The Evolution of Science and Regulation of Dietary Supplements: Past, Present, and Future.

Dietary supplement use in the United States is widespread and increasing, especially among certain population groups, such as older Americans. The science surrounding dietary supplements has evolved substantially over the last few decades since their formal regulation in 1994. Much has been learned about the mechanisms of action of many dietary supplement ingredients, but the evidence on their health effects is still building. As is true of much nutrition research, there are many studies that point to health effects, but not all are at the level of scientific evidence (e.g., randomized controlled interventions), rigor, or quality needed for definitive statements of efficacy regarding clinical end points. New technologies and approaches are being applied to the science of dietary supplements, including nutrigenomics and microbiome analysis, data science, artificial intelligence (AI), and machine learning-all of which can elevate the science behind dietary supplements. Products can contain an array of bioactive compounds derived from foods as well as from medicinal plants, which creates enormous challenges in data collection and management. Clinical applications, particularly those aimed at providing personalized nutrition options for patients, have become more sophisticated as dietary supplements are incorporated increasingly into clinical practice and self-care. The goals of this article are to provide historical context for the regulation and science of dietary supplements, identify research resources, and suggest some future directions for science in this field.

Sympathetic Innervation of White Adipose Tissue: to Beige or Not to Beige?

Obesity research progresses in understanding neuronal circuits and adipocyte biology to regulate metabolism. However, the interface of neuro-adipocyte interaction is less studied. We summarize the current knowledge of adipose tissue innervation and interaction with adipocytes and emphasize adipocyte transitions from white to brown adipocytes and vice versa. We further highlight emerging concepts for the differential neuronal regulation of brown/beige versus white adipocyte and the interdependence of both for metabolic regulation.

Early Data From Case Series of Tracheostomy in Patients With SARS-CoV-2.

Thirty-eight tracheostomies were performed on patients with respiratory failure secondary to SARS-CoV-2 infection over the month of April at North Shore University Hospital and Lenox Hill Hospital (members of Northwell Health System in Long Island and New York City). Follow-up by May 14 revealed that 21 (55.2%) had been weaned from ventilators and 7 (18.4%) underwent decannulation. Two patients (5.3%) expired in the weeks following tracheostomy. Between the 2 institutions, 10 attending surgeons performed all of the tracheostomies using appropriate personal protective equipment, and none demonstrated seroconversion within 1 to 2 weeks of this article.

Incorporating Midline Platysmaplasty with Lateral Superficial Muscular Aponeurotic System Facelifting.

Management of the platysma is key to achieving an ideal neck contour during rhytidectomy. This article reviews platysmal anatomy, indications for platysmaplasty, preoperative patient assessment, surgical technique for midline platysmaplasty, postoperative management, long-term outcomes, and the senior author's experience and philosophy on midline platysmaplasty in the setting of lateral superficial muscular aponeurotic system facelifting.

Anatomy of the Facial Profile.

The facial profile is an essential part of facial analysis and significantly impacts surgical decision making. Knowledge of the underlying anatomy, which creates the facial profile, and the anatomic sources of the common abnormalities in the profile can help to ensure adequate surgical correction of the abnormality.

The Past, Present and Future of Facial Plastic and Reconstructive Surgery: Facelift.

Facelift or rhytidectomy has been performed in some form for over 100 years. This article seeks to explore the evolution of this surgical procedure, focusing on the advances of the most recent 40 years. From minimal intervention to aggressive techniques and back to the minimally invasive again, the authors follow the journey of surgical intervention for facial rejuvenation and discuss some thoughts for the future.

Advances in Face-lift Techniques, 2013-2018: A Systematic Review.

IMPORTANCE: Rhytidectomy, or face-lift surgery, is the mainstay of facial rejuvenation and is constantly evolving. There is continuous research to improve outcomes and minimize complications of this surgery. OBJECTIVE: To synthesize the updated techniques in rhytidectomy published during the past 5 years, including surgical technique, advances in anesthetic technique, minimally invasive techniques, and adjunctive procedures performed at the time of rhytidectomy. EVIDENCE REVIEW: On February 8, 2018, a literature search was performed of the PubMed and Cochrane databases using the search terms, face-lift or rhytidectomy and techniques. Articles published from February 8, 2013, to February 8, 2018, that related to techniques of facial rejuvenation in the lower one-third of the face by lifting and supporting tissue with 5 or more patients were included. Systematic reviews and primary literature were considered; narrative reviews, validation studies, and anatomic studies were eliminated. The initial search resulted in 604 articles after duplicates were removed. This was reduced to 84 articles after dual independent review screening. FINDINGS: Of the 84 articles included, 51 (61%) regarding techniques of face-lifting in the past 5 years pertained to soft-tissue techniques; 14 (17%) pertained to implants or adjunctive medications, such as tissue sealants; and 12 (14%) related to adjunctive techniques performed in addition to face-lifting, such as fat grafting, resurfacing, and liposuction. All studies found the techniques reported therein to be effective, with similar or fewer complications compared with the literature. However, according to the Oxford Centre for Evidence-Based Medicine criteria, the level of evidence of the studies was generally poor, because 45 of the studies (54%) were case series (level 4 of evidence). CONCLUSIONS AND RELEVANCE: Several new techniques have been explored for rhytidectomy or face-lift in the past 5 years, including soft-tissue techniques, introduction of implants or topical medications such as tissue sealants, and concomitant adjunctive techniques to enhance results. The overall quality of the evidence is poor, with most articles using case series with nonvalidated measures to evaluate outcomes. There is considerable room for improvement in the literature if additional studies using cohort designs and validated outcomes are performed to validate the quality of the techniques introduced during the past 5 years.

Postoperative Care in Facial Implants.

Facial augmentation is a growing field, secondary to the appreciation of the changes seen in the facial skeleton with aging and the growing acceptance/popularity of facial fat grafting and facial fillers. In addition, it plays a significant role in patients with congenital facial deficiencies as well as those interested in facial feminization/masculinization surgery. Several facial implants are discussed in this article including classic facial implants such as malar, submalar, chin, and prejowl implants as well as newer facial implants such as mandible, temporal, forehead, and skull implants. Special care is given to the postoperative care of these implants. Custom-made implants with three-dimensional computed tomography reconstruction are also discussed.

An Extract of Artemisia dracunculus L. Promotes Psychological Resilience in a Mouse Model of Depression.

Stress-induced peripheral inflammation contributes to depression-like behaviors in both human and experimental models. PMI 5011, a botanical extract of Artemisia dracunculus L., was previously shown to have multiple bioactivities, including anti-inflammatory activity. In this work, using a repeated social defeat stress (RSDS) model of depression, we demonstrate that oral administration of the botanical extract PMI 5011 promotes resilience to RSDS-mediated depression-like phenotypes. We also show that the behavioral improvements are associated with attenuation of stress-mediated induction of inflammatory cytokines in the periphery and alteration of synaptic plasticity in the nucleus accumbens (NAc). Our studies provide experimental evidence that botanical extracts such as PMI 5011, which target pathological mechanisms (i.e., peripheral inflammation) not addressed by currently available antidepressants, could be further developed as novel therapeutics for the treatment of stress disorders and anxiety in humans.

Managing the Lower Eyelid Complex in the Thick-Skinned Patient.

Thick skin presents a unique set of challenges within the realm of facial plastic surgery, and addressing the lower lid complex is no exception. There are several procedures for addressing the lower lids, the first and foremost being lower lid blepharoplasty. However, the remaining procedures combined with surgical techniques have exclusive implications in thick skin. Understanding the anatomy and various techniques that can be applied to thick skin can help achieve aesthetically more pleasing results in comparison to those of thin skin. As will be discussed in this article, patients with skin color of Fitzpatrick's grade III or higher have several characteristics associated with their skin, including thicker dermis as well as different patterns of aging, which have implications for addressing the lower lid complex. The senior author has extensive experience performing lower lid procedures and seeks to impart how best to understand and adapt for these differences to allow for the best aesthetic result.

Gene expression and lymphocyte population at the fetal-maternal interface in sheep pregnancies established by somatic cell nuclear transfer.

The hypothesis of this study was that the leukocyte populations and expression levels of genes related to immune response, growth factors and apoptosis would be altered at the fetal-maternal interface in somatic cell nuclear transfer (SCNT)-generated sheep pregnancies. Placental and endometrial samples from sheep pregnancies established by SCNT and natural breeding (control) were collected at 45 days and at term. Expression of genes related to growth factors, apoptosis and immune response was examined using quantitative reverse transcription polymerase chain reaction. Endometrial leukocyte populations and major histocompatibility class I (MHC-I) protein expression were examined by immunohistochemistry. At term we observed altered expression of genes related to apoptosis, growth factors and immune response in placental and endometrial tissue of SCNT pregnancies. In Day-45 pregnancies there was less-pronounced abnormal expression and only genes related to apoptosis and growth factors were abnormal in the placenta. Endometrial gene expression profiles were similar to age-matched controls. Placental MHC-I protein expression was similar in SCNT and controls at 45 days but increased in the SCNT at term. The altered gene expression at the fetal-maternal interface likely contributes to the placental dysfunction and overgrowth observed in sheep SCNT pregnancies.

Systematic Review and Meta-analysis of Studies Evaluating Functional Rhinoplasty Outcomes with the NOSE Score.

Objective To provide aggregate data regarding the ability of functional rhinoplasty to improve nasal obstruction as measured by the Nasal Obstruction Symptom Evaluation (NOSE) score. Data Sources PubMed, EMBASE, Cochrane databases. Review Methods A search was performed with the terms "nasal obstruction" and "rhinoplasty." Studies were included if they evaluated the effect of functional rhinoplasty on nasal obstruction with the NOSE score. Case reports, narratives, and articles that did not use the NOSE score were excluded. Functional rhinoplasty was defined as surgery on the nasal valve. This search resulted in 665 articles. After dual-investigator independent screening, 16 articles remained. Study results were pooled with a random effects model of meta-analysis. Change in NOSE score after surgery was assessed via the mean difference between baseline and postoperative results and the standardized mean difference. Heterogeneity was assessed and reported through the I2 statistic. Results Patients in the included studies had moderate to severe nasal obstructive symptoms at baseline. The NOSE scores were substantially improved at 3-6, 6-12, and ≥12 months, with absolute reductions of 50 points (95% CI, 45-54), 43 points (95% CI, 36-51), and 49 points (95% CI, 39-58), respectively. All of these analyses showed high heterogeneity. Conclusions Nasal obstruction as measured by the NOSE survey is reduced by 43 to 50 points (out of 100 points) for 12 months after rhinoplasty. Our confidence in these results is limited by heterogeneity among studies, large variability in outcomes beyond 12 months, and the inherent potential for bias in observational studies.

An Extubation Protocol for Angioedema.

Angioedema-nonpitting edema of the mucous membranes and skin-most commonly occurs as a complication from the use of angiotensin-converting enzyme inhibitors. At our institution, the otolaryngology department has incorporated the use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy to aid in timing for extubation of angioedema patients. Prospective data collection of patients presenting to the emergency department with angioedema was performed. Of 76 patients with angioedema, 9 required fiberoptic intubation. Intubation was performed at a median of 73 hours (range, 44-118). An endotracheal tube cuff-leak test was performed in 7 patients prior to extubation, and bedside direct laryngoscopy was also performed in 3 of these 7 patients to document resolution of laryngeal edema. The use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy is an easy and inexpensive method to help determine eligibility for extubation in patients intubated for angioedema.

A Systematic Review of Eligibility and Outcomes in Tinnitus Trials: Reassessment of Tinnitus Guideline.

OBJECTIVE: To analyze existing tinnitus treatment trials with regard to eligibility criteria, outcome measures, study quality, and external validity and to recognize the effect of patient demographics, symptom duration, severity, and otologic comorbidity on research findings to help practitioners apply them to patient encounters. DATA SOURCES: Systematic literature search conducted by an information specialist for development of the American Academy of Otolaryngology-Head and Neck Surgery Foundation's tinnitus clinical practice guideline. REVIEW METHODS: Articles were assessed for eligibility with the PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and data extracted by 2 independent investigators. Studies were assessed for methodological quality, inclusion and exclusion criteria, patient demographics, and outcome measures. RESULTS: A total of 147 randomized trials met inclusion criteria. Nearly all studies took place in a specialist setting. More than 50% did not explicitly define tinnitus, and 44% used a subjective severity threshold, such as "severely disturbing." Fifty-four percent required symptom duration of at least 6 months for study eligibility, and up to 33% excluded patients with "organic" hearing loss or otologic conditions. Mean age was 52.2 years, and median follow-up was 3 months. Only 20% had a low risk of bias. CONCLUSION: Randomized trials of tinnitus interventions are most applicable to older adults with tinnitus lasting ≥ 6 months who are evaluated in specialty settings. High risk of bias, short follow-up, and outcome reporting raise concerns about the validity of findings and may influence how clinicians apply trial results to individual patients and establish treatment expectations, thus demonstrating the need for further quality research in this field.

Reporting of Postoperative Pain Management Protocols in Randomized Clinical Trials of Mandibular Fracture Repair: A Systematic Review.

IMPORTANCE: The control of pain associated with mandibular fractures is an important treatment outcome that affects function, adherence to treatment regimens, and patient comfort and satisfaction. OBJECTIVE: To explore the pain management protocols reported in studies of mandibular fractures, including the reporting of quality-of-life measures. EVIDENCE REVIEW: PubMed/MEDLINE, EMBASE, Cochrane CENTRAL, and clinicaltrials.gov were searched for randomized clinical trials published from 1970 to July 2014. We followed PRISMA reporting standards to assess study eligibility and extract data. Studies of patients older than 16 years who underwent operative mandibular fracture management were included. The primary data collected included the type of analgesic prescribed, associated adverse effects of the analgesic, method of pain assessment, and use of quality-of-life measures. A pain attentiveness score was assigned to studies based on the comprehensiveness of the information reported. Several variables were reviewed to determine the factors that predict reporting of pain-related data. Assessments of risk for bias were performed using the Cochrane Collaboration's domain-based evaluation method. FINDINGS: The initial search identified 111 articles, of which 38 met inclusion criteria. Among the 38 reviewed articles, there were 38 trials and 1808 unique patients represented. Among the 38 articles, the procedures reported included maxillomandibular fixation only in 6 (16%), open reduction with internal fixation only in 20 (53%), and both in 12 (32%). Specific analgesics prescribed were reported in only 5 of the 38 studies (13%), and 3 of these used a combination of nonsteroidal anti-inflammatory drugs and acetaminophen (paracetamol). Thirteen studies (34%) reported pain assessments and 5 (13%) included quality-of-life measures. Geographic region was the only variable that predicted pain attentiveness, with studies from Europe (3 of 11 studies [27%]) and Asia (6 of 16 studies [38%]) most likely to have a high pain attentiveness score. A low rating was least common in the United States (2 of 5 studies [40%]) (P = .047, Fisher exact test). Most of the studies had unclear (n = 27) or high (n = 6) risks for bias in the key domains assessed. CONCLUSIONS AND RELEVANCE: Pain management is a neglected outcome in randomized clinical trials of mandibular trauma; most studies did not describe the specific analgesics used. Many randomized clinical trials (13 [34%]) assessed pain levels among patients without providing information about the agents prescribed. The incorporation of validated pain measures and quality-of-life scores in future studies of mandibular trauma would focus attention on this key outcome measure.

Prolonged proteasome inhibition cyclically upregulates Oct3/4 and Nanog gene expression, but reduces induced pluripotent stem cell colony formation.

There is ample evidence that the ubiquitin-proteasome system is an important regulator of transcription and its activity is necessary for maintaining pluripotency and promoting cellular reprogramming. Moreover, proteasome activity contributes to maintaining the open chromatin structure found in pluripotent stem cells, acting as a transcriptional inhibitor at specific gene loci generally associated with differentiation. The current study was designed to understand further the role of proteasome inhibition in reprogramming and its ability to modulate endogenous expression of pluripotency-related genes and induced pluripotent stem cells (iPSCs) colony formation. Herein, we demonstrate that acute combinatorial treatment with the proteasome inhibitors MG101 or MG132 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) increases gene expression of the pluripotency marker Oct3/4, and that MG101 alone is as effective as VPA in the induction of Oct3/4 mRNA expression in fibroblasts. Prolonged proteasome inhibition cyclically upregulates gene expression of Oct3/4 and Nanog, but reduces colony formation in the presence of the iPSC induction cocktail. In conclusion, our results demonstrate that the 26S proteasome is an essential modulator in the reprogramming process. Its inhibition enhances expression of pluripotency-related genes; however, efficient colony formation requires proteasome activity. Therefore, discovery of small molecules that increase proteasome activity might lead to more efficient cell reprogramming and generation of pluripotent cells.

Gene expression profile in human skeletal muscle cells infected with human adenovirus type 36.

Human adenovirus type-36 (HAdV-36) is a specific pathogen that may lead to increased adiposity and obesity. In order to evaluate the effects of HAdV-36 on gene transcription, a microarray analysis of muscle cells infected with HAdV-36 was performed. Gene expression profile was determined by microarray analysis in cultured human skeletal muscle cells with or without HAdV-36 infection. Quantitative real-time PCR (qPCR) assay was performed in selected 35 genes to verify the results of the microarray analysis. A total of 13,060 unique genes were detected in the HAdV-36 infected muscle cells infected with HAdV-36. Among them, 1,004 genes were significantly altered by using a cut-off point at fold change ≥1.5 and P value <0.05. Most of the principal 100 altered genes were involved in development, immune response, signal transduction, transcriptional regulation as well as carbohydrate, lipid and protein metabolism. Thirty-two genes (91.4%) from the 35 selected genes were confirmed by qPCR assay. In addition, HAdV-36 altered 252 genes that are associated with cancer. The study showed HAdV-36 infection upregulated host cell antiviral defense. HAdV-36 also induces changes in gene expression related to cellular signaling pathways of signal transduction, transcriptional regulation as well as carbohydrate, lipid and protein metabolism. However, it remains to be investigated if HAdV-36 infection could lead to oncogenesis.

PPARgamma-independent increase in glucose uptake and adiponectin abundance in fat cells.

Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)γ induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPARγ or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPARγ, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPARγ and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected or human adenoviruses Ad36 or Ad2-infected cell types under the following conditions: 1) undifferentiated human-adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPARγ inhibitor, 4) NIH/3T3 that have impaired PPARγ expression, and 5) PPARγ-knockout mouse embryonic fibroblasts. Mouse embryonic fibroblasts with intact PPARγ served as a positive control. Additionally, to determine natural Ad36 infection, human sera were screened for Ad36 antibodies. In undifferentiated or differentiated hASC, or despite the inhibition, down-regulation, or the absence of PPARγ, Ad36 significantly enhanced glucose uptake and PPARγ, adiponectin, glucose transporter 4, and glucose transporter 1 protein abundance, compared with mock or Ad2-infected cells. This indicated that Ad36 up-regulates glucose uptake and adiponectin secretion independent of adipogenesis or without recruiting PPARγ. In humans, natural Ad36 infection predicted greater adiponectin levels, suggesting a human relevance of these effects. In conclusion, Ad36 provides a novel template to metabolically remodel human adipose tissue to enhance glycemic control without the concomitant increase in adiposity or PPARγ induction associated with TZD actions.

Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model.

Evidence for the important role for poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic nephropathy is emerging. We previously reported that PARP inhibitors counteract early Type 1 diabetic nephropathy. This study evaluated the role for PARP in kidney disease in long-term Type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15,427, Eisai Inc.), 30mgkg(-1)d(-1), for 26 weeks after first 2 weeks without treatment. PARP activity in the renal cortex was assessed by Western blot analysis of poly(ADP-ribosyl)ated proteins. Urinary albumin, isoprostane, and 8-hydroxy-2'-deoxyguanosine excretion, and renal concentrations of transforming growth factor-beta(1), vascular endothelial growth factor, soluble intercellular adhesion molecule-1, fibronectin, and nitrotyrosine were evaluated by ELISA, and urinary creatinine and renal lipid peroxidation products by colorimetric assays. PARP inhibition counteracted diabetes-associated increase in renal cortex poly(ADP-ribosyl)ated protein level. Urinary albumin, isoprostane, and 8-hydroxy-2'-deoxyguanosine excretions and urinary albumin/creatinine ratio were increased in diabetic rats, and all these changes were at least partially prevented by GPI-15,427 treatment. PARP inhibition counteracted diabetes-induced renal transforming growth factor-beta(1), vascular endothelial growth factor, and fibronectin, but not soluble intercellular adhesion molecule-1 and nitrotyrosine, accumulations. Lipid peroxidation product concentrations were indistinguishable among control and diabetic rats maintained with or without GPI-15,427 treatment. In conclusion, PARP activation plays an important role in kidney disease in long-term diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies, for prevention and treatment of diabetic nephropathy.