Bioprinted Schwann and Mesenchymal Stem Cell Co-Cultures for Enhanced Spatial Control of Neurite Outgrowth.

Bioprinting nerve conduits supplemented with glial or stem cells is a promising approach to promote axonal regeneration in the injured nervous system. In this study, we examined the effects of different compositions of bioprinted fibrin hydrogels supplemented with Schwann cells and mesenchymal stem cells (MSCs) on cell viability, production of neurotrophic factors, and neurite outgrowth from adult sensory neurons. To reduce cell damage during bioprinting, we analyzed and optimized the shear stress magnitude and exposure time. The results demonstrated that fibrin hydrogel made from 9 mg/mL of fibrinogen and 50IE/mL of thrombin maintained the gel's highest stability and cell viability. Gene transcription levels for neurotrophic factors were significantly higher in cultures containing Schwann cells. However, the amount of the secreted neurotrophic factors was similar in all co-cultures with the different ratios of Schwann cells and MSCs. By testing various co-culture combinations, we found that the number of Schwann cells can feasibly be reduced by half and still stimulate guided neurite outgrowth in a 3D-printed fibrin matrix. This study demonstrates that bioprinting can be used to develop nerve conduits with optimized cell compositions to guide axonal regeneration.

Structural changes in hand related cortical areas after median nerve injury and repair.

Transection of the median nerve typically causes lifelong restriction of fine sensory and motor skills of the affected hand despite the best available surgical treatment. Inspired by recent findings on activity-dependent structural plasticity of the adult brain, we used voxel-based morphometry to analyze the brains of 16 right-handed adults who more than two years earlier had suffered injury to the left or right median nerve followed by microsurgical repair. Healthy individuals served as matched controls. Irrespective of side of injury, we observed gray matter reductions in left ventral and right dorsal premotor cortex, and white matter reductions in commissural pathways interconnecting those motor areas. Only left-side injured participants showed gray matter reduction in the hand area of the contralesional primary motor cortex. We interpret these effects as structural manifestations of reduced neural processing linked to restrictions in the diversity of the natural manual dexterity repertoire. Furthermore, irrespective of side of injury, we observed gray matter increases bilaterally in a motion-processing visual area. We interpret this finding as a consequence of increased neural processing linked to greater dependence on vision for control of manual dexterity after median nerve injury because of a compromised somatosensory innervation of the affected hand.

Questionnaire about the adverse events and side effects following botulinum toxin A treatment in patients with cerebral palsy.

Botulinum toxin A (BoNT-A) injections for treatment of spasticity in patients with cerebral palsy (CP) have been used for about two decades. The treatment is considered safe but a low frequency of adverse events (AE) has been reported. A good method to report AEs is necessary to verify the safety of the treatment. We decided to use an active surveillance of treatment-induced harm using a questionnaire we created. We studied the incidence of reported AEs and side effects in patients with CP treated with BoNT-A. We investigated the relationship between the incidence of AEs or side effects and gender, age, weight, total dose, dose per body weight, Gross Motor Function Classification System (GMFCS) and number of treated body parts. Seventy-four patients with CP participated in our study. In 54 (51%) of 105 BoNT-A treatments performed in 45 (61%) patients, there were 95 AEs and side effects reported, out of which 50 were generalized and/or focal distant. Severe AEs occurred in three patients (4%), and their BoNT-A treatment was discontinued. Consecutive collection of the AE and side-effect incidence using our questionnaire can increase the safety of BoNT-A treatment in patients with CP.

Sensory neuron death after upper limb nerve injury and protective effect of repair: clinical evaluation using volumetric magnetic resonance imaging of dorsal root Ganglia.

BACKGROUND: Extensive death of sensory neurons after nerve trauma depletes the number of regenerating neurons, contributing to inadequate cutaneous innervation density and poor sensory recovery. Experimentally proven neuroprotective neoadjuvant drugs require noninvasive in vivo measures of neuron death to permit clinical trials. In animal models of nerve transection, magnetic resonance imaging (MRI) proved a valid tool for quantifying sensory neuron loss within dorsal root ganglia (DRG) by measuring consequent proportional shrinkage of respective ganglia. OBJECTIVE: This system is investigated for clinical application after upper limb nerve injury and microsurgical nerve repair. METHODS: A 3-T clinical magnet was used to image and measure volume (Cavalieri principle) of C7-T1 DRG in uninjured volunteers (controls, n = 14), hand amputees (unrepaired nerve injury, n = 5), and early nerve repair patients (median and ulnar nerves transected, microsurgical nerve repair within 24 hours, n = 4). RESULTS: MRI was well tolerated. Volumetric analysis was feasible in 74% of patients. A mean 14% volume reduction was found in amputees' C7 and C8 DRG (P < .001 vs controls). Volume loss was lower in median and ulnar nerve repair patients (mean 3% volume loss, P < .01 vs amputees), and varied among patients. T1 DRG volume remained unaffected. CONCLUSION: MRI provides noninvasive in vivo assessment of DRG volume as a proxy clinical measure of sensory neuron death. The significant decrease found after unrepaired nerve injury provides indirect clinical evidence of axotomy-induced neuronal death. This loss was less after nerve repair, indicating a neuroprotective benefit of early repair. Volumetric MRI has potential diagnostic applications and is a quantitative tool for clinical trials of neuroprotective therapies.

Transfer of data or re-creation of knowledge - experiences of a shared electronic patient medical records system.

BACKGROUND: A shared electronic medical record (EMR) can improve communication between primary and secondary care. A consideration of the contents using Data-Information-Knowledge-Wisdom (DIKW) hierarchy could help inform further development of such systems regarding communication about prescribed medication. OBJECTIVES: To investigate primary and secondary care doctors' experiences of the shared EMR in Uppsala, Sweden, focusing on the creation, use and cross-sector transfer of data, information, knowledge and wisdom about individual patients' prescribed medication. METHOD: Nine focus groups were held with hospital doctors, of different grades and medical specialties, working at a single large teaching hospital in Uppsala, Sweden and primary care doctors worked in the same geographical area, in urban and rural primary care centers. The transcribed data were analyzed used the constant comparative method, based on data from the participants and application of the DIKW hierarchy. RESULTS: The doctors were very positive about accessing and using the shared EMR. Data and information in the system were efficiently retrieved and combined with newly collected data and information to create further knowledge. However, they also described a data and information overload, where it was difficult to get a general overview of what had happened over time, coupled with the frequent lack of knowledge being created and shared by other healthcare providers. Doctors were, instead, either explicitly asked or implicitly expected to read and interpret all available data and information and recreate knowledge themselves. CONCLUSIONS: This study highlighted the differences between access to data and information and access to knowledge in a shared EMR. In rolling out such a system, an increased availability of data and information should not be at the expense of a reduced availability of knowledge.

Secondary care doctors' perception of appropriate prescribing.

RATIONALE, AIM AND OBJECTIVE: As the prescribing of drugs in secondary care is known to influence prescribing in primary care and because an understanding of prescribers' reasoning is essential for evaluating prescribing appropriateness, the aim of this study was to investigate secondary care doctors' views of appropriate prescribing, using qualitative individual interviews. METHOD: Qualitative, semi-structured individual interviews were conducted with 15 hospital doctors working in different medical specialities. The interviews, covering the doctors' views of the meaning of 'appropriate' prescribing, were audiotaped and analysed from an interpretivist perspective. RESULTS: Three different main themes were identified in the analysis of how the doctors perceived appropriate prescribing: 'individualization of treatment', 'cost' and 'time'. Most importantly, treatment should be adjusted to the individual patient, although cost should also be justified. Ongoing medication reviews should be carried out, to adjust to changes in patient-related factors over time. CONCLUSIONS: The hospital doctors brought up continuous review as a necessary part of appropriate prescribing. Thus, from the prescribers' point of view, this time perspective should be explicitly incorporated in definitions of appropriate prescribing, in addition to individualization of treatment and cost considerations.

Clinical evaluation of a resorbable wrap-around implant as an alternative to nerve repair: a prospective, assessor-blinded, randomised clinical study of sensory, motor and functional recovery after peripheral nerve repair.

Peripheral nerve injures are common and often result in impaired functional recovery. The majority of injuries involve the arm and/or the hand. The traditional treatment for peripheral nerve injuries is repair by using microsurgical techniques, either by primary nerve suture or nerve graft, but research to find more successful methods that could improve recovery is ongoing. Tubulisation has been investigated by several authors and is suggested as an alternative to microsurgical techniques. The resorbable poly[(R)-3-hydroxybutyrate] (PHB) is one of the materials that has been previously tested experimentally. In this prospective, randomised, assessor-blinded clinical study, PHB was investigated as an alternative to epineural suturing in the treatment of peripheral nerve injuries at the wrist/forearm level of the arm. Twelve patients, with a complete, common, sharp injury of the median and/or ulnar nerve at the wrist/forearm level, were treated by either using PHB or microsurgical epineural end-to-end suturing. All patients were assessed using a battery of tests, including evaluation of functional, sensory and motor recovery by means of clinical, neurophysiological, morphological and physiological evaluations at 2 weeks and 3, 6, 9, 12 and 18 months after surgery. No adverse events or complications considered as product related were reported, and thus PHB can be regarded as a safe alternative for microsurgical epineural suturing. The majority of the methods in the test battery showed no significant differences between the treatment groups, but one should consider that the study involved a limited number of patients and a high variability was reported for the evaluating techniques. However, sensory recovery, according to the British Medical Research Council score and parts of the manual muscle test, suggested that treating with PHB may be advantageous as compared to epineural suturing. This, however, should be confirmed by large-scale efficacy studies.

Hospital doctors' views of factors influencing their prescribing.

RATIONALE, AIM AND OBJECTIVE: Factors influencing doctors in prescribing of drugs have mostly been studied in primary care. Studies performed in hospital care have primarily focused on new drugs, not prescribing in general. An in-depth understanding of the prescribing process in the more specialized secondary care is not only important for secondary care itself, but because it also influences prescribing in primary care. The aim of this study is therefore to identify factors that secondary care doctors believe influence them in prescribing drugs, using a qualitative approach. METHOD: Semi-structured interviews were conducted with 15 hospital doctors in different medical specialities and the interviews were analysed from an interpretivist perspective. The information gathered was on how prescribing decisions were made in general and how the doctors chose a specific drug therapy, including information sources used. RESULTS: According to our interviews, the hospital doctors took patient-specific factors and cost into consideration when prescribing, informed by different written information sources and commercial verbal information. Personal practice, colleagues and therapeutic tradition at the hospital or clinic, were influential in the prescribing of drugs. The themes identified should not to be seen as individual influences; many of them probably act in combination. CONCLUSIONS: If changes in prescribing behaviour are desired, factors warranting more attention include understanding how to influence therapeutic traditions and the doctor's personal habits for prescribing. The importance of clinical experience and information exchange with colleagues should not be underestimated in providing information about drugs to hospital doctors.

Sensory recovery after hand reimplantation: a clinical, morphological, and neurophysiological study in humans.

Despite fairly good return of motor function, patients who have amputated hands reimplanted demonstrate poor sensory recovery and severe cold intolerance, two variables that are difficult to quantify reliably. In this study we wanted to find out if there is a correlation between morphological findings of sensory and sympathetic reinnervation and clinical and neurophysiological variables. Skin was biopsied from the reimplanted and corresponding area in the normal hands of eight patients who had sustained a hand amputation and subsequent reimplantation. The sections were immunostained using markers for both sensory and sympathetic nerve fibres. Comparison between the reimplanted and normal sides in each individual showed a mean loss of sensory immunoreactive nerve fibres of 30%, and for sympathetic immunoreactivity the loss was 60%. There was measurable two-point discrimination in the injured hand only in patients below the age of 40 years, corresponding to the better recovery of mechanical thresholds evaluated neurophysiologically for this age group. These results confirm the extensive loss of sensory nerve fibres after nerve injury, probably correlated to loss of sensory neurons. We have also shown that it is possible to correlate the results of clinical and neurophysiological evaluation with morphological results of skin reinnervation specific to the repaired nerve, and so improve the possibility for the quantification of sensory recovery.