Rejected

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in CAD patients without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n=22) or placebo (n=20) on Days 0 and 7, then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of Weeks 23, 25, 26], avoidance of transfusion and study-prohibited CAD therapy [Weeks 5-26]) were met by 16 patients (73%) on sutimlimab and three patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval 2.9, 88.0; P<0.001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by Week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at Week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment emergent adverse event. Headache, hypertension, rhinitis, Raynaud's phenomenon, and acrocyanosis were more frequent with sutimlimab versus placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued due to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. (ClinicalTrials.gov: NCT03347422).

The purpose was to study self-reported chronic pain and fatigue symptoms among adults with molecularly verified Loeys-Dietz and vascular Ehlers-Danlos syndrome using a cross-sectional questionnaire design. Seventy adults were invited through a National Resource Centre for Rare Disorders. A study specific questionnaire including Brief Pain Inventory, Standardized Nordic Questionnaire, Fatigue Severity Scale, Hospital Anxiety & Depression Scale, questions on physical activity, and disease burden was used. Fifty-two persons participated, n = 34 with Loeys-Dietz and n = 18 with vascular Ehlers-Danlos syndrome, aged 18-68 years, 58% women. Chronic pain (79%) and fatigue (58%) symptoms were common. Half developed pain during childhood/adolescence. Sleep problems and high multi-organ burden were significantly associated with chronic pain (p = 0.004, p = 0.014) and high fatigue (p < 0.001, p < 0.001). Chronic pain was associated with higher scores of fatigue (p = 0.002). Higher scores of fatigue were associated with lower level of physical activity (p = 0.014), higher cardiovascular burden (p = 0.025), and higher symptoms of anxiety (p = 0.001). In this study, symptoms of chronic pain, fatigue, sleep problems, and disease burden seemed to mutually reinforce each other. Initiatives should consider interventions aimed at postponing the onset and reducing symptoms of pain, fatigue, and sleep problems and thus reduce the total disease burden at an early stage in patients with these complex conditions.

The selection of a control group should foremost be determined by the study's primary intended outcome and trial design. When examining the effects of the physical movements that comprise yoga postures, an active control group, with physical exercise as the control, is often recommended.

To define the instruments for the Assessment of SpondyloArthritis international Society-Outcomes Measures in Rheumatology (ASAS-OMERACT) core domain set for axial spondyloarthritis (axSpA).

Following concussion, symptoms such as headache, dizziness, and fatigue may transiently worsen or reemerge with increased exertion or activity. Standardized tests have been developed to assess symptom increases following aerobic, cognitive, or vestibular/oculomotor challenge. Although neurophysiological mechanisms are proposed to underlie symptom increases following exertion, psychological factors such as anxiety and misinterpretation of normal bodily sensations may also play a role. In this study, we examined the contribution of psychological factors to symptom provocation testing outcomes.

We report a case of a preschool age girl, previously healthy, referred to our hospital on ventilatory support with a history of vomiting, headache, and rapid neurological worsening within 24 hours in the form of seizures, encephalopathy and loss of consciousness. On presentation, she was deeply comatose with dilated non-reactive pupils, absent brainstem reflexes and flaccid quadriplegia. Diagnosis of acute haemorrhagic leukoencephalitis was considered based on laboratory and neuroimaging findings. MRI of the brain showed fluffy white matter hyperintensities and microhaemorrhages in bilateral cerebral hemispheres and thalami. Aggressive treatment with methylprednisolone, plasmapheresis and intravenous immunoglobulin showed dramatic improvement with no neurological sequelae. Our case is unique in a way that despite the hyperacute onset and rapid deterioration, with a fulminant course in the intensive care unit, the child recovered dramatically with aggressive management.

We developed a novel lentiviral vector, pseudotyped with the F and HN proteins from Sendai virus (rSIV.F/HN), that produces long-lasting, high-efficiency transduction of the respiratory epithelium. Here we addressed whether this platform technology can secrete sufficient levels of a therapeutic protein into the lungs to ameliorate a fatal pulmonary disease as an example of its translational capability. Pulmonary alveolar proteinosis (PAP) results from alveolar granulocyte-macrophage colony-stimulating factor (GM-CSF) insufficiency, resulting in abnormal surfactant homeostasis and consequent ventilatory problems. Lungs of GM-CSF knockout mice were transduced with a single dose of rSIV.F/HN-expressing murine GM-CSF (mGM-CSF; 1e5-92e7 transduction units [TU]/mouse); mGM-CSF expression was dose related and persisted for at least 11 months. PAP disease biomarkers were rapidly and persistently corrected, but we noted a narrow toxicity/efficacy window. rSIV.F/HN may be a useful platform technology to deliver therapeutic proteins for lung diseases requiring long-lasting and stable expression of secreted proteins.

Chronic, non-cancer pain impacts approximately 50 million adults in the USA (20%), approximately 25% of whom receive chronic prescription opioids for pain despite limited empirical efficacy data and strong dose-related risk for opioid use disorder and opioid overdose. Also despite lack of efficacy data, there are many reports of people using cannabis products to manage chronic pain and replace or reduce chronic opioids. Here we describe the protocol for a randomised trial of the effect of cannabis, when added to a behavioural pain management and prescription opioid taper support programme, on opioid utilisation, pain intensity and pain interference.

 The aim of this study was to evaluate factors contributing to the need for non-elective explant following surgical repair of tibial tuberosity avulsion fractures.

: To investigate whether published systematic reviews of randomized controlled trials provide sufficient clarity to inform prescribing of cannabinoid products aimed for medicinal use, we examined their features and findings in two well-researched areas: chronic cancer/noncancer pain and multiple sclerosis (MS)-related symptoms.