Inotersen (TEGSEDI™) is a 2′-O-(2-methoxyethyl)-modified antisense oligonucleotide, intended for treating hereditary transthyretin (TTR) amyloidosis with polyneuropathy. The potential immunogenicity (IM) response to inotersen was evaluated in chronic nonclinical safety studies and the pivotal phase 2/3 clinical study. The evaluation was designed to assess the characteristics of antidrug antibodies (ADAs) and their effects on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety in animals and humans. No immunogenic response was observed after long-term treatment with inotersen in mice. In monkeys, the incidence rate of IM to inotersen appeared to be dose dependent, with 28.6%-50.0% of animals developing ADAs after 36 weeks of treatment. This was characterized as late onset (median onset of 185 days) with low titers (median titer of 8, or 400 if minimum required dilution of 50 is included). The overall incidence rate of patients who developed ADAs was 30% after 65 weeks of treatment with median onset of 203 days and median peak titer of 300. IM had minimal effect on plasma peak (Cmax) and total exposure (i.e. area under curve, AUC) of inotersen, but showed elevated plasma trough levels in both IM-positive animals and humans. However, ADAs had no effect on tissue exposure, TTR messenger RNA, or plasma TTR levels in the long-term monkey study. Similarly, IM showed no effect on plasma TTR levels in clinical studies. Thus, ADAs antibodies were binding antibodies, but not neutralizing antibodies. Finally, no association was observed between IM and toxicity findings (eg, platelet, complement activation, and histopathology findings) in the inotersen 9-month monkey study. In humans, no difference was observed in hematology, including platelets, kidney function tests, or incidence of adverse events between IM-positive and -negative patients. Overall, IM showed no effect on toxicity or safety of inotersen evaluated in both monkeys and humans. ClinicalTrials.gov Identifier NCT01737398.Impaired mobility is common in people with multiple sclerosis (MS). Changes in gait have different causes and require individualised gait rehabilitation. A common and often early cause of mobility impairment is footdrop, inability to lift the foot during the swing phase of gait, with increased risk of falls, effortful walking and fatigue. Using literature review, we have characterised published data on footdrop treatment in MS, specifically functional electrical stimulation (FES) to better understand the reported outcomes relevant to the user. We discuss the strengths and weaknesses of FES and how far it meets the needs of people with footdrop. Physiotherapy combined with FES may further enhance the benefits of FES. MS studies emphasise the value of maintaining activity levels in early MS but discussion on how to achieve this is lacking. We emphasise the value of qualitative measures to broaden our understanding and improve treatment and adherence and identify areas for further research. Supplementary video material illustrates key features of MS gait and its correction using FES and physiotherapy.Background Obesity causes significant morbidity and mortality and continues to be a significant public health concern. Unfortunately, lifestyle modification and pharmacotherapy do not produce durable results. This has led to bariatric surgical procedures playing an increasingly prominent role in the management of medically complicated obesity. Roux-en-Y gastric bypass and sleeve gastrectomy are the most commonly performed bariatric surgeries in North America and produce mechanical restriction with accelerated gastrointestinal transit accompanied by increased postprandial secretion of glucagon-like peptide-1 (GLP-1). GLP-1 is a gastrointestinal hormone that delays gastric emptying and causes satiety and weight loss. This raises the possibility that the postprandial rise in GLP-1 might affect feeding behavior over and above the mechanical restriction produced by bariatric surgery. Omecamtiv mecarbil supplier Methods We, therefore, sought to determine the effects of GLP-1 receptor blockade using exendin-9,39-a competitive antagonist of the actions of GLP-1 at its receptor-on caloric intake and gastrointestinal transit in subjects after sleeve gastrectomy and after Roux-en-Y gastric bypass compared with weight-matched controls. Results GLP-1 receptor blockade did not alter caloric intake in people after bariatric surgery. However, caloric intake was decreased in age-, weight- and sex-matched control subjects, and the mechanisms require further study. Conclusions Given the known effects of GLP-1 on gastric accommodation, future studies should ascertain effects of GLP-1 receptor blockade on gastric accommodation, which might be a useful and novel strategy to decrease caloric intake in humans with an intact upper gastrointestinal tract. The Clinical Trial Resigtration number is NCT02779075.Endometriosis was induced (autotransplant) in Wistar rats. After 21 days, the rats were randomly divided into two groups (16 female rats each). Control group was forced-fed 0.9% sodium chloride solution, and the ginger group was forced-fed 0.5 mg/100 g of Zingiber officinale Roscoe fresh extract, both by gavage, for 14 days, in addition to their normal diet. After that, an anesthetic dose (ketamine/xylazine) was administered until euthanasia. Peritoneal lavage fluid was collected to evaluate tumor necrosis factor (TNF)-α and interleukin (IL)-6, and autotransplant was measured and excised to evaluate histology. The final mean volumes were larger in the control group (120.92 mm3 ± 78.91) than in the ginger group (40.50 mm3 ± 19.57) (P = .01). The endometriosis foci increased in the control group from 45.10 mm3 ± 29.96 at 21 days postimplantation to 120.92 mm3 ± 78.91 on the day of euthanasia (P = .02). In the ginger group, a slight increase was observed from 38.43 mm3 ± 19.96 to 40.50 mm3 ± 19.57, without statistical difference (P = .83). In addition, a greater increase in growth of the endometriosis foci was found when compared with the control (75.81 mm3 ± 58.95) and ginger groups (2.07 mm3 ± 18.87) (P = .004). No difference was found in TNF-α (P = .51) and in IL-6 (P = .12). The degree of lesion atrophy was higher in the ginger group (1 ± 0.92) than in the control group (2.25 ± 1.16) (P = .03). The ginger extract reduced and atrophied autotransplanted endometriosis foci, but did not reduce IL-6 and TNF-α in the peritoneal lavage fluid.