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Background: Frequently reported outcomes of clinical trials in chronic rhinosinusitis with nasal polyps (CRSwNP) may have limited relatability for patients., Objective: To enhance the patient relatability of outcomes in dupilumab clinical trials for CRSwNP, daily symptom scores were used to determine new patient‑centered end points: mild-to-no-symptom months (MSM) and symptom-free months (SFM)., Methods: This work is a post hoc analysis of patients receiving dupilumab 300 mg or placebo every 2 weeks for 24 weeks (SINUS-24 study; NCT02912468) or 52 weeks (SINUS‑52; NCT02898454). Patients recorded symptom severity scores daily for each of nasal congestion, loss of smell, and anterior and posterior rhinorrhea on a scale of 0 to 3 (0 = no symptoms; 1 = mild; 2 = moderate; 3 = severe). We assessed the proportions of patients reporting only MSM or SFM throughout the 28‑day period before randomization, week 24 (pooled studies), and week 52 (SINUS‑52)., Results: Significantly more dupilumab‑treated than placebo-treated patients achieved MSM for all 4 symptoms (week 24: 31.0% vs 4.4%; odds ratio [OR] 12.9 [95% CI 6.4-25.8]; week 52: 38.3% vs 2.6%; OR 15.6 [5.9-41.0]; both P < .0001). In addition, significantly more dupilumab-treated than placebo‑treated patients achieved SFM for at least 1 of the 4 symptoms (week 24: 35.4% vs 10.8%; OR 4.9 [95% CI 3.1-7.8]; week 52: 50.0% vs 9.2%; OR 9.1 [95% CI 4.6-17.9]; both P < .0001)., Conclusion: One-third of patients with severe CRSwNP treated with dupilumab achieved MSM for all 4 cardinal symptoms (nasal congestion, loss of smell, and anterior and posterior rhinorrhea). Moreover, half of the patients achieved SFM for at least 1 of the 4 symptoms. These results support the benefit of dupilumab in improving patient‑centered outcomes., Trial Registration: ClinicalTrials.gov Identifiers: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52)., Competing Interests: Disclosures Professor Bachert is an advisory board member for AstraZeneca, Novartis, and Sanofi. Professor Hopkins is an advisory board member for AstraZeneca, BioInspire Technologies, GlaxoSmithKline, and Sanofi. Professor Han is an advisory board member for AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals Inc, and Sanofi. Professor Fokkens has received research grants from BioInspire Technologies, GlaxoSmithKline, Mylan, Novartis, and Sanofi. Dr Khan, Dr Mannent, Mr Msihid, and Dr Rowe are employees of Sanofi and may hold stock and/or stock options in the company. Dr Borsos and Dr Jacob-Nara are former employees of Sanofi and may hold stock and/or stock options in the company. Mr Kamat, Dr Nash, and Dr Deniz are employees and shareholders of Regeneron Pharmaceuticals Inc. Dr Sacks is an employee of Regeneron Pharmaceuticals Inc and a shareholder in OptiNose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss., Methods: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0-8), nasal congestion/obstruction (NC, 0-3), Lund-Mackay CT-scan score (LMK-CT, 0-24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0-110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0-3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks., Results: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS -1.90 (-2.56, -1.25) and -1.95 (-2.20, -1.70) in the moderate and severe baseline LoS subgroups, respectively; NC -.35 (-.64, -.06) and -1.00 (-1.13, -.87); LMK-CT -6.30 (-7.88, -4.72) and -6.22 (-6.82, -5.63); RS-VAS -1.18 (-2.20, -.16) and -3.47 (-3.90, -3.03); and SNOT-22 -7.52 (-14.55, -.48) and -21.72 (-24.63, -18.82); all nominal P  < .05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS., Conclusion: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss., Competing Interests: Declaration of Conflicting InterestsThe authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Zachary M. Soler has been a consultant or advisory board member for Lyra, Novartis, Olympus, and Optinose; he has received speaker's fees from GlaxoSmithKline and Regeneron Pharmaceuticals Inc.; and held the post of medical director at Healthy Humming. Zara M. Patel has been a consultant or advisory board member for Dianosic, InfiniteMD, Mediflix, Medtronic, and Optinose and the Chief Medical Officer of Olfera Therapeutics. Joaquim Mullol has participated in a speakers’ bureau or advisory board or received a research grant from AstraZeneca, Genentech, Inc., GlaxoSmithKline, Glenmark, Menarini, Mitsubishi-Tanabe, Merck Sharp & Dohme, Viatris (Mylan-MEDA), Novartis, Procter & Gamble, Regeneron Pharmaceuticals Inc., Sanofi, and the NOUCOR/Uriach Group. Jose Mattos has no financial disclosures or conflicts of interest. Scott Nash, Changming Xia, Zhixiao Wang, Harry Sacks, and Yamo Deniz are employees of Regeneron Pharmaceuticals and may hold stock and/or stock options in the company. Kinga Borsos is a former employee of Sanofi and may hold stock and/or stock options in the company. Mark Corbett, Juby A. Jacob-Nara, and Paul Rowe are employees of Sanofi and may hold stock and/or stock options in the company. Andrew P. Lane is a member of the advisory boards of Sanofi and Regeneron Pharmaceuticals Inc.

The TRAVERSE study demonstrated the long-term efficacy of dupilumab for the treatment of patients with uncontrolled, moderate-to-severe, type 2 asthma across a range of baseline demographics and disease characteristics up to 96 weeks https://bit.ly/3XSwX62., Competing Interests: Conflict of interest: M.E. Weschler reported personal fees from AstraZeneca, Boehringer Ingelheim, Equillium, Gala Therapeutics, Genentech, Genzyme, Mylan, Novartis, Pulmatrix, Regeneron Pharmaceuticals Inc., resTORbio, Sentien Biotechnologies and Teva; and grants and personal fees from GSK and Sanofi. Conflict of interest: L. Rogers reported research support from American Lung Association, NIH and Sanofi; consultancy for AstraZeneca, Genentech, Novartis and Sanofi; and payments for organising educational events from AstraZeneca and Genentech. Conflict of interest: G.W. Canonica reported speaker fees from ALK, AstraZeneca, Boehringer Ingelheim, GSK, HAL Allergy, Menarini, Mundipharma, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, Stallergenes Greer and Uriach; and advisory board membership for ALK, AstraZeneca, Boehringer Ingelheim, GSK, HAL Allergy, Menarini, Mundipharma, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, Stallergenes Greer and Uriach. Conflict of interest: A. Bourdin reported nonfinancial support during the conduct of the study from GSK; other support from Acceleron Pharma, Actelion, Galapagos, Merck Sharp & Dohme, Nuvaira, Pulmonx, United Therapeutics and Vertex Pharmaceuticals; grants and personal fees from Boehringer Ingelheim; and personal fees from AstraZeneca, Chiesi, GSK, Regeneron Pharmaceuticals Inc. and Sanofi. Conflict of interest: A. Altincatal, M. Hardin, P.J. Rowe and J.A. Jacob-Nara are employees of Sanofi, and may hold stock and/or stock options in the company. Conflict of interest: X. Soler and Y. Deniz are employees and shareholders of Regeneron Pharmaceuticals Inc. Conflict of interest: H. Sacks is an employee of Regeneron Pharmaceuticals Inc. and a shareholder in Optinose., (Copyright ©The authors 2024.)

Objective: Loss of sense of smell is a cardinal symptom of chronic rhinosinusitis with nasal polyps (CRSwNP) and significantly impacts health-related quality-of-life. Dupilumab significantly improved smell outcomes (loss of smell [LoS] score; University of Pennsylvania Smell Identification Test [UPSIT]) versus placebo in the phase 3 SINUS-24/-52 studies (clinicaltrials.gov, NCT02898454/NCT02912468) in patients with severe CRSwNP. This post hoc analysis investigated the effect of dupilumab on olfaction using UPSIT smell impairment categories., Methods: Patients with baseline smell impairment (UPSIT ≤34/≤33 [women/men; score range 0-40] AND LoS score ≥1 [0-3] AND smell/taste item of the 22-item Sinonasal Outcome Test >0 [SNOT-22; 0-5]) treated with dupilumab 300 mg or placebo once every 2 weeks on background intranasal corticosteroids were analyzed., Results: Of 724 patients, 665 (91.9%) had smell impairment at baseline; most had anosmia (UPSIT 0-18) (dupilumab/placebo: 80.9%/79.8%). At week 24, the proportion of dupilumab-treated patients with anosmia decreased to 28.5%, while 14.9% achieved normosmia; most placebo-group patients (79.2%) remained anosmic and only 1.2% achieved normosmia (odds ratio = 17.3; 95% confidence interval = 5.1-59.0; p <.0001); results were similar at week 52. Improvements in Nasal Polyp Score, nasal congestion, and SNOT-22 total score were moderately correlated with improvements in UPSIT at weeks 24 and 52 (r = -.38 to -.50)., Conclusion: Most patients with severe CRSwNP had anosmia at baseline. Dupilumab treatment significantly improved smell versus placebo, with 14.9% achieving normosmia by week 24. There was a trend for better clinical outcomes in patients with greater smell improvement.

Reduced sense of smell is a common symptom in patients with chronic rhinosinusitis (CRS). Although it is often under-diagnosed by healthcare providers, reduced sense of smell can have a substantial negative impact on patient's quality of life as measured by health-related quality of life (HRQoL) assessments and patient-reported outcomes. This narrative review describes current smell loss diagnosis and management guidelines in CRS, and the relationship between smell loss and CRS. Reduced sense of smell can be an indication of CRS disease severity in patients with (CRSwNP) and without nasal polyps (CRSsNP), and recovery of smell can be an indicator of successful CRS treatment. The current first-line therapeutic options for smell loss are intranasal corticosteroids and nasal irrigation, and second-line therapeutic options include systemic steroids and surgery. Shared decision-making between patient, caregiver, and healthcare provider is important when choosing the most appropriate CRS treatment option. Emerging biologic therapies that target type 2 inflammation signaling pathways, such as dupilumab, omalizumab, and mepolizumab, have been shown to improve smell and taste in randomized controlled trials of patients with CRSwNP.A graphical abstract and video abstract are available with this article., (© 2024. The Author(s).)

Background: Responder analyses of SINUS phase 3 study data have shown clinically meaningful improvements across multiple outcomes of treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) with dupilumab., Objective: Our aim was to gain a better understanding of dynamics of the response to dupilumab over 52 weeks., Methods: We used data from the SINUS-52 (ClinicalTrials.gov identifier NCT02898454) intention-to-treat population to perform a post hoc analysis of patients with severe CRSwNP who had received dupilumab, 300 mg once every 2 weeks, or placebo. Response, which was defined as an improvement from baseline of at least 1 point in Nasal Polyp Score (NPS), nasal congestion (NC) score, and loss of smell (LoS) score, as well as an improvement of at least 8.9 points on the 22-Item Sino-Nasal Outcome Test (SNOT-22), was assessed for rapidity, maintenance, and durability., Results: The study included 303 patients (150 of whom received dupilumab and 153 of whom received placebo). For each outcome measure, a greater proportion of patients achieved a first response by week 16 (rapidity) with dupilumab versus with placebo; NPS, 75.3% versus 39.2%; NC score, 60.0% versus 24.2%; LoS score, 60.7% versus 15.7%; and SNOT-22 score, 83.3% versus 66.0%, respectively. Of those patients given dupilumab who had a response by week 16, more than 80% maintained their response at week 52 (maintenance). Over 52 weeks, greater proportions of those patients given dupilumab than patients given placebo were responders on at least 80% of time points: NPS, 46.7% versus 2.6%; NC score, 46.7% versus 9.2%; LoS score, 47.3% versus 3.9%; and SNOT-22 score, 62.0% versus 21.6%, respectively (durability)., Conclusion: Most patients with CRSwNP achieve clinically meaningful responses to dupilumab by week 16, and most such patients in our study had maintenance and durability of response with continued treatment over time., Competing Interests: Disclosure statement Supported by Sanofi, France, and Regeneron Pharmaceuticals, Inc, United States. Disclosure of potential conflict of interest: C. Bachert is an advisory board member of AstraZeneca, Novartis, and Sanofi. W. J. Fokkens reports research grants from BioInspire Technologies, GlaxoSmithKline, Mylan, Novartis, and Sanofi. C. Hopkins is an advisory board member of AstraZeneca, BioInspire Technologies, GlaxoSmithKline, and Sanofi. P. Gevaert reports clinical trial funding from and is an advisory board member of 3NT, Argenx, Genentech, Novartis, Regeneron Pharmaceuticals, Roche, Sanofi, and Stallergenes Greer. J. K. Han is an advisory board member of AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, and Sanofi. P. W. Hellings is an advisory board member of Regeneron Pharmaceuticals and Sanofi. S. E. Lee reports receiving clinical trial funding from and being an advisory board member of AstraZeneca, Genentech, GlaxoSmithKline, and Sanofi and being an advisory board member of Novartis and Regeneron Pharmaceuticals. A. H. Khan, J. Msihid, J. A. Jacob-Nara, and P. J. Rowe are employees of Sanofi and may hold stock and/or stock options in the company. S. Nash and Y. Deniz are employees and shareholders of Regeneron Pharmaceuticals. H. Sacks is an employee of Regeneron Pharmaceuticals and a shareholder of Optinose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The phase 3 VOYAGE (NCT02948959) and open-label extension EXCURSION (NCT03560466) studies evaluated dupilumab in children (6-11 years) with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed the efficacy and safety of add-on dupilumab 200 mg every 2 weeks (q2w), the largest dose cohort in both studies, in children from VOYAGE who participated in EXCURSION., Methods: Annualized rate of severe asthma exacerbations (AERs), change in prebronchodilator percent predicted forced expiratory volume in 1 s (ppFEV 1 ), and treatment-emergent adverse events were assessed in children with moderate-to-severe asthma who received dupilumab 200 mg q2w in VOYAGE and EXCURSION (dupilumab/dupilumab arm) and those who received placebo in VOYAGE and dupilumab 200 mg q2w in EXCURSION (placebo/dupilumab arm). These endpoints were also assessed in children with moderate-to-severe type 2 asthma (defined as blood eosinophil count ≥150 cells/µL or FeNO ≥20 ppb at the parent study baseline [PSBL])., Results: In the overall population, dupilumab reduced AER and improved prebronchodilator ppFEV 1 in the dupilumab/dupilumab arm (n = 158) for up to 2 years. Children receiving placebo/dupilumab (n = 85) showed similar reductions after initiation of dupilumab 200 mg q2w in EXCURSION. Similar results were observed for children with type 2 asthma at PSBL. The safety profile was consistent with the known safety profile of dupilumab., Conclusion: In children (6-11 years) with uncontrolled moderate-to-severe type 2 asthma, dupilumab 200 mg reduced exacerbation rates and improved lung function for up to 2 years and showed safety consistent with the known dupilumab safety profile., (© 2024 Sanofi and The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Increased understanding of the underlying pathophysiology has highlighted the heterogeneity of asthma and identified that most children with asthma have type 2 inflammation with elevated biomarkers, such as blood eosinophils and/or fractional exhaled nitric oxide. Although in the past most of these children may have been categorized as having allergic asthma, identifying the type 2 inflammatory phenotype provides a mechanism to explain both allergic and non-allergic triggers in pediatric patients with asthma. Most children achieve control with low to medium doses of inhaled corticosteroids. However, in a small but significant proportion of children, asthma remains uncontrolled despite maximum conventional treatment, with an increased risk of severe exacerbations. In this review, we focus on the role of type 2 inflammation and allergic processes in children with asthma, together with evidence of the efficacy of available treatment options for those who experience severe symptoms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Despite the success rate of the Pavlik method in the treatment of developmental dislocation of the hip, there is a subset of hips that do not reduce with harness use. The purpose of this study was to determine the outcomes after closed reduction (CR), open reduction (OR) and combined open reduction and pelvic osteotomy (OR+PO) in patients with infantile hip dislocations who initially failed the Pavlik method., Methods: This was a retrospective cohort study of patients with infantile hip dislocations who failed the Pavlik method and subsequently underwent a secondary procedure for persistent hip dislocation. The primary outcome measure was the Severin classification of the involved hip 3 years after the secondary procedure. Other outcomes assessed included rates of redislocation, residual acetabular dysplasia and proximal femoral growth disturbance., Results: Twenty-three patients were included; seven subsequently underwent CR, three underwent isolated OR and 13 proceeded directly to OR+PO. The overall successful outcome rate at final follow-up (as determined by radiographic Severin class I or II) was 11/23 (48%). However, patients undergoing OR+PO had significantly higher rates of successful outcomes (77%) compared with CR (15%) and OR (0%), P  < 0.05. The rate of residual acetabular dysplasia and proximal femoral growth disturbance was significantly lower in patients treated with OR+PO compared with CR and isolated OR, P  < 0.05., Conclusion: Patients with dislocated hips who failed Pavlik harness treatment had better radiographic outcomes 3 years after OR+PO in comparison to patients undergoing CR or isolated OR., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This post hoc analysis assessed disease characteristics and response to dupilumab treatment in male and female patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (SINUS-52 study; NCT02898454)., Methods: Patients received dupilumab 300 mg or placebo every 2 weeks for 52 weeks on background intranasal corticosteroids. Efficacy was assessed through Week 52 using nasal polyp score (NPS), nasal congestion/obstruction score, loss of smell score and University of Pennsylvania Smell Identification Test score. Disease-specific health-related quality of life (HRQoL) was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22)., Results: The analysis included 192 male and 111 female patients. Female patients had higher mean SNOT-22 total score (56.6 vs. 49.1, P  < 0.01) and more coexisting asthma (78.4% vs. 46.4%, P  < 0.0001) and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) (38.7% vs. 18.8%, P  = 0.0001) than male patients, but other baseline characteristics were similar. Dupilumab significantly improved CRSwNP outcomes vs. placebo at Week 52, regardless of gender: least squares mean differences (95% confidence interval) for NPS were -2.33 (-2.80, -1.86) in male and -2.54 (-3.18, -1.90) in female patients (both P  < 0.0001 vs. placebo), and for SNOT-22 were -19.2 (-24.1, -14.2) in male and -24.4 (-31.5, -17.3) in female patients (both P  < 0.0001 vs. placebo). There were no significant efficacy-by-gender interactions., Conclusion: Female patients had greater asthma, NSAID-ERD and HRQoL burden at baseline than male patients. Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender., Competing Interests: WJF receives research grants from BioInspire Technologies, GlaxoSmithKline, Meda Pharmaceuticals and Sanofi. CB is an advisory board member and receives speakers' fees from ALK, AstraZeneca, GlaxoSmithKline, Mylan, Novartis, Sanofi and Stallergenes Greer. AP, PJR and JAJ‐N are employees and may hold stock and/or stock options in Sanofi. CH is an advisory board member of AstraZeneca, Dianosic, GlaxoSmithKline and Sanofi. OM reports no conflicts of interest. SN, YD and HS are employees and may hold stock and/or stock options in Regeneron Pharmaceuticals Inc., (© 2024 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients., Competing Interests: CB is an advisory board member for ALK, ASIT Biotech,AstraZeneca, GlaxoSmithKline, Intrexon Actobiotics, Novartis, Sanofi, and Stallergenes Greer. AH and JJ-N are employees and may hold stock and/or stock options in Sanofi. SG reports advisory board fees from Sanofi and GlaxoSmithKline. AP reports advisory board fees and research support from AstraZeneca, Regeneron Pharmaceuticals, Inc., and Sanofi, and consulting fees and research support from Optinose. PG reports clinical trial funding from and is an advisory board member of 3NT, Argenx, Genentech, Novartis, Regeneron Pharmaceuticals Inc., Roche, Sanofi, and Stallergenes Greer. SN, JH, and HS are employees of and may hold stock and/or stock options in Regeneron Pharmaceuticals Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bachert, Hicks, Gane, Peters, Gevaert, Nash, Horowitz, Sacks and Jacob-Nara.)

Background: Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration-approved for the most common form, CRS without nasal polyps (also called "chronic sinusitis"). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays., Objective: Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps)., Methods: Two randomized, EDS-placebo-controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week 24., Results: ReOpen1 (N = 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -1.58 and -1.60 versus -0.62 (P < .001, P < .001); ReOpen2 (N = 223), -1.54 and -1.74 versus -0.81 (P = .011, P = .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was -5.58 and -6.20 versus -1.60 (P = .045, P = .018), and in ReOpen2, -7.00 and -5.14 versus +1.19 (P < .001, P = .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P = .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverse events were similar to standard-delivery intranasal steroids., Conclusions: EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction Pulmonary symptoms are the most prominent manifestations of Coronavirus disease 2019 (COVID-19). However, gastrointestinal (GI) symptoms have been reported widely as well. Literature describing the relation of these symptoms with outcomes of COVID-19 patients is limited in terms of sample size, geographic diversity, and the spectrum of GI symptoms included. We aim to evaluate the association of GI symptoms with outcomes of hospitalized COVID-19 patients. Methods A systematic review and meta-analysis of observational studies assessing GI symptoms and outcomes in COVID-19 patients were undertaken using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist. Details on outcomes included ICU vs. non-ICU admission, severe vs. non-severe disease, invasive mechanical ventilation (IMV) vs. no-IMV use, oxygen saturation <90% vs. >90%, in-hospital mortality vs. discharged alive and survivors. We obtained the odds ratio (OR), 95% confidence interval (95%CI), and forest plots. Sensitivity analysis was used to analyze publication bias and heterogeneity. Results In 35 studies with 7931 confirmed COVID-19 patients, we found that anorexia (pooled OR:2.05; 95%CI: 1.36-3.09, p=0.0006) and abdominal pain (OR 2.80; 95%CI: 1.41-5.54, p=0.003) were associated with a higher risk of poor outcomes and no such association was found for diarrhea (OR 1.04; 95%CI: 0.85-1.26, p=0.71), nausea (OR 0.73; 95%CI: 0.38-1.39, p=0.34) and vomiting (OR 1.24; 95%CI 0.86-1.79, p=0.25). Conclusion The meta-analysis concludes that anorexia and abdominal pain are associated with poor outcomes in hospitalized COVID-19 patients, while diarrhea, nausea, and vomiting have no association. Future research should focus on whether detecting GI invasion in conjunction with fecal polymerase chain reaction (PCR) testing can aid in the early triage of high-risk individuals and improve outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Mehta et al.)

Objective: To histologically evaluate the effects of a novel human recombinant amelogenin (rAmelX) on periodontal wound healing/regeneration in intrabony defects., Method and Materials: Intrabony defects were surgically created in the mandible of three minipigs. Twelve defects were randomly treated with either rAmelX and carrier (test group) or with the carrier only (control group). At 3 months following reconstructive surgery, the animals were euthanized, and the tissues histologically processed. Thereafter, descriptive histology, histometry, and statistical analyses were performed., Results: Postoperative clinical healing was uneventful. At the defect level, no adverse reactions (eg, suppuration, abscess formation, unusual inflammatory reaction) were observed with a good biocompatibility of the tested products. The test group yielded higher values for new cementum formation (4.81 ± 1.17 mm) compared to the control group (4.39 ± 1.71 mm) without reaching statistical significance (P = .937). Moreover, regrowth of new bone was greater in the test compared to the control group (3.51 mm and 2.97 mm, respectively, P = .309)., Conclusions: The present results provided for the first-time histologic evidence for periodontal regeneration following the use of rAmelX in intrabony defects, thus pointing to the potential of this novel recombinant amelogenin as a possible alternative to regenerative materials from animal origins.

Although phenotypically different, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) are able to produce heat through non-shivering thermogenesis due to the presence of mitochondrial uncoupling protein 1 (UCP1). The appearance of thermogenically active beige adipocytes in iWAT is known as browning. Both brown and beige cells originate from mesenchymal stem cells (MSCs), and in culture conditions a browning response can be induced with hypothermia (i.e. 32 °C) during which nuclear leptin immunodetection was observed. The central role of leptin in regulating food intake and energy consumption is well recognised, but its importance in the browning process at the cellular level is unclear. Here, immunocytochemical analysis of MSC-derived adipocytes established nuclear localization of both leptin and leptin receptor suggesting an involvement of the leptin pathway in the browning response. In order to elucidate whether leptin modulates the expression of brown and beige adipocyte markers, BAT and iWAT samples from leptin-deficient (ob/ob) mice were analysed and exhibited reduced brown/beige marker expression compared to wild-type controls. When MSCs were isolated and differentiated into adipocytes, leptin deficiency was observed to induce a white phenotype, especially when incubated at 32 °C. These adaptations were accompanied with morphological signs of impaired adipogenic differentiation. Overall, our results indicate that leptin supports adipocyte browning and suggest a potential role for leptin in adipogenesis and browning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objectives: To histologically evaluate the effects of a novel human recombinant amelogenin (rAmelX) on periodontal wound healing / regeneration in recession-type defects., Materials and Methods: A total of 17 gingival recession-type defects were surgically created in the maxilla of three minipigs. The defects were randomly treated with a coronally advanced flap (CAF) and either rAmelX (test), or a CAF and placebo (control). At three months following reconstructive surgery, the animals were euthanized, and the healing outcomes histologically evaluated., Results: The test group yielded statistically significantly (p = 0.047) greater formation of cementum with inserting collagen fibers compared with the control group (i.e., 4.38 mm ± 0.36 mm vs. 3.48 mm ± 1.13 mm). Bone formation measured 2.15 mm ± 0.8 mm in the test group and 2.24 mm ± 1.23 mm in the control group, respectively, without a statistically significant difference (p = 0.94)., Conclusions: The present data have provided for the first-time evidence for the potential of rAmelX to promote regeneration of periodontal ligament and root cementum in recession-type defects, thus warranting further preclinical and clinical testing., Clinical Relevance: The present results set the basis for the potential clinical application of rAmelX in reconstructive periodontal surgery., (© 2023. The Author(s).)

➤: Sports participation can improve gait, muscle strength, and functional abilities in patients with a wide variety of disabilities. Para athletes are also at substantial risk for injury during sports participation., ➤: Ambulant athletes with cerebral palsy are at risk for soft-tissue injuries about the knee as well as foot and ankle injuries. Wheelchair athletes are at risk for osteoporotic fractures and shoulder girdle injuries. Limb-deficient athletes are prone to low back pain and overuse injuries of the contralateral extremity., ➤: Para athletes are vulnerable to abuse during sports participation, and physicians should promptly report any possible abuse or mistreatment., ➤: Orthopaedic surgeons should understand disability and sport-specific risk factors for injury in para athletes in order to initiate early management and injury prevention protocols., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H136 )., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Developmental dysplasia of the hip (DDH) is the most common congenital abnormality in newborns. Untreated DDH can cause significant impairments, including chronic hip pain, osteoarthritis, limb length discrepancy, altered gait, and joint contractures. Treatment outcomes are significantly worse with increasing delay in presentation, making early screening and detection critical. The purpose of this review is to provide a comprehensive guide for the pediatric primary care provider on the cause, diagnosis, and management of DDH. Screening practices, physical examination, imaging modalities, and treatment will be discussed. A missed hip dislocation in a walking-age child is a devastating but preventable event; pediatric primary care providers should have a high index of suspicion for DDH and promptly refer any patient with concerning findings to a pediatric orthopedic surgeon. [ Pediatr Ann . 2022;51(9):e346-e352.] .

Purpose: Several studies have explored opioid consumption and opioid prescriber education for upper extremity procedures; however, less literature has focused on patient-centered interventions and their impact on opioid consumption after surgery. The purpose of this study was to create a standardized perioperative patient education program regarding postoperative pain management after hand surgery and to determine if it could reduce opioid use after hand surgery., Methods: Patients scheduled to undergo elective outpatient hand surgery comprising minor soft tissue procedures at and distal to the wrist were randomized to receive pain management education or standard care. Before the surgery, all patients viewed a webinar with instructions for participation, whereas the education group received an additional 10 minutes of education on postoperative pain management and a pain management reference card for review after the surgery. All patients completed a postoperative daily log documenting the number of opioids consumed, other pain management modalities used, and pain scores. The primary outcome of the number of opioid pills consumed by the patients was compared between the groups. We constructed a linear regression model to determine the risk factors for postoperative opioid use after surgery., Results: One hundred seventy-four patients completed the study (n = 90 education group; n = 84 standard care group). Patients in the education group took significantly fewer opioid pills (median = 0, range 0-13) than those in the standard care group (median = 0.5, range 0-40). A linear regression model showed that average week-1 pain (B = 0.93; 95% confidence interval, 0.56-1.3) and the number of pills prescribed (B = 0.12; 95% confidence interval, 0.017-0.22) were predictive of greater opioid use., Conclusions: Perioperative patient education significantly reduced postoperative opioid use following a minor soft tissue hand surgery, with greater than 70% of the patients taking no opioids., Type of Study/level of Evidence: Prognostic II., (Copyright © 2022 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background Inflammation in epicardial adipose tissue (EAT) may contribute to coronary atherosclerosis. Myocardial bridge is a congenital anomaly in which the left anterior descending coronary artery takes a "tunneled" course under a bridge of myocardium: while atherosclerosis develops in the proximal left anterior descending coronary artery, the bridged portion is spared, highlighting the possibility that geographic separation from inflamed EAT is protective. We tested the hypothesis that inflammation in EAT was related to atherosclerosis by comparing EAT from proximal and bridge depots in individuals with myocardial bridge and varying degrees of atherosclerotic plaque. Methods and Results Maximal plaque burden was quantified by intravascular ultrasound, and inflammation was quantified by pericoronary EAT signal attenuation (pericoronary adipose tissue attenuation) from cardiac computed tomography scans. EAT overlying the proximal left anterior descending coronary artery and myocardial bridge was harvested for measurement of mRNA and microRNA (miRNA) using custom chips by Nanostring; inflammatory cytokines were measured in tissue culture supernatants. Pericoronary adipose tissue attenuation was increased, indicating inflammation, in proximal versus bridge EAT, in proportion to atherosclerotic plaque. Individuals with moderate-high versus low plaque burden exhibited greater expression of inflammation and hypoxia genes, and lower expression of adipogenesis genes. Comparison of gene expression in proximal versus bridge depots revealed differences only in participants with moderate-high plaque: inflammation was higher in proximal and adipogenesis lower in bridge EAT. Secreted inflammatory cytokines tended to be higher in proximal EAT. Hypoxia-inducible factor 1a was highly associated with inflammatory gene expression. Seven miRNAs were differentially expressed by depot: 3192-5P, 518D-3P, and 532-5P were upregulated in proximal EAT, whereas miR 630, 575, 16-5P, and 320E were upregulated in bridge EAT. miR 630 correlated directly with plaque burden and inversely with adipogenesis genes. miR 3192-5P, 518D-3P, and 532-5P correlated inversely with hypoxia/oxidative stress, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG1a), adipogenesis, and angiogenesis genes. Conclusions Inflammation is specifically elevated in EAT overlying atherosclerotic plaque, suggesting that EAT inflammation is caused by atherogenic molecular signals, including hypoxia-inducible factor 1a and/or miRNAs in an "inside-to-out" relationship. Adipogenesis was suppressed in the bridge EAT, but only in the presence of atherosclerotic plaque, supporting cross talk between the vasculature and EAT. miR 630 in EAT, expressed differentially according to burden of atherosclerotic plaque, and 3 other miRNAs appear to inhibit key genes related to adipogenesis, angiogenesis, hypoxia/oxidative stress, and thermogenesis in EAT, highlighting a role for miRNA in mediating cross talk between the coronary vasculature and EAT.

Background: The relaxation of telemedicine (TM) restrictions during the COVID-19 pandemic accelerated adoption of this technology by many orthopedic practices. The purpose of this study was to examine the demographics of the orthopedic patients who utilized TM visits during the COVID-19 pandemic to identify opportunities to improve access. Methods: All patients who underwent orthopedic TM visits at one urban academic medical center between January and April 2020 were included. Demographic data including primary zip code, primary language, and visit type were collected. The demographics of the TM cohort were compared with those of patients seen in the outpatient (OP) setting at the same institution the prior year as well as with patients in the metropolitan area (M). Results: Five thousand thirty-five TM visits met the inclusion criteria. The TM cohort was significantly younger than the OP cohort, with mean age of 48.7 ± 19.0 years for TM and 55.2 ± 18.0 years for OP, and with 22% of TM being 65 or older versus 35% of OP being 65 or older ( p  = 0.001). The TM cohort had a lower percentage of minority patients (41.3%) than the OP cohort (48.2%). The TM cohort had a significantly lower percentage of black 12.9% versus 14.1%, Asian. 5.1% versus 5.8%, and Spanish/Hispanic 1.9% versus 15.4%, than the M and the OP cohort from the prior year ( p < 0.026, p < 0.001, p < 0.001). For socioeconomic status, only 13.8% of TM patients were from ZIP codes with median household incomes <50k. A total of 96.2% of TM visits were performed in English, where only 61% of individuals in the metropolitan area report English as their primary language. Conclusions: As the largest analysis of the use of TM in orthopedics, this study highlights both the future potential of TM and areas of improvement to ensure better access to care for all patient populations. Maintenance of the provisions to allow audio-only visits to be considered TM and billed as such is one important measure.

Purpose: Semaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic approach for neuroprotection via inhibition of the Sema-3A pathway., Methods: To develop potent and specific Sema-3A antagonists, we isolated monoclonal anti-Sema-3A antibodies from a human antibody phage display library and optimized low-molecular weight Sema-3A signaling inhibitors. The best inhibitors were identified using in vitro scratch assays and semiquantitative repulsion assays., Results: A therapeutic approach for neuroprotection must have a long duration of action. Therefore, antibodies and low-molecular weight inhibitors were formulated in extruded implants to allow controlled and prolonged release. Following release from the implants, Sema-3A inhibitors antagonized Sema-3A effects in scratch and repulsion assays and protected retinal ganglion cells in animal models of optic nerve injury, retinal ischemia, and glaucoma., Conclusions and Translational Relevance: Collectively, our findings indicate that the identified Sema-3A inhibitors should be further evaluated as therapeutic candidates for the treatment of Sema-3A-driven central nervous system degenerative processes.

Objective: To evaluate association between biomarkers and outcomes in COVID-19 hospitalised patients. COVID-19 pandemic has been a challenge. Biomarkers have always played an important role in clinical decision making in various infectious diseases. It is crucial to assess the role of biomarkers in evaluating severity of disease and appropriate allocation of resources., Design and Setting: Systematic review and meta-analysis. English full text observational studies describing the laboratory findings and outcomes of COVID-19 hospitalised patients were identified searching PubMed, Web of Science, Scopus, medRxiv using Medical Subject Headings (MeSH) terms COVID-19 OR coronavirus OR SARS-CoV-2 OR 2019-nCoV from 1 December 2019 to 15 August 2020 following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines., Participants: Studies having biomarkers, including lymphocyte, platelets, D-dimer, lactate dehydrogenase (LDH), C reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, procalcitonin (PCT) and creatine kinase (CK), and describing outcomes were selected with the consensus of three independent reviewers., Main Outcome Measures: Composite poor outcomes include intensive care unit admission, oxygen saturation <90%, invasive mechanical ventilation utilisation, severe disease, in-hospital admission and mortality. The OR and 95% CI were obtained and forest plots were created using random-effects models. Publication bias and heterogeneity were assessed by sensitivity analysis., Results: 32 studies with 10 491 confirmed COVID-19 patients were included. We found that lymphopenia (pooled-OR: 3.33 (95% CI: 2.51-4.41); p<0.00001), thrombocytopenia (2.36 (1.64-3.40); p<0.00001), elevated D-dimer (3.39 (2.66-4.33); p<0.00001), elevated CRP (4.37 (3.37-5.68); p<0.00001), elevated PCT (6.33 (4.24-9.45); p<0.00001), elevated CK (2.42 (1.35-4.32); p=0.003), elevated AST (2.75 (2.30-3.29); p<0.00001), elevated ALT (1.71 (1.32-2.20); p<0.00001), elevated creatinine (2.84 (1.80-4.46); p<0.00001) and LDH (5.48 (3.89-7.71); p<0.00001) were independently associated with higher risk of poor outcomes., Conclusion: Our study found a significant association between lymphopenia, thrombocytopenia and elevated levels of CRP, PCT, LDH, D-dimer and COVID-19 severity. The results have the potential to be used as an early biomarker to improve the management of COVID-19 patients, by identification of high-risk patients and appropriate allocation of healthcare resources in the pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Coronavirus disease-2019 (COVID-19), a pandemic that brought the whole world to a standstill, has led to financial and health care burden. We aimed to evaluate epidemiological characteristics, needs of resources, outcomes, and global burden of the disease., Methods: Systematic review was performed searching PubMed from December 1, 2019, to March 25, 2020, for full-text observational studies that described epidemiological characteristics, following MOOSE protocol. Global data were collected from the JHU-Corona Virus Resource Center, WHO-COVID-2019 situation reports, KFF.org, and Worldometers.info until March 31, 2020. The prevalence percentages were calculated. The global data were plotted in excel to calculate case fatality rate (CFR), predicted CFR, COVID-19 specific mortality rate, and doubling time for cases and deaths. CFR was predicted using Pearson correlation, regression models, and coefficient of determination., Results: From 21 studies of 2747 patients, 8.4% of patients died, 20.4% recovered, 15.4% were admitted to ICU and 14.9% required ventilation. COVID-19 was more prevalent in patients with hypertension (19.3%), smoking (11.3%), diabetes mellitus (10%), and cardiovascular diseases (7.4%). Common complications were pneumonia (82%), cardiac complications (26.4%), acute respiratory distress syndrome (15.7%), secondary infection (11.2%), and septic shock (4.3%). Though CFR and COVID-19 specific death rates are dynamic, they were consistently high for Italy, Spain, and Iran. Polynomial growth models were best fit for all countries for predicting CFR. Though many interventions have been implemented, stern measures like nationwide lockdown and school closure occurred after very high infection rates (>10cases per 100 000population) prevailed. Given the trend of government measures and decline of new cases in China and South Korea, most countries will reach the peak between April 1-20, if interventions are followed., Conclusions: A collective approach undertaken by a responsible government, wise strategy implementation and a receptive population may help contain the spread of COVID-19 outbreak. Close monitoring of predictive models of such indicators in the highly affected countries would help to evaluate the potential fatality if the second wave of pandemic occurs. The future studies should be focused on identifying accurate indicators to mitigate the effect of underestimation or overestimation of COVID-19 burden., Competing Interests: Conflicts of interest: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2020 by the Journal of Global Health. All rights reserved.)

Beige adipocytes possess the morphological and biochemical characteristics of brown adipocytes, including the mitochondrial uncoupling protein (UCP)1. Mesenchymal stem cells (MSCs) are somatic multipotent progenitors which differentiate into lipid-laden adipocytes. Induction of MSC adipogenesis under hypothermic culture conditions (ie 32°C) promotes the appearance of a beige adipogenic phenotype, but the stability of this phenotypic switch after cells are returned to normothermic conditions of 37°C has not been fully examined. Here, cells transferred from 32°C to 37°C retained their multilocular beige-like morphology and exhibited an intermediate gene expression profile, with both beige-like and white adipocyte characteristics while maintaining UCP1 protein expression. Metabolic profile analysis indicated that the bioenergetic status of cells initially differentiated at 32°C adapted post-transfer to 37°C, showing an increase in mitochondrial respiration and glycolysis. The ability of the transferred cells to respond under stress conditions (eg carbonyl cyanide-4-phenylhydrazone (FCCP) treatment) demonstrated higher functional capacity of enzymes involved in the electron transport chain and capability to supply substrate to the mitochondria. Overall, MSC-derived adipocytes incubated at 32°C were able to remain metabolically active and retain brown-like features after 3 weeks of acclimatization at 37°C, indicating these phenotypic characteristics acquired in response to environmental conditions are not fully reversible., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background/aims: Glutamine is the most abundant amino acid in the body and has a metabolic role as a precursor for protein, amino sugar and nucleotide synthesis. After glucose, glutamine is the main source of energy in cells and has recently been shown to be an important carbon source for de novo lipogenesis. Glutamine is synthesized by the enzyme glutamine synthetase, a mitochondrial enzyme that is active during adipocyte differentiation suggesting a regulatory role in this process. The aim of our study was therefore to investigate whether glutamine status impacts on the differentiation of adipocytes and lipid droplet accumulation., Methods: Mouse mesenchymal stem cells (MSCs) were submitted to glutamine deprivation (i.e. glutamine-free adipogenic medium in conjunction with irreversible glutamine synthetase inhibitor, methionine sulfoximine - MSO) during differentiation and their response was compared with MSCs differentiated in glutamine-supplemented medium (5, 10 and 20 mM). Differentiated MSCs were assessed for lipid content using Oil Red O (ORO) staining and gene expression was analysed by qPCR. Intracellular glutamine levels were determined using a colorimetric assay, while extracellular glutamine was measured using liquid chromatography-mass spectrometry (LC-MS)., Results: Glutamine deprivation largely abolished adipogenic differentiation and lipid droplet formation. This was accompanied with a reduction in intracellular glutamine concentration, and downregulation of gene expression for classical adipogenic markers including PPARγ. Furthermore, glutamine restriction suppressed isocitrate dehydrogenase 1 (IDH1) gene expression, an enzyme which produces citrate for lipid synthesis. In contrast, glutamine supplementation promoted adipogenic differentiation in a dose-dependent manner., Conclusion: These results suggest that the glutamine pathway may have a previously over-looked role in adipogenesis. The underlying mechanism involved the glutamine-IDH1 pathway and could represent a potential therapeutic strategy to treat excessive lipid accumulation and thus obesity., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Respirometry is the gold standard measurement of mitochondrial oxidative function, as it reflects the activity of the electron transport chain complexes working together. However, the requirement for freshly isolated mitochondria hinders the feasibility of respirometry in multi-site clinical studies and retrospective studies. Here, we describe a novel respirometry approach suited for frozen samples by restoring electron transfer components lost during freeze/thaw and correcting for variable permeabilization of mitochondrial membranes. This approach preserves 90-95% of the maximal respiratory capacity in frozen samples and can be applied to isolated mitochondria, permeabilized cells, and tissue homogenates with high sensitivity. We find that primary changes in mitochondrial function, detected in fresh tissue, are preserved in frozen samples years after collection. This approach will enable analysis of the integrated function of mitochondrial Complexes I to IV in one measurement, collected at remote sites or retrospectively in samples residing in tissue biobanks., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

The increasing COVID-19 cases in the USA have led to overburdening of healthcare in regard to invasive mechanical ventilation (IMV) utilization as well as mortality. We aim to identify risk factors associated with poor outcomes (IMV and mortality) of COVID-19 hospitalized patients. A meta-analysis of observational studies with epidemiological characteristics of COVID-19 in PubMed, Web of Science, Scopus, and medRxiv from December 1, 2019 to May 31, 2020 following MOOSE guidelines was conducted. Twenty-nine full-text studies detailing epidemiological characteristics, symptoms, comorbidities, complications, and outcomes were included. Meta-regression was performed to evaluate effects of comorbidities, and complications on outcomes using a random-effects model. The pooled correlation coefficient ( r ), 95% CI, and OR were calculated. Of 29 studies (12,258 confirmed cases), 17 reported IMV and 21 reported deaths. The pooled prevalence of IMV was 23.3% (95% CI: 17.1-30.9%), and mortality was 13% (9.3-18%). The age-adjusted meta-regression models showed significant association of mortality with male ( r : 0.14; OR: 1.15; 95% CI: 1.07-1.23; I 2 : 95.2%), comorbidities including pre-existing cerebrovascular disease ( r : 0.35; 1.42 (1.14-1.77); I 2 : 96.1%), and chronic liver disease ( r : 0.08; 1.08 (1.01-1.17); I 2 : 96.23%), complications like septic shock ( r : 0.099; 1.10 (1.02-1.2); I 2 : 78.12%) and ARDS ( r : 0.04; 1.04 (1.02-1.06); I 2 : 90.3%), ICU admissions ( r : 0.03; 1.03 (1.03-1.05); I 2 : 95.21%), and IMV utilization ( r : 0.05; 1.05 (1.03-1.07); I 2 : 89.80%). Similarly, male ( r : 0.08; 1.08 (1.02-1.15); I 2 : 95%), comorbidities like pre-existing cerebrovascular disease ( r : 0.29; 1.34 (1.09-1.63); I 2 :93.4%), and cardiovascular disease ( r : 0.28; 1.32 (1.1-1.58); I 2 : 89.7%) had higher odds of IMV utilization. COVID-19 patients with comorbidities including cardiovascular disease, cerebrovascular disease, and chronic liver disease had poor outcomes. Diabetes and hypertension had higher prevalence but no association with mortality and IMV. Our study results will be helpful in right allocation of resources towards patients who need them the most., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© Springer Nature Switzerland AG 2020.)

Introduction: Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time., Methods: This phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests., Results: Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved., Conclusions: PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo. Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo, drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult humans.

Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects. PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design. Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher C max and 1.3-fold higher AUC compared with the oromucosal spray. T max following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ∼15-fold increase in C max and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray. PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications., (© 2017, The American College of Clinical Pharmacology.)

Although brown adipose tissue (BAT) is one of the smallest organs in the body, it has the potential to have a substantial impact on both heat production as well as fat and carbohydrate metabolism. This is most apparent at birth, which is characterised with the rapid appearance and activation of the BAT specific mitochondrial uncoupling protein (UCP)1 in many large mammals. The amount of brown fat then gradually declines with age, an adaptation that can be modulated by the thermal environment. Given the increased incidence of maternal obesity and its potential transmission to the mother's offspring, increasing BAT activity in the mother could be one mechanism to prevent this cycle. To date, however, all rodent studies investigating maternal obesity have been conducted at standard laboratory temperature (21°C), which represents an appreciable cold challenge. This could also explain why offspring weight is rarely increased, suggesting that future studies would benefit from being conducted at thermoneutrality (~28°C). It is also becoming apparent that each fat depot has a unique transcriptome and show different developmental pattern, which is not readily apparent macroscopically. These differences could contribute to the retention of UCP1 within the supraclavicular fat depot, the most active depot in adult humans, increasing heat production following a meal. Despite the rapid increase in publications on BAT over the past decade, the extent to which modifications in diet and/or environment can be utilised to promote its activity in the mother and/or her offspring remains to be established., (© 2018 Society for Endocrinology.)

Brown adipose tissue (BAT) undergoes pronounced changes after birth coincident with the loss of the BAT-specific uncoupling protein (UCP)1 and rapid fat growth. The extent to which this adaptation may vary between anatomical locations remains unknown, or whether the process is sensitive to maternal dietary supplementation. We, therefore, conducted a data mining based study on the major fat depots (i.e. epicardial, perirenal, sternal (which possess UCP1 at 7 days), subcutaneous and omental) (that do not possess UCP1) of young sheep during the first month of life. Initially we determined what effect adding 3% canola oil to the maternal diet has on mitochondrial protein abundance in those depots which possessed UCP1. This demonstrated that maternal dietary supplementation delayed the loss of mitochondrial proteins, with the amount of cytochrome C actually being increased. Using machine learning algorithms followed by weighted gene co-expression network analysis, we demonstrated that each depot could be segregated into a unique and concise set of modules containing co-expressed genes involved in adipose function. Finally using lipidomic analysis following the maternal dietary intervention, we confirmed the perirenal depot to be most responsive. These insights point at new research avenues for examining interventions to modulate fat development in early life.

There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex ® ). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma C max than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of T max were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Brown and beige adipocytes are characterised as expressing the unique mitochondrial uncoupling protein (UCP)1 for which the primary stimulus in vivo is cold exposure. The extent to which cold-induced UCP1 activation can also be achieved in vitro, and therefore perform a comparable cellular function, is unknown. We report an in vitro model to induce adipocyte browning using bone marrow (BM) derived mesenchymal stem cells (MSC), which relies on differentiation at 32 °C instead of 37 °C. The low temperature promoted browning in adipogenic cultures, with increased adipocyte differentiation and upregulation of adipogenic and thermogenic factors, especially UCP1. Cells exhibited enhanced uncoupled respiration and metabolic adaptation. Cold-exposed differentiated cells showed a marked translocation of leptin to adipocyte nuclei, suggesting a previously unknown role for leptin in the browning process. These results indicate that BM-MSC can be driven to forming beige-like adipocytes in vitro by exposure to a reduced temperature. This in vitro model will provide a powerful tool to elucidate the precise role of leptin and related hormones in hitherto functions in the browning process.

The global prevalence of obesity and related cardiometabolic disease continues to increase through the 21st century. Whilst multi-factorial, obesity is ultimately caused by chronic caloric excess. However, despite numerous interventions focussing on reducing caloric intake these either fail or only elicit short-term changes in body mass. There is now a focus on increasing energy expenditure instead which has stemmed from the recent 're-discovery' of cold-activated brown adipose tissue (BAT) in adult humans and inducible 'beige' adipocytes. Through the unique mitochondrial uncoupling protein 1 (UCP1), these thermogenic adipocytes are capable of combusting large amounts of chemical energy as heat and in animal models can prevent obesity and cardiometabolic disease. At present, human data does not point to a role for thermogenic adipocytes in regulating body weight or fat mass but points to a pivotal role in regulating metabolic health by improving insulin resistance as well as glucose and lipid homeostasis. This review will therefore focus on the metabolic benefits of BAT activation and the mechanisms and signalling pathways by which these could occur including improvements in insulin signalling in peripheral tissues, systemic lipid and cholesterol metabolism and cardiac and vascular function.

Women who inject drugs have been shown to have higher incidence of HIV and risk behaviours than men, but there are conflicting reports about hepatitis C virus (HCV) incidence. We systematically reviewed the literature to examine the female-to-male (F:M) HCV incidence in female and male persons who inject drugs (PWID), and also to explore the heterogeneity (i.e. methodological diversity) in these differences. We searched PubMed and EMBASE for studies published between 1989 and March 2015 for research that reported incidence of HCV infection by sex or HCV incidence F:M rate ratio. A total of 28 studies, which enrolled 9325 PWID, were included. The overall pooled HCV incidence rate (per 100 person-years observation) was 20.36 (95% CI: 13.86, 29.90) and 15.20 (95% CI: 10.52, 21.97) in females and males, respectively. F:M ratio was 1.36:1 (95% CI: 1.13, 1.64) with substantial heterogeneity (I-squared=71.6%). The F:M ratio varied by geographic location from 4.0 (95% CI: 1.80, 8.89) in China to 1.17 (95% CI: 0.95, 1.43) in the U.S. In studies which recruited participants from community settings, the F:M ratio was 1.24 (95% CI: 1.03, 1.48), which was lower than that reported in the clinical settings (1.72, 95% CI: 0.86, 3.45). The number of studies included provided sufficient statistical power to detect sex differences in this analysis. Our findings raise questions and concerns regarding sex differences with respect to the risk of HCV. Both behavioural and biological studies are needed to investigate causes and potential mechanisms as well as sex-specific prevention approaches to HCV infection., Competing Interests: Authors have no commercial or other association that might pose a conflict of interest., (© 2016 John Wiley & Sons Ltd.)

Intervertebral disc (IVD) degeneration is the leading trigger of low back pain, which causes disability and leads to enormous healthcare toll worldwide. Biological treatment with growth factors has evolved as potential therapy for IVD regeneration. Bone morphogenetic protein 2 (BMP-2) and BMP-7 have shown promise in this regard. In the current study, we evaluated the effect of BMP-2/7 heterodimer for disc regeneration both in vitro and in organ culture. Nucleus pulposus (NP) cells isolated from bovine caudal disc were cultured in a fibrin-hyaluronan (FBG-HA) hydrogel for up to 14 days. BMP-2/7 heterodimer covalently incorporated within the hydrogel up-regulated the aggrecan and type II collagen gene expression, and glycosaminoglycan synthesis of NP cells. The activity of the BMP-2/7 heterodimer was dose dependent. The higher dose of BMP-2/7 was further assessed in an IVD whole organ system. After 14 days of culture with cyclic dynamic load, the BMP-2/7 heterodimer delivered into the nucleotomized region showed potential to stimulate the gene expression and synthesis of proteoglycan in the remaining NP tissue after partial nucleotomy. The gene expression level of type I collagen and alkaline phosphatase in the native disc tissue were not affected by BMP-2/7 treatment, indicating no adverse fibroblastic or osteogenic effect on the disc tissue. Intradiscal delivery of BMP-2/7 heterodimer may be a promising therapeutic approach for NP regeneration. The current IVD whole organ partial nucleotomy model may be utilized for screening of other biomaterials or drugs to treat early degenerative disc disorders. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:51-60, 2017., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Many diseases and disease symptoms still lack effective treatment. At the same time, certain controversial Schedule I drugs, such as heroin and cannabis, have been reputed to have considerable therapeutic potential for addressing significant medical problems. Yet, there is a paucity of U.S. clinical studies on the therapeutic uses of controlled drugs. For example, people living with HIV/AIDS experience a variety of disease- and medication-related symptoms. Their chronic pain is intense, frequent, and difficult to treat. Nevertheless, clinical trials of compassionate management for their chronic symptoms, which should be a research priority, are stymied. We employed qualitative methods to develop an understanding of the barriers to research on potential therapeutic uses of Schedule I drugs so that they might be addressed. We elicited the perspectives of key stakeholder groups that would be involved in such studies: people living with HIV/AIDS, clinicians, and members of institutional review boards. As we identified obstacles to research, we found that all of the stakeholder groups arrived at the same conclusion, that clinical research on the therapeutic potential of these drugs is ethically required., (Copyright 2016 The Journal of Clinical Ethics. All rights reserved.)

Studies in rodents and newborn humans demonstrate the influence of brown adipose tissue (BAT) in temperature control and energy balance and a critical role in the regulation of body weight. Here, we obtained samples of epicardial adipose tissue (EAT) from neonates, infants, and children in order to evaluate changes in their transcriptional landscape by applying a systems biology approach. Surprisingly, these analyses revealed that the transition to infancy is a critical stage for changes in the morphology of EAT and is reflected in unique gene expression patterns of a substantial proportion of thermogenic gene transcripts (~10%). Our results also indicated that the pattern of gene expression represents a distinct developmental stage, even after the rebound in abundance of thermogenic genes in later childhood. Using weighted gene coexpression network analyses, we found precise anthropometric-specific correlations with changes in gene expression and the decline of thermogenic capacity within EAT. In addition, these results indicate a sequential order of transcriptional events affecting cellular pathways, which could potentially explain the variation in the amount, or activity, of BAT in adulthood. Together, these results provide a resource to elucidate gene regulatory mechanisms underlying the progressive development of BAT during early life.