Tezepelumab for the treatment of severe asthma: a plain language summary of the PATHWAY and NAVIGATOR studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of 2 clinical studies that looked at a medicine called tezepelumab. Tezepelumab is approved in the United States of America (USA), the European Union (EU) and several other countries for the treatment of severe, uncontrolled asthma in people aged 12 and above. The results of these 2 studies, called PATHWAY and NAVIGATOR, formed the basis for tezepelumab's approval for use. Tezepelumab is a type of biologic treatment called an antibody. Biologics are treatments that target certain cells or proteins in the body and often in the immune system - the body's natural defence system against infections and diseases - to reduce patients' disease. It works by blocking a key first step in the body's chain reaction leading to inflammation in the airways of people with severe asthma. The clinical studies were done to learn if tezepelumab can be used to treat people with severe, uncontrolled asthma and to find out about its safety. In both studies, tezepelumab was compared to placebo. A placebo is a dummy treatment that looked like tezepelumab but did not have any medicine in it. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: In both studies, tezepelumab reduced the number of severe asthma attacks that the participants had per year compared with placebo. It also increased the volume of air that the participants could breathe out in 1 second compared with placebo. Tezepelumab was well-tolerated, and a similar number of participants had health issues in the tezepelumab and placebo treatment groups. The most common health issues that the participants had during the PATHWAY study were: Worsening of asthma, common cold, headache, and inflammation of the airways. The most common health issues that the participants had during the NAVIGATOR study were: Common cold, infection of the sinuses, throat and airways, headache, worsening of asthma, and inflammation of the airways. WHAT ARE THE KEY TAKEAWAYS?: The results showed that participants who had monthly doses of tezepelumab had fewer severe asthma attacks and better lung function than those who had placebo. In both studies, the health issues that the participants had were similar between the tezepelumab and placebo treatment groups. Overall, the studies showed that tezepelumab worked in a broad population of people with severe asthma and that the study participants had an acceptable level of health issues during the studies. These results led to the approval of tezepelumab for people with severe asthma aged 12 and above in the USA, EU and other countries. Clinical Trial Registration: PATHWAY study: NCT02054130; NAVIGATOR study: NCT03347279 (ClinicalTrials.gov).

Multidimensional evaluation of voice outcomes following total laryngectomy: a prospective multicenter cohort study.

PURPOSE: The purpose of this study is to assess the general course of acoustic, patient rated, and clinician-rated voice outcomes from pre- up to 12 months post total laryngectomy. METHODS: Patients admitted to a total laryngectomy in five participating hospitals in Australia and The Netherlands were included. Assessments took place at pre-, 3 months, 6 months, and 12 months post-surgery. Voice outcomes are evaluated with the Acoustic Voice Quality Index (AVQI), perceptual scales, and patient-reported outcome measures including VHI-10 and EQ-5D-5L. Statistical analyses include descriptive statistics, t tests (pre- to 6 months post-surgery), Linear Mixed Effect models. RESULTS: The study included 43 participants. A significant worsening of AVQI is seen from pre- to post-surgery evaluated with t test (p < 0.001). The Linear Mixed Effect model confirmed Time as a significant factor in predicting AVQI score (p ≤ 0.001), as well as perceptual rated voice quality by the clinician (p = 0.015) and patient-reported perceptual rated voice quality (p = 0.002). No statistical significance was found in VHI-10 scores over time. CONCLUSION: Successful TE-speech was achieved in most participants, some had to rely on augmentative alternative communication methods. Patient-reported outcomes indicate acceptance of the condition and sufficient coping in the long term. However, acoustic rated voice quality is abnormal at all post-surgery time-points. AVQI proved to be a useful instrument to evaluate TE-speech. There is a need for validation and determination of cut-off values for VHI-10 and AVQI for use in TE-speech.

A Patient-Centered Description of Severe Asthma: Patient Understanding Leading to Assessment for a Severe Asthma Referral (PULSAR)

BACKGROUND: Although severe asthma can be life-threatening, many patients are unaware they have this condition. OBJECTIVES: Patient Understanding Leading to Assessment for a Severe Asthma Referral (PULSAR) is a novel, multidisciplinary working group aiming to develop and disseminate a global, patient-centered description of severe asthma to improve patient understanding of severe asthma and effect a change in patient behavior whereby patients are encouraged to visit their healthcare professional, when appropriate. METHODS: Current definitions from patient organization websites, asthma guidelines, and medication information for key asthma drugs were assessed and informed a multidisciplinary working group, convened to identify common concepts and terminology used to define severe asthma. A patient-centered description of severe asthma and patient checklist were drafted based on working-group discussions and reviewed by an external behavioral scientist for patient understanding and relevance. These were tested using an online US/Canadian survey. RESULTS: The patient-centered description of severe asthma and patient checklist were reviewed and re-drafted by the authors. The text was simplified following the behavioral-scientist review. The survey (n = 153) included 105 patients with severe asthma. Of those with severe asthma, 92.2% of patients reported that the description was consistent with their experiences of severe asthma and 92.6% of patients reported that the PULSAR initiative would encourage them to visit their healthcare provider. CONCLUSION: A patient-centered description of severe asthma has been developed and tested using patients with severe asthma; this description will allow patients to assess whether they might have severe asthma and prompt them to visit their healthcare provider, if appropriate.

Severe asthma is a serious form of asthma. It can be harmful to your health and affect the way you live your life. Some patients do not know that they have severe asthma or visit their doctor and ask for help. A new group, called Patient Understanding Leading to Assessment for a Severe Asthma Referral (PULSAR), would like to help patients understand their asthma symptoms. They have developed a description of severe asthma and a checklist. These may help patients decide if their symptoms require a visit to the doctor.The PULSAR description and checklist were developed in four parts. Part 1 looked at if patients and doctors/nurses defined severe asthma in the same way. Results showed that patients defined severe asthma using symptoms and doctors defined severe asthma using treatments. In Part 2, patients, patient advocacy group members, nurses, doctors, specialists, and a scientist talked about the ways severe asthma were described in Part 1. The group agreed on a set of words to describe severe asthma. These words were then used in the PULSAR description and checklist. In Part 3, a behavioral scientist reviewed the PULSAR description and checklist. They said that simple language would make it easy to understand. In Part 4, patients with severe asthma were asked what they thought about the description and checklist using an online survey. The survey showed that almost all patients understood the description and checklist. Many patients said that the description and checklist encouraged them to see a doctor.A new description of severe asthma and checklist have been developed by PULSAR. Testing shows that they should encourage patients to visit their doctor when needed. This may help patients understand their symptoms and help doctors make the correct diagnosis. This should help patients get the support and treatment they need.

Hypertonic saline reduces skeletal muscle injury and associated remote organ injury following ischemia reperfusion injury.

BACKGROUND AND PURPOSE: Pharmacological modulation of skeletal muscle reperfusion injury after traumaassociated ischemia may improve limb salvage rates and prevent the associated systemic sequelae. Resuscitation with hypertonic saline restores the circulating volume and has favorable effects on tissue perfusion and blood pressure. We evaluated the effects of treatment with a bolus of hypertonic saline on skeletal muscle ischemia reperfusion (IR) injury and the associated end-organ injury. METHODS: Adult male Sprague-Dawley rats (n = 27) were randomized into 3 groups: (1) a control group, (2) an IR group treated with normal saline, and (3) an IR group treated with hypertonic saline. Bilateral hindlimb ischemia was induced by application of a rubber band proximal to the level of the greater trochanters for 2.5 h. The treatment groups received either normal saline (4 mL/kg) or hypertonic saline (4 mL/kg) prior to tourniquet release. Following 12 h of reperfusion, the tibialis anterior muscle was dissected and muscle function was assessed electrophysiologically. The animals were then killed, and skeletal muscle and lung tissue were harvested for evaluation. RESULTS: Hypertonic saline significantly attenuated skeletal muscle reperfusion injury, as shown by reduced myeloperoxidase content, wet-to-dry ratio, and electrical properties of skeletal muscle. There was a corresponding reduction in lung injury, as demonstrated by reduced myeloperoxidase content and reduced wet-to-dry ratio. INTERPRETATION: Treatment with hypertonic saline attenuates skeletal muscle ischemia reperfusion injury and its associated systemic sequelae.

Statins attenuate polymethylmethacrylate-mediated monocyte activation.

BACKGROUND: Periprosthetic osteolysis precipitates aseptic loosening of components, increases the risk of periprosthetic fracture and, through massive bone loss, complicates revision surgery and ultimately is the primary cause for failure of joint arthroplasty. The anti-inflammatory properties of HMG-CoA reductase inhibitors belonging to the statin family are well recognized. We investigated a possible role for status in initiating the first stage of the osteolytic cycle, namely monocytic activation. METHODS: We used an in vitro model of the human monocyte/macrophage inflammatory response to poly-methylmethacrylate (PMMA) particles after pretreat-ing cells with cerivastatin, a potent member of the statin family. Cell activation based upon production of TNF-alpha and MCP-1 cytokines was analyzed and the intracellular Raf-MEK-ERK signal transduction pathway was evaluated using western blot analysis, to identify its role in cell activation and in any cerivastatin effects observed. RESULTS: We found that pretreatment with cerivastatin significantly abrogates the production of inflammatory cytokines TNF-alpha and MCP-1 by human monocytes in response to polymethylmethacrylate particle activation. This inflammatory activation and attenuation appear to be mediated through the intracellular Raf-MEK-ERK pathway. INTERPRETATION: We propose that by intervening at the upstream activation stage, subsequent osteoclast activation and osteolysis can be suppressed. We believe that the anti-inflammatory properties of statins may potentially play a prophylactic role in the setting of aseptic loosening, and in so doing increase implant longevity.

Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury.

BACKGROUND: Revascularization of a limb following prolonged ischemia results in substantial skeletal muscle injury. Statins play a well-understood role in the treatment of hypercholesterolemia but are also known to have anti-inflammatory properties. The purpose of this study was to examine the effects of pravastatin pre-treatment in the setting of skeletal muscle ischemia reperfusion injury (IRI). METHODS: Adult male Sprague Dawley rats (n = 27) were randomized into 3 groups: control group, I/R group, IR group pre-treated with pravastatin. Bilateral hind-limb ischemia was induced by rubber band application proximal to the level of the greater trochanters for 2.5 h. Treatment groups received normal saline in equal volumes prior to tourniquet release. Following 12 h reperfusion, the tibialis anterior muscle was dissected and muscle function assessed electrophysiologically by electrical field stimulation. The animals were then killed and skeletal muscle harvested for evaluation. RESULTS: We found that pre-treatment with pravastatin reduces the tissue oxidative damage and edema associated with skeletal muscle reperfusion injury. Skeletal muscle injury, measured by edema, leucosequestration and electrical properties were significantly lower with pravastatin pre-treatment compared to the non-treated group. INTERPRETATION: We feel that pravastatin pre-treatment may be a potential therapeutic intervention for skeletal muscle ischemia reperfusion injury in the clinical setting.

Pelvic girdle sepsis in childhood. An illustrative case of the difficulty in diagnosis.

The child who presents with fever, limp and hip pain will often undergo multiple diagnostic procedures before a definitive diagnosis is made. We describe a diagnostically challenging case of a 14-year-old boy presenting with an atraumatic painful limp and pyrexia. Eventually the diagnosis of obturator internus muscle abscess with associated ischial osteomyelitis was made. Of the 19 previous cases reported, four children had associated osteomyelitis and were of an older age. Symptomatology varies, clinical examination is non-specific and the diagnosis can be difficult. Haematological indices are more predictive than in cases of classical osteomyelitis or septic arthritis. Subtle features on conventional radiography and isotope bone scanning should not be overlooked while CT and MRI may be complementary in diagnosis.

Comparison of outcomes following uncemented hemiarthroplasty and dynamic hip screw in the treatment of displaced subcapital hip fractures in patients aged greater than 70 years.

As health care costs increase, evaluating treatment methods in femoral neck fractures to determine the most effective treatment paradigm will become increasingly important. The current study compared two methods of treatment in similar cohorts of displaced femoral neck fractures. One hundred and twenty two patients were randomly assigned to two groups: In Group A, 62 patients were treated with a hemiarthroplasty. In group B, 60 patients were treated with dynamic screw fixation. Patients were evaluated at a minimum 3 year follow-up. Using the Matta functional hip score, 42% of group A and 70% of group B had good to excellent results. This difference was significant (p = 0.004). A significant agreement between physician assessment using the Matta score, and patient perception of outcome using the SF-36 scale was demonstrated (r = 0.64). No statistical difference between groups for revision surgery existed. Both physician based and patient based outcome scores favour retention and internal fixation of the femoral head in this cohort of patients at a short-term follow-up.