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Supplemental Digital Content is Available in the Text. Human sodium channel NaV1.7 in induced pluripotent stem cell–derived sensory neurons sets the action potential threshold but does not support subthreshold depolarizations., The chronic pain syndrome inherited erythromelalgia (IEM) is attributed to mutations in the voltage-gated sodium channel (NaV) 1.7. Still, recent studies targeting NaV1.7 in clinical trials have provided conflicting results. Here, we differentiated induced pluripotent stem cells from IEM patients with the NaV1.7/I848T mutation into sensory nociceptors. Action potentials in these IEM nociceptors displayed a decreased firing threshold, an enhanced upstroke, and afterhyperpolarization, all of which may explain the increased pain experienced by patients. Subsequently, we investigated the voltage dependence of the tetrodotoxin-sensitive NaV activation in these human sensory neurons using a specific prepulse voltage protocol. The IEM mutation induced a hyperpolarizing shift of NaV activation, which leads to activation of NaV1.7 at more negative potentials. Our results indicate that NaV1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes significantly to the action potential upstroke. Thus, our model system with induced pluripotent stem cell–derived sensory neurons provides a new rationale for NaV1.7 function and promises to be valuable as a translational tool to profile and develop more efficacious clinical analgesics.

Background; The prevalence of pain is very common in the oldest age group. Managing pain successfully is a key topic in primary care, especially within the ageing population. Different care settings might have an impact on the prevalence of pain and everyday life. Methods: Participants from the German longitudinal cohort study on Needs, Health Service Use, Costs and Health-related Quality of Life in a large Sample of Oldest-old Primary Care Patients (85+) (AgeQualiDe) were asked to rate their severity of pain as well as the impairment with daily activities. Besides gender, age, education, BMI and use of analgesics we focused on the current housing situation and on cognitive state. Associations of the dependent measures were tested using four ordinal logistic regression models. Model 1 and 4 consisted of the overall sample, model 2 and 3 were divided according to no cognitive impairment (NCI) and mild cognitive impairment (MCI). Results: Results show a decline in pain at very old age but nonetheless a high prevalence among the 85+ year olds. Sixty-three per cent of the participants report mild to severe pain and 69% of the participants mild to extreme impairment due to pain with daily activities. Use of analgesics, depression and living at home with care support are significantly associated with higher and male gender with lower pain ratings. Conclusions: Sufficient pain management among the oldest age group is inevitable. Outpatient care settings are at risk of overlooking pain. Therefore focus should be set on pain management in these settings.

Background Musculoskeletal complaints are frequent and have large consequences for public health. Information about the prognosis after presentation in general practice is far from complete. Knowledge about determinants of the clinical course of musculoskeletal complaints is essential for management decisions and to inform patients about their prognosis. The purpose of this study is to provide information about the prognosis of musculoskeletal complaints other than low back pain by studying the course of these complaints in general practice and to identify determinants of this course. Methods Patients of 18 years and older, who present in general practice with a new episode of a musculoskeletal complaint of the neck, shoulder, elbow, wrist, hand, arm, hip, knee, ankle or foot, are recruited by their general practitioner (GP). Participants will receive complaint-specific questionnaires by mail at baseline and after 3, 6, 12 and 18 months. The following putative determinants of the course of the complaints will be investigated: sociodemographic characteristics, characteristics of the complaint, psychosocial job characteristics, physical workload, physical activity during leisure time, pain coping, mood, kinesiophobia, social support, optimism. The primary outcomes are perceived recovery, pain, functional status, sick leave and overall quality of life.