Cumulative trauma load and timing of trauma prior to military deployment differentially influences inhibitory control processing across deployment.

Military personnel experience high trauma load that can change brain circuitry leading to impaired inhibitory control and posttraumatic stress disorder (PTSD). Inhibitory control processing may be particularly vulnerable to developmental and interpersonal trauma. This study examines the differential role of cumulative pre-deployment trauma and timing of trauma on inhibitory control using the Go/NoGo paradigm in a military population. The Go/NoGo paradigm was administered to 166 predominately male army combat personnel at pre- and post-deployment. Linear mixed models analyze cumulative trauma, trauma onset, and post-deployment PTSD symptoms on NoGo-N2 and NoGo-P3 amplitude and latency across deployment. Here we report, NoGo-N2 amplitude increases and NoGo-P3 amplitude and latency decreases in those with high prior interpersonal trauma across deployment. Increases in NoGo-P3 amplitude following adolescent-onset trauma and NoGo-P3 latency following childhood-onset and adolescent-onset trauma are seen across deployment. Arousal symptoms positively correlated with conflict monitoring. Our findings support the cumulative trauma load and sensitive period of trauma exposure models for inhibitory control processing in a military population. High cumulative interpersonal trauma impacts conflict monitoring and response suppression and increases PTSD symptoms whereas developmental trauma differentially impacts response suppression. This research highlights the need for tailored strategies for strengthening inhibitory control, and that consider timing and type of trauma in military personnel.

Neural stem and progenitor cells support and protect adult hippocampal function via vascular endothelial growth factor secretion.

Adult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses broadly throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs.

Learning-related changes in cellular activity within mouse dentate gyrus during trace eyeblink conditioning.

Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of associative memories. Previous findings in rabbit had recorded populations of cells within dentate gyrus that may bridge the temporal gap between stimuli to support memory formation during trace eyeblink conditioning, an associative learning task. However, this previous work was unable to identify the types of cells demonstrating this type of activity. To explore these changes further, we did in vivo single-neuron recording in conjunction with physiological determination of cell types to investigate the functional role of granule cells, mossy cells, and interneurons in dentate gyrus during learning. Tetrode recordings were performed in young-adult mice during training on trace eyeblink conditioning, a hippocampal-dependent temporal associative memory task. Conditioned mice were able to successfully learn the task, with male mice learning at a faster rate than female mice. In the conditioned group, granule cells tended to show an increase in firing rate during conditioned stimulus presentation while mossy cells showed a decrease in firing rate during the trace interval and the unconditioned stimulus. Interestingly, populations of interneurons demonstrated learning-related increases and decreases in activity that began at onset of the conditioned stimulus and persisted through the trace interval. The current study also found a significant increase in theta power during stimuli presentation in conditioned animals, and this change in theta decreased over time. Ultimately, these data suggest unique involvement of granule cells, mossy cells, and interneurons in dentate gyrus in the formation of a trace associative memory. This work expands our knowledge of dentate gyrus function, helping to discern how aging and disease might disrupt this process.

Sleep and fear conditioning, extinction learning and extinction recall: A systematic review and meta-analysis of polysomnographic findings.

Sleep may contribute to the long-lasting consolidation and processing of emotional memories. Experimental fear conditioning and extinction paradigms model the development, maintenance, and treatment of anxiety disorders. The literature provides compelling evidence for the involvement of rapid eye movement (REM) sleep in the consolidation of such memories. This meta-analysis correlated polysomnographic sleep findings with psychophysiological reactivity to the danger (CS+) and safety stimuli (CS-), to clarify the specific role of sleep stages before and after fear conditioning, extinction learning and extinction recall. Overall, there was evidence that more pre-learning sleep stage two and less slow wave sleep was associated with higher psychophysiological reactivity to the safety stimulus during extinction learning. Preliminary evidence found here support the role of REM sleep during the post-extinction consolidation sleep phase in clinical populations with disrupted sleep, but not in healthy controls. Furthermore, the meta-regressions found that sex moderated the associations between sleep and psychophysiological reactivity throughout the paradigm providing evidence for diverging correlations in male and females. Specifically, increased post-extinction REM was associated with poorer extinction and safety recall in females while the opposite was found in males. These results have implications for future research in the role of sleep in emotional memory processing.

Lower estradiol predicts increased reinstatement of fear in women.

Low levels of estradiol in women have been associated with impaired fear extinction recall, with suggestions this may promote the return of fear and heighten the female vulnerability for anxiety disorders. A particularly important measure for the return of fear is reinstatement, but no human studies to date have examined the impact of estradiol on fear reinstatement. Forty-two healthy females completed a differential fear conditioning, extinction and reinstatement task with skin conductance response (SCR) amplitude indexing level of conditioned fear. Saliva samples were taken to measure estradiol and progesterone. To examine fear reinstatement, SCR amplitude was compared between the last trial of the late extinction phase to the first re-extinction trial following the unsignaled presentation of two aversive electric shocks. No significant effects of estradiol were found for acquisition of fear conditioning or fear extinction learning. Lower estradiol predicted a significantly larger generalized SCR amplitude at re-extinction (post-reinstatement) in women. This provides novel evidence suggesting a protective role of estradiol in potentially reducing the relapse of fear following re-exposure to aversive stimuli, although further research is necessary in clinical populations to clarify this effect.

The impact of posttraumatic stress disorder on event-related potentials in affective and non-affective paradigms: A systematic review with meta-analysis.

Post-traumatic stress disorder (PTSD) is associated with neural processing deficits affecting early automatic and later conscious processing. Event-related Potentials (ERPs) are high resolution indices of automatic and conscious processing, but there are no meta-analyses that have examined automatic and conscious ERPs in PTSD across multiple paradigms. This systematic review examined 69 studies across affective and non-affective auditory and visual paradigms. Individuals with PTSD were compared to trauma-exposed and non-trauma controls on ERPs reflecting automatic (N1, P1, N2, P2) and conscious (P3, LPP) processing. Trauma exposure was associated with increased automatic ERP amplitudes to irrelevant auditory information. PTSD further showed increased automatic and conscious allocation of resources to affective information, reduced automatic attending and classification as well as reduced attention processing and working memory updating of non-affective information. Therefore, trauma exposure is associated with enhanced early processing of incoming stimuli, and PTSD with enhanced processing of affective stimuli and impaired processing of non-affective stimuli. This review highlights the need for longitudinal ERP studies in PTSD, adopting standardized procedures and methodological designs.

Genetic Ablation of Neural Progenitor Cells Impairs Acquisition of Trace Eyeblink Conditioning.

Adult-born neurons are believed to play a role in memory formation by providing enhanced plasticity to the hippocampus. Past studies have demonstrated that reduction of neurogenesis impairs associative learning, but these experiments used irradiation or neurotoxic substances, which may have had unintended off-target effects. Therefore, to investigate the role of these adult-born neurons more precisely, we used nestin-HSV-TK transgenic mice (Nes-TK) to selectively ablate newborn neurons. Nes-TK mice were fed a chow infused with valganciclovir to induce the ablation of neural progenitor cells. After being on this diet for 4 weeks, mice were trained on trace eyeblink conditioning, a hippocampus-dependent temporal associative memory task. Following the completion of training, brain sections from these animals were stained for doublecortin, a marker for immature neurons, to quantify levels of neurogenesis. We found that male transgenic mice on valganciclovir had significantly decreased amounts of doublecortin relative to male control animals, indicating a successful reduction in levels of neurogenesis. In conjunction with this reduction in neurogenesis, the male transgenic mice on valganciclovir learned at a significantly slower rate than male control mice. The female Nes-TK mice on valganciclovir showed no significant decrease in neurogenesis and no behavioral impairment relative to female control mice. Ultimately, the results are consistent with, and expand upon, prior studies that demonstrated that adult-born neurons are involved in the formation of associative memories. This study also provides a foundation to continue to explore the physiological role of newborn neurons with in vivo recordings during behavioral training.

Joint registry approach for identification of outlier prostheses.

BACKGROUND AND PURPOSE: Joint Replacement Registries play a significant role in monitoring arthroplasty outcomes by publishing data on survivorship of individual prostheses or combinations of prostheses. The difference in outcomes can be device- or non-device-related, and these factors can be analyzed separately. Although registry data indicate that most prostheses have similar outcomes, some have a higher than anticipated rate of revision when compared to all other prostheses in their class. This report outlines how the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) has developed a method to report prostheses with a higher than expected rate of revision. These are referred to as "outlier" prostheses. MATERIAL AND METHODS: Since 2004, the AOANJRR has developed a standardized process for identifying outliers. This is based on a 3-stage process consisting of an automated algorithm, an extensive analysis of individual prostheses or combinations by registry staff, and finally a meeting involving a panel from the Australian Orthopaedic Association Arthroplasty Society. Outlier prostheses are listed in the Annual Report as (1) identified but no longer used in Australia, (2) those that have been re-identified and that are still used, and (3) those that are being identified for the first time. RESULTS: 78 prostheses or prosthesis combinations have been identified as being outliers using this approach (AOANJRR 2011 Annual Report). In addition, 5 conventional hip prostheses were initially identified, but after further analysis no longer met the defined criteria. 1 resurfacing hip prosthesis was initially identified, subsequently removed from the list, and then re-identified the following year when further data were available. All unicompartmental and primary total knee prostheses identified as having a higher than expected rate of revision have continued to be re-identified. INTERPRETATION: It is important that registries use a transparent and accountable process to identify an outlier prosthesis. This paper describes the development, implementation, assessment, and impact of the approach used by the Australian Registry.

Five-year results of the ASR XL Acetabular System and the ASR Hip Resurfacing System: an analysis from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: Articular Surface Replacement (ASR) hip prostheses, which have metal-on-metal bearing surfaces, were manufactured by DePuy Orthopaedics (Warsaw, Indiana) for use in both conventional total hip arthroplasty and hip resurfacing. Both the ASR XL Acetabular System and the ASR Hip Resurfacing System were recently recalled worldwide by the manufacturer. This report summarizes an analysis by the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) of the outcome of arthroplasties involving the ASR prostheses. METHODS: The first recorded use of the ASR XL Acetabular System in Australia occurred in 2004, and the Registry recorded 4406 procedures involving this system through December 31, 2009. The first recorded use of the ASR Hip Resurfacing System in Australia occurred in 2003, and the Registry recorded 1167 procedures through December 31, 2009. The Kaplan-Meier method and proportional-hazard modeling were used to compare the revision rate of primary total hip arthroplasties involving the ASR XL Acetabular System with that of arthroplasties involving all other conventional prostheses as well as with that of arthroplasties involving all other conventional prostheses with a metal-on-metal-articulation. In addition, the revision rate of primary arthroplasties involving the ASR Hip Resurfacing System was compared with that of arthroplasties involving all other hip resurfacing prostheses. Patient demographics, prosthesis characteristics, and information regarding the type of revision and the reason for revision were also compared. RESULTS: Arthroplasties involving both ASR designs had a significantly greater revision rate compared with those involving all other prostheses. The cumulative revision rate of arthroplasties involving the ASR XL Acetabular System at five years postoperatively was 9.3% (95% confidence interval [CI], 7.3% to 11.9%) compared with 3.4% (95% CI, 3.3% to 3.5%) for total hip arthroplasties involving all other conventional prostheses. The cumulative revision rate of arthroplasties involving the ASR Hip Resurfacing System at five years postoperatively was 10.9% (95% CI, 8.7% to 13.6%) compared with 4.0% (95% CI, 3.7% to 4.5%) for arthroplasties involving all other resurfacing prostheses. Arthroplasties involving the ASR XL Acetabular System had a greater rate of revision due to implant loosening and/or osteolysis and due to metal sensitivity compared with total hip arthroplasties involving all other conventional prostheses. Arthroplasties involving the ASR XL Acetabular System also had a significantly greater revision rate compared with total hip arthroplasties involving all other conventional metal-on-metal prostheses. Arthroplasties involving the ASR Hip Resurfacing System had a greater rate of revision due to metal sensitivity compared with total hip arthroplasties involving all other resurfacing prostheses. CONCLUSIONS: ASR prostheses used in conventional hip arthroplasty and in hip resurfacing exhibited a greater revision rate compared with other prostheses in the AOANJRR. These results are consistent with those derived from other registries and from published studies of individual cohorts.

What is the benefit of introducing new hip and knee prostheses?

BACKGROUND: New joint replacement prostheses are being continually introduced into the market. The underlying purpose of the introduction of new devices is to improve patient outcomes. This study was undertaken to determine how many new prostheses were associated with improved patient outcomes. BACKGROUND: Data were obtained from a comprehensive national database. Outcome analysis was performed on all new hip and knee prostheses introduced into the market between January 1, 2003, and December 31, 2007, and used on at least 100 occasions. The findings were compared with the combined results of the three best performing established hip and knee prostheses with a minimum duration of follow-up of five years. The principal outcome measures were the rate of revision per observed component years and the time to first revision, with use of Kaplan-Meier estimates of implant survivorship. RESULTS: Most prostheses introduced into the market during the study period were used on fewer than 100 occasions. Analysis of those that had been used in a sufficient number of procedures showed that 27% (nine of thirty-three) of the hip replacements and 29% (eight of twenty-eight) of the knee replacements had a significantly higher rate of revision than the established prostheses. None of the newer prostheses had a lower rate of revision than the established prostheses. CONCLUSION: This study indicates that there was no benefit to the introduction of new prostheses into this national market during the five-year study period. Importantly, 30% of the new prostheses were associated with a significantly worse outcome compared with the prostheses with a minimal duration of follow-up of five years.

Competing risks survival analysis applied to data from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND AND PURPOSE: The Kaplan-Meier (KM) method is often used in the analysis of arthroplasty registry data to estimate the probability of revision after a primary procedure. In the presence of a competing risk such as death, KM is known to overestimate the probability of revision. We investigated the degree to which the risk of revision is overestimated in registry data. PATIENTS AND METHODS: We compared KM estimates of risk of revision with the cumulative incidence function (CIF), which takes account of death as a competing risk. We considered revision by (1) prosthesis type in subjects aged 75­84 years with fractured neck of femur (FNOF), (2) cement use in monoblock prostheses for FNOF, and (3) age group in patients undergoing total hip arthroplasty (THA) for osteoarthritis (OA). RESULTS: In 5,802 subjects aged 75­84 years with a monoblock prosthesis for FNOF, the estimated risk of revision at 5 years was 6.3% by KM and 4.3% by CIF, a relative difference (RD) of 46%. In 9,821 subjects of all ages receiving an Austin Moore (non-cemented) prosthesis for FNOF, the RD at 5 years was 52% and for 3,116 subjects with a Thompson (cemented) prosthesis, the RD was 79%. In 44,365 subjects with a THA for OA who were less than 70 years old, the RD was just 1.4%; for 47,430 subjects > 70 years of age, the RD was 4.6% at 5 years. INTERPRETATION: The Kaplan-Meier method substantially overestimated the risk of revision compared to estimates using competing risk methods when the risk of death was high. The bias increased with time as the incidence of the competing risk of death increased. Registries should adopt methods of analysis appropriate to the nature of their data.

Outcome of primary resurfacing hip replacement: evaluation of risk factors for early revision.

BACKGROUND AND PURPOSE: The outcome of modern resurfacing remains to be determined. The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) started collection of data on hip resurfacing at a time when modern resurfacing was started in Australia. The rate of resurfacing has been higher in Australia than in many other countries. As a result, the AOANJRR has one of the largest series of resurfacing procedures. This study was undertaken to determine the results of this series and the risk factors associated with revision. PATIENTS AND METHODS: Data from the AOANJRR were used to analyze the survivorship of 12,093 primary resurfacing hip replacements reported to the Joint Replacement Registry between September 1999 and December 2008. This was compared to the results of primary conventional total hip replacement reported during the same period. The Kaplan-Meier method and proportional hazards models were used to determine risk factors such as age, sex, femoral component size, primary diagnosis, and implant design. RESULTS: Female patients had a higher revision rate than males; however, after adjusting for head size, the revision rates were similar. Prostheses with head sizes of less than 50 mm had a higher revision rate than those with head sizes of 50 mm or more. At 8 years, the cumulative per cent revision of hip resurfacing was 5.3 (4.6-6.2), as compared to 4.0 (3.8-4.2) for total hip replacement. However, in osteoarthritis patients aged less than 55 years with head sizes of 50 mm or more, the 7-year cumulative per cent revision for hip resurfacing was 3.0 (2.2-4.2). Also, hips with dysplasia and some implant designs had an increased risk of revision. INTERPRETATION: Risk factors for revision of resurfacing were older patients, smaller femoral head size, patients with developmental dysplasia, and certain implant designs. These results highlight the importance of patient and prosthesis selection in optimizing the outcome of hip resurfacing.

Outcome of revision of unicompartmental knee replacement.

BACKGROUND AND PURPOSE: Despite concerns regarding a higher risk of revision, unicompartmental knee arthroplasty (UKA) continues to be used as an alternative to total knee arthroplasty (TKA). There are, however, limited data on the subsequent outcome when a UKA is revised. We examined the survivorship for primary UKA procedures that have been revised. METHODS: We used data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) to analyze the survivorship of 1,948 revisions of primary UKA reported to the Registry between September 1999 and December 2008. This was compared to the results of revisions of primary TKA reported during the same period where both the femoral and tibial components were revised. The Kaplan-Meier method for modeling survivorship was used. RESULTS: When a primary UKA was revised to another UKA (both major and minor revisions), it had a cumulative per cent revision (CPR) of 28 and 30 at 3 years, respectively. The CPR at 3 years when a UKA was converted to a TKA was 10. This is similar to the 3-year CPR (12) found earlier for primary TKA where both the femoral and tibial components were revised. INTERPRETATION: When a UKA requires revision, the best outcome is achieved when it is converted to a TKA. This procedure does, however, have a major risk of re-revision, which is similar to the risk of re-revision of a primary TKA that has had both the femoral and tibial components revised.

Poor outcome of revised resurfacing hip arthroplasty.

BACKGROUND AND PURPOSE: Recent years have seen a rapid increase in the use of resurfacing hip arthroplasty despite the lack of literature on the long-term outcome. In particular, there is little evidence regarding the outcome of revisions of primary resurfacing. The purpose of this analysis was to examine the survivorship of primary resurfacing hip arthroplasties that have been revised. PATIENTS AND METHODS: Over 12,000 primary resurfacing hip arthroplasties were recorded by the Australian Orthopaedic Association National Joint Replacement Registry between September 1, 1999 and December 31, 2008. During this time, 397 revisions for reasons other than infection were reported for these primary resurfacings and classified as acetabular, femoral, or both acetabular and femoral revisions. The survivorship of the different types of revisions was estimated using the Kaplan-Meier method and compared using proportional hazard models. Additionally, the outcome of a femoral-only revision was compared to that of primary conventional total hip arthroplasty. RESULTS: Acetabular-only revision had a high risk of re-revision compared to femoral-only and both acetabular and femoral revision (5-year cumulative per cent revision of 20%, 7%, and 5% respectively). Femoral-only revision had a risk of re-revision similar to that of revision of both the acetabular and femoral components. Femoral-only revision had over twice the risk of revision of primary conventional total hip arthroplasty. INTERPRETATION: Revision of a primary resurfacing arthroplasty is associated with a major risk of re-revision. The best outcome is achieved when either the femoral-only or both the acetabular and femoral components are revised. Technically straightforward femoral-only revisions generally have a worse outcome than a primary conventional total hip arthroplasty.

Higher protein and energy intake is associated with increased weight gain in pre-term infants.

AIM: To characterise and compare the nutritional management and growth in infants <33 weeks' gestation in two tertiary centres. METHODS: An audit of daily intake and growth from birth to discharge home was undertaken in two neonatal units: The KK Women's and Children's Hospital Singapore and the Adelaide Women's and Children's Hospital, South Australia. Mixed models were used to model intake and daily weight (g/day) accounting for repeated day per subject. RESULTS: The clinical characteristics of the two cohorts were similar. The Adelaide cohort had a higher initial energy intake in the first 5 days compared with the Singapore cohort, and a significantly greater weekly increase of 21.0 kcal/week (95% CI 7.7-34.3; P = 0.002). The Adelaide cohort also had a higher initial protein intake and a significantly greater weekly increase of 0.88 g/week (95% CI 0.5, 1.3), P < 0.001) compared with the Singapore cohort. The weight gain of the Adelaide cohort was 9 g/day more than the Singapore cohort (95% CI 7.3, 10.7; P < 0.001). Post-natal growth failure was evident in 32% (n = 64) of the Adelaide cohort and 64% (n = 94) of the Singapore cohort. CONCLUSIONS: The two centres showed distinct differences in nutritional management. A higher energy and protein intake was associated with improved growth yet growth in both cohorts was still below current recommendations.