In vitro modelling of human proprioceptive sensory neurons in the neuromuscular system.

Proprioceptive sensory neurons (pSN) are an essential and undervalued part of the neuromuscular circuit. A protocol to differentiate healthy and amyotrophic lateral sclerosis (ALS) human neural stem cells (hNSC) into pSN, and their comparison with the motor neuron (MN) differentiation process from the same hNSC sources, facilitated the development of in vitro co-culture platforms. The obtained pSN spheroids cultured interact with human skeletal myocytes showing the formation of annulospiral wrapping-like structures between TrkC + neurons and a multinucleated muscle fibre, presenting synaptic bouton-like structures in the contact point. The comparative analysis of the genetic profile performed in healthy and sporadic ALS hNSC differentiated to pSN suggested that basal levels of ETV1, critical for motor feedback from pSN, were much lower for ALS samples and that the differences between healthy and ALS samples, suggest the involvement of pSN in ALS pathology development and progression.

Rapid Manufacturing of Multilayered Microfluidic Devices for Organ on a Chip Applications.

Microfabrication and Polydimethylsiloxane (PDMS) soft-lithography techniques became popular for microfluidic prototyping at the lab, but even after protocol optimization, fabrication is yet a long, laborious process and partly user-dependent. Furthermore, the time and money required for the master fabrication process, necessary at any design upgrade, is still elevated. Digital Manufacturing (DM) and Rapid-Prototyping (RP) for microfluidics applications arise as a solution to this and other limitations of photo and soft-lithography fabrication techniques. Particularly for this paper, we will focus on the use of subtractive DM techniques for Organ-on-a-Chip (OoC) applications. Main available thermoplastics for microfluidics are suggested as material choices for device fabrication. The aim of this review is to explore DM and RP technologies for fabrication of an OoC with an embedded membrane after the evaluation of the main limitations of PDMS soft-lithography strategy. Different material options are also reviewed, as well as various bonding strategies. Finally, a new functional OoC device is showed, defining protocols for its fabrication in Cyclic Olefin Polymer (COP) using two different RP technologies. Different cells are seeded in both sides of the membrane as a proof of concept to test the optical and fluidic properties of the device.

Neuromuscular Activity Induces Paracrine Signaling and Triggers Axonal Regrowth after Injury in Microfluidic Lab-On-Chip Devices.

Peripheral nerve injuries, including motor neuron axonal injury, often lead to functional impairments. Current therapies are mostly limited to surgical intervention after lesion, yet these interventions have limited success in restoring functionality. Current activity-based therapies after axonal injuries are based on trial-error approaches in which the details of the underlying cellular and molecular processes are largely unknown. Here we show the effects of the modulation of both neuronal and muscular activity with optogenetic approaches to assess the regenerative capacity of cultured motor neuron (MN) after lesion in a compartmentalized microfluidic-assisted axotomy device. With increased neuronal activity, we observed an increase in the ratio of regrowing axons after injury in our peripheral-injury model. Moreover, increasing muscular activity induces the liberation of leukemia inhibitory factor and glial cell line-derived neurotrophic factor in a paracrine fashion that in turn triggers axonal regrowth of lesioned MN in our 3D hydrogel cultures. The relevance of our findings as well as the novel approaches used in this study could be useful not only after axotomy events but also in diseases affecting MN survival.

Dementia-related neuropsychiatric symptoms: inequalities in pharmacological treatment and institutionalization.

BACKGROUND: Dementia-related neuropsychiatric symptoms (NPS) are the main determinant of family stress and institutionalization of patients. This study aimed to identify inequalities by gender and socioeconomic status in the management of NPS in patients diagnosed with dementia. METHODS: An observational study was carried out to study all the cases of dementia in the corporate database of the Basque Health Service (29,864 patients). The prescription of antipsychotics and antidepressants and admission to a nursing home were used to establish the presence of NPS. The socioeconomic status of individuals was classified by a deprivation index. Logistic regressions were used to identify drivers for drug prescriptions and institutionalization. RESULTS: NPS are poorly recorded in the clinical databases (12%). Neuropsychiatric symptoms were severe enough in two thirds of patients with dementia to be treated with psychoactive medication. Institutionalization showed an increase from those who did not receive medication to those who had been prescribed antidepressants (OR: 1.546), antipsychotics (OR: 2.075) or both (OR: 2.741). The resulting inequalities were the increased prescription of antidepressant drugs in women and more nursing-home admissions for women who were the least socioeconomically deprived and men who were the most deprived. CONCLUSIONS: In large clinical databases, psychoactive drugs prescriptions can be useful to underscore the considerable burden of dementia-related NPS. Specific tools are needed to monitor social and health care programs targeted to dementia-related NPS from a population perspective. Programs aimed at reducing the family burden of care of dementia patients at home become the key elements in reducing inequalities in these patients' care. Socioeconomic status is the most important driver of inequality, and gender inequality may simply be hidden within the social environment. Integrated programs boosting the continuity of care are an objective for which compliance could be measured according to the NPS coding in the electronic health record.

Challenges and Future Prospects on 3D in-vitro Modeling of the Neuromuscular Circuit.

Movement of skeletal-muscle fibers is generated by the coordinated action of several cells taking part within the locomotion circuit (motoneurons, sensory-neurons, Schwann cells, astrocytes, microglia, and muscle-cells). Failures in any part of this circuit could impede or hinder coordinated muscle movement and cause a neuromuscular disease (NMD) or determine its severity. Studying fragments of the circuit cannot provide a comprehensive and complete view of the pathological process. We trace the historic developments of studies focused on in-vitro modeling of the spinal-locomotion circuit and how bioengineered innovative technologies show advantages for an accurate mimicking of physiological conditions of spinal-locomotion circuit. New developments on compartmentalized microfluidic culture systems (cµFCS), the use of human induced pluripotent stem cells (hiPSCs) and 3D cell-cultures are analyzed. We finally address limitations of current study models and three main challenges on neuromuscular studies: (i) mimic the whole spinal-locomotion circuit including all cell-types involved and the evaluation of independent and interdependent roles of each one; (ii) mimic the neurodegenerative response of mature neurons in-vitro as it occurs in-vivo; and (iii) develop, tune, implement, and combine cµFCS, hiPSC, and 3D-culture technologies to ultimately create patient-specific complete, translational, and reliable NMD in-vitro model. Overcoming these challenges would significantly facilitate understanding the events taking place in NMDs and accelerate the process of finding new therapies.

Telemonitoring in-home complex chronic patients from primary care in routine clinical practice: Impact on healthcare resources use.

BACKGROUND: Recent evidence indicates that home telemonitoring of chronic patients reduces the use of healthcare resources. However, further studies exploring this issue are needed in primary care. OBJECTIVES: To assess the impact of a primary care-based home telemonitoring intervention for highly unstable chronic patients on the use of healthcare resources. METHODS: A one-year follow-up before and after exploratory study, without control group, was conducted. Housebound patients with heart failure or chronic lung disease, with recurrent hospital admissions, were included. The intervention consisted of patient's self-measurements and responses to a health status questionnaire, sent daily from smartphones to a web-platform (aided by an alert system) reviewed by healthcare professionals. The primary outcome measure was the number of hospital admissions occurring 12 months before and after the intervention. Secondary outcomes were length of hospital stay and number of emergency department attendances. Primary care nurses were mainly in charge of the telemonitoring process and were assisted by the general practitioners when required. RESULTS: For the 28 patients who completed the follow-up (out of 42 included, 13 patients died and 1 discontinued the intervention), a significant reduction in hospitalizations, from 2.6 admissions/patient in the previous year (standard deviation, SD: 1.6) to 1.1 (SD: 1.5) during the one-year telemonitoring follow-up (P <0.001), and emergency department attendances, from 4.2 (SD: 2.6) to 2.1 (SD: 2.6) (P <0.001) was observed. The length of hospital stay was reduced non-significantly from 11.4 to 7.9 days. CONCLUSION: In this small exploratory study, the primary care-based telemonitoring intervention seemed to have a positive impact decreasing the number of hospital admissions and emergency department attendances.

Online training course on critical appraisal for nurses: adaptation and assessment.

BACKGROUND: Research is an essential activity for improving quality and efficiency in healthcare. The objective of this study was to train nurses from the public Basque Health Service (Osakidetza) in critical appraisal, promoting continuous training and the use of research in clinical practice. METHODS: This was a prospective pre-post test study. The InfoCritique course on critical appraisal was translated and adapted. A sample of 50 nurses and 3 tutors was recruited. Educational strategies and assessment instruments were established for the course. A course website was created that contained contact details of the teaching team and coordinator, as well as a course handbook and videos introducing the course. Assessment comprised the administration of questionnaires before and after the course, in order to explore the main intervention outcomes: knowledge acquired and self-learning readiness. Satisfaction was also measured at the end of the course. RESULTS: Of the 50 health professionals recruited, 3 did not complete the course for personal or work-related reasons. The mean score on the pre-course knowledge questionnaire was 70.5 out of 100, with a standard deviation of 11.96. In general, participants' performance on the knowledge questionnaire improved after the course, as reflected in the notable increase of the mean score, to 86.6, with a standard deviation of 10.00. Further, analyses confirmed statistically significant differences between pre- and post-course results (p < 0.001). With regard to self-learning readiness, after the course, participants reported a greater readiness and ability for self-directed learning. Lastly, in terms of level of satisfaction with the course, the mean score was 7 out of 10. CONCLUSIONS: Participants significantly improved their knowledge score and self-directed learning readiness after the educational intervention, and they were overall satisfied with the course. For the health system and nursing professionals, this type of course has the potential to provide methodological tools for research, promote a research culture, and encourage critical thinking for evidence-based decision making.

Predictive risk modelling in the Spanish population: a cross-sectional study.

BACKGROUND: An increase in chronic conditions is currently the greatest threat to human health and to the sustainability of health systems. Risk adjustment systems may enable population stratification programmes to be developed and become instrumental in implementing new models of care.The objectives of this study are to evaluate the capability of ACG-PM, DCG-HCC and CRG-based models to predict healthcare costs and identify patients that will be high consumers and to analyse changes to predictive capacity when socio-economic variables are added. METHODS: This cross-sectional study used data of all Basque Country citizens over 14 years of age (n = 1,964,337) collected in a period of 2 years. Data from the first 12 months (age, sex, area deprivation index, diagnoses, procedures, prescriptions and previous cost) were used to construct the explanatory variables. The ability of models to predict healthcare costs in the following 12 months was assessed using the coefficient of determination and to identify the patients with highest costs by means of receiver operating characteristic (ROC) curve analysis. RESULTS: The coefficients of determination ranged from 0.18 to 0.21 for diagnosis-based models, 0.17-0.18 for prescription-based and 0.21-0.24 for the combination of both. The observed area under the ROC curve was 0.78-0.86 (identifying patients with a cost higher than P-95) and 0.83-0.90 (P-99). The values of the DCG-HCC models are slightly higher and those of the CRG models are lower, although prescription information could not be used in the latter. On adding previous cost data, differences between the three systems decrease appreciably. Inclusion of the deprivation index led to only marginal improvements in explanatory power. CONCLUSION: The case-mix systems developed in the USA can be useful in a publicly financed healthcare system with universal coverage to identify people at risk of high health resource consumption and whose situation is potentially preventable through proactive interventions.

Monitoring the prevalence of chronic conditions: which data should we use?

BACKGROUND: Chronic diseases are an increasing threat to people's health and to the sustainability of health organisations. Despite the need for routine monitoring systems to assess the impact of chronicity in the population and its evolution over time, currently no single source of information has been identified as suitable for this purpose. Our objective was to describe the prevalence of various chronic conditions estimated using routine data recorded by health professionals: diagnoses on hospital discharge abstracts, and primary care prescriptions and diagnoses. METHODS: The ICD-9-CM codes for diagnoses and Anatomical Therapeutic Chemical (ATC) codes for prescriptions were collected for all patients in the Basque Country over 14 years of age (n=1,964,337) for a 12-month period. We employed a range of different inputs: hospital diagnoses, primary care diagnoses, primary care prescriptions and combinations thereof. Data were collapsed into the morbidity groups specified by the Johns Hopkins Adjusted Clinical Groups (ACGs) Case-Mix System. We estimated the prevalence of 12 chronic conditions, comparing the results obtained using the different data sources with each other and also with those of the Basque Health Interview Survey (ESCAV). Using the different combinations of inputs, Standardized Morbidity Ratios (SMRs) for the considered diseases were calculated for the list of patients of each general practitioner. The variances of the SMRs were used as a measure of the dispersion of the data and were compared using the Brown-Forsythe test. RESULTS: The prevalences calculated using prescription data were higher than those obtained from diagnoses and those from the ESCAV, with two exceptions: malignant neoplasm and migraine. The variances of the SMRs obtained from the combination of all the data sources (hospital diagnoses, and primary care prescriptions and diagnoses) were significantly lower than those using only diagnoses. CONCLUSIONS: The estimated prevalence of chronic diseases varies considerably depending of the source(s) of information used. Given that administrative databases compile data registered for other purposes, the estimations obtained must be considered with caution. In a context of increasingly widespread computerisation of patient medical records, the complementary use of a range of sources may be a feasible option for the routine monitoring of the prevalence of chronic diseases.

An answer to chronicity in the Basque Country: primary care-based population health management.

Chronic conditions have an impact on individuals since they represent a restraint on quality of life, functional status, and productivity of people who suffer from them but they also compromise the sustainability of health systems. In 2010, the Strategy for Tackling the Challenge of Chronicity in the Basque Country was published. It contains policies and projects aimed at reinventing the health delivery model with the purpose of improving the quality of care for chronic patients and advancing toward a more sustainable, proactive, and integrated model. We present 3 projects here: population stratification, integrated care initiatives, and innovation from health care staff.