OnabotulinumtoxinA for Treatment of Moderate to Severe Crow's Feet Lines: A Review

Lateral canthal lines or crow's feet lines (CFL) may be treated with onabotulinumtoxinA. We identified several key concepts important to understanding the use of onabotulinumtoxinA for treatment of moderate-to-severe CFL. To contextualize and integrate data on the recommended dose and injection patterns of onabotulinumtoxinA for treatment of CFL, we summarized data from pivotal clinical studies in the development of onabotulinumtoxinA for treatment of CFL. Data from key studies of onabotulinumtoxinA for CFL are presented. The efficacy and safety of onabotulinumtoxinA treatment of moderate-to-severe CFL were evaluated in 2 randomized, controlled phase 3 studies comprising 1362 patients. The 24U total dose of onabotulinumtoxinA used in these studies was based on a phase 2 dose-ranging trial. Two injection patterns were available to investigators; each involved 3 injection sites per side in the lateral orbicularis oculi muscle. A cross-sectional analysis of photographs from the phase 3 trials provided detailed information on the frequency of 4 distinct CFL patterns. In the primary efficacy analysis for each phase 3 trial, CFL responder rates were significantly greater with onabotulinumtoxinA vs placebo at day 30 ( P < .001). Eyelid edema (1%) was the only adverse event reported in ≥1% of patients receiving onabotulinumtoxinA, occurring more frequently with onabotulinumtoxinA than with placebo. The studies showed that onabotulinumtoxinA is effective and generally well-tolerated for CFL treatment. Additionally, 2 different injection patterns allow physicians to tailor treatment based on a patient's CFL pattern

VERITAS discovery of very high energy gamma-ray emission from S3 1227+25 and multiwavelength observations

We report the detection of very high energy gamma-ray emission from the blazar S3 1227+25 (VER J1230+253) with the Very Energetic Radiation Imaging Telescope Array System (VERITAS). VERITAS observations of the source were triggered by the detection of a hard-spectrum GeV flare on May 15, 2015 with the Fermi-Large Area Telescope (LAT). A combined five-hour VERITAS exposure on May 16th and May 18th resulted in a strong 13$\sigma$ detection with a differential photon spectral index, $\Gamma$ = 3.8 $\pm$ 0.4, and a flux level at 9% of the Crab Nebula above 120 GeV. This also triggered target of opportunity observations with Swift, optical photometry, polarimetry and radio measurements, also presented in this work, in addition to the VERITAS and Fermi-LAT data. A temporal analysis of the gamma-ray flux during this period finds evidence of a shortest variability timescale of $\tau_{obs}$ = 6.2 $\pm$ 0.9 hours, indicating emission from compact regions within the jet, and the combined gamma-ray spectrum shows no strong evidence of a spectral cut-off. An investigation into correlations between the multiwavelength observations found evidence of optical and gamma-ray correlations, suggesting a single-zone model of emission. Finally, the multiwavelength spectral energy distribution is well described by a simple one-zone leptonic synchrotron self-Compton radiation model.Comment: 18 pages, 6 figures. Accepted for publication in the Astrophysical Journal (ApJ

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy.

Peer reviewe

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Nucleotide-mediated intracellular and intercellular communication in spinal astrocytes

The work presented in this thesis is focused on the effects of extracellular nucleotides on dorsal spinal astrocytes. Extracellular nucleotides stimulate the elevation of intracellular Ca2+ in astrocytes. Ca 2+ signalling in astrocytes is a principal means for responding to environmental stimuli and increases in [Ca2+]i lead to growth, differentiation and release of neuroactive mediators. In addition, astrocytes are capable of homologous and heterologous intercellular signaling via the spread of Ca2+ waves. Dorsal spinal astrocytes were found to spread waves of elevated intracellular calcium to other astrocytes following mechanical stimulation. The spread of Ca2+ wave was prevented in the presence of blockers of G-protein coupled nucleotide receptors. The G-protein coupled nucleotide receptors on dorsal spinal astrocytes were identified, both molecularly and pharmacologically, as the P2Y1 and P2Y2 receptors. Heterologous expression of either of these receptors in the 1321N1 cell line was sufficient to permit the spread of Ca 2+ waves between these cells. To probe for differences in signaling between these two receptors, P2Y1 or P2Y2 receptors on spinal astrocytes were exposed to continuous application of specific agonists for each receptor. Persistent activation of the P2Y2 receptor generated a prolonged elevation of [Ca2+]i which was converted to a transient elevation in the absence of extracellular Ca2+. Stimulation of P2Y1 receptors generated only a transient elevation in [Ca2+]i. These results reveal the specific role of P2Y receptors in the mechanisms underlying the spread of Ca2+ waves in spinal astrocytes and this may represent a general principle underlying gliotransmission in the CNS. The characteristics of Ca2+ waves spreading via activation of each receptor subtype were examined and a significant difference was found in the rate at which Ca2+ waves spread in cells expressing one or the other receptor. P2Y1-1321N1 cells spread Ca2+ waves slowly, whilst in P2Y2-1321N1 cells Ca2+ waves spread significantly faster. The basis of this difference was determined to be due to a difference in the rate at which P2Y1 and P2Y2 receptors generate a Ca2+ i elevation in response to stimulation by ATP. Stimulation of P2Y1 receptors with ADP, its preferred agonist, generated a rate of Ca2+ signaling comparable to that of P2Y2 receptors. This was confirmed by forcing Ca 2+ waves to propagate via ADP in cell lines expressing P2Y1 receptors only, where Ca2+ waves were observed to spread as quickly as those in P2Y2-expressing cells.Ph.D

Immunogenicity of botulinum toxins

Botulinum neurotoxins are formulated biologic pharmaceuticals used therapeutically to treat a wide variety of chronic conditions, with varying governmental approvals by country. Some of these disorders include cervical dystonia, post-stroke spasticity, blepharospasm, migraine, and hyperhidrosis. Botulinum neurotoxins also have varying governmental approvals for cosmetic applications. As botulinum neurotoxin therapy is often continued over many years, some patients may develop detectable antibodies that may or may not affect their biological activity. Although botulinum neurotoxins are considered “lower risk” biologics since antibodies that may develop are not likely to cross react with endogenous proteins, it is possible that patients may lose their therapeutic response. Various factors impact the immunogenicity of botulinum neurotoxins, including product-related factors such as the manufacturing process, the antigenic protein load, and the presence of accessory proteins, as well as treatment-related factors such as the overall toxin dose, booster injections, and prior vaccination or exposure. Detection of antibodies by laboratory tests does not necessarily predict the clinical success or failure of treatment. Overall, botulinum neurotoxin type A products exhibit low clinically detectable levels of antibodies when compared with other approved biologic products. This review provides an overview of all current botulinum neurotoxin products available commercially, with respect to the development of neutralizing antibodies and clinical response