First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy.

BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12-18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. RESULTS: No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). CONCLUSIONS: Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.

Mapping the Landscape of Equitable Access to Advanced Neurotechnologies in Canada.

Geographic, social, political, and economic factors shape access to advanced neurotechnologies, yet little previous research has explored the barriers, enablers, and areas of opportunity for equitable and meaningful access for diverse patient communities across Canada. We applied a mixed-mode approach involving semi-structured interviews and rating scale questions to consult with 24 medical experts who are involved in the care of patients who undergo functional neurosurgery targeting the brain. Seven major themes emerged from the qualitative analysis: Health care system, Neurotechnology features, Patient demographics, Target condition features, Ethics, Upstream barriers and enablers, and Areas of opportunity. Descriptive statistics of the Likert-scale responses suggest that interviewees perceive a disparity between the imperative of access to advanced neurotechnologies for people living in rural and remote areas and the likelihood of achieving such access. The results depict a complex picture of access to functional neurosurgery in Canada with pockets of excellence and a motivation to improve the availability of care for vulnerable populations through the expansion of distributed care models, improved health care system efficiencies, increasing funding and support for patient travel, and increasing awareness about and advocacy for advanced neurotechnologies.

Establishing a comprehensive search strategy for Indigenous health literature reviews.

BACKGROUND: Appropriate search strategies are essential to ensure the integrity and reproducibility of systematic and scoping reviews, as researchers seek to capture as many relevant resources as possible. In the case of Indigenous health reviews, researchers are met with the special challenge of creating a search strategy that can encompass this large, diverse population group with no universally agreed upon identification criteria. MAIN BODY: With an aim to promote improved review methodologies that uphold standards of justice, autonomy, and equity for Indigenous peoples and other heterogeneous populations, we describe critical gaps and approaches to close them. We report organizational and transparency issues around how Indigenous populations are indexed in several major databases, and draw on examples of published reviews and protocols to demonstrate the challenges inherent to creating a comprehensive search strategy. CONCLUSIONS: The conduct and communication of results from health literature research on global Indigenous populations are compromised by challenges of methodology that are rooted in the complexities inherent to defining Indigenous peoples. These challenges must be urgently addressed to improve this important field of inquiry moving forward.

Behavioural and emotional concerns reported by parents of children attending a neurodevelopmental diagnostic centre.

BACKGROUND: Behavioural and emotional problems are a salient concern for parents of children with neurodisability, but little is known about the nature of such concerns in this population, nor about the distribution of concern types across ostensibly different subpopulations. METHODS: Information about behavioural and emotional concerns was extracted from clinical reports of developmental paediatricians (N = 12) who had assessed children aged 3 to 8 years (N = 129) through three clinics at a major developmental and rehabilitation service centre. All concerns were captured at a granular level. A two-stage, consensus-based interdisciplinary concept-sorting technique was used to identify and group thematically related behavioural and emotional concerns into First Stage Groupings, intended to preserve detail and specificity, and a reduced number of Second Stage Clusters. RESULTS: A total of 669 discrete concerns were encountered, aggregated to 58 First Stage Concern Groupings and 28 Second Stage Concern Clusters. Findings of the salience of Groupings related to Attention, Concentration and Distractibility, and Anxiousness, Shyness, and Emotional Sensitivity reflect existing literature for children with neurodevelopmental concerns. "Social Isolation/Peer Engagement," "Tantrums/Outbursts/Meltdowns" and "Volatility/Self-regulation Difficulties," and "Sensory Issues" emerged as areas of significant concern and salience as well. Across clinics, three Clusters recurred among the top five observed for each clinic: "Tantrums/Outbursts/Meltdowns," "Inflexibility/Gets Stuck or Fixated," and "Social Behaviours." CONCLUSIONS: This rich descriptive dataset affords insight into the phenomenology of behaviour and emotional concerns in the daily lives of parents whose children have known or suspected neurodisability. Study findings can inform and sensitize clinicians working with this population. Usefulness is enhanced by inclusion of behavioural material that is subthreshold for a formal psychopathologic diagnosis. Certain concern types are encountered commonly across different clinical subpopulations, supporting a noncategorical view of behavioural and emotional problems as functional attributes that cross neurodisability diagnostic categories.

Donohue syndrome: A review of literature, case series, and anesthetic considerations.

BACKGROUND: Donohue syndrome is a rare autosomal recessive disorder of insulin resistance, causing a functional defect in insulin receptor function, and affecting the ability of the insulin to bind the receptor. Features include severe hyperinsulinism and fasting hypoglycemia, along with severe failure to thrive despite feeding. An accelerated fasting state results in muscle wasting, decreased subcutaneous fat, and an excess of thick skin. A reduced thoracic diameter is accentuated by increased abdominal distension, which impacts on respiratory reserve. Cardiac disease develops early in life, with progressive hypertrophic cardiomyopathy as a result of hyperinsulinism. Prognosis is poor with the majority of patients dying in infancy of sepsis. The aim of this review is to report our experience of providing anesthesia for patients with Donohue syndrome, and inform guidance for safe management of these children, based on a comprehensive literature review. METHODS: A literature search was carried out using PubMed, Medline, and the Cochrane Library, and using the MESH search terms detailed below. Patients were identified by formal request to the department of pediatric endocrinology at Great Ormond Street Hospital. Each patient's notes were searched manually and electronically for both clinical presentation and outcome, and anesthesia records. DISCUSSION: There is currently no published literature relating to anesthetic management of Donohue syndrome. We report a case series of 5 patients with Donohue syndrome who have presented to our institution. This small series of children with this complex disorder demonstrates a clearly increased risk of general anesthesia. Many of the risks relate to restrictive lung disease and abdominal distension which worsens with bag valve mask ventilation and limited respiratory reserve which leads to precipitous desaturation. During induction, a spontaneously breathing technique is recommended. If required, bag valve mask ventilation should be accompanied by constant gastric aspiration. Intubation is challenging, and a difficult airway plan, including a second experienced anesthetist and ENT support, should be in place. These children are predisposed to developing cardiomyopathy and therefore at risk of cardiovascular collapse under anesthesia.

Cardiac Dysrhythmias in Children Undergoing Extracorporeal Shock Wave Lithotripsy Under General Anesthesia or Propofol Sedation: A Prospective, Observational Cohort Study.

OBJECTIVE: To assess the frequency and severity of cardiac dysrhythmias and identify any intraoperative or postoperative complications in children undergoing extracorporeal shock wave lithotripsy (ESWL). METHODS: All children coming to our institution for ESWL from June 2014 to January 2015 were prospectively enrolled in an observational cohort study. Intraoperative cardiac dysrhythmias and perioperative and postoperative complications were recorded. RESULTS: In total, 21 children aged 1-18 years were enrolled receiving a total of 26 treatments. Intravenous sedation was used in 19 cases and general anesthesia with an inhalational agent in 7 cases. Cardiac dysrhythmias occurred in 58% of children. No hemodynamic instability was noted. No therapies were terminated because of dysrhythmias, and there were no postoperative cardiac dysrhythmias. CONCLUSION: ESWL remains a safe therapy for children with urinary stone disease. Although we experienced more dysrhythmias than currently published literature, there were no long-term adverse outcomes and children were able to go home the same day.

Increasing source-to-image distance to reduce radiation dose from digital radiography pelvic examinations.

PURPOSE: To investigate the effects of increasing source-to-image distance (SID) on radiation dose and image quality for digital radiography examinations of the pelvis. METHODS: Using a Carestream DirectView DR 7500 unit, anteroposterior pelvic images were obtained on 97 consecutive patients at a standard 115-cm SID (group 1). Ninety-nine patients were examined using the same equipment and acquisition parameters but with the maximum achievable SID (group 2). For each examination, tube potential, milliampere seconds, SID, and source-to-skin distances were recorded. This facilitated the calculation of entrance surface dose, including backscatter, and effective dose using Quality Assurance Dose Data System software. The resultant images were independently assessed for image quality by 3 blinded observers-2 reporting radiographers and 1 consultant radiologist. Image quality was graded using an established scoring system, which assessed image quality at multiple anatomical locations. RESULTS: For group 1, median (interquartile range [IQR]; the median value is presented with the corresponding interquartile range in parentheses) entrance surface dose with backscatter was 1.95 mGy (1.23 mGy-3.10 mGy), which was lower by 1.15 mGy (0.78 mGy-2.22 mGy) for the increased SID group (22 patients at 135 cm, 77 patients at 144 cm) (Mann-Whitney U test, P < .001). Effective dose calculations generated a median (IQR) of 0.32 mSv (0.13 mSv-0.52 mSv) for group 1 and a lower median of 0.19 mSv (0.13 mSv-0.37 mSv) for group 2 (P < .001). No observers (intraclass correlation coefficient = 0.675) found a significant change in image quality by increasing SID (group 1, 2.0 ± 1.8; group 2, 1.6 ± 1.4; P > .05) when comparing the difference in image quality scores with the maximum score available. DISCUSSION: Our results demonstrate a reduction in entrance surface dose, including backscatter and effective dose, of 39% and 41%, respectively, when operating at extended SIDs. Results were generated from a clinically based study and included a wide spectrum of patients. Multiple regression confirmed that increasing the SID contributes to a dose reduction. Increasing SID is a simple and cost-effective method for reducing radiation dose and can be applied to all patients by all radiographers and with all commercially available digital radiography units. CONCLUSION: For digital pelvic radiography, increasing SID is a potential method for reducing entrance surface and effective radiation doses without compromising image quality.

A new twist in the pediatric difficult airway.

Difficult intubation of a 2.4 kg ex premature, suspected Pierre Robin Sequence with upper airway obstruction causing respiratory failure. Multiple failed intubation attempts by an experienced pediatric anesthetist using described techniques and adjuncts. A description of a simple new maneuvre using a GlideScope and a stylet. By twisting the stylet into a spiral shape, the endotracheal tube was given improved maneuverability that allowed the intubator to place the endotracheal tube tip to the glottis opening. Then by rotating the tube in a clockwise direction it could be manipulated past the vocal cords into the trachea.

Hypercapnia and acidosis during open and thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia: results of a pilot randomized controlled trial.

OBJECTIVE: We aimed to evaluate the effect of thoracoscopy in neonates on intraoperative arterial blood gases, compared with open surgery. BACKGROUND: Congenital diaphragmatic hernia (CDH) and esophageal atresia with tracheoesophageal fistula (EA/TEF) can be repaired thoracoscopically, but this may cause hypercapnia and acidosis, which are potentially harmful. METHODS: This was a pilot randomized controlled trial. The target number of 20 neonates (weight > 1.6 kg) were randomized to either open (5 CDH, 5 EA/TEF) or thoracoscopic (5 CDH, 5 EA/TEF) repair. Arterial blood gases were measured every 30 minutes intraoperatively, and compared by multilevel modeling, presented as mean and difference (95% confidence interval) from these predictions. RESULTS: Overall, the intraoperative PaCO2 was 61 mm Hg in open and 83 mm Hg [difference 22 mm Hg (2 to 42); P = 0.036] in thoracoscopy and the pH was 7.24 in open and 7.13 [difference -0.11 (-0.20 to -0.01); P = 0.025] in thoracoscopy. The duration of hypercapnia and acidosis was longer in thoracoscopy compared with that in open. For patients with CDH, thoracoscopy was associated with a significant increase in intraoperative hypercapnia [open 68 mm Hg; thoracoscopy 96 mm Hg; difference 28 mm Hg (8 to 48); P = 0.008] and severe acidosis [open 7.21; thoracoscopy 7.08; difference -0.13 (-0.24 to -0.02); P = 0.018]. No significant difference in PaCO2, pH, or PaO2 was observed in patients undergoing thoracoscopic repair of EA/TEF. CONCLUSIONS: This pilot randomized controlled trial shows that thoracoscopic repair of CDH is associated with prolonged and severe intraoperative hypercapnia and acidosis, compared with open surgery. These findings do not support the use of thoracoscopy with CO2 insufflation and conventional ventilation for the repair of CDH, calling into question the safety of this practice. The effect of thoracoscopy on blood gases during repair of EA/TEF in neonates requires further evaluation. (ClinicalTrials.gov Identifier: NCT01467245).

Digital pelvic radiography: increasing distance to reduce dose.

PURPOSE: To investigate the effect of varying source-to-image distance (SID) on image quality and radiation dose using direct digital radiography (DR). METHODS: An anthropomorphic pelvic phantom was positioned for a standard anteroposterior DR examination. The SID was initially set at 100 cm, and the tube potential remained constant at 80 kVp. Two exposures were taken at this SID, and the entrance surface dose (ESD) and effective dose (ED) were calculated. Images were sent to a reporting-grade picture archiving and communication system workstation for image quality analysis. The SID was then varied by 10-cm intervals, up to its maximum (80 cm to 147 cm), with 2 exposures taken for each interval. Grid usage also was varied to determine its effect on radiation dose and image quality. Image quality was assessed by 4 observers (2 images per SID interval) who were blinded to the measurements, using a rating system adapted from the European Guidelines on Quality Criteria for Diagnostic Radiographic Images. RESULTS: Increasing SID results in lower ESD and ED compared with the standard 100-cm SID (147 cm: 2.56 mGy and 0.44 mSv, respectively, vs 100 cm: 3.00 mGy and 0.51 mSv, respectively; P<.05). Reduction of the SID resulted in an increased ESD and ED (80 cm: 3.79 mGy and 0.65 mSv, respectively; P<.05). Analysis of the resultant images demonstrated a statistically nonsignificant minor increase in image quality when increasing SID (P=.276). Image quality for 60 cm, 80 cm, 100 cm, 120 cm, 140 cm, and 147 cm was given a mean score of 17.5, 30, 31, 33, 33, and 32, respectively. Removal of the grid resulted in lower image quality but a significantly lower overall ESD and ED. CONCLUSION: Significant reductions in ESD and ED can be achieved, without loss of image quality, with a larger-than-normal SID for AP pelvic DR examinations.

Adaptation to warming but not cooling at slow rates of stimulus change in thermal threshold measurements.

The relationship between thermal detection threshold and rate of temperature change of the thermal stimulus when slow (<1 degrees C s(-1)) rates of change are employed was investigated. Using both the reaction time (RT) inclusive Method of Limits and RT exclusive Method of Levels healthy volunteers had warming (WDT) and cooling detection thresholds (CDT) measured at four different rates of temperature change (0.3, 0.5, 0.7 and 1.0 degrees C s(-1)) from the thenar and/or mental regions using a contact thermode. With the Method of Limits, CDT increased linearly with rate of temperature change suggesting increments were due to RT artefacts. This was further supported by threshold assessment with the Method of Levels which showed CDT were unaffected by the rate of change in the RT exclusive method (P > 0.1). In contrast, WDT did not increase linearly with rate of stimulus temperature change when the Method of Limits was used and threshold assessment with the Method of Levels showed WDT assessed using a 0.3 degrees C s(-1) ramp rate were significantly higher than those measured with a 1 degrees C s(-1) rate of change (P < 0.05). This study indicates that adaptation to a warming stimulus can occur at faster rates of stimulus change than previously anticipated and identifies differences in warming and cooling pathways in sensitivity to adaptation.

Computation of tactile object properties requires the integrity of praxic skills.

We describe a series of experiments to examine the tactile identification of objects over the course of neurological recovery in a patient with an intracerebral haemorrhage involving the left inferior and superior parietal lobe. Tactile agnosia in this case involved the ipsilesional as well as the contralesional hand, allowing us to observe the effects of dominant parietal lobe damage without the confounding effects of hemiparesis. The findings demonstrate that both apraxia and tactile apperceptive agnosia may result from a unilateral lesion involving the left parietal lobe. The findings further suggest that the computation of macro-geometrical and micro-geometrical tactile object properties is dissociable. Macro-geometrical tactile analysis depends on intact programming of exploratory hand movements, while the role of such movements in micro-geometrical analysis is less clear.

Differential effects of neuropathic analgesics on wind-up-like pain and somatosensory function in healthy volunteers.

OBJECTIVES: To investigate the effects of gabapentin, carbamazepine, and amitriptyline on temporal summation, simple nociceptive pain, and innocuous touch sensation in healthy volunteers. METHODS: A placebo controlled four-way crossover double-blind randomized protocol was followed. Seventeen healthy subjects, male and female, aged 18 to 24, took part. Punctate pain, temporal summation pain to repeat punctate stimulation, and vibration detection threshold were assessed in triplicate. Study drugs were given as bedtime and early morning doses with assessments carried out midmorning. RESULTS: Gabapentin and carbamazepine significantly reduced the intensity of temporal summation pain (P < 0.001 and P < 0.01 respectively), whereas amitriptyline significantly increased temporal summation pain (P < 0.001). None of the drugs affected pain produced by a single punctate stimulus (P > 0.05). Carbamazepine increased vibration detection thresholds (P < 0.05), but neither gabapentin nor amitriptyline had any detectable effect on vibration. DISCUSSION: We have shown that gabapentin, carbamazepine, and amitriptyline, three pharmacologically different drugs, have distinct and quantifiable effects on somatosensory pathways in healthy volunteers. These findings provide a link between pharmacology of the study drugs and clinical effectiveness. The effects of gabapentin and carbamazepine on temporal summation pain show that these drugs can block centrally amplified wind-up pain in the absence of a neuropathic disorder.

A novel treatment of postherpetic neuralgia using peppermint oil.

BACKGROUND: Postherpetic neuralgia remains a difficult problem to treat. A number of therapies have been shown to be effective, but some patients have intractable pain. PATIENT: The case of a 76-year-old woman whose pain had been resistant to standard therapies is described. The pattern of quantitative sensory testing results for this patient led the authors to believe that she had an "irritable nociceptor" type of pathophysiology. INTERVENTION: The patient was instructed to apply neat peppermint oil (containing 10% menthol) to her skin, resulting in an almost immediate improvement in her pain. This pain relief persisted for 4-6 hours after application of the oil. RESULTS: The patient was successfully treated with topical peppermint oil. During 2 months of follow-up she has had only a minor side effect, with continuing analgesia. The authors believe this is the first evidence of peppermint oil (or menthol) having a strong analgesic effect on neuropathic pain. The possible mechanisms of action of peppermint oil are discussed.

The GPCOG: a new screening test for dementia designed for general practice.

OBJECTIVES: To design and test a brief, efficient dementia-screening instrument for use by general practitioners (GPs). DESIGN: The General Practitioner Assessment of Cognition (GPCOG) consists of cognitive test items and historical questions asked of an informant. The validity of the measure was assessed by comparison with the criterion standard of diagnoses of dementia derived from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). SETTING: Primary care doctors' offices. PARTICIPANTS: Sixty-seven GPs administered the GPCOG to 283 community-dwelling patients aged 50 to 74 with memory complaints or aged 75 and older. MEASUREMENTS: The Cambridge Mental Disorder of the Elderly Examination, the Abbreviated Mental Test (AMT), the Mini-Mental State Examination (MMSE), the 15-item Geriatric Depression Scale, and the 12-item Short-Form Health Survey. RESULTS: The GPCOG was reliable and superior to the AMT (and possibly to the MMSE) in detecting dementia. The two-stage method of administering the GPCOG (cognitive testing followed by informant questions if necessary)had a sensitivity of 0.85, a specificity of 0.86, a misclassification rate of 14%, and positive predictive value of 71.4%. Patient interviews took less than 4 minutes to administer and informant interviews less than 2 minutes. The instrument was reported by GPs to be practical to administer and was acceptable to patients. CONCLUSION: The GPCOG is a valid, efficient, well-accepted instrument for dementia screening in primary care.