Polyethylene Glycol 20k. Does It Fluoresce?

Polyethylene glycol (PEG) is a polyether compound commonly used in biological research and medicine because it is biologically inert. This simple polymer exists in variable chain lengths (and molecular weights). As they are devoid of any contiguous π-system, PEGs are expected to lack fluorescence properties. However, recent studies suggested the occurrence of fluorescence properties in non-traditional fluorophores like PEGs. Herein, a thorough investigation has been conducted to explore if PEG 20k fluoresces. Results of this combined experimental and computational study suggested that although PEG 20k could exhibit "through-space" delocalization of lone pairs of electrons in aggregates/clusters, formed via intermolecular and intramolecular interactions, the actual contributor of fluorescence between 300 and 400 nm is the stabilizer molecule, i.e., 3-tert-butyl-4-hydroxyanisole present in the commercially available PEG 20k. Therefore, the reported fluorescence properties of PEG should be taken with a grain of salt, warranting further investigation.

Medication Use Among Patients Reporting Xerostomia of an Academic Dental Clinic.

Background: Global prevalence of xerostomia has been reported at 22% (range 0.01%-45%), negatively impacting oral health, nutrition intake, and quality of life. The causal relationship between xerostomia and medications remains uncertain but greater understanding could guide interventions. Objective: To describe the demographic characteristics and medication regimens in patients with xerostomia of an academic dental clinic. Method: This is a retrospective academic dental clinic record review from July 1, 2018 to October 27, 2020. Patient records were obtained from the University at Buffalo, School of Dental Medicine. Xerostomia status was determined via query of electronic health records and validated by manual review. Pharmacologic class and xerostomic potential of medications were identified by the Veterans Affairs Drug Classification System and drug compendia, respectively. Predictors of medication use were assessed using a multiple logistic regression model. Results: Of 37 403 examined records, 366 (0.98%) were identified as xerostomic. After excluding confounding factors (Sjogren's and radiation), 275 of 317 patients received at least one xerostomic medication, majority were female (240, 66%) versus male (126, 34%). Mean ± (SD) age was 64.9 ± 15.11 years. A total of 208 (57%) patients were aged ≥65. The median number of total and xerostomic medications were 8 (interquartile range [IQR], 4-12) and 4 (IQR, 2-7), respectively. The 3 most prevalent xerostomic pharmacologic classes were antidepressants (131, 35%), gastric medications (101, 28%), and vitamin D (87, 24%). Conclusion: Despite observed prevalence of xerostomia lower than global prevalence, xerostomic medication burden for patients experiencing xerostomia was high. Pharmacist-led interprofessional collaborations should be investigated to reduce xerostomic burden.

Comparison of citation rates between Covid-19 and non-Covid-19 articles across 24 major scientific journals.

Covid-19 has been front and center in the global landscape since the beginning of 2020. In response, the scientific field has dedicated enormous amounts of resources to researching the virus and its effects. The number of times Covid-19 publications are being cited throughout the literature appears remarkably high but has not been directly compared to non-Covid-19 papers in the same journals over an extended period. In our study, we use Clarivate's Web of Science-Science Citation Index Expanded™ database to identify Covid-19 papers published in 24 major scientific journals over a period of 24 months from January 1, 2020 to December 31, 2021. We conduct our search using keywords "Covid-19", "coronavirus", and "sars-cov-2" to locate publications with these words in the title. We then quantify the number of citations these papers have received and compare rates to non-Covid-19 papers in the same journals over the same timeframe. We find that, across 24 open-access and subscription-based scientific journals, Covid-19 papers published in the past 2 years currently have a median citation rate of 120.79 compared to 21.63 for non-Covid-19 papers. When negative binomial regression is used to minimize the influence of other variables such as article number variation and field of research, Covid-19 papers have still experienced more than 80% increase in citations relative to non-Covid-19 papers. These novel findings demonstrate that Covid-19 papers are being cited at remarkably higher rates than non-Covid-19 articles contained within the same journals. This suggests that journal impact factor, which is a product of the number of citations that recently published articles receive, will likely be drastically influenced by the number of Covid-19 papers that a journal has included within its pages in the previous years.

BigMouth: development and maintenance of a successful dental data repository.

Few clinical datasets exist in dentistry to conduct secondary research. Hence, a novel dental data repository called BigMouth was developed, which has grown to include 11 academic institutions contributing Electronic Health Record data on over 4.5 million patients. The primary purpose for BigMouth is to serve as a high-quality resource for rapidly conducting oral health-related research. BigMouth allows for assessing the oral health status of a diverse US patient population; provides rationale and evidence for new oral health care delivery modes; and embraces the specific oral health research education mission. A data governance framework that encouraged data sharing while controlling contributed data was initially developed. This transformed over time into a mature framework, including a fee schedule for data requests and allowing access to researchers from noncontributing institutions. Adoption of BigMouth helps to foster new collaborations between clinical, epidemiological, statistical, and informatics experts and provides an additional venue for professional development.

Medial patellofemoral ligament MRI abnormalities in the setting of MCL injuries: are they clinically relevant?

OBJECTIVE: To assess MRI abnormalities of the medial patellofemoral ligament (MPFL) in patients with clinically and MRI-proven superficial medial collateral ligament (sMCL) injuries and determine the clinical significance. MATERIALS AND METHODS: High-field strength knee MRI examinations were selected which demonstrated sMCL injuries. These cases were retrospectively reviewed for the presence, location, and severity of MPFL abnormality. The MPFL was divided into a more superior transverse component arising from a femoral attachment (tMPFL), and a broader more inferior oblique decussation component (odMPFL) arising from the anterior margin of the upper sMCL. Chart review was performed to determine the clinical relevance of any MPFL findings. RESULTS: One hundred patients with MCL injury were identified. These included 37 grade I sprains, 33 partial tears, 20 high-grade partial tears, and 10 full thickness tears. Abnormal edema was present at the femoral attachment of the tMPFL in 83%. The odMPFL was abnormal in 90%, most commonly involving the femoral third. No patients had imaging evidence of concurrent lateral patellar dislocation on the initial MRI study. No patients had documented patellofemoral instability at the time of original injury or upon follow-up. No patients required MPFL reconstruction. CONCLUSION: The MRI appearance of the MPFL is abnormal in the majority of patients with clinically and MRI-documented sMCL sprains and tears. These cases had no evidence of concurrent lateral patellar dislocation on the initial MRI and did not develop patellar instability symptoms.

Vitamin D and COVID-19: A review on the role of vitamin D in preventing and reducing the severity of COVID-19 infection.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus causing COVID-19 infection. The interaction between the SARS-CoV-2 spike protein and the human receptor angiotensin-converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide-thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID-19. However, the molecular-level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID-19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID-19 infection or reducing the severity of the disease.

Electronic Health Records and Pulmonary Function Data: Developing an Interoperability Roadmap. An Official American Thoracic Society Workshop Report.

A workshop "Electronic Health Records and Pulmonary Function Data: Developing an Interoperability Roadmap" was held at the American Thoracic Society 2019 International Conference. "Interoperability" is defined as is the ability of different information-technology systems and software applications to directly communicate, exchange data, and use the information that has been exchanged. At present, pulmonary function test (PFT) equipment is not required to be interoperable with other clinical data systems, including electronic health records (EHRs). For this workshop, we assembled a diverse group of experts and stakeholders, including representatives from patient-advocacy groups, adult and pediatric general and pulmonary medicine, informatics, government and healthcare organizations, pulmonary function laboratories, and EHR and PFT equipment and software companies. The participants were tasked with two overarching Aobjectives: 1) identifying the key obstacles to achieving interoperability of PFT systems and the EHR and 2) recommending solutions to the identified obstacles. Successful interoperability of PFT data with the EHR impacts the full scope of individual patient health and clinical care, population health, and research. The existing EHR-PFT device platforms lack sufficient data standardization to promote interoperability. Cost is a major obstacle to PFT-EHR interoperability, and incentives are insufficient to justify the needed investment. The current vendor-EHR system lacks sufficient flexibility, thereby impeding interoperability. To advance the goal of achieving interoperability, next steps include identifying and standardizing priority PFT data elements. To increase the motivation of stakeholders to invest in this effort, it is necessary to demonstrate the benefits of PFT interoperability across patient care and population health.

A novel rabbit derived anti-HER2 antibody with pronounced therapeutic effectiveness on HER2-positive breast cancer cells in vitro and in humanized tumor mice (HTM).

BACKGROUND: Antibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients. Trastuzumab that targets the human epidermal growth factor related receptor 2 (HER2) is one of the greatest success stories in this field. For decades, trastuzumab based treatment regimens are significantly improving the prognosis of HER2-positive breast cancer patients both in the metastatic and the (neo-) adjuvant setting. Nevertheless, ≥ 50% of trastuzumab treated patients experience de-novo or acquired resistance. Therefore, an enhanced anti-HER2 targeting with improved treatment efficiency is still aspired. METHODS: Here, we determined cellular and molecular mechanisms involved in the treatment of HER2-positive BC cells with a new rabbit derived HER2 specific chimeric monoclonal antibody called "B100″. We evaluated the B100 treatment efficiency of HER2-positive BC cells with different sensitivity to trastuzumab both in vitro and in the presence of a human immune system in humanized tumor mice. RESULTS: B100 not only efficiently blocks cell proliferation but more importantly induces apoptotic tumor cell death. Detailed in vitro analyses of B100 in comparison to trastuzumab (and pertuzumab) revealed equivalent HER2 internalization and recycling capacity, similar Fc receptor signaling, but different HER2 epitope recognition with high binding and treatment efficiency. In trastuzumab resistant SK-BR-3 based humanized tumor mice the B100 treatment eliminated the primary tumor but even more importantly eradicated metastasized tumor cells in lung, liver, brain, and bone marrow. CONCLUSION: Overall, B100 demonstrated an enhanced anti-tumor activity both in vitro and in an enhanced preclinical HTM in vivo model compared to trastuzumab or pertuzumab. Thus, the use of B100 is a promising option to complement and to enhance established treatment regimens for HER2-positive (breast) cancer and to overcome trastuzumab resistance. Extended preclinical analyses using appropriate models and clinical investigations are warranted.

The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.

Nonmelanoma Skin Cancer.

This article reviews the most common nonmelanoma skin cancers affecting the head and neck region. Although the most common of these malignancies rarely result in mortality, local morbidity caused by the tumors and their extirpation cannot be underestimated. Complete tumor extirpation with pathologically confirmed negative margins is the gold standard. Regional and distant metastases are rare, but must be treated appropriately should they occur. Although reconstructive surgery can be life changing for the patients and rewarding for the clinicians, it behooves the treating surgeons to remain true to oncologic principles above all else.

Discovery and optimization of a novel series of pyrazolyltetrahydropyran N-type calcium channel (Cav 2.2) blockers for the treatment of pain.

A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.

Primary care specialty career choice among Canadian medical students: Understanding the factors that influence their decisions.

OBJECTIVE: To identify which factors influence medical students' decision to choose a career in family medicine and pediatrics, and which factors influence their decision to choose careers in non-front-line specialties. DESIGN: Survey that was created based on a comprehensive literature review to determine which factors are considered important when choosing practice specialty. SETTING: Ontario medical school. PARTICIPANTS: An open cohort of medical students in the graduating classes of 2008 to 2011 (inclusive). MAIN OUTCOME MEASURES: The main factors that influenced participants' decision to choose a career in primary care or pediatrics, and the main factors that influenced participants' decision to choose a career in a non-front-line specialty. RESULTS: A total of 323 participants were included in this study. Factors that significantly influenced participants' career choice in family medicine or pediatrics involved work-life balance (acceptable hours of practice [P = .005], acceptable on-call demands [P = .012], and lifestyle flexibility [P = .006]); a robust physician-patient relationship (ability to promote individual health promotion [P = .014] and the opportunity to form long-term relationships [P < .001], provide comprehensive care [P = .001], and treat patients and their families [P = .006]); and duration of residency program (P = .001). The career-related factors that significantly influenced participants' decision to choose a non-front-line specialty were as follows: becoming an expert (P < .001), maintaining a focused scope of practice (P < .001), having a procedure-focused practice (P = .001), seeing immediate results from one's actions (P < .001), potentially earning a high income (P < .001), and having a perceived status among colleagues (P < .001). CONCLUSION: In this study, 8 factors were found to positively influence medical students' career choice in family medicine and pediatrics, and 6 factors influenced the decision to choose a career in a non-front-line specialty. Medical students can be encouraged to explore a career in family medicine or pediatrics by addressing misinformation, by encouraging realistic expectations of career outcomes in the various specialties, and by demonstrating the capacity of primary care fields to incorporate specific motivating factors.

Coronary artery bypass surgery in diabetic patients - risk factors for sternal wound infections.

The incidence of sternal wound infections (SWI) after coronary artery bypass surgery (CABG) as reported worldwide is low. However, it is associated with significant increase of postoperative mortality and treatment costs. The major risk factors discussed are diabetes mellitus and bilateral IMA harvesting of the internal mammary artery. This study analyses data of 590 patients receiving CABG concerning the risk factors for SWI. Sternal wound infections occur significantly more often in diabetic patients, one crucial and significant additional risk factor is obesity.

Objective Evaluation of Otoscopy Skills Among Family and Community Medicine, Pediatric, and Otolaryngology Residents.

INTRODUCTION: The objective of this study is to evaluate and compare the perceived need for otolaryngology training and otoscopy diagnostic skills in primary care (Family and Community Medicine, Pediatric Medicine), and Otolaryngology Head and Neck Surgery (OTO-HNS) postgraduate trainees. Participant otoscopy skills were evaluated using the OtoSim simulator. METHODS: Family and Community Medicine, Pediatric, and OTO-HNS residents were recruited. Each resident participated in 3 separate otoscopy training and assessment sessions. The ability to correctly identify middle ear pathology was objectively evaluated using OtoSim™. Pretest, posttest, and 3-month retention test results were compared among residents in a paired comparison paradigm. Survey data assessing exposure to OTO-HNS during undergraduate and postgraduate training were also collected. RESULTS: A total of 57 residents participated in the study. All residents reported limited exposure to OTO-HNS during undergraduate medical training. Primary care trainees performed poorly on pretest assessments (30% ± 7.8%; 95% CI). Significant improvement in diagnostic accuracy was demonstrated following a single 1-hour teaching session (30%-62%; p < 0.001). Primary care residents demonstrated a significant decrease in diagnostic accuracy at a 3-month follow-up assessment (62%-52%, p < 0.001). Self-perceived comfort with otology was poorly correlated to pretest performance among primary care trainees (r = 0.26) and showed a stronger positive correlation among OTO-HNS trainees (r = 0.56). CONCLUSIONS: A single teaching session with an otoscopy simulator significantly improved diagnostic accuracy in primary care and OTO-HNS trainees. Improved performance is susceptible to deterioration at 3 months if acquired skills are not frequently used. Self-perceived comfort with otology may not be an accurate predictor of otoscopic diagnostic skill.

TRPV1 antagonist JNJ-39439335 (mavatrep) demonstrates proof of pharmacology in healthy men: a first-in-human, double-blind, placebo-controlled, randomized, sequential group study.

This double-blind, randomized, placebo-controlled, sequential group, phase 1 study was designed to assess in healthy men, the safety, tolerability, pharmacokinetics, and translational pharmacodynamics of JNJ-39439335 (mavatrep), a transient receptor potential vanilloid subtype 1 antagonist; it was preceded by a translational preclinical study which assessed the ability of JNJ-39439335 to block capsaicin-induced flare in rats, providing predictive pharmacokinetic and pharmacodynamic data that informed the subsequent phase 1 clinical study. The clinical study consisted of 2 parts: part 1 assessed pharmacokinetics and pharmacodynamics, including heat pain detection threshold and heat pain tolerance, of JNJ-39439335, and part 2 assessed pharmacodynamic effect of JNJ-39439335 on capsaicin-induced flare and sensory testing on naïve and UVB-sensitized skin in humans. Plasma concentrations of JNJ-39439335 peaked at approximately 2 to 4 hours postdose, then declined multiexponentially, with a prolonged terminal phase (half-life: 30-86 hours). Renal clearance of JNJ-39439335 was negligible. JNJ-39439335 treatment resulted in clear, consistent dose-related increases in heat pain detection threshold, heat pain tolerance, and heat pain latency. JNJ-39439335 reduced the capsaicin-induced flare area and flare intensity, with complete blocking observed in the 50-mg dose group at 144 hours postdose. This was consistent with the capsaicin flare results observed with JNJ-39439335 in rats. The most common adverse events observed in the clinical study were related to increases in body temperature after JNJ-39439335 treatment; these were predominately mild to moderate in severity with no evidence of exposure dependence up to 225 mg. JNJ-39439335 was well tolerated at single doses up to 225 mg, recommending its suitability for further clinical development.

A Linear Epitope in the N-Terminal Domain of CCR5 and Its Interaction with Antibody.

The CCR5 receptor plays a role in several key physiological and pathological processes and is an important therapeutic target. Inhibition of the CCR5 axis by passive or active immunisation offers one very selective strategy for intervention. In this study we define a new linear epitope within the extracellular domain of CCR5 recognised by two independently produced monoclonal antibodies. A short peptide encoding the linear epitope can induce antibodies which recognise the intact receptor when administered colinear with a tetanus toxoid helper T cell epitope. The monoclonal antibody RoAb 13 is shown to bind to both cells and peptide with moderate to high affinity (6x10^8 and 1.2x107 M-1 respectively), and binding to the peptide is enhanced by sulfation of tyrosines at positions 10 and 14. RoAb13, which has previously been shown to block HIV infection, also blocks migration of monocytes in response to CCR5 binding chemokines and to inflammatory macrophage conditioned medium. A Fab fragment of RoAb13 has been crystallised and a structure of the antibody is reported to 2.1 angstrom resolution.

Benzo[d]imidazole Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep).

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.

Prevention of hepatitis C virus infection and spread in human liver chimeric mice by an anti-CD81 monoclonal antibody.

UNLABELLED: CD81 is a required receptor for hepatitis C virus (HCV) infection of human hepatocytes in vitro. We generated several high-affinity anti-human CD81 monoclonal antibodies (mAbs) that demonstrated potent, specific, and cross-genotype inhibition of HCV entry. One of these mAbs, K04, was administered to human liver chimeric mice before or after HCV infection to determine its ability to prevent HCV infection or spread of HCV infection, respectively. All vehicle control mice established HCV infection, reaching steady-state levels of serum HCV RNA by day 21. Pretreatment of mice with K04 prevented HCV infection in all mice (n = 5). Treatment of mice with mAb K04 every 3 days for 21 days, starting at 6 hours postinfection, resulted in effective inhibition of virus spread. In 3 mice that were sacrificed on day 24, serum HCV levels remained detectable, below the limit of quantification (LOQ), indicating that infection was established, but virus spread was blocked, by the anti-CD81 mAb. In 5 additional mice that were followed for a longer time, virus remained detectable, below LOQ, until days 24 and 30 in 4 of 5 mice. In the fifth mouse, viral load was quantifiable, but reduced to 64-fold below the mean viral load in vehicle control at day 24. In addition, 2 of 5 mice cleared the infection by day 30 and 1 mouse had undetectable virus load from day 6 onward. CONCLUSION: These results demonstrate that CD81 is required for HCV infection and virus spread in vivo, and that anti-CD81 antibodies such as K04 may have potential as broad-spectrum antiviral agents for prevention and treatment of HCV infection.

The aesthetic unit principle of facial aging.

IMPORTANCE: In youth, facial aesthetic units flow together without perceptible division. The face appears as a single dynamic structure with a smooth contour and very little if any shadowing between different anatomical regions. As one ages, facial aesthetic units slowly become distinct. This process may be a consequence of differences in skin thickness, composition of subcutaneous tissue, contour of the facial skeleton, and location of facial ligaments. Although the impact of aesthetic unit separation is clinically apparent, its fundamental role in perceived facial aging has not yet been defined empirically. OBJECTIVES: To evaluate and define the effect of aesthetic unit separation on facial aging and to empirically validate the rationale for the blending of aesthetic units as a principle for facial rejuvenation. DESIGN, SETTING, AND PARTICIPANTS: We prepared the photographs of 7 women for experimental evaluation of the presence or absence of facial aesthetic unit separation. Photographic stimuli were then presented to 24 naive observers in a blinded paired comparison. For each stimulus pair, observers were asked to select the facial photograph that they considered to be more youthful in appearance. Each stimulus was compared with all others. MAIN OUTCOMES AND MEASURES: We calculated a preference score for the total number of times any photograph was chosen to be more youthful compared with all others. Paired t tests were used to compare the preference scores between the facial stimuli with and without aesthetic unit separation. RESULTS: We generated 4032 responses for analysis. Photographs without facial aesthetic unit separation were consistently judged to be more youthful than their aged original or modified counterparts, with mean preference scores of 0.66 and 0.33, respectively (P ≤ .047). When we selected the paired stimulus that directly compared one photograph with aesthetic unit separation with another with blended aesthetic units (2015 pairs), observers indicated that the photograph with the blended aesthetic unit was younger 95% of the time. Within-rater reliability was found to be very good (r = 0.88). CONCLUSIONS AND RELEVANCE: Our data support the hypothesis that facial aesthetic unit separation influences perceived facial youthfulness among photographs of women. The presence of facial aesthetic unit separation results in a less youthful appearance. Based on these empirical data, the concept of facial aesthetic unit separation appears to play a significant role in perceived facial aging. LEVEL OF EVIDENCE: NA.