Redirecting Care: Compassionate Management of the Sick or Preterm Neonate at the End of Life.

The primary moral commitment of medical care has traditionally been based on a belief in the intrinsic value and significance of human life and a desire to protect the most vulnerable from harm. In this respect, the care of newborn infants who are at the border of viability is no different. Despite the intrinsic value of the life of every newborn, all agree that there is no moral duty of doctors to provide every possible treatment where the prognosis is hopeless. Instead, every action and treatment should be orientated towards the best interests of the individual child and towards the minimisation of serious harm. Decisions about the withholding or withdrawal of life-supportive treatment should be made collaboratively between professionals and parents, with discussion starting prior to delivery wherever possible. The goals of neonatal palliative care are to prevent or minimise pain and distressing symptoms and to maximise the opportunity for private, loving interaction between the dying baby and his or her parents and the wider family. Physical contact, gentle stroking, cuddles and tender loving care are of central importance for the dying baby. At the same time, we must provide psychological support for parents and family as they go through the profound and painful life experience of accompanying their baby to death. To enable a baby to die well, pain-free and in the arms of loving parents and carers is not a failure but a triumph of neonatal care.

Natural Language Processing and Its Use in Orthopaedic Research.

PURPOSE OF REVIEW: This review aims to demonstrate how natural language processing is used in orthopaedic research. RECENT FINDINGS: Natural language processing is a form of artificial intelligence that involves encoding human-generated text or speech into a form which can be interpreted by computers to perform a variety of tasks. Natural language processing gathers, processes, and organizes large amounts of free-text data more efficiently than humans. In orthopaedics, it has been utilized for retrospective chart review, automated reporting of electronic health record data, analyzing operative notes and radiology reports, and patient reviews of physicians and practices. Although still in its infancy, natural language processing promises to be a valuable tool in the future of orthopaedic research. It will not eliminate the need for the essential human component of questioning involved in research, but natural language processing can improve the quality, efficiency, and thoroughness of research, thus improving patient care.

Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia.

OBJECTIVE: Seizures are common among newborns with hypoxic-ischaemic encephalopathy (HIE) but the relationship between seizure burden and severity of brain injury among neonates receiving therapeutic hypothermia (TH) for HIE is unclear. We tested the hypothesis that seizure burden is associated with cerebral tissue injury independent of amplitude-integrated EEG (aEEG) background activity. STUDY DESIGN: Term neonates undergoing 72 h of TH at four centres were selected for study if they had continuous aEEG and MRI. The aEEG with corresponding 2-channel raw EEG (aEEG/EEG), was classified by severity of background and seizure burden; MR images were classified by the severity of tissue injury. RESULTS: Of 85 neonates, 52% had seizures on aEEG/EEG. Overall, 35% had high seizure burden, 49% had abnormal aEEG background in the first 24 h and 36% had severe injury on MRI. Seizures were most common on the first day, with significant recurrence during and after rewarming. Factors associated with severe injury on MRI were high seizure burden, poor aEEG background, 10 min Apgar and the need for more than one anticonvulsant. In multivariate logistic regression, high seizure burden was independently associated with greater injury on MRI (OR 5.00, 95% CI 1.47 to 17.05 p=0.01). Neither aEEG background, nor 10 min Apgar score were significant. CONCLUSIONS: Electrographic seizure burden is associated with severity of brain injury on MRI in newborns with HIE undergoing TH, independent of degree of abnormality on aEEG background. Seizures are common during cooling, particularly on day 1, with a significant rebound on day 4.

Identification and interpretation of microstructural abnormalities in motor pathways in adolescents born preterm.

There has been extensive interest in assessing the long-term effects of preterm birth on brain white matter microstructure using diffusion MRI. Our aim in this study is to explore diffusion MRI differences between adolescents born preterm and term born controls, with a specific interest in characterising how such differences are manifested in white matter regions containing predominantly single or crossing fibre populations. Probabilistic high angular resolution tractography together with large deformation spatial normalisation were used to objectively investigate diffusion tensor parameters at regular intervals along fibre tracts of 45 adolescents born before 33 weeks of gestation and 30 term-born typically developing adolescents. Diffusion parameters were significantly different between preterms and controls at several levels along the cortico-spinal, thalamo-cortical and transcallosal pathways. Within the predominantly single fibre regions of the corpus callosum and internal capsule, in the preterms mean diffusivity (MD) was found to be increased while fractional anisotropy (FA) was decreased compared to controls. In contrast, however, where these pathways traversed the centrum semiovale, FA and MD were both significantly increased. The major contributor to reduced FA in preterms in predominantly single fibre regions was the increased radial eigenvalue (i.e. increased radial diffusivity). In predominantly crossing-fibre regions, the tensor eigenvalues are not meaningful, and the observed increase in FA is likely to be due to a decrease in anisotropy in one of the contributing fibre bundles. Similar differences (although less pronounced) were observed after excluding preterms with radiological signs of preterm brain injury from the sample. In summary, white matter microstructure was found to be altered in motor pathways in adolescents born preterm. Disruption of white matter (WM) microstructure in a single fibre region with resulting higher radial diffusivity leads to lower FA, whereas selective disruption of one fibre population in a crossing fibre region is observed to lead to higher FA. These findings challenge the common simplistic interpretation of FA as a measure of WM tract integrity.

Redundant safety features in a high-channel-count retinal neurostimulator.

Safety features embedded in a 256-channel retinal prosthesis integrated circuit are presented. The biology of the retina and the electrochemistry of the electrode-tissue interface demand careful planning and design of the safety features of an implantable retinal stimulation device. We describe the internal limits and communication safety features of our ASIC, but we focus on monitoring and protection circuits for the electrode-tissue interface. Two independent voltage monitoring circuits for each channel measure the electrode polarization voltage at two different times in the biphasic stimulation cycle. The monitors ensure that the charged electrode stays within the electrochemical water window potentials, and that the discharged electrode is within a small window near the counter electrode potential. A switch to connect each electrode to the counter electrode between pulses protects against a wide range of device failures. Additionally, we describe work on an active feedback system to ensure that the electrode voltage is at zero.

Interhemispheric temporal lobe connectivity predicts language impairment in adolescents born preterm.

Although language difficulties are common in children born prematurely, robust neuroanatomical correlates of these impairments remain to be established. This study investigated whether the greater prevalence of language problems in preterm (versus term-born) children might reflect injury to major intra- or interhemispheric white matter pathways connecting frontal and temporal language regions. To investigate this, we performed a comprehensive assessment of language and academic abilities in a group of adolescents born prematurely, some of whom had evidence of brain injury at birth (n = 50, mean age: 16 years, mean gestational age: 27 weeks) and compared them to a term-born control group (n = 30). Detailed structural magnetic resonance imaging and diffusion-tractography analyses of intrahemispheric and interhemispheric white matter bundles were performed. Analysis of intrahemispheric pathways included the arcuate fasciculus (dorsal language pathway) and uncinate fasciculus/extreme capsule (ventral language pathway). Analysis of interhemispheric pathways (in particular, connections between the temporal lobes) included the two major commissural bundles: the corpus callosum and anterior commissure. We found language impairment in 38% of adolescents born preterm. Language impairment was not related to abnormalities of the arcuate fasciculus (or its subsegments), but was associated with bilateral volume reductions in the ventral language pathway. However, the most significant volume reduction was detected in the posterior corpus callosum (splenium), which contains interhemispheric connections between the occipital, parietal and temporal lobes. Diffusion tractography showed that of the three groups of interhemispheric fibres within the splenium, only those connecting the temporal lobes were reduced. Crucially, we found that language impairment was only detectable if the anterior commissure (a second temporal lobe commissural pathway) was also small. Regression analyses showed that a combination of anatomical measures of temporal interhemispheric connectivity (through the splenium of the corpus callosum and anterior commissure) explained 57% of the variance in language abilities. This supports recent theories emphasizing the importance of interhemispheric connections for language, particularly in the developing brain.

Speech and oromotor outcome in adolescents born preterm: relationship to motor tract integrity.

OBJECTIVE: To assess speech abilities in adolescents born preterm and investigate whether there is an association between specific speech deficits and brain abnormalities. STUDY DESIGN: Fifty adolescents born prematurely (<33 weeks' gestation) with a spectrum of brain injuries were recruited (mean age, 16 years). Speech examination included tests of speech-sound processing and production and speech and oromotor control. Conventional magnetic resonance imaging and diffusion-weighted imaging was acquired in all adolescents born preterm and 30 term-born control subjects. Radiological ratings of brain injury were recorded and the integrity of the primary motor projections was measured (corticospinal tract and speech-motor corticobulbar tract [CST/CBT]). RESULTS: There were no clinical diagnoses of developmental dysarthria, dyspraxia, or a speech-sound disorder, but difficulties in speech and oromotor control were common. A regression analysis revealed that presence of a neurologic impairment, and diffusion-weighted imaging abnormalities in the left CST/CBT were significant independent predictors of poor speech and oromotor outcome. These left-lateralized abnormalities were most evident at the level of the posterior limb of the internal capsule. CONCLUSION: Difficulties in speech and oromotor control are common in adolescents born preterm, and adolescents with injury to the CST/CBT pathways in the left-hemisphere may be most at risk.

ASIC design and data communications for the Boston retinal prosthesis.

We report on the design and testing of a custom application-specific integrated circuit (ASIC) that has been developed as a key component of the Boston retinal prosthesis. This device has been designed for patients who are blind due to age-related macular degeneration or retinitis pigmentosa. Key safety and communication features of the low-power ASIC are described, as are the highly configurable neural stimulation current waveforms that are delivered to its greater than 256 output electrodes. The ASIC was created using an 0.18 micron Si fabrication process utilizing standard 1.8 volt CMOS transistors as well as 20 volt lightly doped drain FETs. The communication system receives frequency-shift keyed inputs at 6.78 MHz from an implanted secondary coil, and transmits data back to the control unit through a lower-bandwidth channel that employs load-shift keying. The design's safety is ensured by on-board electrode voltage monitoring, stimulus charge limits, error checking of data transmitted to the implant, and comprehensive self-test and performance monitoring features. Each stimulus cycle is initiated by a transmitted word with a full 32-bit error check code. Taken together, these features allow researchers to safely and wirelessly tailor retinal stimulation and vision recovery for each patient.

White matter and cognition in adults who were born preterm.

BACKGROUND AND PURPOSE: Individuals born very preterm (before 33 weeks of gestation, VPT) are at risk of damage to developing white matter, which may affect later cognition and behaviour. METHODS: We used diffusion tensor MRI (DT-MRI) to assess white matter microstructure (fractional anisotropy; FA) in 80 VPT and 41 term-born individuals (mean age 19.1 years, range 17-22, and 18.5 years, range 17-22 years, respectively). VPT individuals were part of a 1982-1984 birth cohort which had been followed up since birth; term individuals were recruited by local press advertisement. General intellectual function, executive function and memory were assessed. RESULTS: The VPT group had reduced FA in four clusters, and increased FA in four clusters relative to the Term group, involving several association tracts of both hemispheres. Clusters of increased FA were associated with more severe neonatal brain injury in the VPT group. Clusters of reduced FA were associated with lower birth weight and perinatal hypoxia, and with reduced adult cognitive performance in the VPT group only. CONCLUSIONS: Alterations of white matter microstructure persist into adulthood in VPT individuals and are associated with cognitive function.

Communication and Control System for a 15-Channel Hermetic Retinal Prosthesis.

A small, hermetic, wirelessy-controlled retinal prosthesis has been developed for pre-clinical studies in Yucatan minipigs. The device was attached conformally to the outside of the eye in the socket and received both power and data wirelessly from external sources. Based on the received image data, the prosthesis drove a subretinal thin-film polyimide array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing a 15-channel stimulator and receiver chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by power amplifiers. Power was delivered by a 125 KHz carrier, and data were delivered by amplitude shift keying of a 15.5 MHz carrier at 100 Kbps. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. The final assembly was tested in vitro in physiological saline and in vivo in two minipigs for up to five and a half months by measuring stimulus artifacts generated by the implant's current drivers.

A hermetic wireless subretinal neurostimulator for vision prostheses.

A miniaturized, hermetically encased, wirelessly operated retinal prosthesis has been developed for preclinical studies in the Yucatan minipig, and includes several design improvements over our previously reported device. The prosthesis attaches conformally to the outside of the eye and electrically drives a microfabricated thin-film polyimide array of sputtered iridium oxide film electrodes. This array is implanted into the subretinal space using a customized ab externo surgical technique. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete circuit components. Feedthroughs in the case connect the stimulator chip to secondary power and data receiving coils on the eye and to the electrode array under the retina. Long-term in vitro pulse testing of the electrodes projected a lifetime consistent with typical devices in industry. The final assembly was tested in vitro to verify wireless operation of the system in physiological saline using a custom RF transmitter and primary coils. Stimulation pulse strength, duration, and frequency were programmed wirelessly from a Peripheral Component Interconnect eXtensions for Instrumentation (PXI) computer. Operation of the retinal implant has been verified in two pigs for up to five and a half months by detecting stimulus artifacts generated by the implanted device.

Total brain white matter is a major determinant of IQ in adolescents born preterm.

OBJECTIVE: In preterm infants, white matter (WM) abnormalities detected on magnetic resonance imaging (MRI) at term-age are associated with early developmental delay. We set out to study this association in adolescents born pre-term, by examining intellectual outcome in relation to markers of brain injury, focusing on the effects of WM reduction. METHODS: Seventy-nine participants were recruited and assessed at a mean age of 16 years: 49 adolescents born preterm (<32 weeks' gestation) with a wide spectrum of brain injuries (including 22 with no identifiable brain injury at birth) and 30 term-born controls. Data collected included: brain MRI scans, full-scale intelligence quotient (IQ) scores, educational attainments, and behavioral scores. Measures of WM reduction included total volume, cross-sectional area of the corpus callosum (CC), and ventricular dilatation. Cerebellar volumes and neuroradiological ratings were also included. RESULTS: WM volume and IQ were reduced in the preterm groups (both with and without brain injury). Total WM volume and CC area jointly explained 70% of IQ variance in the adolescents born preterm, irrespective of the presence or severity of brain abnormalities detected at birth or on follow-up MRI. This relationship was not seen in controls. Importantly, correlations were also found with real-world measures of academic achievement and behavioral difficulties. INTERPRETATION: Preterm birth has a long-term effect on cognition, behavior, and future academic success primarily as a consequence of global brain WM reduction. This emphasizes the need for early therapeutic efforts to prevent WM injury and promote or optimize its development in preterm neonates.

Development of the boston retinal prosthesis.

A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre-clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, and it received both power and data wirelessly from external sources. The prosthesis drove a sub-retinal thin-film array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing the 16-channel stimulator chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by a power amplifier. Power was delivered by a 500 KHz carrier, and data were delivered by frequency shift keying. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. Through an 'outbound' telemetry channel, electrode impedances were monitored by an on-board analog to digital converter that sampled the output voltage waveforms. The final assembly was tested in vitro in physiological saline and in vivo in two mini-pigs for up to three months by measuring stimulus artifacts generated by the implant's current drivers.

Overview of the boston retinal prosthesis: challenges and opportunities to restore useful vision to the blind.

A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre-clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, and it received both power and data wirelessly from external sources. The prosthesis drove a sub-retinal thin-film array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing the 16-channel stimulator chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by a power amplifier. Power was delivered by a 500 KHz carrier, and data were delivered by frequency shift keying. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. Through an 'outbound' telemetry channel, electrode impedances were monitored by an on-board analog to digital converter that sampled the output voltage waveforms. The final assembly was tested in vitro in physiological saline and in vivo in two mini-pigs for up to three months by measuring stimulus artifacts generated by the implant's current drivers.

Ophthalmological, cognitive, electrophysiological and MRI assessment of visual processing in preterm children without major neuromotor impairment.

Many studies report chronic deficits in visual processing in children born preterm. We investigated whether functional abnormalities in visual processing exist in children born preterm but without major neuromotor impairment (i.e. cerebral palsy). Twelve such children (< 33 weeks gestation or birthweight < 1000 g) without major neuromotor impairment and 12 born full-term controls were assessed at 8-12 years of age by means of ophthalmological assessment (visual acuity, colour vision, stereopsis, stereoacuity, visual fields, ocular motility, motor fusion), cognitive tests of visual-motor, visual-perceptual and visual-spatial skills and pattern-reversal visual evoked potentials (PR-VEPs). All participants also underwent magnetic resonance imaging (MRI) of the brain and neuromotor assessments. No significant differences were found between the groups on the ophthalmological, visual cognitive, neurological, neuromotor or MRI measures. The P100 component of the PR-VEP showed a significantly shorter latency in the preterm compared with the full-term participants. Whilst this P100 finding suggests that subtle abnormalities may exist at the neurophysiological level, we conclude that visual dysfunction is not systematically associated with preterm birth in the context of normal neurological status.

Ethical challenges in the use of therapeutic hypothermia in Indian neonatal units.

Trials in developed countries have shown that therapeutic hypothermia reduces the risk of death or severe disability in infants with neonatal encephalopathy. Cooling has been adopted as a standard of care in some parts of the world. Some Indian neonatal units have considered or even embarked upon cooling encephalopathic term newborn infants. In this article we discuss some of the potential ethical questions that should be considered before introducing therapeutic hypothermia in an Indian setting. Evidence from previous trials may not be relevant given significant differences in the epidemiology of neonatal encephalopathy in countries like India. There is a possibility that hypothermia would be ineffective or harmful. The most appropriate way to answer these concerns would be to perform a large randomized controlled trial of cooling in India. However, such trials will also raise potential ethical challenges. Cooling may also affect decisions about treatment withdrawal, and may create uncertainty about prognosis. It may exacerbate ethical problems relating to lack of neonatal intensive care bed space.

Ethics and hypothermia treatment.

Hypothermia is the first effective neuroprotective intervention for newborns who are critically ill following a life-threatening asphyxial insult. It is not surprising that it has raised complex and controversial ethical dilemmas for investigators and clinicians. Given the history of iatrogenic disasters in neonatology, there has been an understandable reluctance to incorporate hypothermia into routine clinical practice until there is persuasive evidence from high quality randomised trials. This article reviews ethical issues that arose during the design of the original clinical trials, the implications of accumulating evidence of safety and efficacy, and the problems of ensuring informed parental participation in treatment decisions.

Realization of a 15-channel, hermetically-encased wireless subretinal prosthesis for the blind.

A miniaturized, hermetically-encased, wirelessly-operated retinal prosthesis has been developed for implantation and pre-clinical studies in Yucatan mini-pig animal models. The prosthesis conforms to the eye and drives a microfabricated polyimide stimulating electrode array with sputtered iridium oxide electrodes. This array is implanted in the subretinal space using a specially-designed ab externo surgical technique that affixes the bulk of the prosthesis to the surface of the sclera. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete power supply components. Feedthroughs from the case connect to secondary power- and data-receiving coils. In addition, long-term in vitro pulse testing was performed on the electrodes to ensure their stability for the long lifetime of the hermetic case. The final assembly was tested in vitro to verify wireless operation of the system in biological saline using a custom RF transmitter circuit and primary coils. Stimulation pulse strength, duration and frequency were programmed wirelessly using a custom graphical user interface. Operation of the retinal implant has been verified in vivo in one pig for more than three months by measuring stimulus artifacts on the eye surface using a contact lens electrode.