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Retinoic acid receptor β2 (RARβ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARβ agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve-injured rats. We also found that other clinically available retinoids, that are not RARβ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARβ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARβ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions.

The world-wide prevalence of myopia (nearsightedness) is increasing, but its pathogenesis is incompletely understood. Among many putative mechanisms, laboratory and clinical findings have implicated circadian biology in the etiology of myopia. Consistent with a circadian hypothesis, we recently reported a marked variability in diurnal patterns of gene expression in two crucial tissues controlling post-natal refractive development - the retina and choroid-at the onset of form-deprivation myopia in chick, a widely studied and validated model. To extend these observations, we assayed gene expression by RNA-Seq in retina and choroid during the progression of established unilateral form-deprivation myopia of chick. We assayed gene expression every 4 hours during a single day from myopic and contralateral control eyes. Retinal and choroidal gene expression in myopic vs. control eyes during myopia progression differed strikingly at discrete times during the day. Very few differentially expressed genes occurred at more than one time in either tissue during progressing myopia. Similarly, Gene Set Enrichment Analysis pathways varied markedly by time during the day. Some of the differentially expressed genes in progressing myopia coincided with candidate genes for human myopia, but only partially corresponded with genes previously identified at myopia onset. Considering other laboratory findings and human genetics and epidemiology, these results further link circadian biology to the pathogenesis of myopia; but they also point to important mechanistic differences between the onset of myopia and the progression of established myopia. Future laboratory and clinical investigations should systematically incorporate circadian mechanisms in studying the etiology of myopia and in seeking more effective treatments to normalize eye growth in children.

Abstract Background The functional referral system is important in backing-up antenatal, labour and delivery, and postnatal services in the primary level of care facilities. The aim of this study was to evaluate the effectiveness of the maternal referral system through determining proportion of women reaching the hospitals after referral advice, appropriateness of the referral indications, reasons for non-compliance and to find out if compliance to referrals makes a difference in the perinatal outcome. Methods A follow-up study was conducted in Rufiji rural district in Tanzania. A total of 1538 women referred from 18 primary level of care facilities during a 13 months period were registered and then identified at hospitals. Those not reaching the hospitals were traced and interviewed. Results Out of 1538 women referred 70% were referred for demographic risks, 12% for obstetric historical risks, 12% for prenatal complications and 5.5% for natal and immediate postnatal complications. Five or more pregnancies as well as age Conclusion Majority of the maternal referrals were due to demographic risks, where few women complied. To improve compliance to maternal referrals there is need to review the referral indications and strengthen counseling on birth preparedness and complication readiness.

Abstract Background The high rate of antenatal care attendance in sub-Saharan Africa, should facilitate provision of information on signs of potential pregnancy complications. The aim of this study was to assess quality of antenatal care with respect to providers' counselling of pregnancy danger signs in Rufiji district, Tanzania. Methods A cross-sectional study was conducted in 18 primary health facilities. Thirty two providers were observed providing antenatal care to 438 pregnant women. Information on counselling on pregnancy danger signs was collected by an observer. Exit interviews were conducted to 435 women. Results One hundred and eighty five (42%) clients were not informed of any pregnancy danger signs. The most common pregnancy danger sign informed on was vaginal bleeding 50% followed by severe headache/blurred vision 45%. Nurse auxiliaries were three times more likely to inform a client of a danger sign than registered/enrolled nurses (OR = 3.7; 95% CI: 2.1-6.5) and Maternal Child Health Aides (OR = 2.3: 95% CI: 1.3-4.3) and public health nurses (OR = 2.5; CI: 1.4-4.2) were two times more likely to provide information on danger signs than registered/enrolled nurses. The clients recalled less than half of the pregnancy danger signs they had been informed during the interaction. Conclusion Two out of five clients were not counselled on pregnancy danger signs. The higher trained cadre, registered/enrolled nurses were not informing majority of clients pregnancy danger signs compared to the lower cadres. Supportive supervision should be made to enhance counselling of pregnancy danger signs. Nurse auxiliaries should be encouraged and given chance for further training and upgrading to improve their performance and increase human resource for health.

Abstract Background Awareness of the danger signs of obstetric complications is the essential first step in accepting appropriate and timely referral to obstetric and newborn care. The objectives of this study were to assess women's awareness of danger signs of obstetric complications and to identify associated factors in a rural district in Tanzania. Methods A total of 1118 women who had been pregnant in the past two years were interviewed. A list of medically recognized potentially life threatening obstetric signs was obtained from the responses given. Chi- square test was used to determine associations between categorical variables and multivariate logistic regression analysis was used to identify factors associated with awareness of obstetric danger signs. Results More than 98% of the women attended antenatal care at least once. Half of the women knew at least one obstetric danger sign. The percentage of women who knew at least one danger sign during pregnancy was 26%, during delivery 23% and after delivery 40%. Few women knew three or more danger signs. According to multivariate logistic regression analysis having secondary education or more increased the likelihood of awareness of obstetric danger signs six-fold (OR = 5.8; 95% CI: 1.8–19) in comparison with no education at all. The likelihood to have more awareness increased significantly by increasing age of the mother, number of deliveries, number of antenatal visits, whether the delivery took place at a health institution and whether the mother was informed of having a risks/complications during antenatal care. Conclusion Women had low awareness of danger signs of obstetric complications. We recommend the following in order to increase awareness of danger signs of obstetrical complications: to improve quality of counseling and involving other family members in antenatal and postnatal care, to use radio messages and educational sessions targeting the whole community and to intensify provision of formal education as emphasized in the second millennium development goal.

Multifunctional materials offer a possibility to create lighter and more resource‐efficient products and thereby improve energy efficiency. Structural battery composites are one type of such a multifunctional material with potential to offer massless energy storage for electric vehicles and aircraft. Although such materials have been demonstrated, their performance level and consistency must be improved. Also, the cell dimensions need to be increased. Herein, a robust manufacturing procedure is developed and structural battery composite cells are repeatedly manufactured with double the multifunctional performance and size compared to state‐of‐the‐art structural battery cells. Furthermore, six structural battery cells are selected and laminated into a structural battery composite multicell demonstrator to showcase the technology. The multicell demonstrator performance is characterized for two different electrical configurations. The low variability in the multifunctional properties of the cells verifies the potential for upscaling offered by the proposed manufacture technique.

Aging of the peripheral nervous system (PNS) is associated with structural and functional changes that lead to a reduction in regenerative capacity and the development of age-related peripheral neuropathy. Myelin is central to maintaining physiological peripheral nerve function and differences in myelin maintenance, degradation, formation and clearance have been suggested to contribute to age-related PNS changes. Recent proteomic studies have elucidated the complex composition of the total myelin proteome in health and its changes in neuropathy models. However, changes in the myelin proteome of peripheral nerves during aging have not been investigated. Here we show that the proteomes of myelin fractions isolated from young and old nerves show only subtle changes. In particular, we found that the three most abundant peripheral myelin proteins (MPZ, MBP, and PRX) do not change in old myelin fractions. We also show a tendency for high-abundance myelin proteins other than these three to be downregulated, with only a small number of ribosome-related proteins significantly downregulated and extracellular matrix proteins such as collagens upregulated. In addition, we illustrate that the peripheral nerve myelin proteome reported in this study is suitable for assessing myelin degradation and renewal during peripheral nerve degeneration and regeneration. Our results suggest that the peripheral nerve myelin proteome is relatively stable and undergoes only subtle changes in composition during mouse aging. We proffer the resultant dataset as a resource and starting point for future studies aimed at investigating peripheral nerve myelin during aging. Said datasets are available in the PRIDE archive under the identifier PXD040719 (aging myelin proteome) and PXD041026 (sciatic nerve injury proteome).

Abstract Objective To evaluate whether the presence of a certified therapy dog specially trained for working in a dental setting may facilitate dental care of anxious pediatric patients. Methods The Norwegian Regional Committee for Medical and Health Research Ethics approved a randomized cross‐over trial with a study sample of n = 16 children aged between 6 and 12 years. The trial was registered on clinicaltrials.gov. Pediatric patients referred to specialist care at the Public Dental Service Competence Center of Northern Norway (TkNN) because of anxiety were invited to partake in the trial. Study participants met twice for an intraoral examination by a specialist pediatric dentist. Per random allocation, a therapy dog team was present in the clinic operatory during the clinical examination on the first or the second visit. The primary outcome was the assessment of patient compliance during the intraoral examination (yes/no). Secondary outcomes were measurements of child satisfaction and anxiety using the CFSS‐DS scale (Dental subscale of Children's Fear Survey Schedule) completed by a parent/guardian. Supplementary outcomes were salivary cortisol level, heart rate variability, and skin conductance. Results Ten boys and six girls (mean age 8.5) were recruited. All completed both clinical visits and demonstrated full compliance while undergoing a dental examination. All study participants and guardians reported great satisfaction. The salivary cortisol level reduction during the clinical examination on the first visit decreased by 30% in the presence of the therapy dog and 20% without, while the decrease during the clinical examination on the second visit was 29% in the presence of the therapy dog and 3% without. Within the limitations of the experimental setup, the electrophysiological measurements were unreliable in the current study population. Conclusion Dog‐assisted therapy in a dental care setting appears to have a positive effect on children with dental anxiety or children that avoid dental care.

BackgroundNeurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas.MethodsMouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns.ResultsTrametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance.ConclusionMEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

Retinoic acid receptor B2 (RARẞ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARẞ agonist drug, C286, that modulates neuron- glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-a9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve- injured rats. We also found that other clinically available retinoids, that are not RARẞ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARẞ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARẞ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Aims Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and is an important risk factor for ischaemic stroke. Many cases of AF remain undiagnosed due to its paroxysmal, intermittent, and often asymptomatic nature. Early detection of AF through screening and initiation of treatment with oral anticoagulants can prevent stroke, increase life expectancy, and decrease the cost of healthcare for the society. However, participation has been low in previous AF screening studies employing population screening. The aim of this study is to determine whether opportunistic screening is a superior method to increase participation in comparison to population screening. We hypothesize that opportunistic screening will significantly increase participation. Methods and results In our study, STROKESTOP III, a randomized prospective cohort study, we compare two different methods of AF screening in high-risk individuals: population screening vs. opportunistic screening. Sixteen different primary clinics in Värmland, Sweden, serving 75–76-year-old individuals (n = 2954), will be randomized to either population screening or opportunistic screening. The individuals will be instructed to record electrocardiogram (ECG) for 30 s, 3 times daily for 2 weeks, using a handheld one-lead ECG device. Patients with detected AF will be referred to their primary healthcare physician and offered treatment. The main objective of the study is to determine the rate of participation in opportunistic screening in comparison to population screening. Conclusions The STROKESTOP III study will provide valuable information on which screening method to use for improved participation in atrial fibrillation screening. [ABSTRACT FROM AUTHOR]

The world-wide prevalence of myopia (nearsightedness) is increasing, but its pathogenesis is incompletely understood. Among many putative mechanisms, laboratory and clinical findings have implicated circadian biology in the etiology of myopia. Consistent with a circadian hypothesis, we recently reported a marked variability in diurnal patterns of gene expression in two crucial tissues controlling post-natal refractive development ‐ the retina and choroid–at the onset of form-deprivation myopia in chick, a widely studied and validated model. To extend these observations, we assayed gene expression by RNA-Seq in retina and choroid during the progression of established unilateral form-deprivation myopia of chick. We assayed gene expression every 4 hours during a single day from myopic and contralateral control eyes. Retinal and choroidal gene expression in myopic vs. control eyes during myopia progression differed strikingly at discrete times during the day. Very few differentially expressed genes occurred at more than one time in either tissue during progressing myopia. Similarly, Gene Set Enrichment Analysis pathways varied markedly by time during the day. Some of the differentially expressed genes in progressing myopia coincided with candidate genes for human myopia, but only partially corresponded with genes previously identified at myopia onset. Considering other laboratory findings and human genetics and epidemiology, these results further link circadian biology to the pathogenesis of myopia; but they also point to important mechanistic differences between the onset of myopia and the progression of established myopia. Future laboratory and clinical investigations should systematically incorporate circadian mechanisms in studying the etiology of myopia and in seeking more effective treatments to normalize eye growth in children. [ABSTRACT FROM AUTHOR]

Abstract Multifunctional materials facilitate lightweight and slender structural solutions for numerous applications. In transportation, construction materials that can act as a battery, and store electrical energy, will contribute to realization of highly energy efficient vehicles and aircraft. Herein, a multicell structural battery composite laminate, with three state‐of‐the‐art structural battery composite cells connected in series is demonstrated. The experimental results show that the capacity of the structural battery composite cells is only moderately affected by tensile loading up to 0.36% strain. The multicell structural battery laminate is made embedding the three connected structural battery composite cells between carbon fiber/glass fiber composite face sheets. Electrochemical performance of the multicell structural battery is demonstrated experimentally. High charge transfer resistance for the pack as well as the individual cells is reported. Mechanical performance of the structural battery laminate is estimated by classical laminate theory. Computed engineering in‐plane moduli for the multicell structural battery laminate are on par with conventional glass fiber composite multiaxial laminates.

Engineering materials that can store electrical energy in structural load paths can revolutionize lightweight design across transport modes. Stiff and strong batteries that use solid‐state electrolytes and resilient electrodes and separators are generally lacking. Herein, a structural battery composite with unprecedented multifunctional performance is demonstrated, featuring an energy density of 24 Wh kg−1 and an elastic modulus of 25 GPa and tensile strength exceeding 300 MPa. The structural battery is made from multifunctional constituents, where reinforcing carbon fibers (CFs) act as electrode and current collector. A structural electrolyte is used for load transfer and ion transport and a glass fiber fabric separates the CF electrode from an aluminum foil‐supported lithium–iron–phosphate positive electrode. Equipped with these materials, lighter electrical cars, aircraft, and consumer goods can be pursued.