Doubts exist around the value of compiling league tables for cost-effectiveness results for health interventions, primarily due to methods differences. We aimed to determine if a reasonably coherent league table could be compiled using published studies for one high-income country: New Zealand (NZ).Literature searches were conducted to identify NZ-relevant studies published in the peer-reviewed journal literature between 1 January 2010 and 8 October 2017. Only studies with the following metrics were included: cost per quality-adjusted life-year or disability-adjusted life-year or life-year (QALY/DALY/LY). Key study features were abstracted and a summary league table produced which classified the studies in terms of cost-effectiveness.A total of 21 cost-effectiveness studies which met the inclusion criteria were identified. There were some large methodological differences between the studies, particularly in the time horizon (1 year to lifetime) but also discount rates (range 0 to 10%). Nevertheless, we were able to group the incremental cost-effectiveness ratios (ICERs) into general categories of being reported as cost-saving (19%), cost-effective (71%), and not cost-effective (10%). The median ICER (adjusted to 2017 NZ$) was ~ $5000 per QALY/DALY/LY (~US$3500). However, for some interventions, there is high uncertainty around the intervention effectiveness and declining adherence over time.It seemed possible to produce a reasonably coherent league table for the ICER values from different studies (within broad groupings) in this high-income country. Most interventions were cost-effective and a fifth were cost-saving. Nevertheless, study methodologies did vary widely and researchers need to pay more attention to using standardised methods that allow their results to be included in future league tables.The online version of this article (10.1186/s12963-019-0192-x) contains supplementary material, which is available to authorized users. Given the constraints on health sector resources and the large demand for expanded or new health sector interventions, it is important to determine which interventions get the best value for money out of the limited resources available. As part of this prioritisation, cost-effectiveness is an important criterion for policymakers to consider, although it should be considered alongside other issues such as health equity, the size of the health gain, the timing of health gains and costs, issues around intervention feasibility and public acceptability, etc.Previous international work has generated league tables for intervention cost-effectiveness from studies in multiple countries –4, for sThe country in our case study presented here ) is a fairly typical high-income country in which demand for health services is constantly increasing relative to available resources. However, New Zealand does have a single national agency that successfully constrains rising pharmaceutical prices (PHARMAC) and conducts cost-utility analyses as part of its decision-making processes. But elsewhere, in the health sector, there is no agency that routinely does such analyses and systematically prioritises health sector interventions. There is also no government-wide threshold for when gaining a quality-adjusted life-year (QALY) is deemed “cost-effective” or the relative importance of gaining QALYs in different populations as part of reducing health inequalities  and non-Māori in this country).3) Programme . However, in this particular study, we aimed to identify if other published cost-effectiveness analyses (CEAs) performed for New Zealand by different research teams could be included in a single reasonably coherent league table.Despite this, a league table has been published of 21 pharmaceutical interventions in New Zealand . This wo3 Programme, since results from this programme all use a standard methodology and are detailed in an online interactive league table [We first aimed to identify published New Zealand-specific CEAs that meet all of the following criteria: (i) the study was published in a peer-reviewed journal in the time-period 1 January 2010 to 8 October 2017; (ii) the study results included one of the following metrics: a cost per QALY or life-year (LY) gained or a cost per disability-adjusted life-year (DALY) averted; (iii) the study involved New Zealand epidemiological or cost data ; and (iv) the study was not an output of the BODEue table  (with a The specific aspects of the search strategy are detailed in Table A cost-effectiveness threshold from a policymaker's perspective will vary depending on what (dis)investment opportunities are being considered and what new (or requirement to reduce) funding is available, at a given time for a given investment horizon. Therefore, funding agencies usually do not have an official threshold—including in New Zealand. Nevertheless, as a guide, we note that on occasions, New Zealand Government agencies have quoted a value from the New Zealand Treasury of $38,110 per QALY , which After abstracting the key information from each study, we then scaled the incremental cost-effectiveness ratio (ICER) values to 2017 NZ$ using the consumer price index (CPI) and purchasing power parity (PPP) (when translating from other currencies).A total of 21 cost-effectiveness studies were identified and their key characteristics are summarised in Table Table The interventions studied were most commonly for primary prevention (38%), followed by treatment/management (33%) and then secondary prevention/screening 29%)  and 12 other types of CEAs   may not be particularly critical to informed prioritisation of interventions . However, differences larger than these, especially if premised on expert consideration of the assumptions and context of each study being compared, probably make the simple league table comparisons outlined in this study potentially useful for policymaking or at least guiding prioritisation around further research efforts.The high levels of methodological diversity in the identified CEAs suggest the need for researchers to strive harder for methodological compatibility of their work, e.g., with the use of the ISPOR guidelines/CHEERS checklist  and othe3 Programme [The overall pattern of results of many cost-saving and cost-effective interventions was reasonably compatible with other league table work for this particular high-income country (the league tables in these three publications –13 and trogramme ). They arogramme , 7 and orogramme .A strength of this study is that it was the first attempt to produce a league table of interventions covering methodologically diverse health interventions for this particular high-income country. It also included relatively few studies that had industry funding Table  which maFirstly, the search strategy might have missed some published studies given that occasionally cost-effectiveness results might only be found in appendicised information and hence are not readily identified in literature searches. Publication bias may have resulted in some studies not appearing in the peer-reviewed literature if authors or journal editors/reviewers considered the results to be of relatively little interest to policymakers .Secondly, there are limitations with the threshold we used for categorising cost-effectiveness (in terms of GDP per capita as per the WHO CHOICE approach ). Such aThirdly, this study did not attempt to include the components of the size of the health gain and cost impacts in the league table because this is very challenging due to the need to allow for varying population sizes, discerning total population and target population focus, and standardising the time horizon. There was also still variation in the outcome measures  and, of course, the size of these varies with the different discount rates used .Fourthly, more sophisticated critiques of the identified studies are possible  in this high-income country. Most interventions were cost-effective and a fifth were cost-saving. Nevertheless, study methodologies did vary widely and researchers need to pay more attention to using standardised methods that will allow their results to be included in future league tables.Additional file 1:Table A1. Examples of the types of studies that were excluded from this review and league table development . Table A2. Additional commentary on the interventions in Table 2 of the main manuscript for the 21 New Zealand cost-effectiveness studies identified and published in the period 1 January 2010 to 8 October 2017 . Table A3. Additional cost-benefit analysis or other types of cost-effectiveness analyses identified for New Zealand in the period 1 January 2010 to 8 October 2017 . Table A4. Summary of the methods characteristics of the 21 studies with cost-effectiveness analyses for New Zealand in the period 1 January 2010 to 8 October 2017 . Table A5. Results of the included studies for New Zealand in the period 1 January 2010 to 8 October 2017 . (DOCX 200 kb)


Recent developments of burst-mode lasers and imaging systems have opened new realms of simultaneous diagnostics for velocity and density fields at a rate of 1 kHz–1 MHz. These enable the exploration of previously unimaginable shock-driven turbulent flow fields that are of significant importance to problems in high-energy density physics. The current work presents novel measurements using simultaneous measurements of velocity and scalar fields at 60 kHz to investigate Richtmyer-Meshkov instability (RMI) in a spatio-temporal approach. The evolution of scalar fields and the vorticity dynamics responsible for the same are shown, including the interaction of shock with the interface. This temporal information is used to validate two vorticity-deposition models commonly used for initiation of large scale simulations, and have been previously validated only via simulations or integral measures of circulation. Additionally, these measurements also enable tracking the evolution and mode merging of individual flow structures that were previously not possible owing to inherently random variations in the interface at the smallest scales. A temporal evolution of symmetric vortex merging and the induced mixing prevalent in these problems is presented, with implications for the vortex paradigms in accelerated inhomogenous flows. For example, the shock- and blast-induced instabilities, such as Richtmyer-Meshkov instabilities (RMI) and Rayleigh-Taylor Instabilities (RTI) play a dominant role in many applications, such as the mixing of fuel and air by incident shocks in a scramjet engine3, the ‘ignition problem’ of Inertial Confinement Fusion (ICF)5, blast-driven mixing of stellar media surrounding supernovae6 etc. Significant interest in these problems exists, with particular emphasis on effective models5 estimating the mixing effects of simulated hydrodynamics. Understanding and being able to model the shock-driven turbulent mixing of these phenomena is critical to further our understanding of HED physics. For example, a description of the fluid-interface growth in RMI is often provided by considering the vorticity generated by baroclinic torque at the interface due to the interaction of a pressure gradient  misaligned with a density gradient . This initial vorticity evolution was first modeled from linear stability theory7 and, for example, the Samtaney-Zabusky Model8 with good experimental agreement. Furthermore, Balakumar, et al.9 showed that the vortex configuration resulting from the initial shock advects material and neighboring vorticies (which strongly affects the extent of the mixing region) highlighting the importance of vorticity throughout the development of RMI. However, as secondary instabilities develop, the flow departs further from linear theory, and thus it is difficult to analytically describe the complex interactions which follow this regime into the transition and to turbulent mixing. Simulations have studied the evolution of the time-resolved vorticity field and found a significant change in vorticity due to additional production of the same by secondary instabilities10. There is currently no experimental work describing the temporal evolution of vorticity in RMI, much less in conjunction with density field evolution, to study the vortex interactions and induced mixing.The study of hydrodynamics relevant to high-energy-density physics (HEDP) frequently involves complexities and challenges in physics and engineering 11. These laid the foundation for understanding the linear and nonlinear growth regimes of the RMI. However, this is a volume-averaged method and planar techniques such as mie scattering, planar laser induced fluorescence (PLIF) and particle image velocimetry (PIV) have since become increasingly common providing more robust descriptions of the flow (such as mixed mass and turbulent spectra). Conventional research efforts on these fronts have used simultaneous measurements of velocity and density using large ensembles of uncorrelated (and independent) experimental runs with identical initial conditions. Recently a qualitative description of the morphological evolution of the interface and analysis of the growth rate of the mixing region have been provided in high-speed mie scattering and schlieren movies14. While these results do provide qualitative information about the mixing phenomena, their direct utility in providing benchmark validation data is limited. To this end, much pioneering work in the area of simultaneous PLIF and PIV has been performed17, albeit using large ensembles of snapshots from repeated experiments. In essence, simultaneous diagnostics are of interest to understanding the correlation between density and velocity fluctuations, and thus the turbulent mass-flux that is critical to closing RANS models such as the BHR model18 — a model extensively in use today for computations in variable-density turbulent mixing. Examples of such studies to enhance closure physics in variable density turbulence  can be found in recent works20.Early measurements of RMI in shock tubes used schlieren photography to primarily investigate the growth of the overall mixing layerO(1−10 μm) in laboratory experiments], coupled with their extremely short temporal scales [~O(0.5−10 μs)]. These, together with the large scale flow evolution [~O] lead to large desired dynamic ranges from the diagnostics. These requirements have conventionally limited the spatio-temporal detail with which these phenomena could be investigated. These illustrative ‘scale separations’ are for typical laboratory experiments, and the actual application could involve 2−10 orders larger separation than those seen in the laboratory. Recent advances in high-speed imaging and laser sources are paving the way for overcoming these limitations by employing non-intrusive optical measurements in complex reacting and non-reacting flow environments. For example, burst-mode lasers and gate-intensified CCD cameras are used to examine the velocity flow-field of supersonic flows by employing very high speed PIV at up to a MHz-repetition rate in compressible jet flows21, albeit at low resolutions and at considerable noise owing to the nature of the intensified imaging system. At conventional high-speed resolutions, Wernet22 and Beresh, et al.23 have made PIV measurements over hot and cold jets, supersonic jet in cross-flow and transonic flow over a cavity at acquistion rates ~O(10 kHz). Similarly, Wagner, et al.24 have implemented PIV in the wake of a cylinder in a shock-tube to study the harmonics of the transient wake growth. Besides PIV, the application of pulse-burst systems have been demonstrated for high-speed reactive- and passive-tracer PLIF , thermometry26, etc. Additionally, akin to the current work, Miller, et al.27 have demonstrated the ability for simultaneous velocity and qualitative-PLIF measurements at 10 kHz using pulse burst systems. Numerous other application-specific implementations of high-speed diagnostics have been presented in the thorough review of Thurow, et al.28 The current work extends this spatial and temporal dynamic range [≈O(100 μm−100 mm) and ≈O(10 μs−10 ms)] simultaneously in velocity and concentration/density fields to enable studies of shock-driven mixing-related physics that were previously not possible due to insufficient dynamic range.The challenges in experimentally studying and modeling such flows come primarily from the high spatial-resolution requirements inherently imposed by the typical mixing scales . The vortex stretching and inviscid instability mechanisms redistribute this turbulent kinetic energy spatially and spectrally leading to a rich range of velocity  scales. The two-dimensional estimate to the turbulent kinetic energy (TKED2) can be obtained via the in plane velocity fluctuations as the flow is statistically homogenous in the z−direction. Assuming reflective symmetry of the initial conditions and spatial homogeneity in the spanwise direction, Fig. TKED2 in the FOV remains relatively constant owing to the negligible dissipation relative to redistribution mechanisms . These demonstrate the strong inverse cascade of energy expected at early times of the instability growth without a significant dissipation.The turbulent kinetic energy on the interface ultimately responsible for turbulence is deposited by shock at very small length scales  with respect to reshock . The jump velocity, us(s) = us+−us− of the interface from reshock is also measured from the pre-reshock and post-reshock scalar and velocity fields (us− and us+ respectively). The variation of these two quantities along the shock-tube width  is shown in Fig. Similarly, the estimated reshock-deposited-vorticity from the WCB13 can be rewritten for the current assumptions asω asFinally, the distribution of net circulation per unit interface length is computed from the measured vorticity field, σ/cosα), by the two aforementioned models together with the experimentally measured counterparts. The figure shows a remarkable agreement between the two models and the experiments, justifying both the approaches for these conditions. It serves to note that the SRZ98 model as is presented here utilizes only the measured shape [s(y)], and implicitly estimates the jump velocity (us) based on 1-dimensional gas dynamics relations. The WCB13 model, however, directly utilizes the measured jump velocity profile across the interface together with the interface orientation relative to the shock. This latter approach offsets some of the assumptions made in the current work, which lead to the discrepancies. For example, the assumption of single interface interaction  is strictly not valid everywhere , and the ability to specify a jump-velocity profile in WCB13 from experiments improves the estimated vorticity deposition in the corresponding region. This deposited circulation serves as the initial condition for subsequent instability growth, transition and mixing dynamics. While many computational studies have investigated the ability of these models to represent the deposited baroclinic vorticity44, for eg.], the current work experimentally measures the interface orientation and the vorticity before and after reshock in a time-resolved manner to provide a direct validation of slow-fast vorticity deposition.Figure 45 at this time, with very little mixing activity between the two gases. This late time interface before reshock at T1 forms the initial condition for the subsequent vorticity deposition by reflected shock at T2. A phase reversal is noticed as the opposite signed (positive) vorticity deposition occurs, which leads to strong vortical structures. Most of the intermediate-time turbulent mixing post-reshock is observed to be concentrated around these vortical hotspots. The interface sandwiched by these structures undergoes further shear instabilities leading to a sharp rise in scalar mixing, that continues until the advent of the expansion wave.The goal of the current simultaneous diagnostics is to visualize the effect of turbulent velocity scales and mixing simultaneously. Figure 46. Both vortices are formed from the reshock-initiated vortex sheet, and the subsequent roll-up due to its unstable nature. Under their mutual influence, the symmetric-vortices approach each other and eventually merge47. This ‘mode-merging’ of vortices results not only in backward scatter of turbulence energy to smaller wave-numbers , but also in a local spike in scalar mixing as can be seen between Fig. 50, for eg.), experimentally  and using computational tools52, for eg. However, existing studies on the effect of the mode-merging on scalar mixing  are limited in scope and physics by the limitations of mixing models, or to low Reynolds numbers owing to the complexity of the same. The current high spatio-temporal resolution experiments are the first of its kind to capture this mode-merging and the induced mixing, specifically for shock-driven variable density phenomena. These advantages in the current diagnostics enable such studies related to temporal evolution of small scales that were previously not possible with conventional low speed approaches. Other possible directions currently being studied are the studies of vortex-accelerated vorticity deposition (VAVD52), vorticity-based mixing models, etc.Molecular mixing in turbulent environments is an inherently small scale phenomena, and the utility of current measurements lies in the ability to track temporal evolution of these scales. Figure The current work demonstrates of the vortex dominated behavior of the turbulent mixing via time-resolved measurements of the vortex evolution. Further, the constraints on spatial resolution at these high speeds, especially in the velocity fields, is seen at instances where the PLIF images show vortical structures that are not captured individually by the vorticity fields owing to the lower resolution of the latter (see Supplementary video 42 and WCB1338) for computational studies were evaluated with this unique dataset, and it was shown that the WCB13 approach is capable of offsetting the typical assumptions (to a limited extent) via a prescribed interface jump velocity when the same is available via measurements. Further, an illustration of the often-studied symmetric vortex merging47 was demonstrated in a shock-driven variable-density flow for the first time, together with the induced effects on scalar mixing in an unprecedented detail. Detailed analysis on non-stationary physics such as the Vortex Accelerated Vorticity Deposition (VAVD52), vorticity-based stochastic modeling of mixing, etc. are made possible with these techniques, that were previously not amenable to experimental methods. These measurements are one of the first of this kind for high-speed turbulent mixing applications, and highlight the exciting possibilities that the recent advances in diagnostics enable.The current work demonstrates the recent ability for spatio-temporally resolved measurements for shock-driven variable-density mixing, by exploiting the advances in diagnostics for simultaneous velocity and mixture fraction measurements. These enable future studies of turbulent mixing phenomena and modeling for applications in shock-driven hydrodynamics (such as shock- and blast-driven RMI and RTI in HED applications). Important experimental considerations are emphasized for these high-speed measurements, particularly related to the acquisition challenges, laser energy and flow characteristics. The quality of results was assessed and validated by comparing the results to previously published high-resolution, single-shot measurements on Richtmyer-Meshkov Instability. The high-speed vorticity fields enable tracking and temporal analysis of small scale vortical features that are essential to understand the molecular mixing behavior of such turbulent flows. These simultaneous diagnostics are essential to these flows, which are inherently dominated by small scale physics, as the same cannot be achieved using time-uncorrelated independent experiments  or simulations . Two commonly used models for initiation of deposited vorticity (SRZ98supplementary video 1.supplementary video 2supplementary video 3supplementary video 4


A 55-year-old woman reported a 24-hour history of unusual pain in her left carotid area irradiating to the ear. Colour Doppler ultrasound revealed an eccentric hypoechoic thickening  eccentric perivascular infiltration at the level of bifurcation with a median thickness diameter of 5 mm and a median length of 20 mm. Most patients have no associated carotid stenosis. Self-limited associated soft plaque may be present in half of patients and might be induced by the healing phase of the inflammatory process. Non-steroidal anti-inflammatory drugs and high doses of aspirin are the classical treatment, usually leading to a complete relief of pain in a median delay of 13 days.


MOTOR) using the bilateral motor cerebellum, putamen, and dorsal premotor cortex as regions of interest. Patients and healthy controls performed the grip force task equally well without being fatigued. In patients, task-related activity in lobule VI of right motor cerebellum changed in proportion with individual FSMCMOTOR scores. In right dorsal premotor cortex, linear increases in activity across consecutive task blocks scaled with individual FSMCMOTOR scores in healthy controls, but not in patients. In premotor and dorsomedial prefrontal areas, patients were impaired at upscaling task-related activity the more they were affected by motor fatigue. The results support the notion that increased sensorimotor processing in the cerebellum contributes to the experience of motor fatigue and fatigability in multiple sclerosis. Additionally, downscaling of motivational input or sensorimotor processing in prefrontal and premotor areas may constitute an additional pathophysiological factor.Fatigue is a common and highly disabling symptom of multiple sclerosis. Patients experience an effort-independent general subjective feeling of fatigue as well as excessive fatigability when engaging in physical or mental activity. Previous research using functional magnetic resonance imaging (fMRI) has revealed heterogeneous findings, but some evidence implicates the motor system. To identify brain correlates of fatigue, 44 mildly impaired patients with relapsing-remitting multiple sclerosis and 25 age- and gender-matched healthy controls underwent functional magnetic resonance imaging at 3 Tesla, while they performed alternating blocks of rest and a non-fatiguing precision grip task. We investigated neural correlates of fatigue using the motor subscore of Fatigue Scale for Motor and Cognitive Functions (FSMC Fatigue is one of the most common and disabling symptoms in multiple sclerosis (MS) –3. FatigThe precise mechanisms that determine the emergence and magnitude of effort-independent “state” fatigue and effort-evoked “trait” fatigability in a given patient are still largely unknown and treatment remains a challenge . WhateveFunctional magnetic resonance imaging (fMRI) has been used in patients with MS to link task-related brain activity patterns to subjectively experienced fatigue during everyday life, yet results have been relatively incongruent across studies –13. ThisThis current study took a new step in the search of the pathophysiological changes in functional brain networks related to fatigue in a well-defined group of MS patients. Extending previous fMRI studies, we chose a tonic precision grip task as sensorimotor paradigm, because this task required the continuous integration of visual and somatosensory input with the generated motor output to maintain the required target force level . We reas50 patients with relapsing-remitting MS and 25 healthy individuals were initially included in the study. Inclusion criteria were age between 18 to 55 years and right-handedness according to Edinburgh Handedness Inventory . PatientMOTOR) was considered and used to quantify the magnitude of motor fatigue and fatigability experienced during everyday life. Based on the individual FSMCMOTOR score, patients were divided into patients with fatigue (score ≥ 27) and patients without fatigue (FSMCMOTOR score ≥ 27) and patients without fatigue (score ≥ 27) and patients without fatigue (FSMCMOTOR score < 27) corresponding to the cut-off point for moderate motor fatigue [Self-reported fatigue was assessed with the Danish validated version of the Fatigue Scale for Motor and Cognitive Functions (FSMC) , 23. The fatigue . Overall fatigue . Skilled fatigue  and Jebs fatigue . The sev score ≥  and pati fatigue , Symbol  fatigue , Paced A fatigue , Epworth fatigue , 32, and fatigue .Whole-brain MRI was performed with an Achieva 3 Tesla scanner and a 32-channel head coil . Blood oxygen level dependent fMRI  was acquStructural MRI scans were additionally acquired to measure lesion load and brain atrophy and included a three-dimensional high-resolution T1-weighted image acquired with a sagittal magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence . A T2-weighted image was acquired with a turbo spin echo sequence  and a fluid attenuated inversion recovery image (FLAIR) . We also performed diffusion weighted MRI of the brain, which will be reported separately.https://se.mathworks.com/products/matlab.html).Detailed oral and written task instructions were given and the subjects were familiarized with the task before fMRI. Participants were holding a force sensitive device with their right hand using a pincer grip and produced a steady force level, which was individually adjusted to 20% of their maximal force. The force produced by the participant was continuously visualized as expanding circle on a screen. The circle had to match the size of a ring, which indicated the target force level . To avoihttp://www.xinapse.com/). The delineated lesions were checked and if necessary, corrected by an expert using the co-registered T2- and T1-weighted images as support. The individual subject’s T1-weighted image was normalized to Montreal Neurological Institute (MNI) space using Statistical Parametric Mapping software  and the normalization warp was then applied to the lesion mask. The normalized lesion masks were then summed across subjects to form a lesion frequency image in MNI space.Lesions were automatically delineated on the FLAIR images using Jim software  using a standard processing pipeline [Structural reconstruction and volumetric segmentation of structural MRIs were performed with FreeSurfer software  was used to model the fMRI time series. The design matrix modelled task-related activation as a boxcar function reflecting the alternation of task and rest periods convolved with the canonical hemodynamic response function. A second regressor modelled the first-order (linear) modulation of task-related BOLD signal changes across the session orthogonalized to the main task regressor . The desMOTOR score as effect of interest, and the two nuisance regressors “age” and “hand function” measured with the JTHFT. Separate group models were set up for the main effect of task and the first-order modulation of task-related activation during the session.Group analysis of the fMRI data employed random effects analysis to test for voxel-wise significance within and between groups, yielding mean statistical parametric maps for each group and for between-group difference using one-sample and two-sample T-tests, respectively. The group models for within and between group analyses contained the FSMCGroup analyses tested for differences in task-related activity between healthy controls and patients with MS as well as differences between patients with excessive fatigue (FMS group) and patients without fatigue (NFMS group). In the latter analysis, individual BDI-II scores were included as a covariate in the model to isolate the effect of fatigue from those associated with the presence of depressive symptoms.http://eeg.sourceforge.net/doc_m2html/bioelectromagnetism/tal2mni.html). The putamen ROI was defined with the Automated Anatomic Labelling Atlas (AAL) [The correction for multiple non-independent comparisons at the peak voxel level was performed using the family-wise error method implemented in SPM based on Gaussian random fields and the statistical threshold was set to p < 0.05. A single mask consisting of the cerebellum lobule VI, putamen, and PMd of both hemispheres were used to define the region of interest . The PMdas (AAL) . The ceras (AAL) . For voxClinical, behavioural and structural MRI measures are given as mean (± standard deviation) and were analysed with SPSS software , using repeated measures ANOVA, t-tests and Pearson or Spearman correlation when appropriate. Significance threshold was set at p < 0.05.Forty-nine of the 50 patients underwent MRI scanning, but three fMRI data sets could not be used because of motion artefacts or insufficient task compliance. Two additional patients were excluded because of high BDI-II scores. In these two patients, the total BDI-II score indicated the presence of severe symptoms of depression, although these patients had no clinical diagnosis of depression. Thus, 44 MS patients (27 FMS patients and 17 NFMS patients) and 25 healthy controls were included in the group analyses. Clinical characteristics and group data of the structural MRI analyses are summarized in MOTOR scores showed a positive correlation with BDI-II scores  and EDSS scores . The individual FSMCMOTOR scores did not correlate with disease duration or total white matter lesion volume. Accordingly, the FMS group had higher BDI-II and EDSS scores than the NFMS patients, while other clinical scores did not differ significantly between the two groups  N in healthy controls and 16.20 (±2.40) N in MS patients. The mean variability across subjects of the applied force was 0.54 (±0.80) N in healthy controls and 0.52 (±0.31) N in patients. Repeated-measures ANOVA showed no time or group effect and no interaction between time and group for mean force levels and the variability or grip force during the task.The tonic grip force task activated a well-known sensorimotor network that has been shown to be engaged in visually guided control of precision grip force . The netMOTOR scores in the right upper cerebellar lobule VI  and without fatigue (NFMS group). When comparing these groups, we found regional differences in the scaling between task-related activity and FSMC -12, 74 . In thes -12, 74 . This re fatigue . The samMS group .Compared to patients with MS, healthy controls showed a stronger time-dependent increase in task-related activity in the right posterior cingulate cortex and adjacent lingual gyrus . ConversConsidering only the patients with MS, we found a negative linear effect of time on task-related activity in the motor territory of the left cerebellum contralateral to the hand performing the grip force task . In contMOTOR scores and the task-related brain activity revealed a difference in the linear time-dependent modulation of task-related activity  [Here we used task-related fMRI to map sensorimotor brain activity evoked by a tonic right-hand grip force task in mildly impaired patients with MS and healthy controls. We identified distinct regions in the cerebellum and premotor cortex where sensorimotor activity in the non-fatigued state scaled with the amount of motor fatigue that patients experienced during everyday life. Task-related activity in right motor cerebellum increased in proportion with self-reported fatigue. Furthermore, patients lacked a “normal” upscaling of regional task-related activity in premotor and dorsomedial prefrontal areas with the level of subjectively experienced fatigue. As pointed out above, self-reported “motor fatigue”, as probed with the FSMCability) –6.The right motor cerebellum ipsilateral to the grasping hand was the only brain region, where functional activation during a non-fatiguing tonic grip force task scaled significantly with the amount of experienced motor fatigue in patients with MS . This fiFunctional and structural changes in the cerebellum contribute significantly to disease-induced motor disability in MS , 47 as wThe increase in cerebellar motor activity with increasing individual fatigue scores was found during both tonic motor activity in the present study and phasic repetitive activity in the study by Pardini et al. . The senMOTOR scores in healthy controls than in patients with MS. The higher the individual FSMCMOTOR scores, the stronger was the time-dependent increase of task-related cerebellum activity during the fMRI session in healthy controls, but not in MS patients. This finding indicates that not only the constant level of ipsilateral cerebellar sensorimotor activation, but also the lack of temporal modulation of contralateral cerebellar activity during continued task performance may be related to motor fatigue experienced during everyday life.In the left sensorimotor cerebellum contralateral to the grasping hand, patients displayed a time-dependent linear decrease in task-related activity during the fMRI session . In addiThe premotor cortex forms multiple reciprocal loops with the parietal cortex, through which sensory information is processed and transformed into actions –56. The MOTOR scores. In the right caudal PMd, healthy controls showed a stronger time-dependent increase of task-related activity with the experienced magnitude of motor fatigue than MS patients  i.e. the “overwhelming state of lethargy, exhaustion and lack of energy which comes on abruptly and is unrelated to any obvious external causes” during their day-to-day life . Hence, sociated . While fsociated . FurtherThe present study deliberately focussed on relatively mildly affected patients with a relapsing-remitting presentation of MS. Therefore the generalizability to other clinical forms of MS such as primary or secondary progressive MS or more severely impaired patient groups is limited.We used a visual-spatial grip force control task to study neural correlates of motor fatigue in sensorimotor brain networks. While the focus was on the motor component of fatigue, the motor and cognitive subscales of the FSMC questionnaire were highly correlated in our sample, in agreement with the literature . TherefoIn addition, the task did not activate motor networks implicated in the control of other motor effectors such as legs (gait) or mouth . The relatively simple task also did not capture the physical and mental challenges of skilled manipulative actions during everyday life. This implies that the present findings need to be interpreted in the context of the specific motor task and generalization to other motor tasks should be made with caution. Another inherent limitation is that MS leads to motor impairment, and the effects of motor impairment on task-related activation may confound the activation patterns related to motor fatigue. However, we consider it highly unlikely that the present findings were accounted for by disease-related impairment of hand function. Inter-individual differences in hand function were taken into account in our statistical model. In contrast to task-related fMRI, resting state fMRI has the advantage of not being confounded be type of task type or task performance.Patients and healthy controls performed the grip force task equally well during the fMRI session, and there were no between-group differences in task-related brain activation. However, the results of this study are limited by the lack of controlling for regional lesion burden.Finally, it is generally accepted that fatigue and depression constitute two different but closely related conditions . This reThe present study advances the current understanding of the neural underpinnings of fatigue in MS. We show that the functional activation of the motor cerebellum during a non-fatiguing tonic grip force task reflects the severity of motor fatigue and fatigability experienced during daily life. In dorsal and ventral premotor as well as dorsomedial prefrontal areas, inter-individual difference in task-related activation scaled with the level of experienced fatigue during everyday life. MS patients showed a reduced upscaling of task-related activity in this prefrontal-premotor network, the more the patients were affected by motor fatigue. In summary, the results are compatible with the notion that motor fatigue in MS is associated with an upscaling of cerebellar sensorimotor integration along with a downscaling of motivational drive and sensorimotor processing in prefrontal and premotor areas. However, whether these brain activation changes are a response, a cause or a mediator of fatigue cannot be concluded.


Protein encoding genes constitute a small fraction of mammalian genomes. In addition to the protein coding genes, there are other functional units within the genome that are transcribed, but not translated into protein, the so called non-coding RNAs. There are many types of non-coding RNAs that have been identified and shown to have important roles in regulating gene expression either at the transcriptional or post-transcriptional level. A number of recent studies have highlighted that dietary manipulation in mammals can influence the expression or function of a number of classes of non-coding RNAs that contribute to the protein translation machinery. The identification of protein translation as a common target for nutritional regulation underscores the need to investigate how this may mechanistically contribute to phenotypes and diseases that are modified by nutritional intervention. Finally, we describe the state of the art and the application of emerging ‘-omics’ technologies to address the regulation of protein translation in response to diet. There is an increasing body of evidence to suggest that nutrition can alter gene expression, with genes that encode components of the cellular protein translation machinery representing a common target  and the small RNAs which direct its site-specific post-transcriptional modification . In addition to ribosomal components, we discuss transfer RNAs (tRNAs), which recruit the amino acids to the site of polypeptide synthesis and their functional cleavage products (tRNA fragments). Finally, we address the requirement for further investigation into how nutritional modulation of these components might contribute to disease and outline how the application of a range of recently developed ‘-omics’ technologies can be applied to elucidate how nutrition can interact with underlying genetic variation to modulate gene expression at both transcriptional and post-transcriptional levels.rRNAs encoded by the ribosomal DNA (rDNA) are an indispensable structural and catalytic component of the ribosome in which they assist selection of messenger RNA (mRNA) molecules to be translated and catalyse polypeptide bond formation of the amino acids delivered by tRNAs during protein translation . MammaliTranscription of rDNA is tightly coupled to both the general cellular metabolism and specific environmental challenges . Stress Recently, studies in mice have demonstrated rDNA is a genomic target of early life nutritional insult which may contribute to lifelong phenotypic consequences. Altered DNA methylation and transcription of the rRNA genes in offspring of dams fed a protein restricted diet during particular developmental windows has been shown ,14. DietO-ribose methylation and pseudouridylation of specific rRNA nucleotides [SnoRNAs are short non-coding RNA molecules of around 60–300 nucleotides in length which are found mainly in the nucleolus. The well-conserved snoRNA have been reported in a broad variety of organisms ,40. The leotides . These mleotides  and the leotides  as requileotides ,44. Outsleotides ,46,47,48leotides . Moreoveleotides  and to bleotides ,50,51, sNSUN5) induces alterations in protein translation and organism longevity that only become apparent after a nutritional insult [NML) was shown to be associated with high fat diet-induced obesity [Although direct evidence connecting nutrition to changes in snoRNA expression are limited, a recent study has shown that mice fed a protein-restricted diet from weaning into adulthood have altered snoRNA composition within their sperm small RNA complement . This, tl insult . In mice obesity . These sTransfer RNAs (tRNAs) are the most abundant small non-coding RNA molecules making up 4–10% of all cellular RNA . They arRecent studies using high-throughput sequencing have identified small non-coding RNA fragments that are derived from tRNAs ,59,60. TNumerous tRNA fragment types are elevated under stress conditions, and alteration in their abundance has been associated with various human diseases including cancer and neurodegenerative diseases ,64. A nuSharma et al. showed that sperm derived from male mice fed a low protein diet display a 2-3-fold increase in multiple types of 5′ tRNA halves  and use 5′ halves of tRNA-glycine-GCC as an example [5C) [DNMT2), which has been previously implicated in genetic deletion studies as having a role in paternal transmission of putative ‘epigenetic’ phenotypes in mice [Altered expression profile of a subset of 5′ tRNA halves were also observed in the sperm of mice fed a high-fat diet . These 55C) . This sp in mice . Injecti in mice . Adult o in mice . Another in mice . Interes in mice . Taken together, these data indicate that gene regulation in the early embryo can be affected by paternal diet via sperm tRNA fragments, with potential consequences for embryonic development and lifetime phenotypes as a result. The molecular mechanisms for how tRNA fragments mediate these alterations in gene expression are still elusive.Increasingly, there are a diverse array of ‘-omics’ approaches available to profile the molecular landscape of choice. These approaches are characterised by being, to some extent, ‘hypothesis neutral,’ that is, to capture all changes that occur in response to an exposure, rather than looking at a particular predetermined molecular target. High-throughput sequencing approaches have been developed to profile nucleic acid sequences (DNA and RNA) in a quantitative manner. With the increased cost-effectiveness of sequencing, whole-genome sequencing now allows for the high resolution mapping of inter-individual genetic variation. However, understanding the functional consequences of sequence variation and how it interacts with environmental factors such as nutrition requires correlating genomic sequence variation with changes in the expression, structure, and function of gene products. Furthermore, these relationships are likely to be both cell type and exposure dependent. RNA sequencing is a well-established technique and has greatly assisted with understanding how sequence variants can influence the level of transcripts , leading to the identification of expression quantitative trait loci (eQTLs) . HoweverAs discussed above, there is evidence that both snoRNA expression and tRNA modification and fragmentation can be altered by diet in mice ,3,4,5, iEMG1) gene mutation that underlies the fatal Bowen-Conradi syndrome [Some examples in organisms ranging from yeast to human highlight that post-transcriptional modification of rRNA can impact ribosome function in protein translation and may contribute to regulatory functions. The importance of rRNA modifications is demonstrated by the genetic loss of multiple snoRNAs which direct site-specific rRNA modifications causing altered translation efficiency ,71,72, isyndrome ,76, redusyndrome ,78.NSUN2), which methylates cytosine-5 of tRNAs is associated with microcephaly in humans and mice [CDKAL1), which catalyses the 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) modification of A37 in tRNA-Lys-UUU is associated with increased risk of type 2 diabetes mellitus in humans and mice [tRNA post-transcriptional modifications have also been shown to influence protein translation. Modification of uridine at the wobble position (nucleoside 34) modulates the decoding preference of tRNAs , with loand mice , while mand mice ,83,84. These few examples highlight that RNA modifications to the rRNA and tRNA contribute an additional and possibly regulatory mechanism to translational regulation. However, getting a complete picture of the landscape of these modifications is currently limited by the lack of methodologies available to comprehensively map RNA modifications. Here we will discuss techniques to map some specific modifications conferred through snoRNAs and modifications known to be prevalent in tRNAs. Identifying the sites and prevalence of these modifications is an important step in understanding their functional significance.Pseudo uridine is a highly abundant modified nucleoside found in both rRNA (where its site-specific modification involves the H/ACA family of snoRNAs) and in tRNA . PseudouO-methylation (via box C/D snoRNAs), which has also recently been implicated in modulating the capacity for ribosomes to initiate translation from internal ribosome entry sites rather than the 7-methylguanylate cap (m7G-cap) [O-methylation sites has been developed. This technique relies on the resistance of the phosphodiester bond 3′ to the site of modification to random alkaline induced fragmentation. Protection from fragmentation leads to under-representation of sequencing reads that start or end at sites of ribose 2′-O-methylation [The other snoRNA-mediated rRNA modification is ribose 2′-m7G-cap) . A compahylation .tRNA modifications have been implicated in regulating the level of fragmentation in response to nutritional insults . One of There are more than 150 RNA modifications that have been identified, each with a unique set of biochemical properties . So far,We and others have previously shown that dietary nutrition can influence the expression of distinct genetic variants of the core protein translation machinery ,5,14. HoPolysome profiling involves size-fractionating the cellular lysate and collecting fractions containing the small and large ribosome subunits, monosomes, or polysomes. Highly translated mRNAs are engaged with multiple ribosomes and will be contained in the heavier polysome fraction. Poorly translated mRNA will be found in the other fractions. The RNA is then extracted from each fraction and used to prepare high-throughput sequencing libraries. The relative enrichment of specific mRNA species in each fraction compared to the non-fractionated input material is then determined . An alternative approach that provides higher resolution is ribosome profiling . After cWhile translatome profiling technologies provide a snapshot, it is necessary to gain an understanding of how both genetic variation and nutritional interventions impact the stable proteome and metabolic status. Quantitative mass-spectrometry based approaches exist to profile proteins or metabolites. The sensitivity of these techniques is ever-improving, permitting detection of an increasing proportion of the abundant components of any biological sample. The integration of these techniques in parallel to the application of the translatome profiling technologies described above is required to understand the link of changes in translational regulation to cellular and, ultimately, organismal phenotypes.It is well established that both genes and environment contribute to health and disease. Here we highlight that the non-coding RNA molecules involved in protein translation present a common target of nutritional modulation. The study of such effects has so far been limited to animal models. This is because even when genetic background is controlled for , the extent of genetic variation in some of these components  is yet to be determined comprehensively. This is due to the genes encoding these elements of the protein translation machinery being present in very high numbers within a single genome. This greatly reduces the ability to produce accurate assemblies of these genes using the relatively short-read sequencing technologies commonly applied to study genetic variation. As such, the extent of within and inter-individual genetic variation within these non-coding RNA is unknown. Even less is known how both genetic variation and nutritional modulation of these components impact the regulation of protein translation. Elucidating nutritional regulation of the protein translation machinery will need to be driven by animal models in the shorter term due to the limitations of what is known regarding genetic variation within the key components. However, while long-read sequencing technologies hold the promise to resolve our capacity to map and then explore genetic diversity at these elements, a reverse function-over-form approach can be undertaken simultaneously. Integration of the existing ‘-omics’ approaches to study the translatome and proteome will be useful in establishing just how nutritionally responsive post-transcriptional gene regulation is and what role it might have in directing phenotypes, particularly those associated with altered metabolic function, as indicated from studies to date. While most studies of gene-environment interactions (including the impact of nutrition) to date have focussed on classic ‘epigenetic’ markers associated with altered gene transcription , it is highly likely that genetic variation within and nutritional regulation of the protein translational machinery will impact substantially on how an individual will respond to nutritional challenges phenotypically. Now that technology exists to explore these processes, we are posed with an exciting challenge that promises to increase our understanding of how nutrition modifies developmental outcomes and adult disease risk.


Human and animal models suggest that maternal hormonal and physiological adaptations during pregnancy shape maternal brain functioning and behavior crucial for offspring care and survival. Less sensitive maternal behavior, often associated with psychobiological dysregulation and the offspring's behavioral and emotional disorders, has been observed in mothers who have experienced adverse childhood experiences. Strong evidence shows that children who are exposed to domestic violence (DV) are at risk of being abused or becoming abusive in adulthood. Yet little is known about the effect of childhood exposure to DV on the expecting mother, her subsequent caregiving behavior and related effects on her infant. Thus, the present study examined the association of maternal exposure to DV during childhood on prenatal maternal attachment, maternal heart rate reactivity to an infant-crying stimulus and post-natal infant emotional regulation. Thirty-three women with and without exposure to DV during childhood were recruited during the first trimester of pregnancy and followed until 6-month after birth. The Maternal Antenatal Attachment Scale (MAAS) was used to measure prenatal attachment of the mother to her fetus during the second trimester of pregnancy, maternal and fetal heart rate reactivity to an infant-crying stimulus was assessed at the third trimester of pregnancy, and the Infant Behavior Questionnaire-Revised (IBQ-R) was used to assess infant emotional regulation at 6-months. Results showed that pregnant women that were exposed to DV during childhood had a poorer quality of prenatal attachment of mother to fetus, regardless of whether they also experienced DV during adulthood. In addition, maternal exposure to DV during childhood was associated with increased maternal heart rate to infant-crying stimulus and worse infant emotional regulation. These findings highlight the importance of prenatal screening for maternal exposure to DV during childhood as a risk factor for disturbances in the development of maternal attachment, dysfunctional maternal behavior and emotion dysregulation. The experience of domestic violence (DV) has been found to have a likely profound negative impact both on maternal psychological functioning and on the mother-infant relationship –3. One sGrowing evidence supports that the experience of adverse childhood experiences or “ACES,” such as maltreatment, without specific study of childhood exposure to DV known to date, can adversely influence maternal behavior during adulthood . In spitThe mother-infant relationship is an asymmetric, bidirectional system. While maternal behavior through the lens of a more maturely developed complex neurobiological system influences infant physiology and behavior, infant behavior  also induces a maternal physiological response that has been suggested to function as a “preparation for action” in terms of maternal behavior . Of noteEven though exposure to DV during childhood has been shown in and of itself to be a potent risk factor for future involvement in DV relationships , no studWe thus conducted a study to test the following hypotheses: mothers who report having been exposed to DV during childhood would show: (1) Reduced maternal prenatal attachment to the fetus, as well as (2) Altered maternal and fetal heart rate as a marker of the sympathetic nervous system activity in response to a crying infant stimulus. Additionally, (3) 6 months after birth, infants of mothers with histories of childhood DV exposure would show greater behavioral dysregulation.This study is part of a longitudinal project that investigates the influence of prenatal stress on infant psychosocial development. Here we presented data of 33 pregnant women recruited at their first visit (January 2012-January 2015) to the Geneva Obstetric Clinic of the University Hospital (10–12 weeks of gestation) and followed until 6 month after birth. Inclusion criteria for the data collected to be included in the analyses required that mothers to have had a full-term pregnancy without complications requiring medical intervention. Before delivery, one of the women moved to another country and abandoned the study. Thirty-two infants  were all born at term  and had a normal birth weight  and 5-min Apgar scores . At the 6-month visit, six participants dropped out reducing the postnatal sample to 25 subjects. A flow chart with information of participants' sample at each period of data collection is illustrated in Figure a-priori hypothesis concerning the association of M-DV-Ch with target variables, mothers were asked the following question: “Did you experience domestic violence at home in your childhood (up to age 16)?” and were then invited to describe the events if the answer was affirmative. However, no further elaboration or other specific questions about the events was requested so as to avoid upsetting the participants with memories of traumatic events. Eleven participants declared to have been exposed to domestic violence during childhood. The extent of detail regarding the experience of domestic violence differed greatly between participants, though in most the information provided was very scarce, with no specific information regarding period of exposure or DV severity.Maternal exposure to domestic violence during childhood (M-DV-Ch) was assessed during the first visit via the Geneva Prenatal Stress Questionnaire , a screeThe quality of prenatal attachment of mother to her fetus was measured using the Maternal Antenatal Attachment Scale (MAAS) during the second trimester follow-up session. The MAAS  is a 19-N = 6) or participants' unavailability (N = 2), only 25 women underwent cardiac monitoring. Results for fetal heart rate (FHR) are reported for only 24 fetuses, as the FHR data of one participant was excluded when no fetal HR signal was obtained due to an artifact.Maternal and fetal electrocardiograms were recorded simultaneously using the MONICA AN24 wireless fetal monitor  during the third trimester of pregnancy. This portable device permits a non-invasive recording of maternal and fetal cardiac electrical signals and uterine activity using five abdominally-placed electrodes. Data collected were transferred to a laptop and analyzed using the manufacturer's software that allows manual editing for artifacts and to extract maternal and fetal beat-to-beat heart rate (HR). The latter provided HR in bpm in 0.25 s epochs as well as beat-to-beat R–R intervals in 0.25 s epochs. The average maternal and fetal HR measured during relaxation (3 min) and exposure to baby crying auditory stimulus (2 min) was calculated. Because of technical problems during data acquisition (Infant regulatory behavior was measured at 6-months of age with the French translation of the Infant Behavior Questionnaire-Revised Short Form version (IBQ-R-SF) . IBQ-R-SF contains 91-items grouped in 14-scales . Parentsa-priori to exclusively use the Orienting/Regulation Scale to limit comparisons given our small sample size. According to IBQ-R SF scoring, this scale is the overall score of three subscales: (1) Duration of orientation , (2) High Intensity Pleasure , and (3) Soothability .In order to test our hypothesis that infants of mothers with histories of childhood exposure to DV would have poor emotional and behavioral regulatory capacities, we decided Familial socio-economic status (SES) was calculated using the Largo SES Index , a well-In order to gather general information regarding their psychological mental state, participants were asked to complete three questionnaires to assess state anxiety, depression, and psychopathological symptoms.State anxiety was measured with the French adaptation of the State-Trait Anxiety Inventory STAI; , 32], a , a 32)],Depressive symptoms were evaluated at each trimester during pregnancy with the French version of the Edinburgh Postnatal Depression Scale . The EPThe Symptom Checklist-90-Revised  is This study is part of a longitudinal project that investigates the influence of prenatal stress on infant psychosocial development. Here we presented data of 33 pregnant women recruited at their first visit to the Geneva Obstetric Clinic of the University Hospital (10–12 weeks of gestation) and followed until 6 month after birth. Follow-up sessions were performed once at each trimester of pregnancy ; and two postnatal visits, the fourth day after birth (T4) and 6-months afterwards (T5). Oral and written informed consent was obtained from all participants.The data collected at the hospital was as follows Figure : M-DV-ChThe first postnatal session took place at the hospital 4 days after delivery (T4) and information related to delivery and wellbeing of the mother and newborn and physical characteristics of the newborn were gathered. The last postnatal session took place 6-months after delivery (T5), and mothers were asked to complete the IBQ-R-SF.U tests for between-subject comparisons (non-exposed vs. exposed to domestic violence during childhood), and Spearman's non-parametric correlations (rs) was used to test associations between maternal and fetal HR. Effect size, r, was calculated by dividing Z by the square root of N. We used Pearson's X2 to compare nominal variables  between the groups, and φ for effect size. For all analyses, p < 0.05 was considered statistically significant. Post-hoc power analysis for MAAS, maternal and fetal HR and IBQ-R were performed using G*Power 3.1.9.2 .Data were analyzed using the Statistical Package for Social Sciences Software  for Windows. Normal distribution of continuous variables was assessed by Shapiro-Wilk tests. Descriptive statistics for all socio-demographic and other variables were calculated and expressed appropriately in percentages, mean values (M) and standard deviation (SD), or median (Mdn) and mean rank. Non-normally distributed data were analyzed using Mann–Whitney-Data collected at the different time points differed in the constitution of the samples . Table The group of women who were exposed to DV in childhood did not differ in a statistically significant way from the group of women without such exposure in terms of the following measures: maternal age, SES, gestational age at term, weight at birth, Apgar 5-min scores, state anxiety (STAI), depression symptoms (EPDS) or psychopathology  spent less time in attachment mode (p < 0.01) and had lower total MAAS scores compared to the non-exposed group . No differences were found between groups on quality of attachment of mother to fetus.Prenatal attachment was assessed at the second trimester follow-up session using the MAAS. Significant differences between groups were found on attachment mode subscale and total MAAS Table , pregnanN = 16), pregnant women that were exposed to domestic violence during childhood (N = 9) showed increased HR during the infant stimulus (Table p < 0.05). Fetal HR during the infant crying stimulus tended to be lower in M-DV-Ch (N = 9) than in the non-exposed group (N = 15) (Table p = 0.08). Maternal and fetal HR did not differ significantly between groups during relaxation.During the third trimester of pregnancy, maternal and fetal HR was recorded during a short period of relaxation and exposure to an infant crying stimulus. Compared to the non-exposed group  and a tendency to significance during the relaxation/resting time .Maternal and fetal HR showed a negative significant correlation during the infant crying stimulus (rp < 0.05) and on the Orienting/Regulation's subscales though the scores were statistically significant only for the “high intensity pleasure” subscale (p < 0.05); “duration of orientation” subscale and “soothability” subscale were not statistically significant.Compared to the non-exposed group, M-DV-Ch infants received significantly lower scores in the infant's Orienting/Regulation IBQ-R scale , and poorer infant behavioral regulation.In the present study, maternal exposure to DV during childhood  was associated with a poorer maternal quality of attachment to the fetus and with less time spent in attachment mode and less maternal preoccupation with the fetus. The present study's findings together with those of Schwerdtfeger and Goff , indicatFurthermore, the present study found that pregnant women who experienced exposure to DV during childhood displayed increased HR in reaction to a crying infant stimulus. Interestingly, it has been reported that mothers with a strong physiological reaction to infant crying are more likely to present greater irritation and aversive or harsh parenting behavior to infant crying stimuli . MothersThe present study additionally found a significant negative correlation between maternal and fetal HR in response to crying infant stimulus, and a trend toward low FHR during exposure to the crying infant stimulus among mothers exposed to DV during childhood. Though the relationship between maternal and fetal HR involves several factors including fetal behavioral state and level of maturity, maternal stress responses and anxiety during pregnancy have been related to reduced FHR  and reduThe present study also found that infants of mothers exposed to DV during childhood appear to show greater difficulty with emotion regulation and arousal by the age of 6 months. Consistent with this finding is that of Enlow et al.  who founFuture research might also consider potential associations among the quality of maternal mental representations of primary attachment figure(s), the quality of the mother-fetus/infant attachment relationship, and mother-infant interactive behavior –55.Limitations of this study, beyond its small sample size, also include the use of a close-ended “yes/no” screening question concerning DV exposure during childhood and no pressure to elaborate and provide specific information such as age of exposure, frequency, and intensity, important factors in terms of effects on the developing brain . And yetClinical implications of the findings of this study highlight the importance of assessing pregnant women's history of early and subsequent adverse life-events and the quality of attachment to their fetus as possible risk factors for postnatal disturbances. This risk can be reduced by a preventive intervention during pregnancy with focus on (i) reducing physiological arousal to a crying infant stimulus, and (ii) improving the quality of early attachment of mother to fetus. In the early postnatal period, interventions like mentalization-based treatments  or cliniAS-R, MC, SR, ME, PH, FA, and DS conceived and designed the study. AS-R, MC, ZS, and DS together wrote the first drafts of the manuscript. AS-R and MC collected data and prepared all the data for analyses. AS-R, MC, and ZS performed the statistical analysis. All authors critically revised several versions of the manuscript and approved the final version.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.


Indications for upper-extremity replantation include wrist-level and wrist-proximal amputations, due to the devastating loss of function incurred from these severe injuries. Decisions regarding replantation must be made expeditiously at these proximal levels in an effort to minimize ischemia time. This decision-making process becomes more complicated when a patient presents following intentional self-amputation of an extremity, especially in the setting of an associated mood disorder, psychiatric illness, and/or frank psychosis. A case report is presented involving a 28-year-old right-hand dominant male with untreated depression and recent suicidal ideation who sustained a complete left forearm amputation  from a self-inflicted circular saw injury. We conducted a PubMed literature search of other reported cases of intentional self-amputations of the hand and upper extremity. The patient underwent replantation of the left upper extremity. At six years postoperatively, the patient was extremely satisfied with the appearance and function of the replanted extremity. Dash score was 5.8 with a Chen Grade 1 (excellent) functional recovery. A literature search identified 16 cases of self-inflicted upper extremity amputation. One patient died at the scene. 87% (13/15) of patients presenting to the hospital were diagnosed with a psychiatric disorder . 67% (10/15) of these patients were also diagnosed with psychosis. Ten patients underwent replantation (nine at hand/wrist level and one at forearm level), all of which were viable postoperatively. Detailed functional outcome data were not reported in any of the cases. Four patients (40%) were pleased or satisfied with the outcome, but subjective outcomes were not reported for the other six patients. Intentional self-amputation of the hand/upper extremity is an extreme and uncommon act, often presenting with complex psychiatric issues. Although replantation is technically feasible in this patient population, long-term subjective and objective functional outcomes are largely unknown. Future study of this unique group of patients is needed to better assess patient-reported outcomes and functional outcomes of replantation, which could help guide decision making at the time of initial injury.  Traumatic amputations of the upper extremity are devastating, life-changing injuries that have substantial psychological, functional, and socioeconomic sequela -3. The iThe decision-making process becomes even more complicated when a patient presents following the intentional self-amputation of a potentially replantable extremity. This unique patient population may present with an associated mood disorder, psychiatric illness and/or frank psychosis. Included among the relative contraindications to replantation is self-amputation, associated mental instability, or possibly an inability/unwillingness to comply with the involved postoperative therapy regimen ,4-7. AltWe report a case involving a 28-year-old male with untreated depression who presented with a forearm-level complete amputation from a deliberate, self-inflicted circular saw injury. He underwent successful replantation and functional recovery of the extremity. In addition, we conducted a literature search with the intention of providing additional insight into the management of these major, self-inflicted upper extremity injuries.Case ReportA 28-year-old right-hand dominant male with a history of untreated depression and recent suicidal ideation presented with a complete amputation of the left upper extremity (forearm-level) as the result of an intentional, self-inflicted injury with a circular saw following an argument with his wife Figure . The traThe patient underwent emergent replantation of the left upper extremity. Bony stabilization was obtained using plate and screw fixation Figure . The radOn postoperative day six, the patient was returned to the operating room for closure of the hand fasciotomy wounds and split thickness skin grafting of residual forearm wounds. Hand therapy was initiated after confirmation of good skin graft take and was continued throughout the hospitalization. The patient’s depressed mood stabilized, and he demonstrated a good understanding and commitment to his hand therapy regimen while in-house. Length of hospitalization was 19 days prior to discharge to an inpatient psychiatric facility. The patient continued with hand therapy over the next several months. While all joints remained supple, he developed flexor and extensor tendon adhesions, and later underwent flexor and extensor tenolysis at six months after replantation.At six years postoperatively, the patient was extremely satisfied with the function and appearance of the replanted extremity (despite the development of hypertrophic scarring) Figure . He demoMethodsInstitutional Review Board authorization was waived for this study, although individual written consent by the patient was obtained. We performed a PubMed literature search of self-inflicted hand/upper extremity amputations. We confined our search to English language publications involving wrist-level and wrist-proximal amputations. The search terms used were “self-amputation and hand” and “self-amputation and upper extremity”. Self-amputations distal to the wrist-level such as those involving the thumb or digit(s) were excluded. References of relevant papers were reviewed to capture any additional cases and reviews not obtained from the primary search terms. Cases were not included when demographics and/or clinical data were not available, such as in cases of self-amputation that may have been a part of larger series of upper limb amputations. We collected data on patient demographics (including the presence of any psychiatric co-morbidities), mechanism of injury, level of amputation, and whether replantation was performed. In the replantation subgroup, the additional recorded data included: hand/limb viability following replantation, inpatient psychiatry admission postoperatively, hand therapy compliance, follow-up time period, and any available functional outcomes or subjective patient outcomes.ResultsBased on the literature search, 16 cases of self-inflicted upper extremity amputations were identified  underwent replantation and five patients (33%) did not. Eight of the replantation patients were diagnosed with psychosis. The presence (or absence) of psychosis was not reported in two of the replantation patients. Nine of the replants were performed for amputations at the hand/wrist level; one of the replants was done for a forearm level amputation. Postoperative data for the patients who underwent replantation is presented in Table Follow-up time was not consistently reported with only three of the replantation patients with follow-up beyond the immediate postoperative period. Four patients (40%) were pleased or satisfied with the replantation outcome. Patient subjective replantation outcome was not reported in the other six patients (60%). Detailed functional outcome data were not reported; only limited descriptions of function were available and were noted to be favorable in eight of 10 replantation patients. Of the 15 patients who presented to the hospital, five patients (33%) did not undergo replantation. In three patients, the amputated part was in poor condition for replantation. In two other patients, there was a prolonged time period to hospital presentation (>12 hours after forearm-level amputations). For the patients who did not undergo replantation, there was no mention of whether they were ultimately fitted with upper extremity prostheses.DiscussionComplete hand/upper extremity amputations are severe injuries with potentially devastating functional sequela. Limb viability rates following upper extremity replantation have been reported to be as high as 80% to 94%; however, patients who undergo upper extremity replantation exhibit increased utilization of resources including longer length of hospital stay, higher rates of postoperative complications and greater rates of secondary surgical revisions ,20-22. AThe question then becomes whether these successful outcomes for upper extremity replantation can be anticipated in patients who present with deliberate, self-inflicted upper extremity amputations. Although a rare act, self-amputation of the hand/upper extremity could be underreported since patients may feel embarrassed by the mechanism of injury and aren't forthcoming about how the event occurred. Its presence in the literature has been limited to case reports and small series of patients. In our literature review, most of the cases were reported in the psychiatry literature  and focus predominantly on the acute mental health treatment of these patients with minimal emphasis on operative details and important postoperative follow-up data such as hand therapy compliance issues, subjective patient outcomes, and functional outcomes.Self-inflicted amputation has often been considered a relative contraindication to replantation because of concerns related to future self-harm, in addition to other postoperative compliance issues, such as unreliable participation in rehabilitation efforts and poor physician follow-up . The preOur reported case demonstrates that it is possible to obtain excellent functional results with high patient satisfaction following upper extremity replantation as the result of a self-inflicted injury in a patient with mental illness. Nevertheless, based on the lack of available data in the literature, definitive recommendations concerning upper limb replantation in this population cannot be made. More detailed studies are required in this unique group of patients to evaluate long-term functional and patient-reported outcome data. Any decision to replant in this patient population likely needs to be carefully weighed considering several factors: the current psychiatric status of the patient, the anticipated commitment of the patient to several months of intensive hand therapy and to addressing ongoing psychiatric issues (including medication compliance and refrain from further self-harm of the replanted part). Also, the patient should be informed that future secondary surgery is likely following upper extremity replantation -27.Limitations of our literature review include incomplete capture of additional cases of self-amputation that may be present within larger series of upper extremity amputations where detailed data and surgical outcomes were not accessible for this subset of patients. For example, in a series of 62 patients with traumatic upper extremity amputations reported by Larson et al., there were five patients (within a replantation group of 20) that underwent attempted replantation for self-inflicted injuries [Self-amputation of the hand and upper extremity is an extreme and uncommon act. Patients often present with complicated psychiatric issues or even frank psychosis. A review of the literature revealed that these patients often undergo replantation despite these associated psychiatric issues and our case shows that excellent outcomes are possible in these patients. A multi-disciplinary approach with the inpatient psychiatry team is vital for early functional rehabilitation to occur, and to allow appropriate prognostic estimates in these unique patients. Further evaluation of this patient population would be beneficial to better assess patient-reported outcomes and the functional benefits of replantation and allow more definitive recommendations on how to manage and optimize outcomes.