Many studies have investigated the attitudes of mental health nurses towards a range of targets. These targets are person‐oriented  or practice‐oriented (for example practices such as seclusion or restraint).It is thought that attitudes contribute to the practice of mental health nurses because research suggests attitudes have a role in shaping behaviour.To date, research about mental health nurses' attitudes has examined different attitudes in isolation from one another. By demonstrating a lack of connectedness across studies this paper highlights the need for new theory‐informed approaches to attitudinal research.By standardizing measurements across different studies this review demonstrates that the most negatively appraised attitudinal targets—indicated by large proportions of respondents who appraise negatively—concern people with diagnoses of borderline personality disorder, substance misuse, and acute mental health presentations.Significant numbers of mental health nurses may have attitudes, especially towards people with borderline personality diagnoses and those who misuse substances, that may not be concordant with good practice.There is insufficient evidence about what the actual implications this has for practice because the body of relevant research lacks coherence, interconnectedness and a grounding in contemporary theoretical developments.Training programmes that focus on attitudinal change need to be more rigorously evaluated.Attitudes are considered integral to mental health nursing practice.To comprehensively describe the (i) measured attitudes of UK mental health nurses towards people and practice; (ii) effectiveness of interventions to change attitudes; and (iii) relationships between their attitudes, other variables/constructs and practice.Using systematic review methodology, multiple databases  were searched. Eligible studies involved measurement of UK‐based mental health nurses' attitudes with multi‐item scales. Studies were quality appraised, mean (SD) attitudinal data were standardized, and other results converted to standardized effect sizes.N = 42 studies were included. Negatively appraised attitudinal targets were people with a borderline personality disorder diagnosis, substance misuse, and acute mental health presentations. Educational interventions were associated with immediate increases in positive appraisals but sustainability was poorly evidenced. There was very limited study of attitude‐practice links.This review identifies priority attitudinal targets for action but also demonstrates that future work must consider the interconnectedness of attitudes and their relationship with practice.Priority areas for consideration are attitudes to borderline personality disorder, substance misuse and mental health co‐morbidity. Addressing disparities between nurses' attitudes and those of service users is important. More robust research is required into the effectiveness of interventions to change attitudes and into attitude‐practice links. Investigations into attitudes have fallen into two broad categories. First are studies of mental health nurses' attitudes towards the people for whom they provide care including their diagnoses and behaviours. Target attitudes in this category have included diagnostic categories like personality disorder  and are often assumed to be derived from specific beliefs, emotions, and past behaviours [sic] associated with those objects" .Identify whether subgroups of UK‐based mental health nurses  differ in their measured attitudes.Identify whether measured attitudes of UK‐based mental health nurses change over time either in or out of the context of interventions to change attitudes.Identify demonstrable associational or causal links between UK‐based mental health nurses different measured attitudes and between their attitudes, other constructs and practices.Current thinking in the study of attitudinal change suggests three important contextual areas: first, attitudes change in individuals across time as part of human development; second, attitudes exist in, and change resulting from, the context of social relationships, especially contact with powerful communicators; third, they exist in their own socio‐historical context and are subject to shaping by major events , PsycINFO and Web of Science Core Collection electronic databases in addition to Google Scholar. An example search is presented in Table 3.2For inclusion, papers must have described an empirical study conducted with a sample comprising or including UK‐based registered mental health nurses and published in peer‐reviewed journals post‐1999. Studies of nursing students or solely of those working with forensic or older age/dementia populations were not included. Details of the application of inclusion criteria are presented in the PRISMA flow diagram  and standard deviation (SD) scale/subscale scores were converted to a standardized M (SD) score and plotted in order to help gauge the sample's absolute level of attitudinal orientation, that is, the proximity of the mean to the scale midpoint and dispersal (SD) around the mean. As per our “note on terminology” (see above), we use the terms “positive” and “negative” to indicate level of endorsement of the scale items rather than as an indicator about the desired direction of the construct. There was one exception: the Self‐Harm Antipathy Scale  using an online converter , 0.5 (moderate) and 0.8 (large) to interpret effect sizes. Data extraction was conducted by Author 1 while Author 3 independently extracted 50% of data to check for accuracy.We extracted information about study setting, sample , the attitudinal construct investigated, the attitudinal and other tools used . Where possible, study results were extracted. Mean . Under each grouping, we organized evidence about the (i) absolute positivity or negativity of attitudes; (ii) positivity or negativity of attitudes relative to any other group, for example, mental health nurses vs. other professionals or service users or between UK and non‐UK samples; (iii) attitudinal differences within groups of mental health nurses or groups containing mental health nurses, for example, level of experience, gender; (iv) relationships between attitudinal constructs or between attitudinal and non‐attitudinal constructs; and (v) evidence of change in attitudinal constructs. Narrative syntheses were conducted bearing in mind the robustness of measurements based on their reliability and validity. Initial synthesis of the study findings was conducted by Author 1. These were checked and commented on by Authors 2 and 3 and were subsequently redrafted until consensus was achieved.4k = 9; severe mental illness k = 4) and behaviours ; and practice‐oriented targets . A small number of studies included measures of more than one different attitudinal target . The most commonly used tools were the Personality Disorder Knowledge Attitudes and Skills Questionnaire , the Maslach Burnout Inventory depersonalization subscale , the Attitudes to Personality Disorder Questionnaire  and the Attitudes towards Containment Measures Questionnaire . Study quality assessment generated ratings of medium quality (scores of 5 to 8 of a possible 12) for 34 of 42 sample‐attitude tool combinations; three were rated low quality (scores of 4 or below) and five high quality (9 or above).From the literature search strategy, we identified 42 papers describing studies of the attitudes of 35 unique samples comprising or including UK‐based mental health nurses published from 2000 to 2019 (see Table 4.1Person‐oriented attitudes were measured in 24 samples (see Table 4.1.1M (SD) ratings were extracted from 16 studies  ratings lay entirely to the right of the midpoint of their scale suggesting—given assumptions of normal distribution—that the majority of respondents positively endorsed attitudinal statements on that subscale. Contrastingly, negative appraisals (judged by standardized M (SD) ratings to the left of scale midpoint) were reported in relation to seven measures. All other standardized standard deviations were dispersed across the midpoint to some extent. Means with the widest SDs, suggesting more polarized appraisals, were as follows: the extent to which self‐harm represents an intention of manipulation . ACMQ and ASC‐ME relationships reported by Hosie and Dickens  suggeste4.2.4There was little evidence that tested whether practice‐oriented attitudes changed over time; Lavelle et al.  examined4.2.5Multilevel modelling did not find ACMQ to be significantly associated with either all self‐harm or moderate self‐harm (Bowers et al., 5about. We found that studies could be classified quite simply in terms of their attitudinal targets, namely as about either specific groups of people or about specific aspects of practice. We had five specific objectives and we discuss each in turn.This review has unified a sizeable but hitherto disparate literature about the measured attitudes of mental health nurses in the UK. Given that attitudes are generally considered to be specific to particular socio‐geographical‐historical contexts then it makes sense to analyse a meaningful subset of contemporary studies, in this case from the UK 2000 to present. While there have been few cross‐cultural studies, it is instructive that investigations into aggression‐related attitudes across Europe (Jansen et al., 5.1We identified studies of mental health nurses' attitudes related to seven types of person‐oriented targets and five types of practice‐oriented targets. Despite the number of relevant studies, there was strong evidence of negatively oriented attitudes, at least in absolute terms, in relation to a limited range of targets. While essentially arbitrary as an indicator, a sample mean and standard deviation entirely below the midpoint indicates below midpoint mean score for around two thirds of the sample providing as good as available an indicator of where priorities for action may lie. This only occurred in the case of borderline personality disorder (negative emotions subscale; Dickens et al., 5.2There was little evidence that UK mental health nurses' attitudes differed significantly from other professional or occupational groups. They were more positively oriented to nurse prescribing than psychiatrists (Patel et al., Of greater salience was findings about the differences between mental health nurses' attitudes and those of people who use or have used services. In relation to the use both of containment measures (Whittington et al., 5.3Bowers, Whittington, et al.  finding 5.4Most research examining change over time in the context of interventions has been limited by a failure to retain participants beyond the immediate end of intervention assessment and thus demonstrate that any change is sustained. This was the case for intervention targeted at borderline personality disorder‐related attitudes (Acford & Davies, 5.5There has been limited research into this aspect. Specifically, personality disorder‐related attitudes were found not to be related to ward‐level self‐harm rates in Bowers et al.'s  highly pFinally, attitudes as behavioural manifestations of self‐reported depersonalized responses to service users were associated with poorer general health, self‐esteem, stress (Hannigan et al., 6This review has used a number of techniques which add new insight to the collection of work both in terms of the relative import of the various studies and the unified body as a whole. First, extraction and standardization of means from different measurement tools allow a clear picture to be drawn of what the literature tells us about the measured attitudes of UK mental health nurses. Second, the calculation of standardized effect sizes where possible for all correlations or differences also informs interpretation of the import and relevance of individual studies. Third, the quality assessment of studies has facilitated the weighting of evidence. Fourth, and finally, the integration of these study findings in itself highlights the hitherto lack of such an integrated approach. The review highlights that studies have not examined relationships between attitudes and practice. Key contributions of this review, therefore, are the highlighting of the lack of connectedness between investigation of different attitudes and the lack of studies which take the next step and examine relationships between attitudes and behaviour and/or practice. In short, mental health nursing research has fallen behind contemporary theoretical developments in attitudinal research such as the causal attitude network model (Dalege et al., This review concentrates solely on one socio‐geographical‐historical subsample of available attitudinal research, namely that conducted in the UK and from the past 20 years only. Further, studies rarely report mental health nurse data separately from those of other healthcare professionals yet we have included studies which contain only a proportion of mental health nurses. We have concentrated on studies where attitudes are measured using scales. As a result, we excluded a number of studies where questionnaires were administered but results were reported on an item‐by‐item basis. Similarly, we have not included data from qualitative studies. It may be possible for future reviews to widen the socio‐geographical‐historical scope and the type of studies included. Finally, we only included studies of constructs that met our operational definition of “attitude” and other constructs such as “beliefs,” “opinions,” “perceptions” and “ideologies” also warrant attention.7Attitudinal research in UK mental health nursing has proliferated in the last two decades. There is some good evidence that many nurses make negative attitudinal appraisals about personality disorder and substance misuse. However, the extent and importance of this are somewhat shrouded by a lack of connectedness in current approaches to mental health nursing attitudinal research. What is now needed is a focus on a more integrated approach to study using new and innovative techniques based on contemporary models of attitudes.8Attitudes are considered integral to good mental health nursing practice. There has been considerable research about them but the work is disparate and lacks a joined‐up approach. The current paper takes a broader approach and examines the attitudinal literature as a body of work rather than looking at single attitudes. In doing so it highlights where the evidence lies in terms of priorities for future work and identifies the need for new approaches that consider the interconnectedness of attitudes and the links between attitudes and practice.The study is a review of existing literature and did not require ethics review.Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.


However, due to the short‐term nature of CO2 enrichment experiments and the lack of reconciliation between different ecological scales, the effect of e[CO2] on plant biomass stocks remains a major uncertainty in future climate projections. Here, we review the effect of e[CO2] on plant biomass across multiple levels of ecological organization, scaling from physiological responses to changes in population‐, community‐, ecosystem‐, and global‐scale dynamics. We find that evidence for a sustained biomass response to e[CO2] varies across ecological scales, leading to diverging conclusions about the responses of individuals, populations, communities, and ecosystems. While the distinct focus of every scale reveals new mechanisms driving biomass accumulation under e[CO2], none of them provides a full picture of all relevant processes. For example, while physiological evidence suggests a possible long‐term basis for increased biomass accumulation under e[CO2] through sustained photosynthetic stimulation, population‐scale evidence indicates that a possible e[CO2]‐induced increase in mortality rates might potentially outweigh the effect of increases in plant growth rates on biomass levels. Evidence at the global scale may indicate that e[CO2] has contributed to increased biomass cover over recent decades, but due to the difficulty to disentangle the effect of e[CO2] from a variety of climatic and land‐use‐related drivers of plant biomass stocks, it remains unclear whether nutrient limitations or other ecological mechanisms operating at finer scales will dampen the e[CO2] effect over time. By exploring these discrepancies, we identify key research gaps in our understanding of the effect of e[CO2] on plant biomass and highlight the need to integrate knowledge across scales of ecological organization so that large‐scale modeling can represent the finer‐scale mechanisms needed to constrain our understanding of future terrestrial C storage.The degree to which elevated CO The degree to which elevated CO₂ concentrations (e[CO₂]) increase the amount of carbon assimilated by vegetation plays a key role in climate change. Yet, it remains highly uncertain. Here, we review the effect of e[CO₂] on plant biomass across multiple levels of ecological organization, scaling from physiological responses to population‐, community‐, ecosystem‐, and global‐scale dynamics. We find that evidence for a sustained biomass response to e[CO₂] varies across ecological scales. By exploring these discrepancies, we identify gaps in our understanding of the effect of e[CO₂] on plant biomass and highlight the need to integrate knowledge across scales of ecological organization. In CO2 enrichment studies  and the maximum rate of electron transport (Jmax), which are the two main proxies of photosynthetic capacity. Therefore, despite the fact that e[CO2] of ~565 ppm are commonly observed to lead to an instantaneous increase in net photosynthesis of ~40% to ~65% in C3 species , plants may adjust their photosynthetic machinery over time to maintain the highest rate of C fixation in a given environment at the lowest possible cost  has not been a strong research focus in the past, and CO2 enrichment studies have rarely manipulated soil P levels and are scarce in P‐limited, tropical ecosystems .The anticipated negative effect of e[CO2] can intensify the extent of competitive exclusion among plants as they develop. Ultimately, because there is a finite amount of resources  in any location, it is necessary that the number of plants falls as the size of those plants increases  is unaffected by e[CO2], the final stand volume resulting from both slow and fast growth will be identical, even though e[CO2]‐induced faster plant growth can speed up the rate by which this final state is reached. Experiments have shown that site quality can affect self‐thinning curves  plant growth rates is problematic, particularly for long‐lived species with slow generational turnover, and the consideration of self‐thinning dynamics is essential for a meaningful estimate of vegetation levels under e[CO2].Unrelated to survival–growth trade‐offs, increased plant growth under e on survival and growth, the effect of e[CO2] on plant populations is shaped by reproduction dynamics. As e[CO2] increases the C source, more C should be available not only for plant growth but also for energetically costly reproduction  can increase soil N availability and plant N uptake, for example, through the production of extracellular enzymes degrading organic N compounds in the soil , whereas this is not the case for studies using grasses or forbs.Besides possible differences in the effect of e[CO2] over the past decades might already have induced a shift toward woodier plant communities. For example, satellite imagery showed that woody cover over sub‐Saharan Africa increased by 8% between 1986 and 2016  can decrease the time it takes to reach a large enough size to withstand fire damage  of the tissue.The residence time of dead plant C constitutes a major determinant of ecosystem C fluxes  root biomass in combination with the short lifespan of individual fine roots might cause an increase of C inputs to the soil under e[CO2]  pool. This relationship is a primary assumption embedded in most ESMs  were less pronounced and only occurred in studies with N addition or upland soils , with the explicit aim of motivating future research that is needed to improve the accuracy of future climate change projections.Global‐scale studies provide the opportunity to map the effects of rising [CO6.12] have been increasing since the beginning of industrialization, the analysis of historic satellite imagery provides an opportunity to evaluate the effect of e[CO2] on plant biomass from another angle than CO2 enrichment studies. As e[CO2] increases plant WUE, warm and arid ecosystems are expected to show the strongest plant response to e[CO2] , the greening and browning (decrease in vegetation cover) trends of many other regions seemed to be linked to climate change, primarily warming and drying , potentially due to model algorithms not adequately considering emerging nutrient limitation constraints and the effect of changing water availability on the plant response to e[CO2]  indicates a decrease in the effect of e[CO2] on plant biomass over time , and LBM (second Ph.D. advisor) conceived the paper. JM performed the data analysis with the help of LBM and JW. JM drafted the article with major contributions from LBM and TWC; all other authors also assisted with writing the manuscript. LCA, MCB, PBR, AL, MKS, CM, GM, JSD, KZ, and IKS contributed data. All authors approved the final version to be published.Appendix S1Click here for additional data file.


Computational dosimetry software is routinely used to evaluate the organ and effective doses from computed tomography (CT) examinations. Studies have shown a significant variation in dose estimates between software in adult cohorts, and few studies have evaluated software for pediatric dose estimates. This study aims to compare the primary organ and effective doses estimated by four commercially available CT dosimetry software to thermoluminescent dosimeter (TLD) measurements in a 1‐year‐old phantom.One hundred fifteen calibrated LiF ‐TLD 100‐H chips were embedded within an anthropomorphic phantom representing a 1‐year‐old child at positions that matched the approximate location of organs within an infant. The phantom was scanned under three protocols, each with whole‐body coverage. The mean absorbed doses from 25 radiosensitive organs and skeletal tissues were determined from the TLD readings. Effective doses for each of the protocols were subsequently calculated using ICRP 103 formalism. Dose estimates by the four Monte Carlo–based dose calculation systems were determined and compared to the directly measured doses.Most organ doses determined by computation dosimetry software aligned to phantom measurements within 20%. Additionally, comparisons between effective doses are calculated using computational and direct measurement methods aligned within 20% across the three protocols. Significant variances were found in bone surface dose estimations among dosimetry methods, likely caused by differences in bone tissue modeling.All four‐dosimetry software evaluated in this study provide adequate primary organ and effective dose estimations. Users should be aware, however, of the possible estimated uncertainty associated with each of the programs. The mean absorbed dose in an organ, measured in milligray (mGy), is defined as the ratio of the amount of energy deposited by ionizing radiation in the organ to the mass of that organ. The mean absorbed dose is a measurable radiation quantity that can correlate with the radiation risk. The effective dose, expressed in millisieverts (mSv), conveys the overall risk of stochastic effects, such as radiation‐induced cancers.Absorbed dose in an organ and tissue from CT exposure is not readily available from the CT scanner and is complex to directly measure. A comprehensive review of the methodology of estimating patient organ dose with CT scans can be found in the AAPM Report 246.vol) are established for incremental slice positions for each phantom, tube voltage, and scanner model through Monte Carlo photon transport simulations. The culmination of organ dose coefficients from the included slices (selected by the scan range) and user‐entered CTDIvol determines the total organ dose for a given application. However, variance in scanner modeling, computational phantoms, and photon transport algorithms can lead to considerable variation in organ dose coefficients. In particular, variations in the style and size of the computational phantom's characteristics can significantly impact the estimated organ and effective dose. First‐generation computation software used stylized or mathematical phantoms, the organs of which were created from simplistic three‐dimensional volumes.The various software operate using a similar methodology, whereby organ dose coefficients normalized to volumetric CT dose index  were used for organ dosimetry. Initially, all TLDs underwent two annealing cycles before using a programmable annealing oven (SEM Company). Individual sensitivity correction factors (SFs) for each TLD were obtained for absorbed dose by delivering a single 200‐mGy dose from a 6‐MV Varian linear accelerator beam . TLDs were centered 100 cm from the source at a depth of 10 cm in a water‐equivalent phantom (RW3 Slab Phantom) to ensure that a uniform dose was delivered. Readout occurred using an automated Harshaw 5500 unit that heated the TLDs to a maximum temperature of nominally 255°C at a heating rate of 10°C/s to optimize the signal‐to‐noise ratio.One hundred and fifteen high sensitivity lithium fluoride doped with magnesium, copper, and phosphorous  3 × 3 × 0.89 mm2.2A CIRS 704 anthropomorphic phantom  was used to simulate an average 1‐year old. The phantom consists of 25‐mm thick slices with removable inserts for dosimeter placement  by its individual SF and the batch CF and subtracting the background TLD readings (b), as shown in the following equation:For each CT scan, the five calibration TLDs were exposed to a known dose from a calibrated Xstrahl orthovoltage source, with an applied tube voltage of 120 kVp and a halve value layer thickness of 5 mm of aluminum. The calibration exposure parameters (kVp and HVL) were chosen to ensure a close match in each protocol of the unattenuated beam characteristics produced by the CT. In each calibration event, 0.5 Gy was delivered to each of the TLDs. An average calibration factor (CF) in gray per coulomb (Gy/C) was subsequently calculated by dividing the nominal dose by the average TLD response. The dose for each organ‐based TLD was computed by multiplying the TLD's response  and GE Discovery 750 HD  each had acquisition protocols selected. The tube voltages, collimations, and helical pitches selected for each protocol were chosen to reflect the local site's parameters for clinical infant torso CT examinations on each scanner. An additional acquisition at 100 kVp was also performed on the GE Discovery scanner (protocol 2). Table To ensure that the only contribution to the organ doses was from the helical acquisition, TLDs were not embedded within the phantom during the planning (scout) scans. Most computational software packages do not have the functionality to estimate the dose associated with planning scans and hence were not considered as part of this study. The TLDs were instead carefully inserted after alignment and planning scans had been completed. The planning scans were used to prepare the scan coverage for the main acquisition. The filter selected was based on the smallest scan field of view, which encapsulates the entire phantom, as would be done clinically. Additionally, the tube current for each scan was significantly increased (without modulation) from the clinical protocol to increase the dose to the TLDs and reduce measurement uncertainty. Each scan was repeated twice, with the TLDs being read out after each acquisition to ensure the precision and accuracy of the dose measurements. Any TLD readings that varied by more than 20% between the two sets of scans were repeated a third time to remove outlying measurements from the dataset.2.42.4.1[μen(E)ρ] is the mass absorption coefficient at a given energy (E) for a given tissue as defined by ICRU 46,DW is the average measured dose to water, and DT is dose converted to the specific tissue type.As the TLDs were calibrated in dose to water, a factor was required to correct for the difference in radiation absorption among different tissues in the body. As the range of photoelectrons generated at diagnostic energies is much smaller than the minimum dimensions of the TLDs, the Bragg–Gray cavity theory cannot be assumed as photoelectrons generated by photon interactions within the TLD itself contribute to most of the dose. Therefore, a ratio of the mass attenuation coefficients is considered more appropriate. The dose to a given tissue can be calculated by the following equation:As a CT beam consisted of a polychromatic spectrum, the weighted correction was applied over the range of spectral energies that accounted for the different photon energies prevalence within the CT beam. SpekCalc Software v1.1  simulated each protocol's photon energy spectrum, by inputting the nominal tube voltages and known filter characteristics.The mean organ doses were calculated using both sets of TLD measurements for each protocol. The uncertainties in a protocol's organ doses were calculated as the first standard deviation of all dose measurements within the given organ from both sets of TLDs. Tissue doses were determined by calculating the average tissue corrected dose across each TLD within the organ, except for the colon, muscle, skin, active bone marrow, and bone surface that required additional considerations. The total dose to the colon was calculated by the sum of each section's dose, weighted by its contribution to the overall mass of the colon as defined by ICRP 23.2.4.2Due to the intricate and macroscopic structures surrounding bone marrow, the dosimetry associated with the tissue remains complex. Two types of bone marrow exist in most age groups: red and yellow. All bone marrow that an individual is born with is red; however, the marrow turns from red to yellow as the individual ages. In an infant of age 1 year, most of the total marrow is still considered red marrow. Red bone marrow (RBM) is hemopoietically active and is considered highly radiosensitive, whereas yellow bone (inactive) marrow is occupied by mostly fat cells and is considerably less radiosensitive. Active bone marrow occupies the cavities within long bones and fills the space left by trabecular bone in the cranium, pelvis spine, and vertebra. Photoelectrons that originate from the more highly attenuating trabecular bone and that deposit dose through secondary electron interactions in adjacent marrow tissue have a significant impact on the total dose deposited in RBM and, therefore, need to be considered.The shallow marrow is regarded as the surrogate tissue for the osteoprogenitor cells. The ICRP 110 publication defines shallow marrow as the total marrow (both active and inactive) within 50‐μm distance from the bone surfaces.S(E)i is the RBM or shallow marrow DEFs for the skeletal site i, iM is the mass of RBM or shallow marrow or in the given bone, and totalM is the total mass of RBM or shallow marrow in a 1‐year old as defined in the ICRP publication 70 and 89.The RBM and shallow marrow doses at each skeletal site were calculated individually. The total RBM and shallow marrow doses were calculated by a weighted sum, based on the skeletal site's RBM or shallow marrow mass relative to the total RBM or shallow marrow mass throughout the entire skeleton. Shallow marrow mass absorption coefficients also accounted for the cellularity  at each skeletal site.vol and presented.Effective doses were calculated using the ICRP 103 methodology and published tissue weighting factors for each organ dose.2.5vol. Each of the software had a range of computational phantom choices, and the most applicable one to 1‐year‐old dosimetry was selected for each software. The similarities between computational phantoms are indicated in Table softD) and direct TLD measurements (TLDD) were calculated by the following equationIndividual dose simulations were performed by CT‐Expo, NCICT, VirtualDose, and WAZA‐ARI dosimetry software applying the same scan parameters used in the phantom measurements. This included the CT model, tube voltage, pitch, collimation, and CTDI3vol (32‐cm reference phantom), respectively. Doses were normalized by CTDIvol as it accounts for not only tube current time, but also variations in pitch. There was a close agreement between organ and effective doses per CTDIvol between protocols. Small variations in organ doses may be attributed to differences in spectral output caused by different X‐ray tube characteristics and filtrations.Tables Despite the tube output remaining consistent throughout each scan, the thyroid, testes, skin, and bone surface consistently received the highest organ doses. The skin's, testes’, and thyroid's proximity to the surface likely attributed to this outcome. The high bone surface dose is likely caused by an elevated DEF at low photon energies, resulting in a greater dose being deposited.3.1Figures Figures 4This study aimed to compare organ and effective doses estimated using different dosimetry software to TLD measurements performed with a 1‐year‐old phantom for a range of scan protocols and CT scanners. To the best of the author's knowledge, this study is the first to evaluate the different dosimetry software packages and TLD measurements for skeletal tissue doses and effective doses in 1‐year olds.4.1Organ doses estimated by NCICT aligned best with TLD results, with an average variation of 8%. Conversely, organ doses estimated by CT‐Expo varied significantly from TLD measurements, particularly for bone surface and torso organs (average deviation of 32%). The variation in bone surface dose can be attributed to CT‐Expo using a different surrogate tissue for the osteoprogenitor cell dose calculation. NCICT, VirtualDose, WIN‐AZARI, and TLD measurements use inactive and active marrow located within 50 μm from the bone surfaces as the surrogate tissue. CT‐Expo assumes a tissue of hard cortical bone, which holds much higher attenuation properties and significantly overestimates the dose to the osteoprogenitor cells.vol due to a smaller target mass and laws of exponential attenuation. Therefore, simulations performed on smaller phantoms are likely to overestimate the dose absorbed to torso organs. However, due to an infant's head dimensions changing less rapidly during childhood, organs located within the head are less impacted by imperfect phantom selection. Across the three protocols, CT‐Expo's dose estimate of the brain varied by an average of 7%, significantly less variation than what was recorded for organs within the torso.CT‐Expo's overestimation of absorbed doses to torso organs, such as the colon, liver, and small bowel, is likely due to the inability to select a computational phantom that accurately represents the physical stature of a 1‐year‐old infant. The voxelized MIRD “BABY” phantom was designed to mimic the physical dimension of an 8‐week‐old newborn. Smaller bodies will inherently absorb a proportionately higher radiation dose for a given CTDIVirtualDose and WAZA‐ARI provide estimates that closely align with TLD measurements, with the variation of most organ doses being less than 20%. VirtualDose's dose estimates of the heart, breast, and pancreas aligned within 10% across all protocols. The WAZA‐ARI's calculation of bone surface dose was the computational dosimetry method that matched most closely the TLD‐derived results.Phantom measurements and all dosimetry software except CT‐Expo indicated a higher overall effective dose for males than for females. This finding is likely due to male gonads receiving a higher absorbed dose than female gonads because of the testes’ proximity to the skin surface. CT‐Expo's contradictory estimate is expected due to the association of zero organ dose to breast tissue for males, significantly decreasing the overall effective dose due to the high tissue weighting factor associated with breast tissue. Interestingly, however, CT‐Expo showed the greatest agreement to TLD measurements for the effective dose calculations in males. However, this was likely caused by the balance of over‐ and underestimation of individual organ‐absorbed doses.Overall, the findings of this study suggest that organ doses estimated with software that employ 1‐year‐old pediatric phantoms  provide the greatest agreement with TLD results for infant dosimetry. These hybrid phantoms also bear the greatest resemblance to realistic anatomical features, allowing the user to better individualize the dosimetry based on the patient's physical characteristics. Furthermore, these software packages use the new formalism for bone surface, whereas dosimetry software packages that use the MIRD “BABY” phantom (CT‐Expo) assume that the bone surface tissue is composed of cortical bone, which decreases the accuracy associated with these estimates. However, all four‐dosimetry software packages evaluated in this study provide adequate primary organ and effective dose estimations for the purposes of conveying the stochastic risk for an average reference patient. Due to known limitations with the definition of effective dose, dosimetry software should not be used to calculate an individual's stochastic risk.4.2The radiation doses associated with CT procedures and their yearly volume make CT one of the most significant contributors of ionizing radiation to the general population. This is particularly pertinent in highly radiosensitive infants as large‐scale studies indicate an increased stochastic risk after CT examinations.vol, most organ doses align with measurement uncertainty between the studies. Doses to skeletal tissues and effective doses were not evaluated in that study.This study indicates that all dosimetry software packages analyzed provide a reasonably accurate organ and effective dose estimate across the range of scan protocols and CT manufacturers assessed. Regardless of the dosimetry software employed for the dose estimations of infants CT examinations, users should be aware of the variation in dose estimates between software. Effective dose estimates conducted by different dosimetry software have noted differences of 25% between software and as high as 55% and 210% for soft tissue organ and skeletal tissue dose estimates. This finding is consistent with studies looking at variation in effective dose estimates in the adult population.vol normalized data presented in this study can easily be implemented to assess the doses to primary beam organs most at risk during infant examinations that implement different scan coverages. This may be particularly useful for clinicians who may not have access to CT dosimetry software. Future studies should consider assessing the accuracy of organ doses outside the primary scan range.Although whole‐body CT acquisitions in infants are currently limited to a few applications,4.3This research has several limitations that should be considered in further research. First, the physical phantom constraints limit a definitive judgment regarding the supremacy of a single computational software. The phantom used in this study did not include arms that may have a radiation‐shielding effect on the organs located within the torso. Additionally, all organs and tissues  throughout the phantom were created with a homogeneous soft tissue–equivalent density. Denser torso tissues such as the liver would typically have a slight shielding effect on surrounding tissues such as the stomach that cannot be accounted for in this study. The homogeneous density throughout the torso also meant that hollow structures such as the stomach wall and colon were regarded as solid organs. Second, the dosimetry methodology also had relevant limitations. Although high sensitivity 100‐H  TLDs have a smaller energy dependence in the diagnostic energy range than other types of TLDs, there is still an uncertainty caused by the difference in spectral output between the CT protocols and the orthovoltage calibration source. Also, the lack of published DEFs for the shallow marrow dosimetry of pediatrics remains an ongoing issue for all pediatric skeletal dosimetry calculations. Although the assumption that adult DEFs apply for infants may have an associated inaccuracy, other methods that assume a homogenous bone composition and densities are likely to cause even greater uncertainty.5Computational dosimetry software continues to be the preferred method for determining CT doses in clinical settings due to time efficiency and an easy‐to‐use interface. All four computational dosimetry software evaluated in this study provided organ and effective dose estimates, which aligned well to direct TLD phantom measurements across the three clinical CT protocols. Bone surface dose estimations were shown to have the largest variation among methods, likely caused by differences in the target tissue. Although dosimetry software that employs hybrid computational phantoms had a greater congruence with TLD measurements, all software evaluated in this study provided a sufficiently accurate estimate for stochastic risk evaluations in infant CT examinations.No conflicts of interest to disclose.All authors have contributed to the manuscript—including the development of hypotheses, design, and drafting of the paper. The named authors have no conflict of interest financial or otherwise to disclose.


Problem‐orientated dental attenders account for around one‐third of the UK population, these being patients who do not seek regular dental care, instead only attending with dental pain. In order to develop intervention(s) to encourage regular dental attendance in these patients, any previous intervention development should be identified to aid idea generation or retrofitting of interventions.To identify previous interventions which have been developed targeted at problem‐orientated dental attenders to facilitate the development and co‐design of a new intervention.Eight electronic databases were searched for studies which included an intervention targeted at adult problem‐orientated or irregular dental attenders to encourage regular dental attendance. Data on the intervention design mapped to the theoretical domains framework were extracted, alongside effectiveness and patient views where available.Three studies fitted the inclusion criteria for the review. Interventions identified were attendance at a dental anxiety clinic, and a large advertising campaign promoting a free dental update where members of the public could visit local dental practices to look around and meet the dentists. One study looked at the effect of policy change by introducing free dental check‐ups in Scotland. Interventions were poorly reported, with significant omissions in their description and a lack of clear identification of what composed the intervention.There are very few interventions developed targeted at problem‐orientated dental attendance, but important areas to consider in future intervention development include the following: dentist communication; dentist‐patient relationship; increasing the awareness of need; the effect of free dental check‐ups. A systematic review was carried out to identify previously developed interventions targeted at problemorientated dental attendance. Three studies were identified. Interventions included attendance at a dental anxiety clinic, a promotional campaign, and policy change introducing a free dental check‐up. Interventions were poorly reported but identified potential areas for future intervention development. Where possible secondary aims were to establish the effectiveness and to consider views or opinions of any patients or healthcare providers on any existing interventions and healthcare policy identified.2a priori protocol, which was published online on PROSPEROThis systematic review was conducted with an Participants: patients above the age of 18 years old of any gender who were problem‐orientated or irregular dental attenders. Studies of patients below 18 years old and of patients attending with chronic oro‐facial pain were excluded.Interventions: any form of intervention (brief or complex) or policy change that encouraged regular dental attendance instead of problem‐orientated attendance were included.Comparators/Control: No comparator was mandatorily required for inclusion. Where effectiveness was to be specifically considered the comparator or control group was set as patients not receiving the intervention, or for policy change the effect before and after.Outcomes: Primary outcomes were an increase in regular or preventive dental care visiting/utilisation or an increase in emergency attendance at a dentist instead of other healthcare providers.Studies: All peer‐reviewed English language studies of any design were included. Where effectiveness was to be specifically considered, only studies using a comparative design for interventions and controlled before‐after studies for policy change were included.The criteria for considering studies for the systematic review were (PICOS):2.1Eight electronic databases were searched up to 1 April 2021 Appendix : Medline2.2Eligible studies were selected by the first reviewer (CC) according to the inclusion and exclusion criteria based upon the study title and abstract (where available). If it was unclear whether a study should be included or not the full text was reviewed. A second reviewer (JD) reviewed the full text of all potential studies for inclusion, blinded to the journal title, institutions involved and the authors. Any disagreement regarding the inclusion of any study were resolved by discussion and inclusion of a third reviewer.2.3Intervention/policy change design, type and details, classified where possible using the Theoretical Domains Framework (TDF)Target populationOutcome(s)Cost of intervention/policy change (if available)Patient and healthcare provider views (if available)Author's conclusion(s) and recommendation(s)Citation informationA standardised form was created in Microsoft Word  and used to extract data from the included studies. The first reviewer (CC) extracted and entered the data onto the form. To ensure reliability, all of the extracted data were cross‐checked by the second reviewer (JD), again blinded to the study details as described above. Any disagreement was resolved as previously described. Data extracted included the following:A risk of bias assessment was not considered necessary for studies included in the review as the outcome of the assessment would not have affected the decision on whether to develop ideas or components further. If multiple studies had been identified with appropriate study design and comparators to consider effectiveness in detail then the ROBINS‐I tool would have been used for risk of bias assessment.2.4Studies were tabulated to describe the intervention or policy change and to map to the TDF domains where possible. This provided a descriptive analysis to display ideas for further development. Due to substantial heterogeneity between the eligible studies effectiveness was summarised by study and integrated into a narrative synthesis of the main findings with a descriptive analysis only. Where patient or provider views and opinions were available these were considered alongside the intervention or policy change and integrated into a narrative synthesis.3The search strategy initially identified 4803 articles Figure , of whic3.1The included study characteristics are reported in Table 3.2Dailey et al.Anderson and MorganIkenwilo et al.To summarise the three interventions:A summary of the interventions or policy change mapped to the TDF is provided in Table 3.3Key findings from the studies are summarised in Table 3.4Two studiesA large advertising campaign was used to improve the image of dental services to the general public and promote the opportunity to attend for a free dental update; however, this was largely misinterpreted as ‘visit your dentist’, or ‘there's no need to be frightened of the dentist’.4This systematic review highlighted two interventions aiming to increase regular dental attendance in irregular dental attenders and both studies provide areas for consideration in intervention development. Whether attendance at a dental anxiety clinic had a positive behavioural change effect is undeterminable given only half of the patients contacted had changed their attendance behaviour in the longer term, in addition to a large number of patients being lost to follow‐up. However, what was highlighted as having the biggest self‐reported effect on dental anxiety and move into regular dental attendance was the dentist's communication skills and establishing a good dentist‐patient relationship.A large advertising campaign to promote the image of dental services and offer a free dental update was largely unsuccessful due to public misinterpretation of intervention.This review also identified one study examining the effect of policy change by introducing a free dental check‐up in Scotland in 2006.a priori protocol, a formal risk of bias assessment was not carried out for the studies included in this review as the outcome would not have affected inclusion of the intervention components in a future co‐design process. Whilst systematic reviews with studies indicating a low risk of bias are preferable, when developing interventions it is important to consider and present all relevant studies to stakeholders when discussing the evidence and encouraging blue‐sky thinking.As per the Across all studies identified the interventions were poorly described, this poses a problem with replication or retrofitting of the interventions in the future and better reporting of intervention components is required. The use of the TIDierR checklist can facilitate reporting of interventions and includes 12 items: brief name; why; what materials; what procedures; who provided; how; where; when and how much; tailoring; modifications; how well (planned); how well .5This systematic review identified a lack of interventions targeted at problem‐orientated dental attendance, however, data within the studies identified highlights the potential importance of considering dentist communication, the dentist‐patient relationship, increasing the awareness of need and the effect and considerations of free dental check‐ups in future intervention development. The same studies also highlighted the importance of a sound evidence base, theoretical frameworks and involvement of relevant stakeholders in intervention development to maximise acceptability and effectiveness.The authors have no conflicts of interest to declare.C Currie contributed to conception, design, data acquisition and interpretation, analysis, drafted and critically revised the manuscript. V Araujo‐Soares and J Durham contributed to conception, design, data acquisition and interpretation, analysis and critically revised the manuscript. SJ Stone and F Beyer contributed to conception, design, data interpretation, and critically revised the manuscript. All authors gave their final approval and agree to be accountable for all aspects of the work.https://publons.com/publon/10.1111/joor.13244.The peer review history for this article is available at Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.Appendix S3Click here for additional data file.


Testicular ectopia refers to abnormal positioning of testis, which includes a wide variety of variants. An ectopic testis is located off the normal path of male gonadal descent, unlike conventional undescended testis.A 37‐year‐old man presented with the complaint of a palpable lesion in the scrotum. Magnetic resonance imaging of the scrotum revealed bilateral testes on the respective opposite sides of the scrotum with bilateral spermatic cords crossing under the base of the penis. Accordingly, he was diagnosed as “left‐right reversal of the testes within the scrotum.” In retrospect, the “palpable” lesion was thought to be the spermatic cords crossing above the testes. Semen analysis identified deteriorated sperm motility, suggesting possible male infertility.This case of left–right reversal of the testes within the scrotum is probably a new variant of testicular ectopia that has never been reported. Testicular ectopia refers to abnormal positioning of testis and includes a wide variety of variants. An ectopic testis is located off the path of normal descent, unlike conventional undescended testis. We report a case of left–right reversal of the testes within the scrotum, whereby bilateral testes were located on the respective opposite sides of the scrotum with bilateral spermatic cords crossing under the base of the penis. The present case might be a new variant of testicular ectopia that has never been reported.Testicular ectopia is a generic term used to refer to the abnormal positioning of the testis. It accounts for approximately 10% of extrascrotal testes and is sometimes contrasted with undescended testis or cryptorchidism, the commonest genital malformation in boys.A 37‐year‐old man who had a past medical history of proteinuria  and was otherwise healthy visited our department with the complaint of a palpable lesion in the scrotum. He was suspected having left spermatocele by ultrasonography at another clinic 8 years previously but had undergone no further examination. A physical examination of the external genitalia demonstrated no abnormal findings. Laboratory blood tests did not detect any abnormal values, including serum total testosterone (6.71 ng/mL).Ultrasonography of the scrotum showed bilateral spindle‐shaped low‐echoic lesions located above the respective bilateral testes and epididymides, which had blood‐flow signals inside. It also detected normal but slightly small bilateral testes  Fig. . Based oScreening semen analysis identified normal semen volume and sperm concentration and morphology but deteriorated sperm motility , suggesting possible male infertility Table . HoweverThe present report describes a case of left–right reversal of the testes within the scrotum, whereby each testis moves to the opposite side of the scrotum with bilateral spermatic cords crossing under the base of the penis. To the best of our knowledge, this condition has never been described in the literature and might thus be a new variant of testicular ectopia. The patient also presented with deteriorated sperm motility with slightly small testes, suggesting possible male infertility, although its association with his testicular ectopia was unclear.before entering the inguinal canal in transverse testicular ectopia, bilateral testes and spermatic cords move across the midline after leaving the respective inguinal canals and cross each other in the present case, suggesting different underlying mechanisms.Testicular ectopia refers to abnormal positioning of the testis and is distinguished from conventional undescended testis or cryptorchidism by the fact that an ectopic testis is located off the normal path of male gonadal descent.The descent of testes through inguinal canals in the fetus occurs at 26 to 28 weeks as the gubernaculum pulls down the testes into the scrotum, after which the testes are fixed at the bottom of the scrotum at 35 to 40 weeks.Surgical correction is generally recommended for testicular ectopia as well as undescended testis, since it may optimize testicular function, facilitate diagnosis of testicular cancer, provide cosmetic benefits, and prevent complications such as hernia or torsion.In summary, we report for the first time a case of left–right reversal of the testes within the scrotum, which is presumably a new variant of testicular ectopia.Kenjiro Kishitani: Conceptualization; data curation; formal analysis; writing – original draft. Kenji Yoda: Conceptualization; data curation; formal analysis; project administration; writing – review and editing. Satoru Taguchi: Conceptualization; data curation; formal analysis; project administration; writing – original draft. Hikaru Suyama: Data curation; writing – review and editing. Hayato Hoshina: Data curation; writing – review and editing. Yoshiyuki Akiyama: Data curation; writing – review and editing. Yuta Yamada: Data curation; writing – review and editing. Yusuke Sato: Data curation; writing – review and editing. Daisuke Yamada: Data curation; writing – review and editing. Haruki Kume: Project administration; supervision; writing – review and editing.The authors declare no conflict of interest.Not applicable.Not applicable.Not applicable.


Diaphragm muscle atrophy during mechanical ventilation begins within 24 h and progresses rapidly with significant clinical consequences. Electrical stimulation of the phrenic nerves using invasive electrodes has shown promise in maintaining diaphragm condition by inducing intermittent diaphragm muscle contraction. However, the widespread application of these methods may be limited by their risks as well as the technical and environmental requirements of placement and care. Non‐invasive stimulation would offer a valuable alternative method to maintain diaphragm health while overcoming these limitations.We applied non‐invasive electrical stimulation to the phrenic nerve in the neck in healthy volunteers. Respiratory pressure and flow, diaphragm electromyography and mechanomyography, and ultrasound visualization were used to assess the diaphragmatic response to stimulation. The electrode positions and stimulation parameters were systematically varied in order to investigate the influence of these parameters on the ability to induce diaphragm contraction with non‐invasive stimulation.We demonstrate that non‐invasive capture of the phrenic nerve is feasible using surface electrodes without the application of pressure, and characterize the stimulation parameters required to achieve therapeutic diaphragm contractions in healthy volunteers. We show that an optimal electrode position for phrenic nerve capture can be identified and that this position does not vary as head orientation is changed. The stimulation parameters required to produce a diaphragm response at this site are characterized and we show that burst stimulation above the activation threshold reliably produces diaphragm contractions sufficient to drive an inspired volume of over 600 ml, indicating the ability to produce significant diaphragmatic work using non‐invasive stimulation.This opens the possibility of non‐invasive systems, requiring minimal specialist skills to set up, for maintaining diaphragm function in the intensive care setting. We demonstrate that the diaphragm can be exercised using non‐invasive electrical stimulation of the phrenic nerve and characterize the stimulation parameters required to achieve this. This opens the possibility of non‐invasive systems for maintaining diaphragm function in ventilated patients in an intensive care setting. However, disuse of the diaphragm during ventilation can rapidly result in severe dysfunction, with evidence of significant diaphragm weakening after as little as 24 h.complete lack of activity in skeletal muscle that leads to atrophy, and only a small amount of exercise (~200 contractions per day) is needed to prevent it.Stimulation of the phrenic nerves to induce diaphragm contraction is a promising means of maintaining diaphragm condition during mechanical ventilation. It is the There are currently multiple invasive techniques for achieving stimulator‐induced diaphragm activation.Non‐invasive stimulation of the phrenic nerves would offer a means to maintain diaphragm condition during mechanical ventilation while avoiding the risks and technical demands of more invasive approaches. The ability to induce diaphragm contraction using surface electrodes has been demonstrated before, however, these approaches rely on frames,Our group, therefore, aimed to develop a non‐invasive phrenic nerve stimulation system suitable to maintain diaphragm muscle function in ventilated patients in an intensive care setting. This requires reliable ventilator‐synchronized diaphragm contraction using surface electrodes without the application of pressure.Here, we demonstrate that non‐invasive capture of the phrenic nerve is possible and characterize the parameters required to achieve meaningful diaphragm contraction in healthy volunteers. This opens the possibility for non‐invasive methods to maintain diaphragm function in ventilated patients, with the potential to reduce time spent on a ventilator and improve clinical outcomes.2Healthy volunteers with no respiratory or neurological pathologies were recruited. The study was approved by the University of Oxford Central University Research Ethics Committee  and by the Ethics Committee at the Universidad de Concepción, Chile (CEBB 714–2020).2.1Custom electrode geometries were created by modification of commercial (Axelgaard) electrodes. Electrode geometries are shown in Figure For the initial assessment of the efficacy of non‐invasive phrenic nerve stimulation, concentric ring electrodes, with an inner cathode surrounded by a ring‐shaped anode, were used to constrain the area of activation Figure . CirculaIn order to characterize the impact of electrode position on diaphragm response, linear electrode arrays were fabricated Figure . Six 1 c2.2Ω load, i.e., a compliance voltage of 300 V) with a resolution of 1 mA. Pulse trains could be generated with frequencies from 1 Hz to 30 Hz with a resolution of 1 Hz.A custom stimulation and monitoring system were developed for the initial evaluation of the effect of non‐invasive phrenic nerve stimulation Figure . A two‐cTo allow even greater control of stimulation parameters and electrode selection, a detailed assessment of the parameters required to induce diaphragm contraction was performed using a Digitimer DS8R current‐regulated stimulator with a compliance voltage of 400 V. Biphasic, charge‐balanced, symmetric waveforms were used throughout all testing. Each of the six electrodes in the linear array was attached to a Digitimer D188 electrode selector to allow stimulation at individual electrode sites.2.3Evaluation of the effect of non‐invasive phrenic nerve stimulation on the diaphragm was performed by stimulating the nerve bilaterally while performing multi‐modal monitoring Figure .Participants were placed in a supine position. Blood pressure, heart rate, respiratory rate, and oxygen saturation monitors were installed to allow monitoring during stimulation. The diaphragm electromyogram (EMG) was recorded using bipolar electrode pairs in the sixth and eighth intercostal spaces bilaterally to assess the electrical response to stimulation. The use of a bipolar electrode arrangement at a significant distance from the stimulating electrodes on the neck allowed diaphragm EMG to be measured while avoiding significant contamination with stimulation artifacts.Mechanomyography (MMG) was performed using accelerometers placed just medial to the EMG electrodes bilaterally to evaluate the mechanical response to stimulation. Participants were connected to a non‐invasive mechanical ventilator  in continuous mandatory (assist‐control) ventilation mode. This mode allowed patient‐triggered breaths on detection of an inspiratory effort while reverting to ventilator‐triggered breaths at a fixed rate if necessary. This allowed the ventilator to be activated by inspirations generated by stimulation in order to provide pressure support to induced inspirations while enforcing a minimum number of guaranteed breaths per minute if there is an insufficient spontaneous effort to trigger respiration. This allowed the interaction between stimulation‐induced diaphragm contractions and mechanical ventilation to be investigated, including the potential risk of inducing patient‐ventilator asynchronies due to stimulation. Respiratory pressure and flow were measured in line with the ventilator to assess the respiratory response. Diaphragm ultrasound was used to provide direct visualization of the response to stimulation.A calibration procedure was performed to define the electrode position and stimulation parameters used for an initial assessment. A stimulator probe was used to manually apply stimulation to the area just posterior to the sternocleidomastoid muscle at the level of the cricoid cartilage. Diaphragm response was evaluated using the multi‐modal monitoring setup. This was repeated until the area that elicited the maximal diaphragm response, defined as the location that produced the largest area under the curve on pressure and flow waveforms following stimulation with confirmation of diaphragm contraction on EMG, MMG, and direct visualization was identified bilaterally. Concentric electrodes were then placed in these locations and the stimulation parameters were tuned based on the diaphragm response seen during monitoring.2O of pressure support to generate inspirations. Stimulation and ventilation were applied for 10 min while the diaphragm response was monitored to assess the ability to reliably produce diaphragm activation while maintaining respiration without interfering with ventilation.Following identification of the required electrode position, stimulation amplitude, pulse width, and frequency, pulse trains of 1.1 s with an inter‐pulse interval of 2.2 s were delivered. The ventilator was triggered by stimulation‐induced inspiration, corresponding to a 1:2 inspiration: expiration ratio at a respiratory rate of 18 breaths per minute, while the ventilator was set to produce 18 breaths per minute to maintain respiration if stimulation fails to trigger the ventilator. It delivered 4 cmH2.4The parameters required to reliably induce diaphragm activation with non‐invasive stimulation of the phrenic nerve were evaluated using an electrode array attached to a Digitimer DS8R stimulator as described. Respiratory responses to stimulation were measured as parameters were systematically varied and used to update the set of stimulation parameters required Figure . Electro∫PdVdt.Respiratory responses to stimulation were recorded using pressure and flow sensors attached to a pitot tube section of an anesthetic circuit through which participants breathed freely, forming a seal with the lips around its end. Subjects maintained an open glottis and wore a nose clip to prevent the escape of air through the nose. The response of the diaphragm to stimulation was assessed by estimating the work done by the diaphragm following stimulation, providing a measure of the strength of the induced contraction. This was done by calculating the pressure‐volume work over the period following stimulation, i.e., The effect of electrode position was characterized by stimulating each cathode sequentially at a range of amplitudes using single stimulation pulses while the respiratory response was measured. This was performed with the head centered and then while looking to the left or to the right to assess the effect of head position on optimal electrode placement.The electrode that induced a threshold response with the lowest stimulating current was selected. A diaphragmatic response to stimulation was defined as a deflection in the pressure and flow measures following stimulation with a magnitude of greater than three standard deviations from the mean for resting without stimulation. Responses were also visually inspected to manually confirm threshold measurements. The strength‐duration curve for the phrenic nerve was then characterized by measuring the threshold required to produce a measurable diaphragm response for a range of pulse widths using single stimulation pulses. The strength‐duration curve indicates the minimum stimulation current required to produce a response at a range of pulse widths. This provides important information on the responsiveness of the nerve to stimulation and the sensitivity of the nerve to changes in stimulation parameters. This provides valuable data for determining the most efficient stimulation parameters to produce reliable capture of the nerve as well as providing data on the variability of the parameters required to produce a response across a population.The effect of stimulation frequency was investigated by delivering 200 ms pulse trains of varying frequency at the optimal electrode using 100 μs pulses at 125% of the threshold identified. The diaphragmatic pressure‐volume work produced by stimulation was calculated and integrated over the 1 s following stimulation to measure the effect of stimulation.33.1Ten participants  were recruited for an initial assessment of the effect of non‐invasive phrenic nerve stimulation. Participants had a mean age of 31 (range 26–39) years and a mean weight of 77 (range 66–95) kilograms.For a detailed assessment of stimulation parameters, 14 participants were recruited . Participants had a mean age of 28 (range 19–50) years and a mean weight of 71 (range 52–98) kilograms.3.2Bilateral non‐invasive phrenic nerve stimulation produced a diaphragm response, with the agreement of all multi‐modal measures, in all participants. Stimulation successfully produced a sufficient diaphragm response to trigger the ventilator in all participants, producing diaphragm exercise while ensuring consistent respiration during ventilation. The ventilator was driven by stimulation‐induced breaths alone for the full duration of stimulation in all participants, without any need to revert to ventilator‐triggered breaths.Figure The stimulation parameters used to produce consistent diaphragm responses in each participant are shown in Table No adverse reactions occurred during stimulation. All monitored vital signs remained within physiological ranges with no change during or following stimulation. Four participants reported discomfort during stimulation. This was described as a prickling sensation under the electrode. In each case, this appeared to be due to poor electrode adhesion and was successfully remedied by replacing the electrode that was inducing discomfort.3.3The effect of variations in electrode position on the response to stimulation was evaluated using a custom linear array in a larger group of participants. In all participants, one cathode showed a greater response than all the others, with a rapid drop in diaphragm response following stimulation at the neighboring electrodes. An example of an electrode sweep over a range of amplitudes is shown in Figure The distributions of optimal electrodes across all participants for each head position are shown in Figure The optimal electrode for phrenic nerve stimulation could be reliably identified with a single sweep of single pulses at each electrode, allowing extremely rapid determination of the ideal electrode position for stimulation. Using single pulses at 2 Hz, the optimal electrode could be determined out of a set of six potential electrodes in 3 s during a single respiratory cycle. The optimal electrode for phrenic nerve capture also produced minor head movements on stimulation, likely due to activation of the underlying sternocleidomastoid muscle. In some participants, activation lateral to the optimal site for phrenic nerve activation produced movements of the arm and hand, likely due to activation of components of the brachial plexus lateral to the phrenic nerve. The locations for optimal activation of the phrenic nerve and activation of the brachial plexus did not overlap in any participants.3.4The strength‐duration relationship for stimulation parameters was characterized using the optimal electrode identified on assessment of electrode position. This demonstrates the minimum current required to produce nerve activation using a variety of pulse widths, characterizing the variability of parameters needed to produce a response and the sensitivity of responsiveness to changes in stimulation parameters. In all participants, diaphragm activation could be produced using reasonable stimulation parameters without excessive discomfort.R2 = 0.94; mean absolute error = 1.95 mA), as is characteristic of strength‐duration relationships.Threshold amplitudes were variable across individuals. There was a decrease in threshold as pulse width increased in all participants. The individual and mean strength‐duration curves for the phrenic nerve using single stimulation pulses are shown in Figure 3.5Two hundred milliseconds of pulse trains of 100 μs pulses at 125% of the threshold identified on strength‐duration testing and at frequencies above 10 Hz produced a measurable diaphragm contraction in all participants with a nerve capture rate of 100%, i.e., delivery of a pulse train at the optimal electrode at 125% of the threshold amplitude always produced a robust diaphragm contraction.The work produced by stimulation increased as stimulation frequency increased. An example of the measured power (W) following pulse trains at varying frequencies is shown in Figure 4Our results indicate that non‐invasive stimulation of the phrenic nerve for inducing diaphragm contraction is feasible, and this does not require the application of pressure. We have characterized the stimulation parameters required for achieving reliable activation of the nerve.Induction of diaphragm contraction using non‐invasive stimulation was confirmed using multiple modalities, including ultrasonic visualization. Further, this response was maintained during repeated stimulation and could reliably trigger the ventilator without the need to revert to ventilator‐triggered breaths and without interfering with respiration. These results provide strong evidence that non‐invasive stimulation can reliably produce robust diaphragm contractions suitable for maintenance of function during ventilation.Monitoring of vital signs and clinical assessment revealed no adverse events during or following stimulation, suggesting that the phrenic nerve can be activated without producing side effects, such as unintended autonomic effects due to stimulation of the nearby vagus nerve or the carotid sinus higher in the neck. Some participants noted discomfort during stimulation due to the activation of cutaneous afferents and contraction of muscles in the neck. This discomfort was particularly notable at higher‐frequency stimulation. This discomfort during stimulation may limit the application of non‐invasive phrenic nerve stimulation to awake patients for prolonged periods but is unlikely to provide a major barrier to application in sedated, ventilated patients.Activation of nearby structures, such as cutaneous afferents and neck muscles, is due to the lack of selectivity of surface electrodes. All structures under the electrodes are exposed to the electric field produced by stimulation, making targeted stimulation challenging. We found that the use of a concentric electrode arrangement was successful in constraining the area of activation, limiting off‐target effects, and allowing more targeted stimulation of the phrenic nerve. This was achieved by the enclosing anode limiting spread of the produced electric field beyond the area underlying the electrode. In order to allow greater control over the positioning of electrodes for assessment of sensitivity to electrode location and automatic identification of the optimal stimulation position, we further developed a linear electrode array with a surrounding anode. This allowed us to maintain targeted stimulation of the phrenic nerve with minimal off‐target effects while still retaining tight control over the precise location of stimulation.The ability to activate the phrenic nerve non‐invasively is very sensitive to electrode position. Stimulation at the level of the cricoid cartilage reliably produced a response, but the lateral position required varied between individuals. All participants showed a response with stimulation using 1 cm cathodes centered between 56 mm and 80 mm from the midline, with most responding to stimulation centered at 68 mm, but the individual optimum position was variable. This has important implications for the practical application of this technique, as care must be taken to ensure electrodes are positioned appropriately.However, our results also indicate that the optimal surface point for achieving nerve capture does not vary with head position. This is relevant for patients in intensive care, where prone positioning  may be used to improve lung function. Prone positioning requires the head to be rotated up to 90° to the left or right; furthermore, it is generally used intermittently with periodic changes from supine  to prone and back again. Our results suggest that electrodes will not need to be repositioned when the head is turned. Further, our results demonstrate that it is possible to rapidly identify the optimal electrode position from an array using measurements of the diaphragm response; this raises the possibility of automatic electrode selection from a surface array to account for inter‐individual variability.Our characterization of the strength‐duration relationship for non‐invasive stimulation of the phrenic nerve and the relationship between stimulation frequency and inhaled volume provide a demonstration of the ability to achieve meaningfully strong and powerful diaphragm contractions with non‐invasive stimulation with parameters that are achievable with standard stimulation hardware. This further provides a valuable resource for the development of non‐invasive stimulation systems by detailing the stimulation parameters required and their variability.While our results were limited to the assessment of the use of pressure and flow measurements to assess the diaphragmatic response to stimulation, further work on other sensing modalities, such as lung sounds, may identify other methods of quantifying diaphragm activity and optimizing response to stimulation. Similarly, the results presented here used continuous mandatory ventilation to test interactions between stimulation‐induced breathing and ventilation systems by relying on the ability of stimulation‐induced breaths to trigger the ventilator. For application in an intensive care environment, it will also be valuable to implement a method to trigger the stimulator using the recorded respiratory signals in order to synchronize the stimulator with mandatory ventilation as an alternative to relying on assistive ventilation modes. Electrode location is also an important consideration for integration into existing intensive care workflows. Some ventilated patients will require central venous access. A linear array with the configuration presented here may provide a barrier to placing central venous catheters in the internal jugular vein. While using the subclavian vein for central access is a simple alternative, re‐designing the electrode array using the positioning data presented here may allow for reliable stimulation of the phrenic nerve without interfering with central venous access in the neck.Further, while we can demonstrate reliable induction of diaphragm contraction in healthy volunteers, the ability to consistently produce sufficient diaphragmatic work to maintain function during mechanical ventilation in sedated, ventilated patients, whose body composition may vary over a broader range than our healthy volunteers, over the course of multiple days will need to be formally assessed. Similarly, the electrode impedances are likely to change over time and may require electrode replacement in situations where ventilation is required for longer than one week.Overall, these results support the potential clinical validity of non‐invasive methods for maintaining diaphragm conditions and highlight the need for a clinical study of the efficacy of this approach in an intensive care environment. While care must be taken to ensure accurate electrode placement, the stimulation parameters required are well within the range of standard stimulation systems and well within safe limits. This opens the possibility for non‐invasive systems for maintaining diaphragm function in the intensive care setting, potentially improving ventilation outcomes while avoiding the risks and technical limitations of more invasive stimulation techniques.The authors declare no conflict of interest.Conceived of and designed the studies: Conor Keogh, Francisco Saavedra, Sebastian Dubo, Pablo Aqueveque, Paulina Ortega, Jonathan Jarvis, Brian Andrews, and James J. FitzGerald. Designed and fabricated the equipment: Adrian Poulton, Francisco Saavedra, Conor Keogh, Brian Andrews, Britam Gomez, Enrique Germany, Francisco Pastene, Daniela Pinto, and James J. FitzGerald. Collected the data: Conor Keogh, Francisco Saavedra, Brian Andrews, Sebastian Dubo, Britam Gomez, and James J. FitzGerald. Performed the analysis: Conor Keogh and Francisco Saavedra. Wrote the manuscript: Conor Keogh, Francisco Saavedra, Jonathan Jarvis, Brian Andrews, and James J. FitzGerald.Supervised the project: Pablo Aqueveque, Jonathan Jarvis, Brian Andrews, and James J. FitzGerald.Table S1Click here for additional data file.


Military members and veterans are at elevated risk of treatment‐resistant posttraumatic stress disorder (TR‐PTSD) due to higher rates of exposure to potentially traumatic events during the course of duty. Knowledge of TR‐PTSD is limited, and specific protocols or evidence‐based TR‐PTSD therapies are lacking. Multimodal motion‐assisted memory desensitization and reconsolidation (3MDR) therapy is an emerging intervention for combat‐related TR‐PTSD. The purpose of this study was to preliminarily assess the effectiveness of 3MDR in addressing TR‐PTSD in Canadian military members and veterans.This study is a longitudinal mixed‐methods clinical trial. English‐speaking military members and veterans aged 18–60 with TR‐PTSD were recruited to participate. The intervention consisted of six sessions of 3MDR therapy. Quantitative data were collected pretreatment, posttreatment, and longitudinally at 1, 3, and 6 months after completion of 3MDR.Results from the first 11 participants to complete the 3MDR protocol exhibited statistically significant improvement (surviving multiple comparison correction) in clinically administered and self‐reported scores for PTSD (CAPS‐5 and PCL‐5), moral injury (MISS‐M‐SF), depression (PHQ‐9), anxiety (GAD‐7), emotional regulation (DERS‐18), and resilience (CD‐RS‐25).The preliminary and exploratory results from this clinical trial support the growing body of literature illustrating 3MDR as an effective treatment for military‐related TR‐PTSD. These results are notable given participants' previous lack of success with frontline psychotherapeutic and pharmacological interventions. Given that there are currently very limited treatment options for TR‐PTSD, 3MDR could prove to be a valuable treatment option for military members and veterans with TR‐PTSD.  It is possible that missing data may have affected the results, though we do not think this is likely.•Control group data were unavailable at the time of analysis.•Life events, circumstances, and the participant's level of support outside of the intervention varied and could not be fully controlled. The outcomes could have been influenced by factors additional to core intervention in question.3Posttraumatic stress disorder (PTSD) is a condition that may develop following exposure to traumatic events that involve interpersonal violence, combat, life‐threatening accidents, or natural disasters , Cognitive Processing Therapy (CPT), Prolonged Exposure (PE), and Eye‐Movement Desensitization and Reprocessing (EMDR)  has been adopted for the many military members and veterans who do not experience a clinically significant reduction in symptoms following receipt of at least two evidence‐based treatments  therapy is an emerging intervention for combat‐related TR‐PTSD. 3MDR is delivered in an immersive virtual reality system that combines a large visual display with a treadmill, allowing the patient to walk in the virtual environment. Many 3MDR studies have used the Computer‐Assisted Rehabilitation ENvironment (CAREN) or Gait Real‐time Interactive Laboratory (GRAIL) from Motek Medical BV, the Netherlands. The CAREN is a room‐sized, 3‐dimensional, virtual reality system with a centrally located treadmill that is surrounded by 240° floor‐to‐ceiling screens with motion‐capture technology. The multimodal nature of the intervention refers to the inclusion of (1) exposure to virtual reality (VR) visual imagery and auditory input, (2) walking, (3) a dual‐attention task, and (4) therapeutic context and relationship.preplatform phase, during which the patient chooses and orders symbolic representations in the form of pictures and selects music; (B) a platform phase, which involves a brief warm‐up during which the patient walks on the treadmill while listening to self‐selected music, followed by a series of seven 4‐ to 5‐min cycles of active therapy described below, and a cool‐down of walking to music; and (C) a postplatform phase providing an opportunity for review of the session and discussion of new insights and a self‐care plan. In each cycle of active therapy during the platform phase, the patient walks on the treadmill while viewing one of the previously selected images. The image gets larger as the patient approaches it in the virtual environment. A clinician stands alongside the treadmill and provides trauma counseling during this process. While walking and viewing the image, the patient also describes the traumatic scenario related to the image, as well as associated physical sensations, emotions, and thoughts. A subset of the patient's words is typed in by the therapist or an operator and is then displayed on the screen. A ball displaying a series of numbers is also presented on the screen for a period of 60 s, moving back and forth horizontally across the screen in the foreground of both the image and the emotion words. The patient must say the numbers as they appear on the moving ball. This process repeats with a total of seven cycles and seven different self‐selected images, during the platform phase. The theory and progression of 3MDR administration have been detailed in other publications  a 3.2The purpose of this study was to preliminarily assess the effectiveness of 3MDR in addressing TR‐PTSD in Canadian military members and veterans. We hypothesized that mental health measures (clinician and self‐reported standardized questionnaires) would improve with 3MDR treatment and this improvement would still be evident at the 6‐month follow‐up timepoint.44.1A published protocol paper is available which fully describes the materials and methods of this mixed‐methods clinical trial  criteria for a diagnosis of PTSD, with symptoms lasting more than 3 months. To be eligible, participants also required a score of 30 or higher on the Clinician‐Administered PTSD Scale, Fifth Edition (CAPS‐5) interview, had trauma related to combat experiences, and were nonresponse to at least two types of evidence‐based PTSD treatments where at least one of these treatments was a psychotherapeutic intervention. It was permitted that the second treatment could be a pharmacological intervention. Participants were also required to be stable on their psychotropic medication for a period of 4 weeks before entering the trial. Participants with comorbidities were included if they satisfied the other criteria and PTSD was considered the primary diagnosis. Potential participants were also screened by a member of the research team to discuss their military employment/deployments, current and past medical history, history and experiences of previous PTSD interventions, and overall suitability prior to providing verbal and written consent to participate in the study.4.3preplatform phase, platform phase, and postplatform phase, with seven cycles of active therapy in the platform phase. A typical 3MDR session lasts 90 min, including the participant's walking on the platform for 45–60 min. For this study, the intervention consisted of six sessions of 3MDR: one session per week for six consecutive weeks. 3MDR was offered at a rehabilitation hospital in a large urban center in Western Canada.A full description of 3MDR as a therapeutic modality is available in other peer‐reviewed articles         Scale   , and 0.3% of score values were treated as missing because less than 75% of the underlying answers were available. Therefore, in a very small proportion of questionnaire scores, some scores were missing for specific participants, for specific timepoints. In addition, the COVID‐19 pandemic created disruption in some of the data collection sessions, meaning that data were not collected for certain participants for certain timepoints. Handling of missing data is described below.To examine changes in mental health scores over time, linear models and permutation testing were used. For a given score, the dependent values were the scores for each participant at various timepoints. The linear model included a linear term for change over time as well as one offset term per participant to capture between‐subject variability. The model was fit to the data using least squares. The fitted slope parameter from the linear term provided a measure of a score's change over time. Where necessary, the linear model was adjusted to handle missing data by removing the missing data points from the dependent score values and by removing the corresponding values in the linear model, before fitting the model to the data.p value.Permutation testing was used to test the estimated slope parameter for statistical significance, for each score. Permutation testing was chosen because it is a nonparametric method that does not require assumptions about the shape of the statistical distribution of the data . For each score, we generated an empirical distribution of the estimated linear slope parameter including 100,0000 samples. A total of 99,999 iterations of permutation were used to generate all but one of the samples, and the actual estimated slope parameter comprised the last sample, as is standard practice. On each iteration, the timepoint labels were permuted randomly and separately within each participant, and the linear model was then fit to the permuted data to generate an estimated slope parameter. Where missing data points were present, permutation did not interact with the missing data.  The actual estimated slope parameter was then compared against the empirical distribution to generate a In total, permutation tests of linear changes were performed for 21 different scores. To address multiple comparisons, we used the Benjamini–Hochberg procedure for false‐discovery rate (FDR) correction . The p‐value threshold for FDR multiple comparison correction was computed to be .031.Mental health measures, including scores derived from self‐report questionnaires for the different timepoints, are shown in Table 6The purpose of this study was to explore preliminary waitlist‐control trial data evaluating whether 3MDR was an effective trauma intervention for a small sample of Canadian military members and veterans with TR‐PTSD. The results demonstrated statistically significant changes in symptoms of PTSD, major depressive disorder, generalized anxiety disorder, emotional regulation, resilience, social functioning and close to significant changes for peritraumatic stress reactions. Despite the small sample size, these results are notable, considering that participants only received six 1‐h 3MDR sessions without the addition of adjunct pharmacological or psychotherapeutic treatments and considering that these changes were sustained for a period of at least 6 months.The results support the growing body of evidence that 3MDR may be an effective treatment for combat‐related TR‐PTSD. Randomized control trials from the Netherlands and the United Kingdom have all shown a statistically significant reduction in CAPS‐5, PCL‐5, and GAD‐7 scores  may be an important aspect of PTSD  has predominantly focused on the resulting problematic emotions , self‐appraisal, and social isolation  largely due to restrictions related to the COVID‐19 pandemic. Control data are also currently missing as the number of control group participants with complete data was smaller than the intervention group at the time of COVID‐19 restrictions. This would not allow for an accurate and meaningful comparison at this time results from the full waitlist control clinical trial will be forthcoming. Caution regarding possible overgeneralization is highly warranted. Second, it is possible that missing data  within the outcome measures may have impacted results. Third, although additional trauma interventions were controlled for, other life events, circumstances, and the participant's level of support outside of the 3MDR intervention varied and could not be fully controlled. The outcomes described here could have been influenced by factors additional to 3MDR therapy that were not captured in our analysis.This study has a number of limitations. The sample size for this pilot analysis was small (7The exploratory results from this trial support the hypothesis that 3MDR is an effective treatment for combat related TR‐PTSD. The results from the first 11 participants of this study show promise; analysis of this preliminary data demonstrated statistically significant decreases in symptoms of PTSD, generalized anxiety disorder, major depressive disorder, and MI after 3MDR and at 6 months posttreatment. Additionally, participants demonstrated an increase in emotional regulation, resilience, and social functioning. These results are notable given participants' previous lack of success with frontline psychotherapeutic and pharmacological interventions. Given there are currently limited treatment options for TR‐PTSD, 3MDR may prove to be a valuable treatment option for military members and veterans with TR‐PTSD. Further theory and research are needed to address the current lack of understanding of the mechanisms underlying 3MDR's apparent effectiveness.Professor Vermetten created 3MDR but would not stand to benefit financially were it to be adopted into routine clinical practice. The other authors declare no conflicts of interest.https://publons.com/publon/10.1002/brb3.2694The peer review history for this article is available at