Intrathecal non-viral interleukin-10 gene therapy ameliorates neuropathic pain as measured by both classical static allodynia and a novel supra-spinally mediated pain assay, the Two-Arm Rodent Somatosensory (TARS) task.

Intrathecal delivery of interleukin-10 (IL-10) gene therapy has been reported to be effective in suppressing pain enhancement in a variety of rodent models. However, all publications that have tested this treatment have relied upon measures of static allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). As this plasmid DNA IL-10 (pDNA-IL10) therapeutic approach is now in human clinical trials for multiple pain indications, including intrathecal delivery for human neuropathic pain, it is important to consider the recent concerns raised in the pain field that such tests reflect spinal rather than supraspinal processing of, and responsivity to, noxious stimuli. Consequently, this raises the question of whether intrathecal pDNA-IL10 can reverse established neuropathic pain when assessed by a test requiring supraspinal, rather than solely spinal, mediation of the behavioral response. The present study utilizes the rat sciatic chronic constriction injury (CCI) model of neuropathic pain to compare the expression of static allodynia with that of cognitively controlled choice behavior in a two-arm maze, adapted from Hayashida et al. (2019). This modification, termed the Two-Arm Rodent Somatosensory (TARS) task, provides rats free choice to reach a desired goal box via a short "arm" of the maze with tactile probes as flooring versus a longer "arm" of the maze with a smooth surface. Here we demonstrate that static allodynia and avoidance of the nociceptive flooring in TARS develop in parallel over time, and that both behaviors also resolve in parallel following intrathecal pDNA-IL10 gene therapy. Details for the construction and use of this new maze design are also provided. Together, this study documents both: (a) the important finding that intrathecal IL-10 gene therapy does indeed resolve neuropathic pain as measured by a supraspinally-mediated behavioral task, and (b) a new, supraspinally-mediated task that allows behavioral assessments across weeks and allows the analysis of both development and resolution of neuropathic pain by therapeutic interventions. As such, the TARS operant behavior task is an improvement over other approaches such as the mechanical conflict-avoidance system which have difficulties demonstrating development and reversal of pain behavior in a within-subject design.

Awareness of social care needs in people with epilepsy and intellectual disability.

BACKGROUND: Nearly a quarter of people with intellectual disability (ID) have epilepsy with large numbers experiencing drug-resistant epilepsy, and premature mortality. To mitigate epilepsy risks the environment and social care needs, particularly in professional care settings, need to be met. PURPOSE: To compare professional care groups as regards their subjective confidence and perceived responsibility when managing the need of people with ID and epilepsy. METHOD: A multi-agency expert panel developed a questionnaire with embedded case vignettes with quantitative and qualitative elements to understand training and confidence in the health and social determinants of people with ID and epilepsy. The cross-sectional survey was disseminated amongst health and social care professionals working with people with ID in the UK using an exponential non-discriminative snow-balling methodology. Group comparisons were undertaken using suitable statistical tests including Fisher's exact, Kruskal-Wallis, and Mann-Whitney. Bonferroni correction was applied to significant (p < 0.05) results. Content analysis was conducted and relevant categories and themes were identified. RESULTS: Social and health professionals (n = 54) rated their confidence to manage the needs of people with ID and epilepsy equally. Health professionals showed better awareness (p < 0.001) of the findings/recommendations of the latest evidence on premature deaths and identifying and managing epilepsy-related risks, including the relevance of nocturnal monitoring. The content analysis highlighted the need for clearer roles, improved care pathways, better epilepsy-specific knowledge, increased resources, and better multi-disciplinary work. CONCLUSIONS: A gap exists between health and social care professionals in awareness of epilepsy needs for people with ID, requiring essential training and national pathways.

[18F]Sodium fluoride PET-MRI detects increased metabolic bone response to whole-joint loading stress in osteoarthritic knees.

OBJECTIVE: Altered joint function is a hallmark of osteoarthritis (OA). Imaging techniques for joint function are limited, but [18F]sodium fluoride (NaF) PET-MRI may assess the acute joint response to loading stresses. [18F]NaF PET-MRI was used to study the acute joint response to exercise in OA knees, and compare relationships between regions of increased uptake after loading and structural OA progression two years later. METHODS: In this prospective study, 10 participants with knee OA (59 ± 8 years; 8 female) were scanned twice consecutively using a PET-MR system and performed a one-legged squat exercise between scans. Changes in tracer uptake measures in 9 bone regions were compared between knees that did and did not exercise with a mixed-effects model. Areas of focally large changes in uptake between scans (ROIfocal, ΔSUVmax > 3) were identified and the presence of structural MRI features was noted. Five participants returned two years later to assess structural change on MRI. RESULTS: There was a significant increase in [18F]NaF uptake in OA exercised knees (SUV P < 0.001, KiP = 0.002, K1P < 0.001) that differed by bone region. CONCLUSION: There were regional differences in the acute bone metabolic response to exercise and areas of focally large changes in the metabolic bone response that might be representative of whole-joint dysfunction.

Interpreting treatment effect size from single case experimental design data: a preliminary analysis of differential effects of treatments designed to increase or decrease behaviour.

BACKGROUND: Estimates of treatment effect size from single case experimental design (SCED) data may be impacted by the direction for treatment effects (i.e. ascending or descending slope for the dependent variable). Estimating effect sizes for treatments designed to decrease behaviour are potentially more restricted because the intended direction for treatment is zero (i.e. an absolute basal). Conversely, effect sizes for interventions that increase behaviour are less restricted due to a relatively unconstrained ceiling from a pure measurement standpoint (i.e. no absolute ceiling). That is, treatments that increase behaviour have a broader range of possible effect size values as the ceiling is only limited by demand characteristics and the learners' skills and motivation to exhibit the behaviour. METHOD: The current study represents a preliminary analysis of the mean and range of SCED effect sizes for treatments designed to either increase or decrease target behaviour. A within-case Cohen's d measure that was developed for SCED data was used to estimate treatment effect sizes. RESULTS: Results indicated that the mean and range of effect size values for treatments that increased behaviour were significantly greater compared with treatments that decreased behaviour. CONCLUSIONS: Results are discussed in terms of developing standards, or best practices, specific to interpreting effect size values and meeting quality control requirements for inclusion of the data set in future SCED meta-analytic studies estimating treatment effect size. Specifically, preliminary results suggest that benchmarks for low, medium and high SCED effect size values need to be developed separately for treatments that increase or decrease levels of the dependent variable.

[18F]NaF PET-MRI provides direct in-vivo evidence of the association between bone metabolic activity and adjacent synovitis in knee osteoarthritis: a cross-sectional study.

OBJECTIVE: Synovitis is hypothesized to play a role in the development and growth of osteophytes. Our objectives were to use hybrid positron emission tomography-magnetic resonance imaging (PET-MRI) to (1) determine whether synovitis adjacent to peripheral bone subregions with increased metabolic activity is greater than adjacent to regions without increased metabolic activity and (2) assess the association between subregional bone metabolic activity and adjacent synovitis. DESIGN: We recruited 11 participants (22 knees) with a diagnosis of OA in at least one knee. Simultaneous bilateral knee PET-MRI was performed. We quantified bone metabolic activity using the radiotracer [18F]sodium fluoride ([18F]NaF) with calculation of maximum standardized uptake values (SUVmax). Synovitis was quantified using dynamic contrast-enhanced MRI with calculation of Ktrans. Bone subregions were coded as osteophyte (OP), focal increased [18F]NaF uptake without osteophyte (FIU), or normal (no osteophyte or FIU). We used robust linear mixed effects models to assess differences in adjacent Ktrans between different subregion types and to assess association between Ktrans and adjacent SUVmax. RESULTS: 94 OPs were detected (59 MOAKS grade 1, 30 grade 2, 5 grade 3), along with 28 FIU and 18 normal subregions. Ktrans was higher adjacent to FIU (adjusted mean [95% CI] = 0.06 [0.03,0.09]) and OPs (0.08 [0.05,0.11]) when compared to normal bone subregions (0.03 [0.00,0.09]). PET SUVmax was positively associated with adjacent Ktrans (ß[95% CI] = 0.018 [0.008,0.027]). CONCLUSIONS: Synovitis is more intense adjacent to peripheral bone regions with increased metabolic activity than those without, although there is some overlap. Subregional bone metabolic activity is positively associated with intensity of adjacent synovitis.

Assessment of quantitative [18F]Sodium fluoride PET measures of knee subchondral bone perfusion and mineralization in osteoarthritic and healthy subjects.

OBJECTIVE: Molecular information derived from dynamic [18F]sodium fluoride ([18F]NaF) PET imaging holds promise as a quantitative marker of bone metabolism. The objective of this work was to evaluate physiological mechanisms of [18F]NaF uptake in subchondral bone of individuals with and without knee osteoarthritis (OA). METHODS: Eleven healthy volunteers and twenty OA subjects were included. Both knees of all subjects were scanned simultaneously using a 3T hybrid PET/MRI system. MRI MOAKS assessment was performed to score the presence and size of osteophytes, bone marrow lesions, and cartilage lesions. Subchondral bone kinetic parameters of bone perfusion (K1), tracer extraction fraction, and total tracer uptake into bone (Ki) were evaluated using the Hawkins 3-compartment model. Measures were compared between structurally normal-appearing bone regions and those with structural findings. RESULTS: Mean and maximum SUV and kinetic parameters Ki, K1, and extraction fraction were significantly different between Healthy subjects and subjects with OA. Between-group differences in metabolic parameters were observed both in regions where the OA group had degenerative changes as well as in regions that appeared structurally normal. CONCLUSIONS: Results suggest that bone metabolism is altered in OA subjects, including bone regions with and without structural findings, compared to healthy subjects. Kinetic parameters of [18F]NaF uptake in subchondral bone show potential to quantitatively evaluate the role of bone physiology in OA initiation and progression. Objective measures of bone metabolism from [18F]NaF PET imaging can complement assessments of structural abnormalities observed on MRI.

Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.

OBJECTIVE: To assess the cost-effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage. DESIGN: Within-trial economic evaluation and model-based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost-effectiveness acceptability curves. Analyses were performed from the perspective of the UK's National Health Service (NHS). SETTING: Twenty-eight UK NHS early pregnancy units. SAMPLE: A cohort of 711 women aged 16-39 years with ultrasound evidence of a missed miscarriage. METHODS: Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets. MAIN OUTCOME MEASURES: Cost per additional successfully managed miscarriage and quality-adjusted life years (QALYs). RESULTS: For the within-trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7-12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26-£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model-based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model-based evidence suggests that the intervention is a less effective but less costly strategy than surgical management. CONCLUSIONS: The within-trial analysis found that based on cost-effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage. TWEETABLE ABSTRACT: The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

OBJECTIVES: To assess the cost-effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. DESIGN: Economic evaluation alongside a large multi-centre randomised placebo-controlled trial. SETTING: Forty-eight UK NHS early pregnancy units. POPULATION: Four thousand one hundred and fifty-three women aged 16-39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. METHODS: An incremental cost-effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. MAIN OUTCOME MEASURES: Cost per additional live birth at ≥34 weeks of gestation. RESULTS: Progesterone intervention led to an effect difference of 0.022 (95% CI -0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI -£559 to £711) more than the mean cost in the placebo group. The incremental cost-effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014-0.096) and this was associated with a cost saving of £322 (95% CI -£1318 to £673). CONCLUSIONS: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost-effective intervention, particularly for women with previous miscarriage(s). TWEETABLE ABSTRACT: Progesterone treatment is likely to be cost-effective in women with early pregnancy bleeding and a history of miscarriage.

Detecting national human enteric disease outbreaks linked to animal contact in the United States of America.

Enteric pathogens, such as non-typhoidal Salmonella, Campylobacter and Escherichia coli, can reside in the intestinal tract of many animals, including livestock, companion animals, small mammals and reptiles. Often, these animals can appear healthy; nonetheless, humans can become infected after direct or indirect contact, resulting in a substantial illness burden. An estimated 14% of the 3.2 million illnesses that occur in the United States of America (USA) each year from such enteric pathogens are attributable to animal contact. Surveillance for enteric pathogens in the USA includes the compilation and interpretation of both laboratory and epidemiologic data. However, the authors feel that a collaborative, multisectoral and transdisciplinary - or One Health - approach is needed for data collection and analysis, at every level. In addition, they suggest that the future of enteric illness surveillance lies in the development of improved technologies for pathogen detection and characterisation, such as genomic sequencing and metagenomics. In particular, using whole-genome sequencing to compare genetic sequences of enteric pathogens from humans, food, animals and the environment, can help to predict antimicrobial resistance among these pathogens, determine their genetic relatedness and identify outbreaks linked to a common source. In this paper, the authors describe three recent, multi-state human enteric illness outbreaks linked to animal contact in the USA and discuss how integrated disease surveillance was essential to outbreak detection and response. Additional datasharing between public health and animal health laboratories and epidemiologists at the local, national, regional and international level may help to improve surveillance for emerging animal and human health threats and lead to new opportunities for prevention.

Les agents pathogènes entériques tels que les Salmonella non typhiques, Campylobacter et Escherichia coli peuvent coloniser le tractus intestinal d'un grand nombre d'animaux y compris les espèces d'élevage, les animaux de compagnie, les petits mammifères et les reptiles. Les animaux porteurs sont souvent sains en apparence ; néanmoins, les humains peuvent contracter l'infection après un contact direct ou indirect avec un animal atteint, ce qui induit un fardeau significatif associé à ces maladies. D'après les estimations, environ 14 % des 3,2 millions de cas annuels d'infections par des agents pathogènes entériques aux États-Unis d'Amérique ont pour origine un contact avec des animaux. Aux États-Unis, la surveillance des agents pathogènes entériques est basée sur la collecte et l'interprétation des résultats de laboratoire et des données épidémiologiques. Les auteurs sont néanmoins convaincus de la nécessité de recourir à une approche collaborative, multisectorielle et transdisciplinaire (en d'autres termes, une approche Une seule santé) pour la collecte et l'analyse des données, à tous les niveaux. Ils considèrent également que la surveillance des infections entériques reposera à l'avenir sur le développement de technologies avancées dans le domaine de la détection et de la caractérisation des agents pathogènes, notamment le séquençage génomique et la métagénomique. En particulier, le recours au séquençage du génome entier afin de comparer les séquences d'agents pathogènes d'origine humaine, alimentaire, animale et environnementale permettra d'anticiper l'apparition d'antibiorésistances, de déterminer le degré de parenté génétique de ces agents et d'identifier les foyers provenant d'une même source. Les auteurs décrivent trois foyers récents d'infections entériques humaines survenus dans plusieurs états des États-Unis et soulignent à quel point l'exercice d'une surveillance sanitaire intégrée a été déterminant pour la détection de ces foyers et la mise en œuvre d'une réponse appropriée. Un partage accru d'informations entre les laboratoires et les épidémiologistes de santé publique et animale aux niveaux local, national, régional et international pourrait contribuer à améliorer la surveillance des menaces émergentes pesant sur la santé animale et humaine et à mettre en œuvre de nouvelles modalités de prévention.

En el tracto intestinal de muchos animales, entre ellos ganado, mascotas, pequeños mamíferos o reptiles, puede haber patógenos intestinales como salmonelas no tifoideas, Campylobacter o Escherichia coli. A menudo los animales parecen sanos, pese a lo cual las personas pueden infectarse por contacto directo o indirecto con ellos, lo que da lugar a una considerable carga de morbilidad. Se calcula que, de los 3,2 millones de casos de enfermedad que estos patógenos intestinales causan al año en los EE. UU., un 14% es atribuible al contacto con animales. La vigilancia de patógenos intestinales que se practica en los EE. UU. incluye la compilación e interpretación de datos tanto epidemiológicos como de laboratorio. En opinión de los autores, sin embargo, es preciso que la obtención y el análisis de datos respondan a un planteamiento de colaboración multisectorial y transdisciplinar ­ esto es, a la lógica de Una sola salud ­ que abarque todos los niveles. Los autores apuntan además que el futuro de la vigilancia de las enfermedades intestinales pasa por el desarrollo de tecnologías más eficaces de detección y caracterización de patógenos, como la secuenciación genómica o la metagenómica. En particular, el uso de la secuenciación de genomas completos para comparar entre sí las secuencias genéticas de patógenos intestinales presentes en personas, alimentos, animales y el medio ambiente puede ayudar a predecir la aparición de resistencias a los antimicrobianos en estos patógenos, determinar su parentesco genético e identificar brotes vinculados con un origen común. Los autores, tras describir tres recientes brotes de enfermedad intestinal humana ligados al contacto con animales que afectaron a varios estados de los EE. UU., explican la función esencial que cumplió la vigilancia integrada de enfermedades para detectar esos brotes y responder a ellos. El intercambio de más datos entre los laboratorios de salud pública y sanidad animal y los epidemiólogos a escala local, nacional, regional e internacional puede ser de ayuda para mejorar la vigilancia de amenazas sanitarias y zoosanitarias emergentes y abrir nuevas posibilidades de prevención.

What are the perceptions of interventional radiology amongst foundation doctors and how can awareness be improved?

AIM: To assess perceptions of interventional radiology (IR) amongst foundation trainees (FYs) and to explore how awareness can be improved. MATERIALS AND METHODS: Seventy-nine FYs completed a survey developed by the Radiology Department. RESULTS: Forty-five percent of FYs were introduced to IR throughout their training posts, whereas 38% learnt more via self-directed reading. Fifty-nine of the 79 FYs would not consider a career in IR with 53/59 lacking interest in radiology and 13/59 lacking enough information. The majority were aware that interventional radiologists have on-call commitments; however, 55% realised that they attend clinics. Just over 85% were familiar that ultrasound-guided biopsy was performed by IR closely followed by inferior vena cava (IVC) filter and nephrostomy insertions (81% and 72% respectively). Around one-third of FYs thought that interventional radiologists come from a surgical background while 64% knew that juniors are able to apply directly for radiology. Sixty-five percent rejected the notion of learning more about IR; however, the most preferred methods to raise awareness were elective placements and teaching throughout foundation years. CONCLUSION: FYs perception of IR is generally poor due to lack of adequate knowledge. This may dissuade them from selecting radiology as a career. Efforts need to be exerted to raise awareness with the aim of attracting more juniors to IR in order to address the significant shortage of interventional radiologists in the UK.

A multisite, randomized field trial to evaluate the influence of lactoferrin on the morbidity and mortality of dairy calves with diarrhea.

Diarrhea is one of the most common causes of antimicrobial use and mortality in young calves. To reduce antimicrobial use and resistance on dairy farms, research on alternative therapies for calf diarrhea is necessary. Our laboratory previously conducted a randomized clinical trial investigating the effectiveness of lactoferrin, an iron-binding protein found in colostrum, as a treatment for calf diarrhea. The trial showed significantly reduced calf mortality in diarrheic calves that were administered lactoferrin. Thus, the objective of this study was to corroborate the results of our prior clinical trial across multiple farms and to investigate the effect of lactoferrin on the morbidity and mortality of preweaned calves with naturally occurring cases of diarrhea. This randomized field trial was conducted on 5 commercial dairy farms in Ohio. In total, 485 calves (≤21 d of age) were enrolled at first diarrhea diagnosis (fecal score ≥2 defined as loose to watery) and randomly assigned to receive an oral dose of lactoferrin (3 g of lactoferrin powder dissolved in 30 mL of water) or 30 mL of water (control) once daily for 3 consecutive days. Health assessments were conducted on the day of diarrhea diagnosis (d 0) and 1, 2, 3, 7, 14, 21, 28, and 35 d following diagnosis. Producer records of disease treatment and mortality were collected 120 d following diagnosis. A Poisson regression model was used to test differences between treatments in disease frequency through 35 d post-diarrhea diagnosis and the incidence risk of treatment and mortality risk 120 d post-diarrhea diagnosis; the model controlled for calf age at enrollment, farm, and treatment. Median calf age at enrollment was 11 d and ranged from 1 to 26 d of age. At study enrollment, 51.3% (123/240) and 52.2% (128/245) of calves in the control and lactoferrin treatment groups, respectively, were diagnosed with severe diarrhea (fecal score = 3). The frequency of disease (diarrhea, dehydration, depression, signs of respiratory disease) through 35 d following diarrhea diagnosis was not significantly different for calves in the lactoferrin and control groups. Overall mortality risk for enrolled calves was 9.9%, and 10.7% (22/243) and 9.1% (26/242) of calves in the lactoferrin and control groups, respectively, died or were culled in the 120 d following diarrhea diagnosis. The relative risk of death or culling did not differ between treatment groups, however. Therefore, as performed in this study, lactoferrin as a treatment for calf diarrhea was not beneficial.

Intracranial pressure in patients with papilloedema.

OBJECTIVES: Papilloedema is a clinical manifestation of chronically raised intracranial pressure (ICP), often seen in idiopathic intracranial hypertension (IIH). However, the extent of intracranial hypertension required to produce papilloedema is not known. We compare ICP values in IIH patients who developed papilloedema and those who did not. We aim to identify a pathological ICP threshold predictive of the development of papilloedema in IIH patients. MATERIALS AND METHODS: Single-centre cohort of IIH patients (2006-2016) who underwent 24-hour ICP monitoring (ICPM) and ophthalmology assessments, prior to intervention. Papilloedema was graded according to the Frisén scale. An unpaired t-test compared 24-hour ICPM between papilloedema and no-papilloedema groups. Fisher's exact test was used to determine predictive value of ICP. RESULTS: Thirty-six patients with IIH (35 F: 1M), mean age 32.5 ± 9.49 years (mean ± SD) were included. Patients with papilloedema had a mean median 24-hour ICP of 10.4 ± 5.32 mm Hg (n = 25), significantly higher than the group without papilloedema 6.31 ± 3.30 mm Hg (n = 11) (P < .05). The papilloedema group were exposed to higher pressures (10 mm Hg) for 30 minutes or more. Using 24-hour median ICP of 10 mm Hg as a minimum cut-off predictive value gives a specificity = 91%, sensitivity = 48%, PPV = 92% and NPV = 44% of detecting papilloedema. CONCLUSIONS: A 24-hour ICP of 10 mmHg or more is a good predictor for papilloedema and reflects a pathological threshold. The range varied widely suggesting papilloedema can occur at even lower pressures. These results are consistent with emerging evidence suggest that pathologically "high" 24 hours ICP is lower than previously quoted.

Treatment of intractable chronic cluster headache by occipital nerve stimulation: a cohort of 51 patients.

BACKGROUND AND PURPOSE: Chronic cluster headache is a rare, highly disabling primary headache condition. When medically intractable, occipital nerve stimulation can offer effective treatment. Open-label series have provided data on small cohorts only. METHODS: We analyzed 51 subjects to evaluate the long-term outcomes of highly intractable chronic cluster headache with occipital nerve stimulation. Patients with intractable chronic cluster headache were implanted with occipital nerve stimulators during the period 2007-2014. The primary endpoint was improvement in daily attack frequency. Secondary endpoints included attack severity, attack duration, quality-of-life measures, headache disability scores and adverse events. RESULTS: We studied 51 patients [35 males; mean age at implant 47.78 (range 31-70) years; mean follow-up 39.17 (range 2-81) months]. Nineteen patients had other chronic headache types in addition in chronic cluster headache. At final follow-up, there was a 46.1% improvement in attack frequency (P < 0001) across all patients, 49.5% (P < 0.001) in those with cluster headache alone and 40.3% (P = 0.036) in those with multiple phenotypes. There were no significant differences in response in those with or without multiple headache types. The overall response rate (defined as at least a 50% improvement in attack frequency) was 52.9%. Significant reductions were also seen in attack duration and severity. Improvements were noted in headache disability scores and quality-of-life measures. Triptan use of responders dropped by 62.56%, resulting in significant cost savings. Adverse event rates were highly favorable. CONCLUSION: Occipital nerve stimulation appears to be a safe and efficacious treatment for highly intractable chronic cluster headache even after a mean follow-up of over 3 years.

Elective ICP monitoring: how long is long enough?

BACKGROUND: Intracranial pressure monitoring is commonly undertaken to assess and manage acute patients following head injury. However, ICP monitoring can also be a useful diagnostic tool in the management of CSF dynamics in elective patients. To date, there is little published research to suggest how long these elective patients require ICP monitoring in order to gain an accurate picture of a patient's ICP dynamics. At the author's institution, a minimum of 48-h data collection is currently undertaken in patients with a suspected ICP abnormality. METHODS: A retrospective audit was undertaken comparing overall median ICP and overall median pulse amplitude data at three time points, 24 h, 48 h and total time analysed (if longer than 48 h). Paired T-test was used to assess if there were statistically significant differences between 24-h versus 48-h monitoring and total duration of monitoring. All patients admitted over a 6-month period for ICPM who met the inclusion/exclusion criteria were included. RESULTS: Eighteen patients met the criteria. Median age was 45.8 years, range 22-83 years, 12 female and 6 male. No complications were experienced as a result of ICPM. Diagnosis included NPH, IIH, suspected shunt malfunction and Chiari malformation. The results demonstrated that there is no statistical difference between 24 h and 48 h or longer for both overall median ICP and pulse amplitude. CONCLUSION: The results of this study demonstrate that ICP monitoring of elective adult patients using a Spiegelberg intraparenchymal bolt for 24 h gives an accurate picture of a patient's ICP dynamics compared with longer periods of monitoring.

Shunting of the over 80s in normal pressure hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus is predominantly a disease of the elderly. By its nature, many of those who present to clinic are in advanced old age with multiple comorbidities. Majority of patients treated are younger than 80 years old. We present the clinical outcomes and complication rates of patients over the age of 80 years at the time of operation, during the past 11 years at a single institution. METHODS: Retrospective analysis of clinical records of all patients over the age of 80 years, who presented to our institution between 2006 and 2016. Results were analysed for co-morbidities, immediate and delayed complications, change in mobility/cognitive function post shunting of hydrocephalus. RESULTS: 39 patients (24 male, 15 female) met criteria. Mean [SD] age at the time of shunt insertion was 84 years (+/- 3.22) (range 80-94). No patients developed immediate CSF infection or sub-dural collection, or extended length of stay due to surgical or anaesthetic complications. There were no peri-operative or anaesthetic complications. 4 patients required a delayed surgical revision to encourage greater CSF drainage. 3 patients went on to develop delayed subdural haematoma, 1 of which was associated with trauma, 2 through overdrainage. 1 patient experienced poor post-operative wound healing and subsequently underwent removal of shunt. Of the 34 patient followed up, 27 patients (79.4%) improved in their mobility. (64.7%) patients/families reported symptomatic improvement in their cognition and memory. 6 (17.7%) patients did not experience an improvement in either mobility or cognitive function. CONCLUSIONS: Our data supports the assertion that, with proper patient selection, shunting of the over 80s with iNPH is a safe and effective procedure.

DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling.

The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.

Ellipse fitting for interferometry. Part 3: dynamic method.

We describe a dynamically based method for fitting an ellipse to noisy data, which has for interferometric applications a number of advantages over conventional static methods (originally developed for image processing). Our method relies on the observation that each data point belongs to an ordered time series and thus has a well-defined phase parameter. We demonstrate that for real experimental data it can achieve much greater accuracy than static methods. The precision of the fit is limited only by the statistical reliability of the data, even in extreme cases such as ellipses with a minor axis smaller than the measurement noise.

Work and home stress: associations with anxiety and depression symptoms.

BACKGROUND: In the evolving work environment of global competition, the associations between work and home stress and psychological well-being are not well understood. AIMS: To examine the impact of psychosocial stress at work and at home on anxiety and depression. METHODS: In medically healthy employed men and women (aged 30-60), serial regression analyses were used to determine the independent association of psychosocial stress at work and at home with depression symptoms, measured using the Beck Depression Inventory-II (BDI-II), and anxiety symptoms, measured using the Spielberger Trait Anxiety Inventory (STAI). Psychosocial stress at work was measured using the Job Content Questionnaire to assess job psychological demands, job control, job social support and job insecurity. Psychosocial stress at home was assessed by 12 questions including stress at home, personal problems, family demands and feelings about home life. RESULTS: Serial regression analyses in 129 subjects revealed that job insecurity and home stress were most strongly associated with depression and anxiety symptoms. Job insecurity accounted for 9% of the variation both in BDI-II scores and in STAI scores. Home stress accounted for 13 and 17% of the variation in BDI-II scores and STAI scores, respectively. In addition, job social support was significantly and independently associated with STAI scores but not BDI-II scores. CONCLUSIONS: Work and home stress were associated with anxiety and depression symptoms in both men and women. Both work and home stress should be considered in studies evaluating anxiety and depression in working populations.

Predicting preterm birth in women with previous preterm birth and cervical length ≥ 25 mm.

OBJECTIVE: To identify risk factors predicting subsequent spontaneous preterm birth or preterm prelabor rupture of membranes (PPROM) in a cohort of women with a history of spontaneous preterm birth and a cervical length of ≥ 25 mm at 20-24 weeks' gestation. METHODS: We identified all pregnant women who attended our preterm labor clinic between January 2010 and December 2012 because of previous spontaneous preterm birth or PPROM before 34 weeks. Women with a normal cervical length (defined as ≥ 25 mm) between 20 and 24 weeks' gestation were identified and included in the analysis. Maternal characteristics, obstetric history, shortest cervical length and gestational age at shortest cervical length of women who delivered preterm (before 37 weeks) were compared with those who delivered at or after 37 weeks in the index pregnancy. Multiple regression analysis was planned to examine the relationship between significant clinical and cervical-length variables to identify significant clinical predictors of spontaneous preterm birth among high-risk patients with a normal cervix between 20 and 24 weeks' gestation. RESULTS: Of 134 women with a normal cervix at 20-24 weeks, 28 (20.9%) delivered spontaneously or had PPROM before 37 weeks; of these 12 (9.0%) delivered before 34 weeks. None of the selected explanatory variables was predictive of recurrent preterm birth in this cohort. No correlation between absolute cervical length and gestational age at delivery was found (R = 0.01). CONCLUSION: In high-risk women with a cervical length of ≥ 25 mm at 20-24 weeks' gestation, demographic characteristics and absolute cervical length are not useful in predicting subsequent spontaneous preterm birth.

Neural stimulators: a guide to imaging and postoperative appearances.

Implantable neural stimulators have been developed to aid patients with debilitating neurological conditions that are not amenable to other therapies. The aim of this article is to improve understanding of correct anatomical placement as well as the relevant imaging methods used to assess these devices. Potential complications following their insertion and an overview of the current indications and potential mechanism of action of these devices is provided.