2-RBD that docks with the ACE2 receptor. Biophysical measurements confirm that hBD-2 indeed binds to the CoV-2-receptor-binding domain (RBD) (KD ∼ 2µM by surface plasmon resonance), preventing it from binding to ACE2-expressing cells. Importantly, hBD-2 shows specificity by blocking CoV-2/spike pseudoviral infection, but not VSVG-mediated infection, of ACE2-expressing human cells with an IC50 of 2.8 ± 0.4 µM. These promising findings offer opportunities to develop hBD-2 and/or its derivatives and mimetics to safely and effectively use as agents to prevent SARS-CoV-2 infection.

Binding free energy calculation of human beta defensin 3 with negatively charged lipid bilayer using free energy perturbation method.

Human ß defensin type 3 (hBD-3) is a cationic peptide having strong antimicrobial activities even at high salt concentrations. The conserved sequence is believed to contribute to its unique antibacterial activities. To design novel drugs based on hBD-3, predicting the binding free energy contribution of each residue on hBD-3 with bacterial membrane is important. Firstly, the stable binding structure of hBD-3 dimer in analog form bound on POPG lipid bilayer was predicted using NAMD simulations, which was confirmed by RMSD, buried surface area, hydrogen bonds, distance map, and insertion depth map calculations. Then, free energy perturbation (FEP) method was applied to calculate the binding free energy of each residue by mutating it into Alanine. It was found that the positively charged residues on the tail region of hBD-3 contribute significantly to its binding with membrane. The result emphasized the importance of electrostatic interactions to hBD-3's binding with bacterial membrane.

Molecular Dynamics Simulations of Human Beta-Defensin Type 3 Crossing Different Lipid Bilayers.

Human ß defensin type 3 (hBD-3) is a small cationic cysteine-rich peptide. It has a broad spectrum of antimicrobial activities. However, at high concentrations, it also shows hemolytic activity by interrupting red blood cells. To understand the selectivity of hBD-3 disrupting cell membranes, investigating the capability of hBD-3 translocating through different membranes is important. Since hBD-3 in the analogue form in which all three pairs of disulfide bonds are broken has similar antibacterial activities to the wild-type, this project investigates the structure and dynamics of an hBD-3 analogue in monomer, dimer, and tetramer forms through both zwitterionic and negatively charged lipid bilayers using molecular dynamics (MD) simulations. One tetramer structure of hBD-3 was predicted by running all-atom MD simulations on hBD-3 in water at a high concentration, which was found to be stable in water during 400 ns all-atom simulations based on root-mean-squared deviation, root-mean-squared fluctuation, buried surface area, and binding interaction energy calculations. After that, hBD-3 in different forms was placed inside different membranes, and then steered MD simulation was conducted to pull the hBD-3 out of the membrane along the z-direction to generate different configurational windows to set up umbrella-sampling (US) simulations. Because extensive sampling is important to obtain accurate free energy barriers, coarse-grained US MD simulations were performed in each window. Based on the long-term simulation result, membrane thinning was found near hBD-3 in different lipid bilayers and in different hBD-3 oligomer systems. By calculating the root-mean-squared deviation of the z-coordinate of hBD-3 molecules, rotation of the oligomer inside the bilayer and stretching of the oligomer structure along the z-direction were observed. Although reorientation of lipid heads toward the hBD-3 tetramer was observed based on the density profile calculation, the order parameter calculation shows that hBD-3 disrupts 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) lipids more significantly and makes it less ordered than on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. Calculating the free energy of hBD-3 through different lipid bilayers, it was found that generally hBD-3 encounters a lower energy barrier through negatively charged lipid membranes than the zwitterionic membrane. hBD-3 in different forms needs to overcome a lower energy barrier crossing the combined POPC+POPS bilayer through the POPS leaflet than through the POPC leaflet. Besides that, the potential of mean force result suggests that hBD-3 forms an oligomer translocating negatively charged lipid membranes at a low concentration. This study supplied new insight into the antibacterial mechanism of hBD-3 through different membranes.

Molecular dynamics simulations and functional studies reveal that hBD-2 binds SARS-CoV-2 spike RBD and blocks viral entry into ACE2 expressing cells.

New approaches to complement vaccination are needed to combat the spread of SARS-CoV-2 and stop COVID-19 related deaths and long-term medical complications. Human beta defensin 2 (hBD-2) is a naturally occurring epithelial cell derived host defense peptide that has antiviral properties. Our comprehensive in-silico studies demonstrate that hBD-2 binds the site on the CoV-2-RBD that docks with the ACE2 receptor. Biophysical and biochemical assays confirm that hBD-2 indeed binds to the CoV-2-receptor binding domain (RBD) (KD ~ 300 nM), preventing it from binding to ACE2 expressing cells. Importantly, hBD-2 shows specificity by blocking CoV-2/spike pseudoviral infection, but not VSV-G mediated infection, of ACE2 expressing human cells with an IC50 of 2.4± 0.1 µM. These promising findings offer opportunities to develop hBD-2 and/or its derivatives and mimetics to safely and effectively use as novel agents to prevent SARS-CoV-2 infection.

Cutaneous effects associated with fluconazole in patients treated for coccidioidomycosis.

BACKGROUND: Fluconazole is the most commonly used antifungal treatment for various forms of coccidioidomycosis. Although we had anecdotally observed a high proportion of patients reporting cutaneous adverse effects associated with fluconazole treatment, this observation was not well described in the medical literature, and we were unsure of the additional effect of the arid desert environment of Arizona. METHODS: We performed a one-time, voluntary survey of patients with coccidioidomycosis and compared the responses of patients treated with fluconazole with those of untreated patients. RESULTS: From January 1, 2015, to August 22, 2017, 62 fluconazole-treated and 35 untreated patients with coccidioidomycosis provided consent and were enrolled in the study; demographics were similar between the two groups. Among the 62 fluconazole-treated patients, daily dosages ranged from 200 mg to 800 mg. However, most (44/62, 71%) took 400 mg daily, the typical dose for the treatment of coccidioidomycosis. The median fluconazole treatment duration at the time of study participation was 6 months. When compared with untreated patients, those taking fluconazole had more moderate to severe dry lips (74.2% [46/62] vs. 23.5% [8/34]; P < 0.001), dry skin (45.8% [27/59] vs. 22.9% [8/35]; P = 0.03), and alopecia (31.1% [19/61] vs. 11.4% [4/35]; P = 0.004). CONCLUSIONS: For the treatment of coccidioidomycosis, patients receiving fluconazole reported significantly more severe cutaneous effects, including dry lips, dry skin, and alopecia, than untreated patients. Our findings identify an association but do not prove causality.

Mobile medical and health apps: state of the art, concerns, regulatory control and certification.

This paper examines the state of the art in mobile clinical and health-related apps. A 2012 estimate puts the number of health-related apps at no fewer than 40,000, as healthcare professionals and consumers continue to express concerns about the quality of many apps, calling for some form of app regulatory control or certification to be put in place. We describe the range of apps on offer as of 2013, and then present a brief survey of evaluation studies of medical and health-related apps that have been conducted to date, covering a range of clinical disciplines and topics. Our survey includes studies that highlighted risks, negative issues and worrying deficiencies in existing apps. We discuss the concept of 'apps as a medical device' and the relevant regulatory controls that apply in USA and Europe, offering examples of apps that have been formally approved using these mechanisms. We describe the online Health Apps Library run by the National Health Service in England and the calls for a vetted medical and health app store. We discuss the ingredients for successful apps beyond the rather narrow definition of 'apps as a medical device'. These ingredients cover app content quality, usability, the need to match apps to consumers' general and health literacy levels, device connectivity standards (for apps that connect to glucometers, blood pressure monitors, etc.), as well as app security and user privacy. 'Happtique Health App Certification Program' (HACP), a voluntary app certification scheme, successfully captures most of these desiderata, but is solely focused on apps targeting the US market. HACP, while very welcome, is in ways reminiscent of the early days of the Web, when many "similar" quality benchmarking tools and codes of conduct for information publishers were proposed to appraise and rate online medical and health information. It is probably impossible to rate and police every app on offer today, much like in those early days of the Web, when people quickly realised the same regarding informational Web pages. The best first line of defence was, is, and will always be to educate consumers regarding the potentially harmful content of (some) apps.

Social networking sites: emerging and essential tools for communication in dermatology.

IMPORTANCE: The use of social media by dermatology journals and professional and patient-centered dermatology organizations remains largely unknown and, to our knowledge, has yet to be fully evaluated. OBJECTIVE: To evaluate and quantify the extent of involvement of dermatology journals, professional dermatology organizations, and dermatology-related patient advocate groups on social networking sites. DESIGN, SETTING, AND PARTICIPANTS: We obtained an archived list of 102 current dermatology journals from SCImago on the World Wide Web and used the list to investigate Facebook, Twitter, and individual journal websites for the presence of social media accounts. We identified professional and patient-centered dermatology organization activity on social networks through queries of predetermined search terms on Google, Facebook, Twitter, and LinkedIn. The activity of each entity was documented by recording the following metrics of popularity: the numbers of Facebook "likes," Twitter "followers," and LinkedIn "members." MAIN OUTCOMES AND MEASURES: The numbers of Facebook likes, Twitter followers, and LinkedIn members corresponding to each dermatology journal and each professional and patient-related dermatology organization. RESULTS: On July 17, 2012, of the 102 dermatology journals ranked by SCImago, 12.7% were present on Facebook and 13.7% on Twitter. We identified popular dermatology journals based on Facebook likes and Twitter followers, led by the Journal of the American Academy of Dermatology and Dermatology Times, respectively. Popular professional dermatology organizations included dermRounds Dermatology Network (11 251 likes on Facebook and 2900 followers on Twitter). The most popular dermatology patient-centered organizations were the Skin Cancer Foundation (20 119 likes on Facebook), DermaTalk (21 542 followers on Twitter), and the National Psoriasis Foundation (200 members on LinkedIn). CONCLUSIONS AND RELEVANCE: Patient-centered and professional dermatology organizations use social networking sites; however, academic journals tend to lag behind significantly. Although some journals are active in social media, most have yet to recognize the potential benefits of fully embracing popular social networks.

Mobile applications in dermatology.

IMPORTANCE: With advancements in mobile technology, cellular phone-based mobile applications (apps) may be used in the practice and delivery of dermatologic care. OBJECTIVE: To identify and categorize the variety of current mobile apps available in dermatology for patients and providers. DESIGN, SETTING, AND PARTICIPANTS: Dermatology-related search terms were queried in the online app stores of the most commonly used mobile platforms developed by Apple, Android, Blackberry, Nokia, and Windows. Applications were assigned to categories based on description. Popularity, price, and reviews were recorded and target audiences were determined through websites offering online mobile apps. MAIN OUTCOMES AND MEASURES: Number, type, and price of mobile apps in dermatology. RESULTS: A total of 229 dermatology-related apps were identified in the following categories: general dermatology reference (61 [26.6%]), self-surveillance/diagnosis (41 [17.9%]), disease guide (39 [17.0%]), educational aid (20 [8.7%]), sunscreen/UV recommendation (19 [8.3%]), calculator (12 [5.2%]), teledermatology (8 [3.5%]), conference (6 [2.6%]), journal (6 [2.6%]), photograph storage/sharing (5 [2.2%]), dermoscopy (2 [0.9%]), pathology (2 [0.9%]), and other (8 [3.5%]). The most reviewed apps included Ultraviolet ~ UV Index (355 reviews), VisualDx (306), SPF (128), iSore (61), and SpotMole (50). There were 209 unique apps, with 17 apps existing on more than 1 operating system. More than half of the apps were offered free of charge (117 [51.1%]). Paid apps (112 [48.9%]) ranged from $0.99 to $139.99 (median, $2.99). Target audiences included patient (117 [51.1%]), health care provider (94 [41.0%]), and both (18 [7.9%]). CONCLUSIONS AND RELEVANCE: The widespread variety and popularity of mobile apps demonstrate a great potential to expand the practice and delivery of dermatologic care.

Long-term outcome in occipital nerve stimulation patients with medically intractable primary headache disorders.

INTRODUCTION: €‚ Occipital nerve stimulation (ONS) may provide relief for refractory headache disorders. However, scant data exist regarding long-€term ONS outcomes. METHODS: €‚ The methods used were retrospective review of the medical records of all (nonindustry study) patients who were trialed and implanted with occipital nerve stimulator systems at our institution, followed by a phone interview. Up to three attempts were made to contact each patient, and those who were contacted were given the opportunity to participate in a brief phone interview regarding their ONS experience. Data for analysis were gleaned from both the phone interview and the patient's medical records. RESULTS: €‚ Twenty-nine patients underwent a trial of ONS during the 8.5-€year study period. Three patients did not go on to permanent implant, 12 could not be contacted, and 14 participated in the phone interview. Based upon the phone interview (if the patient was contacted) or chart review, ONS was deemed successful in five of the 12 migraine, four of the five cluster headache, and five of the eight miscellaneous headache patients, and therapy was documented as long as 102 months. In one of the 26 patients, success of ONS could not be determined. Among patients deemed to have successful outcomes, headache frequency decreased by 18%, severity by 27%, and migraine disability score by 50%. Fifty-€eight percent of patients required at least one lead revision. DISCUSSION: €‚ These results, although limited by their retrospective nature, suggest that ONS can be effective long term despite technical challenges. The number of patients within each headache subtype was insufficient to draw conclusions regarding the differential effect of ONS. CONCLUSIONS: €‚ Randomized controlled long-€term studies in specific, intractable, primary headache disorders are indicated.

Risk management in a university environment.

Risk is an integral part of quality assurance in higher education in Australia. This paper describes a generic methodology for the identification and management of risk in a university or similar tertiary education environment and outlines a framework that enables the management of risk to be incorporated in the institution's governance cycle. The new approach here is that risk is embedded in the quality assurance framework and, in turn, in the strategic planning and budgeting processes. In many organisations, risk is implemented as a separate process and not considered in any meaningful way as integral to the strategic direction and performance of the university. The paper is based on work carried out by the authors and others between March 2008 and April 2009 to develop a comprehensive system for managing risk in a major Australian university, including processes whereby risk management could be integrated with, and add value to, the overall governance of the university. The case study is described in the appendix to this paper.

Hot tap water legislation in the United States.

Excessively hot tap water results in an estimated 1500 hospital admissions and up to 50 deaths in the United States every year. This study reviewed the current state of tap water temperature regulation in the United States, including the model plumbing code standards on which state legislation in this area is based; assessed the level of public awareness regarding the risk, prevalence, and severity of such injuries; and identified specific prevention measures. Relevant information was obtained from state legislative codes, model code development organizations, the US Consumer Product Safety Commission, and a survey of knowledge, attitudes, and behaviors related to tap water temperature safety. Model building and plumbing codes related to tap water temperature regulation and their subsequent adoption by state legislatures vary widely across the United States. The states also vary with respect to the authority provided to lower levels of government (counties or municipalities) to modify and enforce code provisions. Public awareness of hot tap water hazards and implementation of preventive measures are limited. A broader and more uniform application of codes for regulating tap water temperature in both institutional and residential settings can be achieved through input from affected users, government agencies, legislators, advocacy organizations, and the general public. Safer hot water temperatures and a reduction in scald injuries can be achieved through regulating hot water temperature level at the thermostat, installing temperature-regulating valves at the tap, and raising public awareness of hot tap water hazards.