Aims and method To assess whether a home treatment team acute relapse prevention (ARP) strategy reduces admissions to hospital with mania. A retrospective design was used to analyse records for manic admissions since 2002. The number and length of admissions and detentions pre- and post-ARP were determined and rates of admissions and detentions calculated from this.Results We found reductions in admission and detention rates following the introduction of the ARP: 0.3 fewer admissions per person per year (95% bootstrap CI 0.09–0.62) and 0.25 fewer detentions per person per year (95% bootstrap CI 0.0–0.48). Wilcoxon signed-rank tests gave P<0.0001.Clinical implications A person-centred care plan such as the ARP which enables quick action in response to relapse-warning signs of mania appears to reduce rates of admission to hospital. The ARP could be used anywhere in the UK and fits with current mental health policy. It was designed by members of the home treatment team (HTT) in Plymouth in 2007, following concerns that service users with early relapse signs were not felt to reach HTT thresholds and therefore not taken on to case-load. This led to rapid deterioration and subsequent admissions to psychiatric hospital  which were felt to have been potentially avoidable if quicker action with targeted treatment had been taken.Each person with bipolar affective disorder known to the service is given an opportunity to create their own personalised version of the care plan in collaboration with professionals from the HTT and carers or family if desired. The plan identifies specific relapse signatures for individuals and interventions which can help prevent further deterioration. With the person’s consent the plan is shared with professionals involved in their care and allows general practitioners (GPs), community teams, families, carers or the individual themself to refer to the HTT and be instantly taken on to case-load with no initial assessment, to expedite immediate initiation of their personalised treatment plan. The ARP aims to intervene as early as possible in mania. The purpose of this is to reduce further deterioration, which can be rapid, minimise disruption to lives and help avoid hospital admissions and detentions. People are taken on by the HTT for an initial period of 4 days for assessment and treatment if appropriate. Subsequently, they either stay with the HTT for a longer period or are transferred to their care coordinator or general practitioner.2 however, there has been little work done to quantify their use in allowing instant access to an HTT when early relapse signs of mania are detected which may otherwise fall below the threshold for action by a home treatment or crisis team. No literature was identified which evaluated a structured acute relapse prevention strategy, such as that in Plymouth, in an HTT. However, there is evidence promoting the benefit of helping people with bipolar affective disorder recognise signs of relapse to control their condition and reduce its impact on their lives.8Personalised, collaborative care plans are part of mental health policy in the UK;The study was undertaken to evaluate this specific care plan by finding out whether voluntary and involuntary admissions to hospital were reduced for this group of people after initiation of their ARP care plan.In total, 59 people were included in the analysis. They became known to the service between 4 March 2002 and 25 October 2010 and were aged 18 years or over. The ARP care plans were implemented during the period 19 March 2007 to 21 February 2011. The number of days that people were known to the service prior to the start of an ARP care plan ranged from 28 to 1841, and 435–1870 days since the start of their ARP care plan.Electronic records for service users were retrospectively analysed from 2002 until data collection in May 2012. Depressive relapses were excluded from the data by reading electronic records.Data were used to identify the number of admissions to psychiatric hospital people had before and after an ARP was put into place for them, and the total number of days spent in hospital pre- and post-ARP. They were also used to identify the number of detentions pre- and post-ARP and the total days spent detained pre- and post-ARP. People were either detained under Section 2  or Section 3 (compulsory admission for treatment for up to 6 months) of the Mental Health Act.Rates of admissions and detentions pre- and post-ARP were calculated for each person (admissions/detentions per person per year) to allow for differing time periods before and after an ARP was introduced.10 Data were checked for distributional assumptions using QQ-plots.Statistical analysis was carried out using the ‘R’ environment for statistical computing with the ‘lattice’ package for producing graphics.P<0.05 was determined to be statistically significant; 95% confidence intervals for the medianFor each patient the difference between the pre-ARP and post-ARP rates was calculated, which allows for the different time periods that each person was known to the service pre- and post-ARP. We then tested whether the median of the differences was equal to 0 using Wilcoxon signed-rank tests: Of the 59 people, 46 (80%) were admitted at least once pre-ARP, with 105 admissions in total, and 21 people (36%) were admitted at least once post-ARP, with 54 admissions in total . The numThe number of admissions per year pre-ARP ranged from 0.2 to 12.6 and post-ARP from 0.2 to 1.8. The total number of days spent admitted to hospital was 4162 pre-ARP and 2102 post-ARP.P<0.0001. Therefore, there is evidence that the median difference in admission rates per person per year pre- and post-ARP is not 0.The median patient admission rates were 0.51 admissions per person per year pre-ARP and 0.0 per person per year post-ARP, as illustrated in Overall, 39 people in the study (66%) were detained at least once pre-ARP, with 96 detentions in total and 1 to 8 detentions per person. Post-ARP, 15 people (25%) were detained at least once (range 1 to 8 detentions) and there were 38 detentions in total. There were 42 Section 2 detentions pre-ARP and 10 post-ARP; and 37 Section 3 detentions pre-ARP and 16 post-ARP; 20 people (34%) were never detained with mania.The number of detentions per year pre-ARP ranged from 0.2 to 12.6 and post ARP from 0.2 to 2.3. The total number of days spent detained was 2976 pre-ARP and 1947 post-ARP.The median patient detention rates were 0.4 detentions per person per year pre-ARP and 0.0 per person per year post-ARP, as illustrated in P<0.0001. However, the bootstrap confidence interval for the median difference in detention rates includes 0. Therefore, there is some evidence that the median difference in detention rates per person per year pre- and post-ARP is not 0.A Wilcoxon signed-rank test on the differences in detention rates gives There were fewer admissions and detentions post-ARP than pre-ARP via the HTT, and statistical testing of the differences in the rates of admissions and detentions revealed statistically significant reductions in the rates of admissions and detentions post-ARP compared with pre-ARP. There were 0.3 fewer admissions per person per year equating to almost 1 less admission over 3 years and 0.25 fewer detentions per person per year equating to approximately 1 less detention over 4 years. Although the bootstrap confidence interval for the median difference in detention rates includes 0, there is still some evidence that the median difference in detention rates is not 0. The median length of stay per admission was not significantly reduced.These may seem relatively small values, but given the amount of disruption that can be caused to a person’s life when they become manic, including the risk of being detained in hospital, avoiding even 1 detention every 4 years can be important.12 However, it is also known that people with severe mood disorders may present particular difficulties in home treatment and were the most likely to later require transfer to in-patient care, therefore it was suggested that particular attention be paid to the initial assessment and treatment plan for such patients.14 There is a large body of evidence advocating early recognition and collaborative management of relapse signs of mania, including guidelines from the National Institute for Health and Care Excellence (NICE).6 Self-management approaches based on recognition of early warning signs of mania or depression are also popular with patient groups.7 A randomised controlled trial on the efficacy of using a health professional to teach patients with bipolar affective disorder to recognise, and seek treatment for, early warning signs of mania found that time to relapse was increased four-fold in the intervention group, as well as other clinically important improvements in functioning, including employment.8 A Cochrane review5 found beneficial effects of early warning sign interventions  in time to recurrence, percentage of people hospitalised and functioning of people with bipolar affective disorder. Other systematic reviews18 found psychosocial interventions  to be effective as an adjunct to pharmacological therapy in reducing relapse. However, despite the large body of evidence advocating early recognition and collaborative management of relapse signs of mania,18 there is little literature about a person-centred care plan such as the ARP allowing instant access to and treatment by an HTT, in some cases via self-referral. Our findings on this intervention indicate that this is an effective, innovative and useful approach which adds something a little different to the current evidence on early interventions for mania.To put our results into context, it has been found that crisis teams such as the HTT can reduce in-patient admissions for people with all diagnoses.19 do not suggest major differences to other urban areas in the UK which could mean our results would be unique. Although our sample is relatively small, it could be expected that our results would be generalisable to other parts of the UK should similar care plans be implemented elsewhere. However, intensive treatment at home may work better in urban populations due to the shorter distances needed to travel.Our participants are from Plymouth, which is a medium-sized university town. Figures from UK national statistics specifying the demographics of PlymouthIt is possible that by reducing admissions cost savings are made, although no clear conclusion about this could be drawn from the results of this study. It would be important to ensure an adequately funded and staffed HTT so that crisis response and management could be handled promptly and efficiently. A similar plan could be introduced for bipolar depression and other conditions, such as schizophrenia and borderline personality disorder. However, this type of care plan suits mania in bipolar affective disorder because of the speed of progression in mood elevation that can occur.A control group could not be analysed, as most people with a history of bipolar affective disorder known to the service in Plymouth have an ARP in place.Fifty-nine is a relatively small sample size; however, this was the total number of people with an ARP in Plymouth. We were therefore unable to make a power calculation prior to starting the study. Larger studies over several centres could be planned further to this study, for example, a cohort study including a control group over several geographical areas, if the ARP is introduced elsewhere.There has been an increase in experience and staffing in the Plymouth HTT since 2002, which may have contributed to the reduction in admission and detention rates.We are aware that by calculating patient-specific admission and detention rates we have not allowed for the duration of these events. For example, a person may have had several shorter admissions that do not last as long in total as another person’s one prolonged admission.An ARP strategy in an HTT acts to intervene and treat early at home when people with bipolar affective disorder show relapse-warning signs of mania. Rates of admissions and detentions under the Mental Health Act were statistically significantly reduced in people with bipolar affective disorder and an ARP in Plymouth. The ARP is unique in early warning sign interventions in that it is a care plan aimed at immediate acceptance and intervention from an HTT with strategies known to help an individual. This could be used anywhere in the UK.


Young infants have reduced susceptibility to febrile malaria compared with older children, but the mechanism for this remains unclear. There are conflicting data on the role of passively acquired antibodies. Here, we examine antibody titres to merozoite surface antigens in the protection of children in their first two years of life in two settings with differing malaria transmission intensity and compare these titres to previously established protective thresholds.Plasmodium falciparum recombinant merozoite proteins  were measured by enzyme-linked immunosorbent assay at 1–6, 9, 12, 15 and 18 months of age and compared with the protective thresholds established in Kenyan children.Two cohorts of children aged four to six weeks were recruited in Banfora, Burkina and Keur Soce, Senegal and followed up for two years. Malaria infections were detected by light microscopic examination of blood smears collected at active and passive case detection visits. The titres of antibodies to the Antibody titres were below the protective thresholds throughout the study period and we did not find any association with protection against febrile malaria. Antibodies to AMA1 and MSP1-19 appeared to be markers of exposure in the univariate analysis (and so associated with increasing risk) and adjusting for exposure reduced the strength and significance of this association.The antibody levels we measured are unlikely to be responsible for the apparent protection against febrile malaria seen in young infants. Further work to identify protective antibody responses might include functional assays and a wider range of antigens. These studies have yielded inconsistent associations between anti-malaria antibodies and immunity to malaria We recently conducted a study in Burkina Faso examining the impact of maternally-acquired antibodies against synthetic GLURP and MSP3 on the risk of malaria. We found associations between increasing antibody levels and increasing risk of malaria, and no evidence of protective antibody responses. Limitations of this previous study were the limited number of antigens that were examined, and the lack of standardised controls that meant we could not estimate relative antibody concentrations and therefore could not determine how close these antibody levels were to the protective thresholds.P. falciparum febrile malaria.The present malaria sero-epidemiological study expands the range of antibodies examined and includes standardised controls. Furthermore we describe below how antibody levels vary during the first 18 months of life in two settings with differing transmission intensity and we present the results of the analysis testing the hypothesis of an association between total IgG to merozoite antigens and protection against 22.1The ethical approval for the work in Burkina Faso was obtained from the Institutional Review Board of Centre National de Recherche et de Formation sur le Paludisme (CNRFP) in Burkina Faso. In Senegal, the study was approved by the National Ethics Committee. The parents of each child were informed and an individual written consent obtained prior to performing any study-specific procedure on the child. The studies in both settings were conducted according to the principles of the Declaration of Helsinki.2.2The study was conducted in Banfora, Burkina Faso and in Keur Soce, Senegal.The Banfora site is described elsewhere 2.3In both sites, febrile malaria cases were detected using a combination of active and passive monitoring as detailed elsewhere 2.4The identification and quantification of malaria parasites were done as described elsewhere 2.5For a subset of 40 children in each site , samples at baseline, 2, 3, 4, 5, 6, 9, 12, 15 and 18 months were analysed to compare antibody dynamics. The samples of the remaining children in the Banfora cohort were analysed only at baseline, 3, 6, 9, 12 and 18 months and included in the analysis of the association between antibody levels and risk of clinical malaria in that cohort.2.6The following four recombinant merozoite antigens were tested in this study: the His-tagged AMA1 of the 3D7 allelic form 2.7Serum total IgG titres were measured as described elsewhere 33.1P.f. merozoite antigens between both the sites at baseline. Fractional polynomial regression models were constructed to fit the non-linear relationship between anti-malaria antibody titre and age. The protective thresholds  displayed in the graphs have been taken from the results of studies conducted by Murungi et al. in the Kenyan Coast We used Pearson correlation test on log-transformed values to measure how strong the relationship is between antibody levels to a given antigen from one time point to the following one and between antigen-specific antibody titres. To estimate the overall decline of antibodies, we used a Random-Effects regression model of antibody titres on age to account for between and within-infant variability of antibody titres. We calculated the cut-off value for seropositivity as the mean OD of negative controls plus 3 standard deviations. Fisher's Exact test was used to compare seroprevalence of antibodies to the 3.2The outcome measure, febrile malaria, was defined as the association of fever (axillary temperature ≥37.5 °C and/or reported fever in the past 24 h) plus asexual parasitemia ≥10,000/μL 44.1The characteristics of the Banfora infant cohort, follow up and malaria morbidity are described in detail elsewhere 4.2At baseline, the seroprevalence of the merozoite antigens was significantly higher in the Banfora cohort compared with Keur Soce cohort except for antibodies to MSP1-19 (Table S2). After a steady decline in the first six months of life regardless of the transmission intensity, the seroprevalence to all the antigens tested held below 20% for the remaining monitoring period in Keur Soce, the low transmission area. In Banfora where the transmission is higher, the seroprevalence peaked after six months for MSP1-19 and MSP3-3D7 . Only anti-MSP2 antibodies increased appreciably from month 9 . No confr, 0.86–0.98 in Keur Soce, 0.86–0.91 in Banfora for AMA-1) . After the first 6 months of life, antibody titres were weakly to moderately correlated to each other in Keur Soce  but not correlated in Banfora (−0.21 to 0.03).Antibody titres to AMA1-3D7, MSP1-19, MSP2-Dd2, MSP3-3D7 were strongly correlated from time point to time point during the first six months of life in both settings regardless of the transmission intensity (4.34.3.1p = 0.002) and MSP1-19  were significantly associated with a higher risk of febrile malaria but season was the strongest significant risk factor for febrile malaria . The results of the event count analysis were similar except for anti-AMA1-3D7 antibodies that appeared as significantly associated with protection against febrile malaria episodes . Children with haemoglobin CC type had lower risk of febrile malaria compared with haemoglobin AA children. Age was a significantly associated with risk of febrile malaria (Table S4). In both models, the highest level of education was significantly associated with protection and children born in the last quarter of the year had significantly lower risk of febrile malaria compared with those born in January as previously described This analysis applies to Banfora only. In the time-to-event univariate analysis none of the antigen-specific antibodies, in terms of levels or seropositivity, was associated with protection. Antibodies to AMA1-3D7 . Season remained the strongest risk factor , and exposure index was associated with a risk of malaria . There was a tendency of anti-MSP1-19 antibodies to be associated with higher risk of febrile malaria , but overall the correlation between antibodies and increased risk of malaria was reduced by adjusting for exposure and season. There was no significant deviation from the proportional hazards assumption (p = 0.042) in the event count analysis.There was only limited collinearity between the different antibody titres . In the multivariable time-to-event analysis, foetal haemoglobin rate was weakly but significantly associated with protection  were rather a maker of exposure to malaria, evidenced by the association with risk and the fact that this association was diminished after adjusting for the exposure index.The titres of antibodies to all the four antigens tested were below the protective thresholds except for a few outlying results. After a consistent decline up to six months of age, only antibodies to MSP2 showed a steady increase up to month 18 in the high transmission setting (Banfora). Overall, we did not find any protective effect in the investigation of the association between antibodies to Average antibody decay rates were similar in both settings only for antibodies to MSP1-19. Reduced exposure to infectious bites during the first six months in the high and seasonal transmission setting (Banfora) is a likely explanation of this similarity since only five malaria infections were detected during this period in Banfora, of which three occurred in the first rainy season in children aged above five months. The lack of acquisition of antibodies and the strong correlation of antibody levels between time points in Keur Soce indicates lack of exposure throughout the monitoring period. However in Banfora antibody levels were more variable from time point to time point, indicating that exposure to malaria was stimulating antibody production in some children, and furthermore that increases in antibody titres were often transient .Few studies have examined the role of anti-malaria antibodies in infants. We found that anti-AMA1-3D7 antibodies appeared as a marker of exposure  in our univariate analysis, which is consistent with the conclusions of Riley et al. The apparent variation in results between infants and older children may be explained by the presence of a protective threshold. Murungi et al. and Rono et al. have analysed two independent cohorts of children and established protective threshold concentrations for some merozoite antigens The possibilities are that other antibodies not measured in our work are related to protection 6P. falciparum merozoite antigens  remained low compared with the previously established protective threshold concentrations. In addition, the antibodies were not significantly associated with a reduced risk of malaria raising more questions on the basis of the early apparent protection against febrile malaria.Even at high intensity of malaria transmission, antibody levels to the tested However, these results should be interpreted with caution because of the limitations of this study. The protective thresholds used in the present study have been established in cohorts including children more than 2 years old in addition to infants. In our cohort, the lack of any protective effect did not allow us to determine specific thresholds for this age group. Furthermore, the timing of the study, in which the first few months of life overlapped with the low malaria transmission season, was not ideal to assess the role of maternal antibodies at the higher titres seen in the first few months of life. However, if antibody thresholds are related to real biological phenomena than we would expect, the thresholds should be similar across study sites and age group. Hence the main contribution of our work is the demonstration that antibody levels in infants to selected merozoite antigens are well below previously defined protective thresholds, and therefore that these are unlikely to be responsible for mediating protection in vivo. Further work to identify protective antibody responses might include assessment of antibodies to other targets including red cell surface antigens, and functional assays in which the interaction of antibodies with immune cells is taken into account


Labidochromis caeruleus) could form memories for food-reinforced stimuli that last for 12 days. During the training sessions, fish were reinforced for approaching an upward drifting line grating. After a rest period of 12 days, fish demonstrated a significant preference for the upward drifting grating. To determine whether this preference could also be reversed, fish were then reinforced for approaching a downward drifting line grating after a 20-day rest period. When tested 12 days later, there were no significant differences in preference for either stimulus; however, following a second training period for the downward stimulus, there was a significant preference for the downward drifting grating. This suggests that cichlids are able to form reversible discrimination-based memories for food-reinforced stimuli that remain consolidated for at least 12 days.The formation of long-term memories for food sources is essential for the survival of most animals. Long-term memory formation in mammalian species has been demonstrated through a variety of conditioning tasks, however, the nature of long-term memory in fish is less known. In the current study, we explored whether African cichlids ( Long-term memories for biologically relevant information are an essential mechanism for survival in a wide variety of animals. Memories that span on the order of years have been demonstrated in young monkeys  are able to discriminate between different food-reinforced stimuli and have been successfully trained in spatial learning paradigms  also have associative learning capabilities , for example, can remember the correct location of food reinforcement in a T-maze with colored arms  were shown to have a reduced latency to escape an aversive stimulus almost 1 year after initial exposure to the experimental set up when compared to fish who had never been placed in the testing arena  would create and maintain a reinforcement-based memory over a period of 12 days. Cichlids were reinforced to respond to a drifting line grating pattern that was presented at one end of the training arena, and memory for the pattern was assessed 12 days after training to establish whether a memory trace for the trained pattern existed. We also conducted reversal training, where fish were trained to respond to the opposite drifting pattern in order to establish whether any observed effects were due to the formation of a memory trace and not to an inherent sensory bias. Our results suggest that cichlids are capable of forming reinforcement-based memories for at least a period of 12 days.We evaluated whether “electric yellow” cichlid fish  ranging in age from 0.5 to 1.5 years were housed together in a 60 L tank (30 × 60 × 40 cm) with transparent walls. This community housing tank contained a submersible heater, sand substrate, eight rock hiding spots, and two air-stones that constantly created bubbles in the water. Water (10%) was changed once a day using dechlorinated tap water. Fish were housed with a 12 h light/dark cycle, with lights switched on at 8 AM and off at 8 PM. Fish were normally fed with pelleted food  once a day. Water quality measures daily included temperature, pH and dissolved oxygen. Weekly water quality measures included that of ammonia, nitrates, nitrites, alkalinity, hardness and conductivity. This research was approved by the MacEwan University Animal Research Ethics Board, protocol number 05-12-13, under Canadian Council for Animal Care (CCAC) guidelines.Electric yellow cichlids (The training and testing sessions were conducted in a rectangular arena (91 × 46 × 31.5 cm) that was filled with 8.5 cm of water (26–29°C). Water was aerated with oxygen between training sessions. The stimuli used for reinforcement were two separate drifting sinusoidal gratings that were presented full-screen on two Dell laptop screens (1600 × 900 resolution) placed at each end of the arena , which was marked on the outside of the tank and was not visible to the fish. The experimenter administered reinforcers by dropping a food pellet  into the training zone. Fish were given one food pellet for each training zone entry in which they remained for 5 s. They were given an additional food pellet if they remained in the training zone for a span of 1 min. For each fish the training session lasted for 20 min. Both drifting gratings were presented for the entire session. Training took place once per day between 10 AM and 3 PM and occurred three times during a 5-day period. All training sessions took place before daily feeding.For the first training period, the training zone was assigned to be the upward drifting grating . After a 12-day rest period in the community housing tank, fish were tested following the procedure described below . During testing, movement was recorded using the differencing method in Ethovision XT motion tracking software for 5 min  with the camera mounted 1 m directly above the test apparatus. Trials began immediately after fish were placed in the testing arena. Dependent variables included time spent in training zones (upward or downward), number of zone transitions, and average velocity.t-test for normally distributed data or using Mann-Whitney U for nonparametric data. Velocity and zone transitions (number of times a fish crossed the mid-line of the short axis of the arena) were analyzed with a one-way analyses of variance (ANOVA) or Kruskal-Wallis test for non-parametric data . Data were analyzed using GraphPad Prism 6  and were presented as mean values ± SEM.Data were analyzed for the full 5 min trial. All data were assessed for normality using the Shapiro-Wilk normality test. Time spent in reinforced zones (referred to as “training zones” above) was analyzed using an unpaired p = 0.0379). After this experiment, the same fish were trained with the opposite stimulus (downward training zone) and tested 12 days later. Following this reversal training, fish did not show a significant preference for either zone . The number of zone transitions and velocity did not differ between any of the testing periods  cichlids are able to develop reinforcement-based memories for different moving visual patterns and maintain those memories over a period of at least 12 days. In order to develop these memories, fish needed to develop an association between the stimuli and the food rewards, and also discriminate between the upward and downward drifting gratings. Fish were able to learn to associate the upward moving stimulus with food after only three short training sessions (per fish) and were able to create a lasting memory that was apparent when they were tested 12 days later  have been shown to maintain memory over a period of 10 days when tested using a spatial alteration task  exhibit reduced exploratory behavior during the second encounter with a novel fish 3 months after the initial exposure, suggesting an implicit memory span of at least 3 months  were able to maintain memory for feeding locations 3 months after training. Rainbow fish exhibit faster escape times from an aversive stimulus 11 months after initial exposure and training to the stimulus (Brown, The full capacity of the cichlid memory span is not currently known, but a minimum of 12 days, as seen in our current study, is not unreasonable. The possibility that previous memory for the up-zone training in the fish interfered with reversal training also suggests that the memory span for the initial food location might be as long as 33 days. This time span is consistent with the memory time spans that have been determined in other fish species. Zebrafish (s Brown, . A critis Brown,  and Nilss Brown, , and ourEstablishing memories of food locations is essential for survival. It is especially important for animals to be able to learn not just about new food locations but also about their relative profitability (Warburton, EI, NDA, and TJH conceived and designed the study; EI performed the study; EI and TJH analyzed the data; all authors wrote the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Worldwide, a significant proportion of infants needing therapeutic hypothermia for hypoxia-ischaemia are transported to a higher-level facility for neonatal intensive care. They pose technical challenges to transport teams in cooling them. Concerns exist about the efficacy of passive cooling in neonatal transport to achieve a neurotherapeutic temprature. Servo-controlled cooling in the standard of care on the neonatal unit. The key question is whether the same standard of care in the neonatal unit can be safely used for therapeutic hypothermia during transport of neonates with suspected hypoxia-ischaemia.Methods: A prospective cross-sectional survey of United Kingdom (UK) neonatal transport services (n=21) was performed annually from 2011-2014 with a 100% response. The survey ascertained information about service provision and the method of cooling used during transport.Results: In 2011, all UK neonatal transport services provided therapeutic hypothermia during transport. Servo-control cooling machines were used by only 6 of the 21 teams (30%) while passive cooling was used by 15 of the 21 (70%) teams. In 2012 9 of the 21 teams (43%) were using servo-control. By 2014 the number of teams using servo-control cooling had more than doubled to 15 of the 21 (62%) services. Teams have done this through modification of transport trolleys and dedicated ambulances.Conclusion: Servo-controlled cooling in neonatal transport is becoming more common in the UK. The question remains whether it should be endorsed as a standard of care. Some teams continue to passively cool neonates with hypoxia-ischaemia during transport. This article reviews the drivers, current evidence, safety and processes involved in provision of therapeutic hypothermia during neonatal transport to enable teams to decide what would be the right option for them. Events in the perinatal period severe enough to cause neonatal hypoxic-ischemic encephalopathy (HIE) occur in 3 per 1000 births in the UK -3.The British Association of Perinatal Medicine recommends the transfer of such neonates to centres with experience of providing therapeutic hypothermia. Transport teams should be capable of doing so round the clock .A significant proportion of infants benefiting from therapeutic hypothermia is born outside centres equipped to provide it. In a study conducted by Kendall, et al., 39 neonates were referred to the London neonatal transport service from 18 hospitals for transfer to one of eight specialist cooling centres over a nine-month period . In EastThe transfer process involves different cooling practices, including passive cooling, servo-controlled cooling, and use of adjuncts. Adjuncts used in passive cooling include gel packs, ice, and fans -10.The efficacy of passive, active, and servo-controlled cooling in neonatal transport have been evaluated in a number of studies -14. The This study was a cross-sectional evaluation of the protocols of all neonatal transport services (n=21) in the United Kingdom; it was conducted in November 2011. Transport services were identified by the Neonatal Transport Interest Group service-leads database. Each transport service was sent a paper survey to be completed by a consultant or nurse. There was 100% response. The collected information included the cooling method used during transport, the guidelines followed, the mode of temperature monitoring, and whether the temperatures during transfer were audited. Where the use of servo-controlled cooling during transport was reported, the method used to secure the machine was obtained. A telephone call was placed to each service, and additional information was collected regarding the use of a 24-hour service and the presence/absence of a dedicated ambulance. Longitudinal follow-up was performed through telephone survey for all transport services in December 2012, 2013, and 2014, as a significant proportion of services were moving from passive cooling to servo-controlled cooling in neonatal transport. The factors involved in the decision making were evaluated.No funding was needed. An ethical review was not sought, and no incentives were offered for completion of the survey.Responses were received from all the neonatal transport services across the UK. All transport services offered facilities to transport neonates requiring therapeutic hypothermia during the study period. At the time of the initial survey in 2011, 18 of the 21 (85%) neonatal transport services were operating a 24-hour service for the transport of such neonates (Table Passive cooling was used by 15 of the 21 (70%) neonatal transport teams. These teams used a passive cooling transport guideline produced by the TOBY group . Servo-cOutreach education or other educational events on hypothermia were organised by 17 of the 21 (81%) neonatal transport services within their networks. This assisted in increasing awareness of the need for the early recognition of neonates who met the cooling criteria to enable the prompt transfer of such babies.In the repeat survey performed in December 2012, a further three neonatal transport services were using servo-controlled therapeutic hypothermia, bringing the total to nine out of 21 (43%). All of these services had dedicated ambulances. Outreach education was carried out by 19 of the 21 transport services (90.5%).When the survey was repeated in December 2013 and 2014 Table . NeonateIt is now a nationally endorsed standard to have 24-hour coverage for the transfer of these neonates [Historically, passive cooling has been endorsed by the TOBY group as the method for providing cooling in neonates with hypoxia-ischaemia who meet the TOBY criteria for cooling . DespiteA key question is what the literature says about different cooling methods in neonatal transport. Is the move to servo-controlled cooling evidence-based? There is currently only one randomised trial  comparing the efficacy of servo-control versus passive cooling ± ice gel packs in neonatal transport. This was a multicentre trial carried out in California in nine centres involving 100 neonates. Seventy-two percent of servo-control cooled neonates were within a therapeutic range of temperature within 60 minutes compared to 20% passively cooled. Overall, 80% of neonates cooled with servo-control achieved the target temperature compared to 49% being passively cooled ± ice gel packs . The effThere is a higher incidence of overcooling with passive cooling and non-servo-controlled active cooling. Overcooling in neonates being passively cooled varies from 11-34% -7, 10-11O’Reilly, et al. have proposed that all neonatal transport services should use servo-controlled cooling while transporting neonates with suspected hypoxic-ischemic neonatal encephalopathy . Most neA study done in Scotland using servo-control demonstrated that in 122 rectal temperatures recorded from commencing servo-controlled cooling, only two recordings  were <33°C. Their experience highlights that minimal staff intervention is needed once cooling is started, allowing freedom to focus on other stabilisation tasks. The reduced risk of overcooling also improves safety .Transport teams continuing to use passive cooling have to reconcile other conflicting considerations in addition to the above evidence. Moving to servo-control is expensive, and there is an imperative to provide a service that is safe for everyone involved. A key part of this is ensuring that all the transport equipment is secure in the event of a road traffic incident and that certain international standards are met. The European Committee for Standardisation has produced certain guidelines (CEN 13976-1:2003 and 13976-2:2003) -17. The For some teams, good results may be obtained by teams using passive cooling with minimal side effects. In the study performed by Kendal, et al., 67% of neonates passively cooled during transfer had temperatures within the therapeutic range on arrival to a cooling centre . A studyIf simple passive methods that avoid the challenges and potential risks of installing extra equipment for transport are effective in achieving therapeutic goals, this may be a sensible way to proceed. Regular audits to ensure benchmarking are important. This study shows a high uptake of audits by all UK transfer teams irrespective of the method of cooling in neonatal transport Table .For teams wanting to employ servo-controlled cooling, innovation and adopting new technology is key. Existing transport trolleys can be modified to secure the cooling machine in a secure box within the trolley. This enables use of frontline ambulances. The Tecotherm machine is 7.2 kg compared to the Criticool which is 35 kg. The Criticool or Tecotherm can be secured on a ramp separate to the trolley in the ambulance . For teaA key question is that if servo-control is more efficacious and the risk over overcooling is less, why do some of the teams in the UK continue to passively cool neonates in transport. In this study, six of 21 teams (30%) were continuing with passive cooling in December 2014. When asked why, the reasons provided followed common themes. The use of many front-line ambulances and the lack of a dedicated ambulance was one. Smaller distances with proximity to cooling centres and good results of local audits with passive cooling was another. Other teams felt that the cost involved with the small number of cases being transported for cooling did not justify a move to servo-controlled cooling during transport. For neonates being transferred by air, a helicopter with or without road passive cooling remains the main modality of choice in the UK. It seems logical then that some teams will continue using passive cooling. It must be pointed out that servo-controlled cooling has now been evaluated in cases where multiple modes of transport  are used alone or in combination. This is in the United States and the effectiveness is high (100%) -19.For teams continuing to use passive cooling, is it possible to make it more effective in terms of achieving better thermal outcomes? A retrospective study of neonates transported by the University of Virginia showed that clinicians using a fixed protocol for cooling over a four-year period showed annual improvements in the number of babies achieving therapeutic temperatures. Referred neonates were passively cooled, and where necessary, gel packs were used adjunctively . A retroThe development of a regional neuroprotection team in the East of England has helped with early identification and initiation of cooling. Passive cooling was initiated prior to transfer in all outborn infants (n=36) referred between October 2009 and October 2010. During the study period, there was a continuing trend of earlier referral for cooling and earlier achievement of target temperature . The impIn this author’s opinion, there is an imperative for neonatal transport teams to try and provide the same standard of care for outborn neonates with HIE as for inborn neonates. A recent study demonstrates that the unadjusted rates of adverse outcomes  were higher in the outborn population as compared with the inborn population in both hypothermia-treated and control subgroups with HIE. The study failed to show that birth location has an impact on the treatment effect of hypothermia after HIE. It acknowledges that this might have been because of the small sample size . It is cThis study highlights that irrespective of the method of cooling used, neonatal transport teams in the UK are benchmarking their outcomes and using technology to enhance the care provided to neonates with hypoxia-ischaemia. There has been a significant shift towards servo-controlled cooling. Servo-controlled cooling in neonatal transport has superior efficacy. Neonates receive servo-controlled cooling in transport with a lower risk of overcooling, and there is potential for it to reduce transfer time. There is an imperative for teams to ensure they can deliver it safely. It is also clear that teams are following a regional approach for identification, referral, and round-the-clock provision of transport.


The Mobile Application Rating Scale (MARS) provides a reliable method to assess the quality of mobile health  apps. However, training and expertise in mHealth and the relevant health field is required to administer it.This study describes the development and reliability testing of an end-user version of the MARS (uMARS).The MARS was simplified and piloted with 13 young people to create the uMARS. The internal consistency and test-retest reliability of the uMARS was then examined in a second sample of 164 young people participating in a randomized controlled trial of a mHealth app. App ratings were collected using the uMARS at 1-, 3,- and 6-month follow up.The uMARS had excellent internal consistency , with high individual alphas for all subscales. The total score and subscales had good test-retest reliability over both 1-2 months and 3 months.The uMARS is a simple tool that can be reliably used by end-users to assess the quality of mHealth apps. Mobile health  apps have the potential to provide around-the-clock access to evidence-based health information, education, and treatment to end users on a global scale. There are currently more than 165,000 mHealth apps (free and paid) publicly available , which cend user version of the MARS (uMARS) and provides preliminary evidence for its internal consistency and test-retest reliability.In response to these issues, we developed the Mobile App Rating Scale (MARS) to provide researchers, professionals, and clinicians with a brief tool for classifying and assessing the quality of mHealth apps . The 23-The original MARS was simplified through the following process. The professional version was first reviewed by 2 researchers to remove complex terminology from its items and response scales. Three items requiring professional expertise, pertaining to evidence base, app goals, and accuracy of app description, were removed. Readability of the MARS and the draft uMARS was then determined using the Flesch Reading Ease test ,13, whicRay’s Night Out [Music eScape [Ray’s Night Out uses a harm-minimization approach to increase young people’s alcohol knowledge and awareness of their drinking limits; Music eScape teaches young people how to identify and manage affect using music. Both are available on the iOS Apple app store.The draft uMARS was then pilot-tested with 13 young people, to ensure they understood the item content and response scales. The measure was embedded in prototype testing sessions of 2 mHealth apps: ight Out  and Music eScape . Ray’s NRay’s Night Out group comprised 1 male and 8 females with a mean age of 20.7 years (SD 1.6). The Music eScape group comprised 3 males and 1 female, with a mean age of 21.5 years (SD 1.9). After testing the apps and rating them with the uMARS scale, participants were asked the question “Do you have any comments or suggestions about the uMARS rating scale?” to identify any unclear or difficult items.Eligible participants were Australian residents aged 16 to 25 years, who had access to an iPhone 4 or later model. The The uMARS  providesMusic eScape. The RCT sample comprised 164 Australians aged 19.8 years on average (SD 2.51); 34 males. The highest level of education completed by 59.8% of the sample was secondary school, and 24.4% had completed a bachelor’s degree or higher. Most participants (57.9%) were students and 35.4% had full-time, part-time, or casual employment.The reliability of the uMARS was evaluated as part of a randomized controlled trial (RCT), testing the efficacy and quality of Music eScape app. Young people were asked to use the app as much as they liked over a month, using their own iPhones. The current iOS version at the time of the trial was iOS8. Participants received weekly text messages reminding them to do so. App ratings were collected using the uMARS at 1-, 3-, and 6-month follow-ups in the immediate access group. In the delayed access group, uMARS ratings were collected at 2-, 3-, and 6-month follow-ups . At each assessment point, participants were asked if they had used the app since the last assessment, and only those who reported some use were included in analyses.Participants were randomly allocated via a Web-based research management tool developed at the Queensland University of Technology to receive immediate or 1-month delayed access to the information subscale was recoded as “system missing,” as this option represents a qualitatively different response.The internal consistencies of the uMARS subscales and total score were calculated using Cronbach's alpha. For the purpose of analysis, the “N/A” answer option for items 13-16 of the Test-retest reliabilities were calculated for the subscales and total scores of the uMARS after 1 month of app use and at 3 months post baseline , and over 3 months . Interclass correlation coefficients (ICCs) -18 were Results of the Flesch-Kincaid readability tests are in No suggestions for further scale improvement were made. Seven of the 13 participants who pilot-tested the scale left the comments or suggestions item blank, 4 wrote “no,” and 1 wrote “Well done. Good questions. Well explained.” Another wrote “I thought it was shorter/there is a brief or revised version of it?”A total of 152 of the 164 (92%) participants completed the survey after 1 month of app use. Of these, 19 indicated they never used the app, and were excluded from analyses. For the remaining 133 participants, the total uMARS score had excellent internal consistency . Internal consistencies of its subscales were also very high .good [Test-retest reliabilities are presented in good  levels ofair to good, with the engagement and subjective subscales being particularly robust.This study developed and tested an app user version of the original MARS to assist app developers and researchers with evaluating the quality of mHealth apps. The uMARS  providesThese results indicate that the uMARS provides a reliable measure of app quality in target users. Replication of the current results with multiple types of mHealth apps is required to provide additional confidence in its performance. Tests of its sensitivity to improvements in app quality and an examination of its ability to predict outcomes of mHealth apps are also needed. As the uMARS may potentially have applications beyond mHealth, tests of its performance in other domains are also indicated.Current indications are that the uMARS will offer an unprecedented ability to readily obtain rich information from users about mobile apps. The scale can be used to obtain user feedback on the quality of mobile apps during the development and testing process, which may result in overall improvements in their quality.


M = 21.07 years, SD = 3.38 years) under the following conditions: (i) CS+/aversive imagery, (ii) CS+/aversive imagery and acoustic startle, (iii) CS+/acoustic startle, and (iv) CS+/pleasant imagery. The amplitude of the N170 was enhanced following conditioning with aversive imagery as well as acoustic startle. In the second experiment, 26 healthy control participants were tested  together with 18 depressed participants  and three conditions were used: CS+/aversive imagery, CS+/pleasant imagery, and CS-. N170 amplitude at P7 was increased for the CS+/aversive condition in comparison to CS- in the conditioning blocks versus baseline. No differences between depressed and healthy participants were found. Across both experiments, evaluative conditioning was absent. It was concluded that aversive UCS are capable of modulating early sensory processing of faces, although further research is also warranted in regards to positive UCS.Recent studies have suggested that classical conditioning may be capable of modulating early sensory processing in the human brain, and that there may be differences in the magnitude of the conditioned changes for individuals with major depressive disorder. The effect of conditioning on the N170 event-related potential was investigated using neutral faces as conditioned stimuli (CS+) and emotional imagery and acoustic startle as unconditioned stimuli (UCS). In the first experiment, electroencephalogram was recorded from 24 undergraduate students ( Classical conditioning has a long tradition of use in experimental psychology. This paradigm, in its most basic form, involves the learning of an association between a previously neutral stimulus  and an unconditioned stimulus (UCS) that is inherently appetitive or aversive. From an evolutionary perspective, it is vital for an individual to rapidly process physical stimulus properties associated with threat . For thiFaces are stimuli that are processed in a unique way by the human brain, due to the adaptive importance of rapidly recognizing other humans, and potentially avoiding them in the case of threat. The N170 is an event-related potential (ERP) component that has been found to be strongly associated with facial processing, forming a negative potential at 140–200 ms post-stimulus that is greatest over occipito-temporal sites in the right hemisphere . The N17Previous research suggests that a number of ERP components across a wide latency range may be modulated by emotional stimuli. For example, the late positive potential (LPP) is reliably enhanced in response to emotionally arousing imagery . EmotionIn regards to changes to the N170 in clinical groups it is noteworthy that studies in patients with schizophrenia as well as Huntington’s disease have reported decreased N170 amplitudes, although the decreases were not modulated by facial emotion . HoweverWhilst these previous studies have addressed changes to N170 amplitude as a result of emotional facial expression or emotional state, an unresolved question is whether N170 amplitude may also be altered as a result of conditioning. Electrophysiological measures have been included in a number of recent human fear conditioning studies. These have used a range of aversive UCS including electric shock , aversivIn addition to addressing N170 changes related to conditioning in healthy participants, the question also remains as to whether N170 conditioning is altered as a result of mood disorders, such as major depressive disorder (MDD). According to the neuroplasticity hypothesis of depression , experieIn the current study, changes to N170 amplitude were investigated across two experiments, using differential classical conditioning. The first experiment in healthy participants utilized both visual (aversive or pleasant imagery) and auditory (aversive noise burst) stimuli as UCS, and neutral faces as CS+. In the second experiment in both healthy and depressed participants, aversive and pleasant imagery were used as UCS, and neutral faces were used as CS+. The second experiment addressed two methodological limitations of the first study, by including a baseline measure of N170 amplitude for each CS+ and CS- condition, as well as counter-balancing of faces to different conditions across participants. It was hypothesized that enhancement of N170 amplitude would occur for faces associated with aversive UCS in both experiments, and that the effect would be enhanced for participants with MDD in the second study. In relation to conditioning using pleasant imagery as UCS, no specific predictions were made, as this investigation was exploratory in nature. Subjective ratings of pleasantness for each of the CS+ were also determined before and after conditioning, in order to examine the relationship between electrophysiological change and evaluative conditioning. It was expected that changes to subjective ratings post-conditioning  would be in line with electrophysiological change.M = 21.07 years, SD = 3.38 years)] are included in this report, with 10 excluded due to electroencephalogram (EEG) recording issues and/or artifact contamination. All participants were screened according to the following inclusion criteria: No history of traumatic brain injury or neurological illness, normal or corrected-to-normal vision, not currently taking or having taken in the past 30 days pharmaceutical substances or dietary supplements with known effects on cognition and mood, no history of substance abuse or alcoholism and no history of psychiatric disorder. The Beck Depression Inventory-II  which contained all of the international 10–20 positions. The electrooculogram (EOG) was recorded from four facial electrodes positioned above and below the left orbit vertical EOG (VEOG) and adjacent to the left and right outer canthus of each eye horizontal EOG (HEOG). EEG was also recorded from the left and right mastoids, for the purposes of oﬄine re-referencing. Neuroscan Acquire Software and a SynAmps2 amplifier  were used for all EEG recording. Neuroscan Stim2 software was used for all stimulus presentation, with the Stim2 Auditory System P/N 1105 used for delivery of auditory stimuli . It was ensured that all electrode impedances were below 5 kΩ at the beginning of recording. The participant was grounded by a cap electrode placed between Fz and Fpz and electrodes were referenced to a central in-cap reference located between Cz and CPz. All data was recorded in DC mode using 16-bit A/D conversion at 1000 Hz.Four experimental task blocks were administered in total, with each block taking no more than 20 min to complete. A short break was provided between each task block in order for the participant to rest. The entire duration of the experiment was around 90 min. At the completion of the EEG recording session, participants again completed the subjective face rating task on the DELL laptop.The BDI-II  is a 21-The Positive and Negative Affect Schedule PANAS;  consistsThe National Adult Reading Test NART;  is a 50-A total of 360 images from the International Affective Picture System IAPS;  were utiFive male faces, with neutral facial expression and closed mouth, were selected from the NIMSTIM faces database . At the beginning of the session, prior to beginning the EEG recording, as well at the completion of the experiment, participants were required to rate each face on a 100-point sliding scale ranging from “extremely unpleasant” (0) to “extremely pleasant” (100). The task was programmed and displayed using PsychoPy (v1.78.00). This rating task was included as a measure of evaluative conditioning.Five UCS-face pairing conditions were included in the study as follows: (1) CS+/LVHA: LVHA imagery condition, (2) CS+/LVHA + startle: LVHA imagery and acoustic startle condition, (3) CS+/startle only: acoustic startle condition, with neutral IAPS imagery, (4) CS+/HVHA: HVHA imagery condition, and (5) CS-: neutral imagery control condition. Four conditioning blocks were presented across the experiment, with 200 trials presented in each block . Within each block, 160 CS+  and 40 CS- trials were presented, with a 50% reinforcement schedule applied to all CS+ conditions. This resulted in 320 CS+/paired, 320 CS+/unpaired and 160 CS- trials across the whole experiment  was presented on a black background in the center of the screen for 500 ms. Each face was 225 pixels wide and 270 pixels high, according to a computer monitor with 1024 × 768 resolution. 500 ms following the presentation of the face, an IAPS image (UCS) was presented behind the face, replacing the black background (while the same face remained in the foreground). The IAPS image background, together with the neutral face foreground, were presented together for 1500 ms, before being replaced with a white fixation cross on a black background for the start of the next trial. In trials involving the acoustic startle, the startle probe was administered from 1000 to 1200 ms following the presentation of the IAPS image with face overlay, and the offset time of the image was not altered. The acoustic startle consisted of a white noise sound burst delivered binaurally at 103 dB through Sennheiser HD 280 professional high passive noise attenuation headphones. In order to ensure visual vigilance was maintained, the fixation cross was presented in the color red on 10% of trials. When this occurred the participant was required to press the response pad as quickly as possible with their right hand. An example, stimuli presentation sequence is displayed in Oﬄine EEG analysis was performed using Scan 4.5 . All data were re-referenced oﬄine to linked mastoids and ocular artifact reduction was applied according to the revised aligned-artefact average (RAAA) method . The datN170 scoring was restricted to electrodes P7 and P8. In order to better facilitate the detection of peak components relevant to facial processing each of the selected channels was re-referenced to its corresponding (reversed polarity) frontal channel  and laterality  as within-subject variables. Preliminary analysis regarding the effect of gender on N170 amplitudes did not indicate any main effects or interactions with other variables, and for this reason it not included in subsequent analysis. As an additional analysis to investigate the change in N170 across the course of the experiment, a repeated-measures ANOVA was conducted on the change in N170 peak amplitude from time 1 to time 2, with condition  and laterality  as within-subject variables. Effect size was presented as partial η2.For the analysis of evaluative conditioning, a mixed model repeated-measures ANOVA was conducted on change scores for pleasantness ratings after conditioning in comparison to change scores before conditioning. A subject-specific random intercept term was fitted, together with the fixed effect of stimulus condition , with pleasantness rating before conditioning included as a covariate. Effect size was calculated using estimated marginal means and presented as Cohen’s For all behavioral and ERP measures, planned contrasts were used to compare values between the control condition (CS-) and each of the other conditions separately . In order to assess the relative efficacy of the three aversive conditioning methods , repeated-measures ANOVAs were conducted using difference scores calculated between the CS- condition and each of CS+/LVHA, CS+/LVHA+startle, and CS+/startle (only) conditions. Planned contrasts were then used to compare differences between (i) CS+/LVHA and CS+/LVHA + startle conditions, (ii) CS+/startle and CS+/LVHA + startle conditions, and (iii) CS+/LVHA and CS+/startle conditions. No Bonferroni-type α adjustment was required, due to all contrasts being planned and not exceeding the degrees of freedom for effect . SimilarFigure  Rating data from one participant was unavailable (n = 23).Means and standard deviations of the subjective pleasantness ratings for the faces both before and after the conditioning paradigm are displayed in Supplementary Table p = 0.002, d = –1.12). Pleasantness ratings were decreased for the CS+/LVHA condition in comparison to the both the CS+/LVHA + startle condition  and the CS+/startle (only) condition  post-conditioning.A decreased pleasantness rating was found for the CS+/LVHA condition in comparison to the CS- condition  = 14.285, p = 0.001, partial η2 = 0.383], as well as for the CS+/startle (only) condition in comparison to CS- . The increase in N170 amplitude was greater for the CS+/LVHA condition in comparison to the CS+/LVHA + startle condition . No significant differences in N170 amplitudes were found between the CS+/LVHA and the CS+/startle (only) conditions.N170 amplitude was increased for the CS+/LVHA condition in comparison to CS-  and positive images were rated higher in arousal than neutral images . Overall, arousal ratings were higher for the control group in comparison to the depressed group . The increased arousal rating for positive in comparison to neutral imagery was larger in the control group . No differences between negative-neutral and positive-neutral arousal ratings were found.Negative images were rated higher in arousal than neutral images  and positive images were rated higher in valence than neutral images , with this effect being larger in the control group . Positive-neutral valence ratings were higher than negative-neutral valence ratings .Negative images were rated lower in valence than neutral images . Higher amplitude in the CS+/positive condition was found in comparison to CS- across all blocks . The increase from baseline to conditioning blocks was larger for P8 in comparison to P7 . However, a greater increase in P7 amplitude was observed from baseline to conditioning blocks for the CS+/negative condition versus CS- condition . No significant differences between (CS+/negative—CS-) and (CS+/positive—CS-) conditions were found. (All main effects and interactions are listed in Supplementary Table No differences in N170 amplitudes were found between depressed and control at baseline (pre-conditioning). Higher amplitude was found for the conditioning blocks in comparison to baseline [conditioning > baseline: The primary finding of Experiment 1 was that the pairing of neutral faces with either low valence imagery (LVHA) or acoustic startle resulted in potentiated N170 amplitudes in comparison to the control condition, where faces were unpaired. In relation to enhancement of the N170 for a neutral faces paired with acoustic startle, this finding is consistent with previous research by In contrast to the significant changes to N170 amplitudes found to occur when acoustic startle was used by itself as an UCS in Experiment 1, no changes to either N170 amplitude or evaluative condition was observed when acoustic startle was combined with aversive imagery. To the best of our knowledge, this is the first time that their combination has been examined in the same study, so clarification of this finding by comparison to previous studies is not possible. However, two possible reasons for the lack of significant findings include (i) a stronger habituation effect over the course of the trial for this condition, and/or (ii) an interference effect whereby the simultaneous presentation of aversive auditory and visual stimuli resulted in insufficient attention being directed to either sensory modality, and hence less effective conditioning. In regards to the possibility of more rapid habituation, the absence of a time by condition interaction when the first half of the experiment was compared to the second half of the experiment, suggests that this is unlikely to account for the finding. However, it cannot be discounted that a “rapid” degree of habituation had already occurred within the first half of the experiment (time 1) for this condition, a possibility that is in need of further empirical investigation.In relation to the finding of enhanced N170 amplitude in response to the neutral face paired with unpleasant IAPS imagery in Experiment 1, to the authors’ knowledge this is the first time that this has been demonstrated in humans. Whilst there is previous evidence to suggest that the use of IAPS imagery as UCS may result in changes to early sensory (<100 ms) components associated with visual processing , these sIn relation to the CS+/pleasant condition, no significant changes were observed for either N170 amplitudes or evaluative conditioning. The finding of no change to the N170 amplitude suggests that the face was not attributed any increase or decrease in salience in comparison to the control condition. Similarly, no change in subjective pleasantness rating was observed for this face. The fact that no increase in subjective pleasantness occurred for this face is in line with the N170 results, however, it is also a possibility that the images were not experienced as being significantly more pleasant than the neutral stimuli in the current sample. Though the IAPS has been validated across a wide range of ages and ethnicities, there is a larger degree of variability in subjective arousal and valence ratings for certain images such as erotica images . For thiFigure 4) toward further increase in N170 amplitude across the second half of the experiment, suggests that this post-conditioning change could not be attributed to baseline differences alone. Nevertheless, this limitation was addressed in Experiment 2, whereby counter-balancing of the faces to different conditions across participants ensured that this confound was controlled for.There were two significant limitations to the first experiment that were addressed in Experiment 2. The first limitation was in regards to the experimental design, whereby baseline differences in the sensory and emotional processing of the neutral faces may have had a confounding effect on the N170 amplitudes that were observed following conditioning. In particular, the lower baseline pleasantness rating for the neutral face associated with the CS+/LVHA condition may have contributed to the significant N170 change post-conditioning. If increased salience was afforded this face in comparison to the others, then N170 changes may have been occurring independent of those attributable to conditioning. However, a significant decrease in pleasantness ratings post-conditioning, together with a trend  were non-significant when compared to control, the trend was in line with the main effect for condition, whereby a greater increase in N170 amplitude was observed for both the LVHA and the startle conditions across the second half of the experiment. In Experiment 2, a more detailed analysis of change in N170 responses was made possible by the inclusion of a baseline measure of N170 amplitude for each CS+ and CS- condition.The second limitation of Experiment 1 was that no baseline measure of N170 amplitude was provided, and for this reason, it was unknown to what extent amplitudes changed across the course of the experiment, in particular the first half of the experiment. However, what could be determined in the second half of the experiment (time 1 to time 2) was that due to the lack of a significant main effect for time and lack of a significant time by condition interaction, it appeared that N170 amplitudes neither habituated nor increased significantly for the second half of the experiment in comparison to the first half of the experiment. This finding is in contrast to the study by The main finding of Experiment 2 was that N170 amplitude in the left hemisphere increased to a greater degree from pre- to post-conditioning for the negative CS+ condition in comparison to the CS- condition. In regards to the CS+/negative condition, this finding corroborates the finding of increased N170 amplitude that was observed in Experiment 1 for a neutral face paired with aversive imagery. These findings are again in line with reports from previous studies  whereby p = 0.074). For this reason, the possibility remains that conditioning effects were also occurring in association with the positive imagery, albeit the current study may not have had sufficient power to detect it. In consideration of the fact that no previous investigations have been conducted regarding the effect of positive classical conditioning on N170 responses to facial stimuli, further research is warranted.Whilst N170 amplitude was not found to be significantly increased in the CS+/positive condition in Experiment 2, it is noteworthy that the difference between CS+/negative and CS+/positive was non-significant . Also for this reason, the findings from Experiment 1 cannot be interpreted as strictly representing a healthy  adult sample, due to the presence of some evidence of depressive symptoms. To address this limitation in future studies, a more stringent BDI-II exclusion criteria  would be preferable, together with a structured interview to rule out a diagnosis of depression according to DSM criteria, as done in Experiment 2.Taken together, the two experiments provide evidence to suggest that differential classical conditioning using emotional imagery or acoustic startle are capable of enhancing early sensory facial processing, as revealed by amplitude increase in the N170. However, contrary to expectation no differences in the amplitude of the N170 response were observed for individuals with MDD compared to controls. In future research, further investigation regarding the use of positive UCS is also warranted. A direct comparison of N170 amplitudes in response to fearful, sad, happy, and neutral faces, together with measurement of changes to N170 amplitudes for neutral faces following conditioning, would also be of value in answering the question as to whether conditioning results in the same neural responses as those obtained using inherently emotional stimuli. Also in follow-up studies, a more expanded analysis of ERP components including the P100 and the N250 may further elucidate the network of conditioned changes to cortical activity. The use of neuroimaging technique such as fMRI would additionally help to provide complementary spatial information regarding subcortical structures involved in the re-entrant pathways between sensory and association regions. In regards to further investigation of changes to facial processing with differential conditioning in MDD, a more detailed investigation of the relationship between N170 amplitude change and the expression of somatic, cognitive, or affective symptoms would be highly informative.DC was involved in all aspects of the study, both experimental design, analysis, and manuscript preparation; EK was involved in data collection and analysis for Experiment 1; JM was involved in data collection and analysis for Experiment 2; RC was involved in the design and analysis as well as editing of the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In traumatic and degenerative diseases cervical fusion with anterior cervical plate are commonly used. The increase in the use of cervical plate segment level is also increased risk of developing complications. This case report shows that the increase in the use of cervical plate segment level and also the complications in cervical spinal instrumentation, short-segment cervical plate rare case reported to be broken. Cervical fusion with anterior cervical plate in traumatic and degenerative diseases is commonly used . This arAfter a motor vehicle accident 18 years old male patient was brought to the emergency department. In neurologic examination; confused of consciousness, left hemiparesis, orientation and cooperation of the examinations in patients with limited, and upon detection level of C5-6 dislocation of grade 2, and patients were included in our service. In addition, patients who had pneumothorax, chest tube was inserted by chest surgery and the patient was operated. The disc of C56 space was determined by microscope and C5-6 Anterior cervical discectomy initiative was made using a microscope. One to C56 PEEK cage was placed in the disc space, and then plates were placed on anterior C4-C5-C6. Postoperative patients, Glasgow Coma Scale (GCS) as e3m3v neurosurgical intensive care were included. Patients without post-operative problems, was discharged after 2 months. Postoperative patient made physical therapy neck movement for exersize. Therefore, two years after surgery on the occurrence of severe neck pain were admitted again. Anterior cervical plate is broken at the level of the C45 range was determined by x-ray .There are still ongoing debates about the pathology of cervical trauma is stable or unstable and intervention which will be banned from the anterior or posterior. Both initiatives have the advantages and disadvantages . In the After spinal instrumentation early or late in the several complications arise. Cervical plaque rupture is one of them, but in this case, as mentioned, albeit short segments can be broken plates. For this reason, patients should be informed about the stabilization of the neck in the postoperative period and demanding excessive neck movement can cause damage to the instrument should be warned.


To evaluate possible factors that can guide the clinician to predict potential cases refractoriness to medical treatment for giggle incontinence (GI) and to examine the effectiveness of different treatment modalities.The data of 48 children referred to pediatric urology outpatient clinic between 2000 and 2013 diagnosed as GI were reviewed. Mean age, follow-up, GI frequency, associated symptoms, medical and family history were noted. Incontinence frequency differed between several per day to less than once weekly. Children were evaluated with uroflowmetry-electromyography and post-void residual urine. Clinical success was characterized as a full or partial response, or nonresponse as defined by the International Children's Continence Society. Univariate analysis was used to find potential factors including age, sex, familial history, GI frequency, treatment modality and dysfunctional voiding to predict children who would possibly not respond to treatment.Mean age of the patients was 8.4 years (range 5 to 16). Mean follow-up time and mean duration of asymptomatic period were noted as 6.7±1.4 years and 14.2±2.3 months respectively. While 12 patients were treated with only behavioral urotherapy (Group-1), 11 patients were treated with alpha-adrenergic blockers and behavioral urotherapy (Group-2) and 18 patients with methylphenidate and behavioral urotherapy (Group-3). Giggle incontinence was refractory to eight children in-group 1; six children in-group 2 and eight children in-group 3. Daily GI frequency and dysfunctional voiding diagnosed on uroflowmetry-EMG were found as outstanding predictive factors for resistance to treatment modalities.A variety of therapies for GI have more than 50% failure rate and a standard treatment for GI has not been established. The use of medications to treat these patients would not be recommended, as they appear to add no benefit to symptoms and may introduce severe adverse effects. Giggle incontinence (GI) or enuresis risoria (ER) is characterized by complete or involuntary bladder emptying occurring only with giggling or laughing while awake with normal bladder function at all other times . GI is dThe present study examined possible factors that can guide clinician to predict cases refractory to treatment of GI. The secondary outcome of the present study was to compare GI patients response to treatment modalities of urotherapy, alpha-adrenergic blockers and MPH.After approved by the institutional review board, the data of 48 children referred to pediatric urology outpatient clinic between 2000 and 2013 diagnosed as giggle incontinence were retrospectively investigated. The diagnosis of giggle incontinence was made by definition of the International Children's Continence Society  and Group-3 consisted of children who were treated with behavioral urotherapy and MPH.Behavioral urotherapy consisted of hydration; maintaining an empty bladder including timed and double voiding and avoiding bladder stimulants ; toilet training and bowel management. In Group-2 patients were treated with doxazosin, 0.5mg dose per day and in Group-3 patients were treated with MPH, 5mg dose per day, for at least a 6-month period . They haClinical success was characterized as a full response—100% decrease in symptoms or less than 1 occurrence monthly, a partial response—50% to 89% decrease, or a nonresponse—0% to 49% decrease, as defined by the International Children's Continence Society . All values were expressed as mean±standard error (SEM). Between groups, analyses were performed using chi square test. Univariate Cox regression analysis was performed to evaluate the predictors for resistance to treatment modalities and the 95% CI was selected, and p value of 0.05 was set for statistically significance.A total of 48 patients presented with giggle incontinence at our institution between 2000 and 2013. Of these, 7 patients were excluded from study due to missing data. The remaining 41 patients, 32 females and 9 males with a mean age of 8.4 years (range 5 to 16 years) were identified. Patient characteristics are summarized in In Group-1, 8 children of 12 patients; in Group-2, 6 of 11 patients and 8 children of 18 patients in Group-3 reported 0% to 49% decrease after at least 6 months of treatment and therefore the outcome of treatment was considered refractor to treatment. Univariate analysis was used to find potential factors including age, sex, familial history, GI frequency and dysfunctional voiding (uroflowmetry-EMG) for predictive factors of treatment resistance. Daily GI frequency  and dysfunctional voiding,  were statistically significantly associated with resistance to medical treatment in univariate analyses .GI is a rare condition with unknown cause that is different from stress incontinence and overactive bladder. Typically GI patients report incontinence only with laughter. The incidence may be hidden because of affected patients modify their behavior to avoid embarrassments in social life. The pathophysiology of GI has not been understood therefore a specific treatment has not been established and there is no widely accepted treatment of choice.In the current study, we have determined the predictor factors of refractoriness to treatment modalities for GI and to the best of our knowledge, there is no study evaluating the predictors for resistance to treatment modalities of GI that can guide the clinician to predict potential cases refractory to medical treatment. A second goal of our study was to evaluate the success of behavioral urotherapy, alpha-adrenergic blockers and MPH treatment for GI and we found that similar patient populations of study groups are refractory to treatments.Present study reports that daily GI frequency and dysfunctional voiding diagnosed on uroflowmetry-EMG were the potential predictors of resistance to treatment modalities. Although GI is supplemented by the absence of other voiding symptoms and usually established on history, similar to our study Richardson et al.  reportedIn our daily practice, children with urinary incontinence have behavioral modifications such as frequent bladder emptying with alpha-blocker therapy as a treatment option. GI patients have the same alpha-blocker therapy with bladder emptying treatment and similar to the MPH treatment for GI, children may sometimes be presented with resistance to such therapies. Stimulation of the large concentration of alpha-receptors found in the region of the bladder neck and urethra results in increased outlet resistance. Cain and colleagues  reportedPopulation studies indicate that a major narcolepsy/cataplexy gene is linked to HLA-DR2, which may be related with the strong positive family history of giggle incontinence , 12. A pUnfortunately, our study involved a relatively small number of study groups with unreachable lack of information, which is the major limitation of retrospective review. Future multicenter studies encompassing larger sample size incorporating a prospective double-blind placebo control design with longer follow-up periods are needed to evaluate the success of treatment modalities, predictors that affect the success of treatment modalities and relationship between GI and detrusor inability.Despite the retrospective and non-randomized nature, the results of the present study revealed that medical therapy for GI is accompanied with a failure rate of more than 50%, regardless of the association with any kind of drug therapy. Based on the data from the present study, the use of medication in these patients should be avoided because they appear to add no benefit to the patients and may introduce severe adverse effects.