Prior research has not well examined the degree to which structural plasticity depends on the amount of use across the visual field. Cortical thickness, neurite density, and orientation dispersion were measured at portions of cortex associated with the PRL, the retinal lesion, and a control region in participants with MD as well as age‐matched, gender‐matched, and education‐matched controls. MD participants had significantly thinner cortex in both the cortical representation of the PRL (cPRL) and the control region, compared with controls, but no significant differences in thickness, neurite density, or orientation dispersion were found between the cPRL and the control region as functions of disease or onset. This decrease in thickness is driven by a subset of early‐onset participants whose patterns of thickness, neurite density, and neurite orientation dispersion are distinct from matched control participants. These results suggest that people who develop MD earlier in adulthood may undergo more structural plasticity than those who develop it late in life.Late‐stage macular degeneration (MD) often causes retinal lesions depriving an individual of central vision, forcing them to learn to use peripheral vision for daily tasks. To compensate, many patients develop a preferred retinal locus (PRL), an area of peripheral vision used more often than equivalent regions of spared vision. Thus, associated portions of cortex experience  Retinal sensitivity is measured in both eyes of patients with central vision loss due to macular degeneration. Instead of using the fovea for daily tasks as most people with healthy vision do, many patients use a “Preferred retinal locus” instead. We ask how the anatomy of the cortical projection of that preferred retinal locus changes with experience. This loss of central vision causes a decrease in the patient's ability to perform visual tasks requiring high visual acuity, such as reading and recognizing faces  by comparing MD patients to controls. In particular, Prins et al.  found siThe goal of this study was to investigate potential differences in levels of plasticity based on the amount of use of specific areas of the visual field. We test the hypothesis that cortical structure is impacted by (1) increased reliance on information processed at a cortical region of interest (ROI), separately from (2) deprivation of sensory input, or (3) relatively unchanged use. Another goal was to determine how much the age of disease onset influences structural plasticity in participants whose vision loss occurred well after the critical period. Using a microperimetry visual assessment that can map the location of the PRL in the visual field and a technique to accurately transfer the PRL from visual space to cortical space  or the late‐onset group , and the numbers of each gender were the same between control and MD participants. Early‐onset MD participants had significantly worse visual acuity than the late‐onset group . Written informed consent was obtained from all participants prior to enrollment in the study.Imaging data were acquired from 34 20 MD, 14 control) participants. Demographics and visual health details for each MD participant can be seen in Table 4 control2.2b = 0/1500/3000 s/mm2, TR/TE = 3230/89.20 ms, field of view = 210 mm × 210 mm, multiband acceleration factor = 4, 92 slices, interleaved acquisition, 1.5 mm isotropic voxel size). During the four diffusion MRI runs, q‐space is densely sampled with 185 diffusion‐weighting directions, each acquired twice with opposite phase encoding direction (anterior to posterior (AP), and posterior to anterior (PA); Harms et al., b = 1500 and 3000 s/mm2) in addition to 7 non‐diffusion‐weighted (b = 0 s/mm2) volumes. For the 99‐direction scans, 93 diffusion‐weighted volumes were collected (47 b = 1500 and 46 b = 3000 s/mm2) in addition to 7 nondiffusion‐weighted volumes.All images were acquired on a 3 T Siemens Prisma scanner using a 64‐channel head coil at our site in Birmingham, Alabama. T1‐weighted (T1w) and T2‐weighted (T2w) scans were acquired for anatomical reference . Four diffusion‐weighted runs were acquired . The full‐brain mask output from FSL's eddy was used as the input for NODDI, selecting only gray matter voxels on which to perform NODDI. Previous papers have estimated the intrinsic diffusivity coefficient for optimal calculation of NODDI outcomes in varying tissue types  as well as orientation dispersion index (ODI) for each voxel in the brain mask for each individual, all of which are in native diffusion space after unwarping. These FICVF and ODI volumes were then transformed into the individual's native FreeSurfer space and converted to surfaces using FreeSurfer's 2.4For this study, three different ROIs in visual space were defined: a PRL, a control URL, and a LPZ. Macular integrity assessment (MAIA) microperimetry was performed on each participant, on each eye, if possible (in some cases one eye had vision too poor to perform this assessment). Microperimetry involves simultaneously imaging the retina, and presenting visual stimuli to precise, stabilized locations on the retina. Preferred retinal loci were defined by instructing each participant to fixate a dot and measuring the location on the retina that the participant used for fixation. The center of the PRL was defined as the center of mass of retinal fixation locations over time, and the area of the PRL was calculated as the bivariate contour ellipse area (BCEA) on the retina .PRL eccentricity was measured for each MD participant in both onset groups. Eccentricity was manually calculated in Photoshop as pixel distance from the fovea to the center of the BCEA multiplied by the pixel‐per‐degree conversion factor supplied by the MAIA. According to an independent‐samples 2.5The method for transferring retinal space ROIs to the cortex is described in detail in our recent paper . These were created for every MD and control participant individually Figure  and illu2.6fsaverage using eccentricity values assigned by the Benson atlas  were performed to investigate the effects of ROI location (either PRL vs. URL or the eight eccentricity ROIs), disease state (MD vs. controls), and disease onset (early vs. late) on normalized cortical thickness, neurite orientation dispersion, and neurite density. Although controls do not express “early‐onset” or “late‐onset” phenotypes, we classify them as such because we are interested in how differences between early‐onset and late‐onset MD participants differ compared with controls. If the same pattern of differences is observed between our two control groups as our two MD groups, then these differences are most likely not due to the effects of loss of central vision and ensuing plasticity. For this reason, the effect of disease onset was not interpreted except as an interaction with diagnosis (MD vs. control). This is the case for all reported tests.Our sample of MD participants in this study had PRLs with varying eccentricities as well as PRL and URL ROI sizes, and these differences could have added noise to mask differences in cortical thickness. To account for this in statistical tests at the PRL and URL, the ANOVA was also run as an analysis of covariance (ANCOVA) including as covariates for each participant's average number of vertices of the cPRL and cURL as well as the average eccentricity those vertices represent retinotopically. The eccentricity value was shared between an MD participant and their matched control (if the matched control existed). Average eccentricity was log transformed to better represent distance across cortex  and was also centered after being log transformed.Current age was not included in our statistical models because we have included age‐matched controls for each of the early‐onset and late‐onset groups. Although age does have an effect on cortical thickness . The two‐way interaction of diagnosis and location was nonsignificant , and the two‐way interaction of diagnosis and onset (our hypothesized interaction if age of onset impacts thickness) was nonsignificant but trending . The three‐way interaction between MD diagnosis, onset, and ROI location was non‐significant . Including average eccentricity and vertex count of the PRL ROI as covariates similarly resulted in a significant main effect of diagnosis  as well as a significant interaction of diagnosis and onset , our hypothesized interaction if age of onset impacts thickness. The two‐way interaction of diagnosis and location , the three‐way interaction of diagnosis, onset, and location , and the covariates ROI size  and eccentricity  were all nonsignificant.At the cPRL and cURL, we found a significant main effect of MD diagnosis on normalized thickness  and showed no significant effect of either acuity (p = .919) or age (p = .796). This indicates that any difference between early‐onset and late‐onset MD participants is not due solely to a difference in visual acuity between the groups. The significant interaction of onset by location also indicates that experience using the PRL more than the URL impacts the early and late‐onset MD participants differently. The right side of Figure An interaction of diagnosis and onset indicates that a difference in normalized thickness between early‐onset and late‐onset MD participants varies compared with the difference between their respective controls. To improve the interpretability of this effect, we controlled for visual acuity differences in early‐onset (EO) versus late‐onset (LO) MD participant groups by performing a follow‐up ANCOVA. This ANCOVA examined normalized thickness as a function of ROI location (cPRL and cURL) and onset (early and late) only within the MD group, adding age and visual acuity as covariates along with ROI eccentricity and size (as above). This showed a significant interaction of onset and location on normalized thickness in our MD groups  supporting the effects observed using normalized thicknesses.The same tests were performed using raw cortical thickness values  or interaction of onset and diagnosis .LPZ thicknesses showed no significant differences as a function of either diagnosis , and so degrees of freedom were adjusted using the Hyuhn‐Feldt epsilon value (εHF = 0.56) for effects of ROI location. We found significant main effects of diagnosis  as well as ROI . The two‐way interactions of diagnosis and onset  and diagnosis and ROI  were both nonsignificant. The three‐way interaction of diagnosis, onset, and ROI was also nonsignificant . This indicates that over the entirety of V1, cortex is thinner across all MD participants compared with controls, but there is not a statistically significant difference in patterns of cortical thickness as a function of age of onset. Current age was not included in the model  and ROI . The two‐way interaction of diagnosis and onset  as well as the three‐way interaction of diagnosis, onset, and ROI  were not significant.The same test was performed using raw thickness values . The two‐way interaction of Diagnosis and Location was nonsignificant  and the two‐way interaction of diagnosis and onset was nonsignificant . The three‐way interaction between diagnosis, onset, and ROI location was also nonsignificant . In the same fashion as for the normalized thickness analysis, the eccentricity and size of the cPRL and cURL were added as covariates in an ANCOVA and did not change the results in terms of statistical significance from the main ANOVA. Current age was not included in statistical models . The two‐way interaction of diagnosis and location was nonsignificant  and the two‐way interaction of diagnosis and onset was nonsignificant . The three‐way interaction between diagnosis, onset, and ROI location was also non‐significant . The ANCOVA including the effects of cPRL and cURL eccentricity and size did not have different results in terms of statistical significance from the main ANOVA.A similar ANOVA was performed for ODI Figure . At the For ODI, the main effect of diagnosis  and the interaction of diagnosis and onset  were both nonsignificant. However, tests of differences in neurite density at the LPZ found significantly lower density at the LPZ in MD participants compared with HCs, regardless of MD onset , but the interaction between diagnosis and onset was nonsignificant . The ANCOVA including the effect of cPRL and cURL eccentricity did not have different results in terms of statistical significance from the main ANOVA.Two‐way ANOVAs were performed at the LPZ testing for differences in neurite density as well as ODI as a function of diagnosis and disease onset. 3.2.2fsaverage space and averaged within each eccentricity ROI , and so degrees of freedom were adjusted using the Hyuhn–Feldt epsilon value (εHF = 0.6) for effects of ROI location. The main effect of diagnosis  was nonsignificant, but the main effect of ROI  was highly significant. The two‐way interaction of diagnosis and onset  was nonsignificant, but the interaction of diagnosis and ROI  was highly significant. The three‐way interaction of diagnosis, onset, and ROI was nonsignificant . To further investigate the significant interaction of diagnosis and ROI, post‐hoc tests were performed with independent samples t‐tests at each ROI testing differences in neurite density between all controls and all MD participants. Significant differences were found at ROI representing 0°–2° eccentricity , ROI representing 2°–4.3° eccentricity , and ROI representing 4.3°–6.8° eccentricity , all of which passed FDR correction for multiple comparisons. No significant differences were found in ROIs 4–8.For each participant, neurite density and ODI results were converted to  Figures  with betW = 0.01, p = 2.82 × 10−14), and so degrees of freedom were adjusted using the Hyuhn–Feldt epsilon value (εHF = 0.413) for effects of ROI location. The main effects of diagnosis  as well as ROI  were significant. The two‐way interactions of diagnosis and onset  as well as diagnosis and ROI  were nonsignificant. The three‐way interaction of diagnosis, onset, and ROI was nonsignificant .A similar three‐way ANOVA was performed for ODI values across the same groups Figure . These d4Using MD as a model of central vision loss allows us to test hypotheses about how cortical structure is impacted by (1) increased reliance on information processed at a cortical ROI, separately from (2) deprivation of sensory input, or (3) relatively unchanged use. We examined whether changes in structure after the onset of MD were most evident in (1) the visual region of highest use (cPRL) when compared with (2) a region that has retained no bottom‐up retinal input (LPZ), as well as (3) a peripheral control region where use of vision was relatively unchanged (cURL). We compared cortical regions with disparate visual use within the same individual to determine how the amount of use impacts structure. This design allowed us to look for experience‐driven plasticity in fine‐grained detail across retinotopically defined regions and to measure effects due to loss of vision as well as an increase in the use of vision. This is important because a change in cortical structure may be dependent on adaptive increased use of spared sensation, and not just sensory loss. Additionally, participants were divided into early‐onset and late‐onset MD groups to explore possible differences in the expression of structural plasticity based on the age of onset of degeneration. Results from the discrete, finely detailed retinotopic regions where differential use was documented were also supplemented by analyses covering large divisions of V1 to better describe how MD affects the primary visual cortex as a whole. Overall, our results show that both cortical thickness and cortical microstructure differ across V1, and differ between groups in ways that are consistent with the idea that there is structural change associated with central vision loss in adulthood. However, this change is limited and, based on our data, seems to depend on vision loss, but not increased use of portions of vision.4.1The representations of peripheral vision in both cPRL and cURL were thinner in MD participants than in controls. The early‐onset MD group showed more thinning than the late‐onset group. Comparisons of normalized thickness values, correcting for whole‐brain atrophy at a participant level, showed a significant interaction between diagnosis and onset group when including ROI eccentricity and size as covariates Figure . Tests uContrary to our initial hypothesis that removal of retinal input would cause a decrease in thickness at the representation of central vision (LPZ), no difference in thickness was found between MD groups and their controls. Interestingly, this seems to be the case only for the representation of the very center of the fovea Figure . When teThe critical test of the hypothesis that increased use of peripheral vision (in the PRL) resulted in thickening of the cortex, was to compare the ROI corresponding to peripheral vision: the cPRL and cURL. While no statistical tests showed significant interactions of ROI (cPRL vs. the cURL) by diagnosis (controls vs. MD), the pattern of data shows that in the participants with early‐onset MD, the URL is more thinned (relative to control) than the PRL. In fact, an ANCOVA examining just the patients with MD showed a significant interaction of age of onset by ROI (cPRL vs. cURL). Participants who had vision loss earlier in adulthood had thin cortex in the URL, consistent with atrophy from disuse, whereas the same participants showed less thinning in the cPRL, consistent with less atrophy from disuse. This was not the pattern for the late‐onset participants, who generally had higher normalized cortical thickness, consistent with less cortical change from their baseline. This suggests the possibility that experience using the PRL influences cortical thickness by counteracting some of the cortical thinning effects of living with MD. Future work with larger numbers of early‐onset MD participants will be needed to more strongly test this hypothesis. The current data put two constraints on the possible effects expected from a larger‐scale study, first suggesting that the effect is likely much stronger in people who have altered vision experience earlier in adulthood. Second, the data suggest that if increased use of a specific piece of cortex (the cPRL) results in cortical thickening, it does so in the context of other processes associated with living with central vision loss that promotes more general visual cortical thinning.These results are consistent with Prins et al. , who fouBurge et al.  also fouWe did not find cortical thinning associated with the most central part of the LPZ, though all participants had vision loss in that area. While this result was contrary to our initial hypothesis of deprivation‐driven cortical thinning, there was a trend toward cortical thinning in the MD participants just outside the projection of the fovea. This was consistent with a result from Burge et al. , who fouInterestingly, the across‐eccentricity pattern for the controls for late‐onset and early‐onset participants is somewhat different: The slope of change in thickness by eccentricity is greater for the late‐onset participants than for the early‐onset. This is consistent with previous work showing that healthy older adults have a more steep change in cortical thickness with eccentricity than healthy younger adults , MD (thinner cortex in patients with vision loss than controls), age (older controls show different slopes of thickness across eccentricity than younger controls), and age of onset (early‐onset MD participants have thinner cortex than the late‐onset MD participants). Taken together with the existing literature, this shows evidence toward the idea that patients with central vision loss exhibit thinning of V1 overall, with sparing of the representations of the center of the fovea.4.2Mirroring analyses of cortical thickness, neurite density, and orientation dispersion were analyzed both at fine‐grain retinotopically defined ROIs corresponding to the cPRL and cURL, as well as in broad regions covering the entirety of V1 to provide additional context to the results. We hypothesized that neurites at the PRL of early‐onset MD participants would restructure and grow to connect to LPZ neurons that lost visual input. This would result in higher neurite density at the cPRL but not the cURL. This would also predict a lower ODI at the cPRL but not the cURL, since many new neurites would be oriented in similar directions toward the LPZ. Analyses of NODDI outputs at the cPRL and cURL found no significant differences in neurite density as a function of either disease or onset Figures  and 6. PNeurites reorganizing and growing towards the LPZ to form horizontal connections and recruit deafferented neurons should decrease the orientation dispersion of these neurites, but it is not a given that this effect would be spread evenly across the entire cortical representation of the PRL. The cortical representations of the PRL and URL varied widely in size across participants depending on eccentricity and BCEA . While neurites have the ability to grow over relatively long distances postlesion  and increased use (cPRL), relative to a control region that is neither deprived nor strongly attended in daily life (cURL). This capability is due to the extremely well‐characterized central vision loss of these participants. Overall, our data provide evidence that MD influences cortical structure. While there is a great deal of participant‐to‐participant variance, we saw that overall cortical thickness decreased with experience of vision loss in this population. Consistent with cell death or atrophy in the cortex, we also saw decreases in neurite density, as well as increases in neurite orientation dispersion in participants with central vision loss. The patterns of these changes across cortex suggest that the representation of the center of the fovea may not be as plastic as just outside the fovea. Further, the pattern of data provided no strong evidence for use‐dependent increases in cortical thickness, changes in neurite density, or changes in orientation dispersion in healthy vision. However, our results do suggest possible influences of age of disease onset on all of these structural measures. Early‐onset MD participants showed more distinct differences in thickness, neurite density, and orientation dispersion compared with their controls than late‐onset participants did, and cortical thickness results suggest that in the early‐onset population, there may be competing processes contributing to cortical thickening (at the PRL) in the context of overall visual cortical thinning associated with low vision. Future studies should examine how individual differences in experiences relate to individual differences in cortical thickness and NODDI values. By incorporating complex information about individuals' visual experiences, we can move the field toward understanding what aspects of large‐scale brain structure change with experience.The authors declare that there is no conflict of interest regarding the publication of this article.Figure S1: The participant reported the right eye as the better eye, the left eye was unable to be tracked during the exam.Click here for additional data file.Figure S2: Raw thickness across region of interest (ROI), diagnosis, and onset groups. Cortical thickness is shown at the lesion projection zone (LPZ), cPRL, and cURL as a function of both onset and diagnosis. Error bars represent standard error of the mean. LPZ thicknesses showed no significant differences as a function of either diagnosis  or interaction of onset and diagnosis . Differences in thicknesses at the cortical projection of the preferred retinal locus (cPRL) and projection of unpreferred retinal locus (cURL) were tested as a function of ROI location, onset, and diagnosis, and showed a significant main effect of diagnosis  as well as a significant interaction of diagnosis and onset .Figure S3: raw thickness across eccentricity regions of interest (ROIs). Mean normalized thickness for each MD and control group at each eccentricity ROI are shown. Error bars represent ±1 SEM. Values shown on the x‐axis correspond to the minimum eccentricity for that ROI. A three‐way ANOVA of cortical thickness as a function of diagnosis, onset, and ROI was performed. Main effects of diagnosis  as well as ROI  were significant. The main effect of ROI did not pass Mauchley's test of sphericity  and so the degrees of freedom were adjusted using Hyun–Feldt epsilon (εHF = 0.573). No two‐way or three‐way interactions were significant.Click here for additional data file.


The Magellanic sub‐Antarctic Forest is home to the world's southernmost avian community and is the only Southern Hemisphere analogue to Northern Hemisphere temperate forests at this latitude. This region is considered among the few remaining pristine areas of the world, and shifts in environmental conditions are predominantly driven by climate variability. Thus, understanding climate‐driven demographic processes is critical for addressing conservation issues in this system under future climate change scenarios. Here, we describe annual survival patterns and their association with climate variables using a 20‐year mark–recapture data set of five forest bird species in the Cape Horn Biosphere Reserve. We develop a multispecies hierarchical survival model to jointly explore age‐dependent survival probabilities at the community and species levels in a group of five forest passerines. At the community level, we assess the association of migratory behavior and body size with survival, and at the species level, we investigate the influence of local and regional climatic variables on temporal variations of survival. We found a positive effect of precipitation and a negative effect of El Niño Southern Oscillation on juvenile survival in the white‐crested Elaenia and a consistent but uncertain negative effect of temperature on survival in juveniles and 80% of adults. We found only a weak association of climate variables with survival across species in the community and no temporal trends in survival for any of the species in either age class, highlighting apparent stability in these high austral latitude forests. Finally, our findings provide an important resource of survival probabilities, a necessary input for assessing potential impacts of global climate change in this unique region of the world. In this article, we describe the temporal dynamics in survival probabilities for the world's southernmost forest bird community and their relationship to climatic variables. We develop a multispecies hierarchical survival model using Bayesian inference to jointly explore age‐dependent survival probabilities at the community and species levels in a group of nine forest passerines using a 20‐year mark–recapture data set from the Cape Horn Biosphere Reserve, Chile. We find that winter precipitation and El Niño Southern Oscillation are good predictors of juvenile survival in two species; however, no temporal trends in survival for any species as juveniles or adults were found. Our results provide important baseline data and novel demographic information for several species in an understudied corner of the world. They are often used to assess the impact of climate on avian population dynamics  and ‘when’  weather is most impactful to survival, it is also important to consider the species' migratory behavior. Migratory species are particularly susceptible to the effects of climate change  in Chile. We aim to assess the association of survival probabilities with phenotypic and behavioral traits at the community level and whether they show temporal trends and how they are influenced by climatic variables at the species level. We also compare our survival estimates with those of conspecifics in other studies at different latitudes to assess the evidence for a latitudinal gradient in South America.22.1Nothofagus betuloides and Nothofagus pumilio forest with Drymis winteri understory, and forest edge scrubland dominated by Embothrium coccineum, Chilotrichium difussum, Berberis buxifolia, and Ribes magellanicum , white‐crested Elaenia , house wren (Troglodytes aedon), austral thrush , and Patagonian sierra finch (Phrygilus patagonicus).We used capture–recapture data from the LTER station designed to monitor forest birds. Standardized mist netting was used within the forest for 2 to 6 days each month of the year starting in 2000 (with few exceptions during this period). Here, we use only data collected during the breeding season  to remove possible transient individuals in species that form foraging flocks during winter. The monthly capture data were then collapsed to annual capture histories for estimating annual survival. Mist netting was done at two sites located roughly 500 m from each other. At each site, five 12‐m mist nets were placed individually, separated roughly 50 to 100 m between each mist net. Due to the similarity of the forest composition and proximity between the two sites, we consider them as a single site in the analysis. Among all 27 species with captures at the study site, we selected only those where adequate sample sizes were available, which we here defined to at least 50 captures and 4 recaptures. We finally selected five species to include in the model: thorn‐tailed Rayadito (2.3https://psl.noaa.gov/enso/mei/). Correlations among the three weather and climate variables were all <|0.5|, allowing for all to be included in a single model. We fit a linear regression on the three weather and climate variables to determine if there is evidence of a temporal trend in them over our study period.To assess the association between weather and climatic conditions with the temporal dynamics of survival, we selected three climatic variables known to be important environmental predictors of survival  at both the community and the species levels by fitting a multispecies Cormack–Jolly–Seber (CJS) model using Bayesian inference  and recapture probabilities . The model also contains analogous recapture probability p hyper‐parameters.The species‐specific estimates are denoted by At the community level, we explored the possible influence of migratory behavior (migrant vs. nonmigrant) and mean body size of each species on annual survival. The migratory behavior (MB) of each species at this latitude followed those described by Sandvig et al. . For the recapture probability we assumed no differences between age classes and included an effect of catch effort (the number of hours times the area of nets deployed during each year). We also included a temporal variance term p. For slope parameters we chose vague priors expressed as a normal distribution with a mean of 0 and a precision of 0.1 , which varies between 50% and 100% and refers to the probability that a parameter is strictly positive or negative (described by its posterior distribution). For determining significance, we report the proportion of the Highest Density Interval (HDI) of the parameter that lies within a Region Of Practical Equivalence (ROPE), which can be considered a region of “null” values. If the HDI is completely outside the ROPE, the “null hypothesis” for this parameter is “rejected”. If the ROPE completely covers the HDI, i.e., all most credible values of a parameter are inside the ROPE, the null hypothesis is accepted. Otherwise, whether to accept or reject the null hypothesis is undecided . No temporal trend was found for precipitation or ENSO  to 0.28 , with a mean of 0.22 among the three species. Mean adult apparent survival ranged from 0.36  to 0.60 , with a mean of 0.47 among the five species  and a probable negative effect of ENSO  on juvenile survival of the white‐crested Elaenia  in the three species and for adult survival minimum winter temperature was negative (pd = 77%–89%) in four of the five species , but we did not find strong evidence of effects of these variables on survival in adults. On the other hand, although we did not find strong evidence of an effect of minimum temperature during winter on survival, we found a consistent positive effect on all juvenile estimates and four out of five adults. At the community level, body size and MB were not good predictors of differences in survival among the examined species. Additionally, when comparing survival estimates from species in this community with counterparts at lower latitudes, we found a decreasing latitudinal gradient, as do previous studies comparing survival at different latitudes in the Northern Hemisphere , from the Northern Hemisphere experienced lower survival during La Niña and El Niño conditions. In the case of high‐latitude populations of white‐crested Elaenia, which migrate to northern Brazil for the nonbreeding season , suggesting that in this case the effect would be linked to the conditions experienced during migration or on the nonbreeding range of this species. McKellar et al.  found thEstimates of survival from our model were substantially lower in juveniles than in adults for the three species examined at both age classes. Among the three species, juvenile Patagonian sierra finches showed extremely low interannual survival, with several yearly estimates being indistinguishable from zero. This likely due to the low number of juveniles recaptured the subsequent year in the years of estimates close to zero, which may be related to low interannual site fidelity of juveniles after their initial dispersal; however, no information is available about dispersal in this species. Furthermore, the goodness‐of‐fit test did not show evidence indicative of a transient effect. The highest survival for any species was estimated for the thorn‐tailed Rayadito, one of the most abundant species in these forests ; Tyrannidae, 0.61 (n = 4); Troglodytidae, 0.66 (n = 2); Turdidae, 0.66 (n = 1)) being higher than for the same families on Navarino Island ; Tyrannidae, 0.29 (n = 1); Troglodytidae, 0.52 (n = 1); and Turdidae, 0.45 (n = 1)). Although our comparison only comprises a small number of species, it suggests that survival rates in the southern cone follow the same pattern reported for species in other regions of the globe.Our estimates allowed us to compare survival between our site and those of previous studies at lower latitudes, covering a large latitudinal range in South America. For the three species we found conspecific estimates of survival in the literature, survival rates were lower at higher latitudes, following the same pattern reported for the Northern Hemisphere by Scholer et al. . Additio5The survival estimates we provide in this study are a key resource for predicting population changes in the forest bird community under future climate change scenarios in this unique region of the world. Our results highlight the importance of considering differences in the sensitivities to weather between different age classes and species, as we have documented here that they are not equal throughout the community. Despite temperature often being considered the most important variable related to climate change, we show that variations in precipitation may be more impactful in some communities such as this one in the Magellanic sub‐Antarctic Forest. Finally, the long‐term collection of mark–recapture data is necessary for modeling detailed demographic processes that span a wide breath of temporal variations in climatic conditions. This work at the remote southern tip of South America showcases the importance of LTER projects in often underrepresented areas of the globe.Erik M. Sandvig: Conceptualization (lead); data curation (lead); formal analysis (lead); methodology (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead). Claudio S. Quilodran: Writing – original draft (supporting); writing – review and editing . Tomás A. Altamirano: Writing – original draft (supporting); writing – review and editing . Francisco Aguirre: Data curation (supporting). Omar Barroso: Data curation . Juan Rivero de Aguilar: Data curation ; writing – review and editing (supporting). Michael Schaub: Formal analysis ; methodology ; supervision (lead); writing – original draft (supporting); writing – review and editing (supporting). Marc Kery: Formal analysis ; methodology ; supervision (lead); writing – original draft (supporting); writing – review and editing (supporting). Rodrigo A. Vasquez: Funding acquisition ; supervision ; writing – review and editing (supporting). Ricardo Rozzi: Funding acquisition ; supervision (supporting); writing – review and editing (supporting).https://github.com/Chilesummits/survival‐in‐the‐world‐s‐southernmost‐forests.This article has earned an Open Data badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available at Data S1Click here for additional data file.


Photoelectron Circular Dichroism (PECD) is a forward‐backward asymmetry in the photoemission from a non‐racemic sample induced by circularly polarized light. PECD spectroscopy has potential analytical advantages for chiral discrimination over other chiroptical methods due to its increased sensitivity to the chiral potential of the molecule. The use of anions for PECD spectroscopy allows for mass‐selectivity and provides a path to simple experimental schemes that employ table‐top light sources. Evidence of PECD for anions is limited, and insight into the forces that govern PECD electron dynamics in photodetachment is absent. Here, we demonstrate a PECD effect in the photodetachment of mass‐selected deprotonated 1‐indanol anions. By utilizing velocity map imaging photoelectron spectroscopy with a tunable light source, we determine the energy‐resolved PECD over a wide range of photon energies. The observed PECD reaches up to 11 %, similar to what has been measured for neutral species. −) enantiomers. A unique PECD signature is observed for several isomers and detachment channels of [Ind‐H]−. This work supports the use of anions for future analytical methods of enantiomeric discrimination, and allows for insight into the influence of short‐range interactions on PECD.Energy‐resolved Photoelectron Circular Dichroism (PECD) is demonstrated in the photoelectron spectroscopy of mass‐selected deprotonated 1‐indanol anionic ([Ind‐H] Determination of the enantiomeric excess of a mixed solution of chiral molecules has been pursued by a broad scientific community for many years. Conventional chiroptical methods  rely on interactions with a molecule's magnetic moment to invoke a chiral response. These interactions are weak, thus requiring significantly concentrated samples in solution for analysis. Recently, a new generation of chiroptical techniques has emerged, whose sensitivity to molecular chirality can be rationalized within the electric dipole approximation. As a result, these techniques produce chiral signals that are orders of magnitude greater compared to the methods mentioned above, enabling chiral analysis to be effectively conducted in the gas‐phase. This class of techniques includes enantiomer specific microwave spectroscopy (ESMS),Irradiation of a non‐racemic sample by circularly polarized light (CPL), which results in the removal of an electron from the chiral molecule, leads to the chiral signature of PECD. This signature is a forward‐backward (FW/BW) asymmetry in the photoelectron angular distribution, with respect to the axis of photon propagation. The asymmetry in the electron flux is inverted for the other enantiomer, or when the excitation is conducted using the opposite circular polarization of light. The PECD signal for a given enantiomer is defined as:I(LCP/RCP) are radial electron yields in a given direction. The difference between detachment by left circular polarized light (LCP) and right circular polarized light (RCP) is normalized to the total electron yield.where PECD was first predicted in 1976,In order to realize the analytical potential of this technique, an approach that provides solid information about the molecular source of the photoelectrons, and replaces the use of synchrotron light sources with table‐top lasers would be ideal. Photoelectron photoion coincidence (PEPICO) spectroscopy has been previously employed in order to provide a mass‐tagged PECD signal.11, 14A transition from synchrotron light sources to table‐top lasers has been managed with multiphoton PECD (MP‐PECD), utilizing both femtosecond14, 16The investigation of anions utilizing PECD spectroscopy has both analytical benefits and opportunities for furthering understanding of electron dynamics of this effect. In an analytical context, anions allow for mass selection before photodetachment, thereby simplifying final assignments. Also, the lower electron detachment energies, in comparison to neutral molecules, enable single‐photon electron detachment by ns light pulses from more common UV/Vis lasers. Such analytical advantages have been demonstrated in the electron yield CD of DNA polyanions.To date, there are only two published experimental studies−). Indanol was selected for its rigidity in order to reduce the number of conformers possibly contributing to the photoelectron spectrum. Also, the recent work on the PECD of neutral 1‐indanol enables the direct comparison of similar detachment channels between the deprotonated anion and closed shell neutral.We have built on the success of current experimental work by coupling the PECD technique with pre‐photodetachment mass selection, with VMI‐PES, and with a tunable light source to provide an energy‐resolved PECD signal for the isolated deprotonated 1‐indanol anion . This separation ensures that only anions of a single mass are present in the detachment region at the time of electron detachment. Selected anions are intercepted by the polarized output of an OPO pumped by a ns Nd:YAG laser. Photodetached electrons are focused onto a position sensitive detector by velocity map imaging optics.Using a plasma entrainment source,− , ranging from 2.34 eV to 4.96 eV. The spectra are obtained from the distributions of radial projections of electrons with unique kinetic energies, which carry angular information with respect to the polarization or propagation axis of the light ‐H]−). The formation of this tautomer is calculated to be exothermic, resulting in an excess energy of 0.90 eV. Although other works have shown a single conformer of neutral 1‐indanol present in an expansion of argon, this excess energy is expected to enable the formation of additional isomers.[Photoelectron spectra of [Ind‐H]− Figure  have bee isomers.25−, two conformers have been predicted, where the inversion of the aliphatic ring leads to either an equatorial ([Ind(O)‐H]− eq) or axial ([Ind(O)‐H]− ax) position of the alkoxide, with respect to the 5‐membered ring. [Ind(O)‐H]− eq is the lowest energy conformer and has a calculated vertical detachment energy (VDE) of 2.185 eV. The axial conformer is predicted to lie only 0.069 eV above the equatorial conformer and has a similar VDE of 2.101 eV. These predicted values are close to the detachment energy of feature B, indicating the possibility of both conformers contributing to this feature. The assignment of feature B is additionally complicated by the possibility of detachment from the energetically close HOMO‐1 orbital. The possibility of detachment from the HOMO‐1 orbitals of the conformers is supported by the assignment of feature C to detachment from the HOMO‐2 orbital of [Ind(O)‐H]−.For [Ind(O)‐H]3 position ([Ind(C3)‐H]−), or the C1 position ([Ind(C1)‐H]−). It is important to note that C1 is the stereogenic center of 1‐indanol, and deprotonation at this position leads to an achiral tautomer. These tautomers are expected to have a similar conformational landscape to [Ind(O)‐H]−. Other tautomers are not expected as their acidities are too low for deprotonation by OH− (see Table S1). It is clear from this assignment, that regardless of single mass analysis and careful molecular selection, the formation of anions by deprotonation in the gas phase can still leave one with complex mixtures of isomers.Feature A can be attributed to a combination of two higher energy tautomers, where deprotonation occurs at the Chν near the threshold of detachment.hν=2.76 eV, the broad feature B seen at hν=4.86 eV reveals at least three, reproducible, narrower features . These peaks have a center detachment energy of 2.21(1) eV, 2.28(1) eV, and 2.35(1) eV. As is indicated above, feature B is expected to be comprised of four electronic transitions. Comparisons between the calculated detachment energies of these four transitions and the higher resolution spectrum do not immediately reveal a unique assignment. The spacing between peaks B1 and B3 (0.14 eV) is similar to the frequency calculated for the CO‐stretch of the neutral radical . A Franck–Condon simulation of the [Ind(O)‐H]− eq HOMO detachment supports such assignment . A similar simulation has been conducted for the axial conformer, but it's potential contribution to the spectrum is unclear. The expected accuracy of the calculations and the current experimental resolution do not allow for a confident assignment of peak B2. However, the agreement between our experimental results and the FC simulation suggests that partial vibrational resolution is observed.An advantage of coupling VMI detection with a tunable laser is the ability to reach higher absolute electron kinetic energy (eKE) resolution when utilizing It has been explicitly verified that the relative change in eKE for a given transition  matches that of a single photon process . Therefore, we conclude that the observed PECD originates from the electron detachment of anions; potential contributions resulting from detachment followed by multiphoton ionization of neutral radicals are negligible, or entirely absent.1, B2, and B3 signals reveals that even these narrower features possess distinct PECD. This is evident from the color change from blue via white to red in the reconstructed image over the corresponding energy range ‐H]− (feature B) are mainly nonbonding, lone‐pair, oxygen‐centered orbitals, similar to the HOMO‐2 orbital of neutral 1‐indanol.− suggests that long‐range interactions might not be needed to produce a sufficient PECD signal.As we have measured the PECD for a wide range of − at three hν. For each hν, one feature has been selected to demonstrate the reversal in the sign of the PECD between the enantiomers. Full reconstructed distributions and corresponding raw distributions at each hν are found in the Supporting Information . The racemic sample produces no asymmetry, which verifies that our observed asymmetry cannot be an effect of inherent asymmetries of our instrument. For features B and C, the magnitude of the PECD is the same within the reported experimental error. Although feature A does show a sign reversal for the asymmetry, the magnitude of PECD in the S‐enantiomer is slightly smaller than the magnitude of PECD in the R‐enantiomer. This discrepancy might arise from the slightly different source conditions between the two experiments, leading to different contributions of the chiral and achiral tautomers to this spectral feature. It is noted that the error bars are solely derived from the deconvolution procedure of the images and do not include considerations of the purity of the laser polarization or starting compound.Not only can a difference in electron angular flux be observed upon switching the polarization of light, but basic symmetry considerations require a reversal of the FW‐BW asymmetry with exchange of enantiomer. In Figure By utilizing VMI‐PES, in combination with mass spectrometry and tunable photodetachment, we have demonstrated an energy‐resolved PECD signal for the mass selected, deprotonated (R)‐ and (S)‐1‐indanol anion over a wide range of photon energies. It is clear from our photoelectron spectrum that many isomers can contribute to the photoelectron signal, each providing a unique PECD signature. As PECD is known to be sensitive to conformation and isomerism, the coupling of PECD with a spectroscopic method is crucial in systematically working towards an analytical PECD technique. In addition, an ion source with softer ionization conditions could act to limit convolution of the spectrum by reducing the number of isomers formed in the molecular beam. Weitzel et al. have previously demonstrated the utility of electrospray ionization, a well‐known soft ionization method, in the formation of anions for PECD studies.− PECD that is similar in magnitude to that of neutral 1‐indanol, it is clear that well accepted descriptions of the electron dynamics, which govern the PECD effect, fail to describe the specific dynamics that arise in photodetachment of anions.By providing comparisons to current theoretical predictions and to the experimental results for neutral 1‐indanol, we have taken the first steps in exploring the role of short‐range interactions in PECD. With the observation of a [Ind‐H]There is no conflict of interest to report.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.


Common features of effective learning included a multifaceted approach, with in‐practice learning being blended with additional implementation strategies (e.g. supervision) and didactic learning/worksheets. An important contextual factor was working within an organisational culture which supported shared learning and reflection. This may also help encourage engagement with training, where staff are unwilling to attend if it may compromise care delivery. Future research should focus on the characteristics of trainers and the structure of learning, with more research being needed in in mental and physical morbidities outside the remit of dementia to improve the overall quality of the social care workforce.This review of reviews aimed to identify and synthesise evidence to support the design of learning interventions for non‐registered practitioners supporting older people in long‐term care . Our objectives were to inform the analysis part of the Analysis, Design, Development Implementation and Evaluation framework by finding evidence on the following five components of learning: content, format (teaching strategies and resources/media), structure, contextual factors (barriers and enablers) and measures used when monitoring the effectives of learning. Databases searched included Pro‐quest (ASSIA), Scopus, Ovid , SCIE Online and Cochrane Reviews and reference searching, with the last search being conducted in April 2021. Fifteen papers were identified as eligible for inclusion. Most of the interventions aimed to improve dementia care ( The quality and quantity of the social care workforce is known to be inadequate in the United Kingdom.The training available is often quite generic and does not accommodate for more specialist skills and interests.Training available tends to be oriented to the needs of people with dementia.There is a need for more in‐practice and multifaceted learning that allows opportunity for structured reflectionThere is a growing body of evidence around the training needs of those supporting the LGBT+ communityResearch into the appropriate characteristics of trainers and appropriate learning structure is needed1In 2021, it was estimated that there were over 962 million people aged over 60 globally  jobs in domiciliary care in England StructureContextual factors (barriers and enablers)Measures used when monitoring the effectiveness of learningOur objectives were to find evidence on the following five components of learning design:2.2The search strategy Table  was infoSearch terms were organised into four groups: non‐registered practitioners (population), learning (intervention), community setting (context) and review terms (method), with NOT ‘child*’ being included and older age filters being selected to further refine the results. Titles and abstracts were searched for keywords and reference lists harvested for further relevant reviews with the search concluding in April 2021.2.3A review of reviews allowed us to check the consistency of our findings on the efficacy of interventions, with the best‐quality reviews being highlighted and synthesised separately if inconsistencies in conclusions are found Published since 2000Any countryInclusion criteria:Focus on training for professionally qualified staffFocus on those caring for younger peopleNot in EnglishHospital/clinical settings onlyIf it did not collect outcomes dataDoes not focus on learningReview of reviewsExclusion criteria:https://www.covidence.org/) with one researcher (L.N.) screening titles and abstracts. Three randomly selected full‐texts were identified for further review among the research team  to check for consistency and to refine the eligibility criteria prior to commencing full‐text screening (L.N.).The papers were imported into Covidence  using the AMSTAR 2 checklist. This was chosen as it has been shown to have a high level of inter‐relater reliability and usability in comparison to similar tools  in Excel. Data extracted included information on: author, year, aim of the review, type of review, number of studies included, target group, objectives of interventions, methods of synthesis, successful and unsuccessful intervention components  and outcomes.The data was then synthesised to identify the key components of the intervention found to influence the effectiveness of the learning. The components included the following: the content presented, format (media and teaching strategies), structural components (e.g. length of sessions) and environmental factors that may affect the objective realisation of the learning.2.6The review was conducted by the research team in liaison with the advisory group while following PRISMA guidance , UK (n = 49), Australia (n = 39), Canada (n = 37), Netherlands (n = 21), Sweden (n = 15) Norway (n = 13), Germany (n = 9), France (n = 6), Portugal (n = 4), New Zealand (n = 3) and Taiwan (n = 3). With one research project recruiting participants from both the UK and the Netherlands  of the learning. These findings are described below.3.3Content was categorised in broad themes to help understand how information could be best presented within training. Fourteen papers reported relevant aspects of content. One paper was not included in this section as it reviewed the implementation of mentorship programmes, whereby content is personalised to the learner . ‘Teaching strategies’ encompassed how the learning would be delivered  and by whom.remote (video) or in person lectures , where a range of approaches were not utilised, learners were not as successful at transferring new knowledge to practice  were found to be beneficial  was found to hinder the ability of the learning to achieve the desired change; with certificates, prizes and monetary incentivisation yielding more positive results as it made it more likely that individuals would feel they have a stake in the learning, which encouraged better engagement and participation , this allowed staff more time with service users .This finding of this review suggests a multifaceted approach, based on theory may be best suited to improving learning outcomes in non‐registered care staff, with training consisting of the following:These recommendations may support learning alongside team leaders facilitating an organisational culture in which learners feel able to feedback and reflect openly without fear of criticism  developing the aims and methods used in the review; (2) conducting cross‐coder analysis (3) further drafts and revisions. All authors read and agreed on the content of the final submitted manuscript.This study is funded by the National Institute for Health Research  School for Social Care Research (SSCR). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.The authors declare no conflicts of interest.Table S1.Click here for additional data file.


Neuroticism represents a personality disposition towards experiencing negative emotions more frequently and intensely. Longitudinal studies suggest that neuroticism increases risk of several psychological problems. Improved understanding of how this trait manifests in early life could help inform preventative strategies in those liable to neuroticism.This study explored how a polygenic risk score for neuroticism (NEU PRS) is expressed from infancy to late childhood across various psychological outcomes using multivariable linear and ordinal regression models. In addition, we employed a three‐level mixed‐effect model to characterise child internalising and externalising trajectories and estimate how a child PRS associated with both their overall levels and rates of change in 5279 children aged 3–11 in the Avon Longitudinal Study of Parents and Children cohort.We found evidence that the NEU PRS was associated with a more emotionally sensitive temperament in early infancy in addition to higher emotional and behavioural problems and a higher risk of meeting diagnostic criteria for a variety of clinical disorders, particularly anxiety disorders, in childhood. The NEU PRS was associated with overall levels of internalising and externalising trajectories, with a larger magnitude of association on the internalising trajectory. The PRS was also associated with slower rates of reduction of internalising problems across childhood.Our findings using a large, well‐characterised birth cohort study suggest that phenotypic manifestations of a PRS for adult neuroticism can be detected as early as in infancy and that this PRS associates with several mental health problems and differences in emotional trajectories across childhood. We examined the association between a polygenic risk score for neuroticism and a host of psychological outcomes in addition to its association with trajectories of emotional and behavioural problems in the Children of the 90s. We found that the PRS associated with a more difficult temperament, more emotional and behavioural problems, and greater risk of being diagnosed with a clinical disorder in childhood. The PRS was also associated with higher levels of emotional and behavioural problems trajectories and dampened recovery from emotional problems across childhood. Neuroticism is an important risk factor for mental health problems with a moderate heritable component; however, it is unclear how genetic liability to neuroticism associates with severity and persistence of emotional and behavioural problems across childhood.The present study used a prospective design to examine the association between a polygenic risk score for neuroticism and a host of psychological outcomes in addition to its association with trajectories of emotional and behavioural problems in over 6000 children.We found that the PRS associated with a more difficult temperament, more emotional and behavioural problems, and greater risk of being diagnosed with a clinical disorder in childhood. The PRS was also associated with higher levels of emotional and behavioural problems trajectories and dampened recovery from emotional problems across childhood.Our study illustrates the importance of genetic in the severity and persistence of emotional problems across childhood. Trio analyses may elucidate the causal relationship between genetic liability to neuroticism and child psychiatric outcomes.Neuroticism refers to a personality trait characterised by an individual's tendency to experience negative emotions more frequently and intensely Eysenck, . LongituTwin and family‐DNA informed studies  Research Ethics Committee; informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004).The Avon Longitudinal Study of Parents and Children (ALSPAC), also known as Children of the 90s, is an ongoing prospective population‐based birth cohort study. Between 1990 and 1992, 14,541 pregnant women were recruited in Bristol and the surrounding area, previously known as Avon County. The original mothers and partners (Generation 0: ALSPAC‐G0)  which identified 116 independent genetic variants at a genome‐wide significance threshold (p < 5 × 10−8)  and added error term    Goodman,  is a briChildren's locus of control, self‐esteem, and IQ were assessed using validated scales.Any axis‐I disorders  classified using the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) Bell,  yes vs. were assNegative and positive controls are usually employed in epidemiological analyses to test the validity of the association examined  as covariates. Adjusting for principal components of ancestry is a standard approach to account for population stratification  in genetic analyses  indicate a unit difference increase or reduction in the outcome score for each 1SD increase in the exposure.All analyses were conducted using Stata 16 statistical software To examine the phenotypic manifestation of a NEU PRS across childhood, we used separate multivariable linear regression models with robust standard errors (SEs) to estimate coefficients and 95% CIs for the associations between the child NEU PRS and different continuous psychological outcomes  and ordinal logistic regressions for discrete ordinal outcomes , adjusted for the above‐mentioned covariates. Using robust SEs  can help in addressing potential violations of linear regression assumptions such as normality, heteroscedasticity, or observations that exhibit large residuals. Primary analyses were conducted on the complete case dataset. As a positive and negative control analyses respectively, we investigated whether the child PRS for neuroticism was associated with the neuroticism  subscale as measured by the Big Five at 13 years of age and with the child wearing glasses at 8 and 10 years of age.p‐value threshold was set at p < 0.0014 . However, as we have included subscales which are highly correlated with each other, this threshold is likely to be overly conservative. We do not present Bonferroni‐adjusted p‐values as we discourage a binary interpretation of evidence using the arbitrary cut‐off of 0.05 .To take into account a potential inflated false discovery rate due to multiple testing introduced by using separate models for different time‐points and various subscales, a heuristic Bonferroni adjusted mixed in Stata‐16) with random intercepts and slopes was employed to characterise behavioural and emotional trajectories over time and to examine the association of the child PRS with the overall score of emotional and behavioural problems and how these change according to sex, type of scale, and reporter of the scale. The levels represent a dependence structure where children's scores at different measurement occasions (level 1) are nested within the type of scale  (level 2) which are nested within an individual child (level 3)  Figure .This model allows a separate intercept and slope for each child in each scale and it permits the investigation of the effect of covariates as fixed effects. The model included a random intercept and slopes for the change over time which permitted estimation of individual child variation in score levels, and how these change with time across different scales and reporters. Restricted maximum likelihood (REML) was employed instead of maximum likelihood (ML) for fitting this model. Model adequacy was assessed using information criteria  and examining model assumptions, namely homogeneity of variance (with group variance being constant between groups and predictors), linearity, and normality of residual variances at different levels. This model was selected among five different models (4 hypothesised a priori and 1 tested post‐hoc).The sample used in three‐level linear mixed‐models consisted of 5729 children with at least one observation per internalising and externalising subscale over a maximum of seven occasions per scale. The mean number of measurements was 5.62 (SD = 3.50). The majority (74.5%) of the child questionnaires on the SDQ for this study were answered by the mother for the parent reported scale. To examine whether the child PRS for neuroticism was associated with the overall level of the trajectories, we included the PRS as a fixed‐effect term and we used interaction terms to explore its effects depending on the scale used, the reporter of the scale, and the sex of the child. To examine how the PRS was associated with changes over time in our model, we included a main effect of the PRS and an interaction of the PRS with the fixed‐effect age term.We employed various sensitivity analyses to test the potential presence of differential and dependent measurement error due to the maternal PRS, confounding via maternal genotype, genetic pleiotropy, and bias arising from levels of missingness. For more details about the sensitivity analyses refer to Appendix The numbers of individuals who participated in the different assessments at various visits are shown in Tables Both negative and positive control analyses supported the validity of our analyses  and the largest at age 8, both when reported by the mother  and when reported by the teacher . These findings were consistent independent of whether the outcome was teacher or parent reported  across all seven occasions from 4 to 11 years of age. Effect sizes generally increased throughout childhood with the smallest estimates at age 4 (p = 2.80 × 10−8) increased risk of any anxiety related disorder at 7 and 10 years of age, respectively. When exploring the association between the NEU PRS and any behavioural disorder as measured as a combined score across three traits , we found nominal evidence that the PRS was associated with a 9% (95% CI: 4%–16%) and 9% (95% CI: 3%–16%) increased risk of this combined score at 7 and 10 years of age, respectively. We found little evidence of an association between the child NEU PRS and depressive disorders at 7 years of age , but stronger evidence of an association at 10 years of age   increased risk of generalised anxiety disorder (GAD) and a 14% (95% CI: 8%–21%) increased risk at 7 and 10 years of age, respectively. Similarly, we found strong evidence that children with a higher NEU PRS were at 13% (95% CI: 7%–20%) and 19%  for boys when assessed by the parents. For every SD increase in child NEU PRS, we observed an average 6% (95% CI: 4%–7%) increase in internalising problems in boys as reported by the parent. The magnitude of this effect was halved  when examining externalising problems. We also observed strong evidence of a rate of reduction of 3% (95% CI: 2%–3%) per year of age on the internalising scores in boys when reported by the parents, which was larger than the rate of reduction in girls by 1% (95% CI: 1%–2%). This rate of reduction was more pronounced on the externalising scale . The PRS effect on the rate of change with age became more pronounced on the internalising scale where the rates of change were slower . We observed similar patterns of the effect of the PRS in girls. Differences between sexes mainly consisted of differences in score levels with age according to scale and reporter. Such findings are described by the three‐way interactions between reporters, scale, and sex. For example, we found that teachers scored girls 17% (95% CI: 11%–24%) lower on the externalising scale than parents but the difference between reporters is smaller than when rating boys. Finally, we found that teachers gave lower scores to girls with age on the internalising scale . Further discussion of findings from this model are reported in the Appendix A graphical representation of these marginal model predictions according to age, sex, PRS levels, and reporter is presented in Figure p‐value threshold) found attenuated associations across all SDQ scales with the exception of the emotional subscale, suggesting that the observed association between child NEU PRS and the conduct and behavioural subscales may be driven by underlying symptoms of anxiety  often regulating by late childhood  led to a reduction of the strength of the evidence across all findings, the effects sizes remained comparable with the unadjusted complete case analyses. Findings on internalising domain remained robust to this adjustment. Conversely, we found sharp reductions in all our effect estimates when a PRS at a genome‐wide significance threshold; with little evidence of association remaining for the emotional problems as identified by the SDQ and the anxiety‐specific related problems as identified by the DAWBA. These findings suggest that our results are unlikely to be entirely mediated via genetic liability to neuroticism but likely reflect the effect of pleiotropic pathways from the neuroticism PRS to outcomes examined.This study has several strengths. First, we used a large, well‐characterised, prospective population‐based sample to examine neuroticism‐related phenotypes during childhood, a key period of development that closely predates the start of the sharp rise in incidence of internalising problems    Research Ethics Committee; participants gave written informed data consent. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.Supporting Information S1Click here for additional data file.


Antinuclear antibodies (ANAs) are regarded as a hallmark of connective tissue diseases (CTDs) and play a key role in their diagnosis, but the value of some particular antibodies in management of patients and the disease prognosis is controversial. The mechanism underlying the production of ANAs in CTDs, other chronic inflammatory conditions and even in healthy people, is not completely elucidated. Anti‐DFS70 antibodies connected with the dense fine speckled autoantigen of 70 kD, known as the lens epithelium‐derived growth factor p75, are a subgroup of ANAs. Their presence and coexistence with other antibodies and their clinical significance are the matter of debate.Based on literature data, the authors focused on current knowledge explaining the role of anti‐DFS70 antibodies in selected CTDs.However, the literature data is ambiguous and does not fully support the validity of the anti‐DFS70 assay for a specific CTD diagnosis. Most researchers claim that the presence of anti‐DFS70 as the only one usually exclude the diagnosis of CTD. Nevertheless, its coexistence with other ANAs is not an excluding factor but has predictive value due to more favorable course of CTD. Such situations may also suggest an enhanced risk of the development of a CTD in the future.Although more studies are needed in this field, it seems reasonable to ascertain the presence of anti‐DFS70 in routine clinical practice. The hallmark of autoimmune connective tissue diseases is the production of many different circulating antinuclear antibodies. A newly emphasized antinuclear antibody with its dense fine speckled nuclear immunofluorescence pattern may constitute a differentiating factor, with an anti‐DFS70 antibody assay distinguishing healthy people and autoimmune connective tissue diseases patients among individuals who are ANA‐positive DFS70 pAnti‐DFS70 antibodies were first described in association with interstitial cystitis. The DFS pattern in IIF is also observed in diseases such as atopic dermatitis, psoriasis, alopecia areata, prostate cancer, and asthma. This protein may participate in cell protection against oxidative DNA damage due to the influence of various environmental factors, thereby promoting cell survival.The correct interpretation of the DFS pattern in IIF requires considerable precision and experience due to the difficulties in differentiating it from other patterns, especially a homogeneous nuclear pattern.Current data linked with clinical‐serological correlations revealed some controversial findings.4SLE is an autoimmune‐mediated CTD manifested by a wide range of clinical signs from various organs and also by the presence of serum ANAs, which account for the entry criterion to classify SLE without any scoring value according to the 2019 ACR/EULAR classification criteria.Aragon et al.Dai et al.Different types of ANAs are associated with particular clinical manifestations of lupus. The level of anti‐dsDNA antibodies changes with progression and correlates with the severity of lupus nephropathy.Moreover, studies show that the clinical picture of SLE patients with current anti‐DFS70 antibodies is characterized most by arthritis and photosensitivity, while the results of laboratory tests are more likely to document hemolytic anemia.Further long‐term studies may be crucial for understanding the diagnostic and prognostic significance of anti‐DFS70 antibodies in SLE.5SS is an autoimmune disease in which lymphocytic infiltration of the salivary and lacrimal glands leads to mouth and eye dryness.A study conducted by Hayashi et al.Conticini et al.6SSc is a CTD with a complex etiology characterized by fibrosis of the skin and internal organs. The key factors in its pathogenesis are blood vessel and immunological abnormalities and tissue sclerotization.Numerous studies have shown that ANAs occur with a frequency of over 95% among SSc patients. Considering the relationship between ANAs typical for SSc, such as antibodies directed against topoisomerase I (anti‐Scl‐70) with the clinical picture of the disease, it seems reasonable to determine the specificity of ANAs in the routine diagnosis of SSc, especially in the early stage of the disease.Individuals with SSc rarely exhibit anti‐DFS70 antibodies (1.5%) which were also observed to occur only when SSc‐specific autoantibodies tested positive. Thus, in anti‐DFS70 positive patients with negative SSc‐specific ANAs, the diagnosis of SSc can be ruled out with a reasonable probability.Pulmonary complications such as interstitial lung disease (ILD) are relatively common during SSc.Although ANAs are an important diagnostic marker in SSc, the available literature provides little information about the impact of anti‐DFS70 antibodies on the course of SSc.7IIMs are a broad group of autoimmune diseases including dermatomyositis (DM) and polymyositis (PM). A representative feature of IIM is proximal muscle weakness and elevated serum creatine kinase levels.A number of works have evaluated anti‐DFS70 antibodies in IIM. The study by Hayashi et al.Muro et al.The involvement of anti‐DFS70 antibodies in the process of excluding suspicious cases of DM/PM as well as in alleviating the clinical symptoms of IIM is probable but needs to be confirmed in further long‐term prospective studies.8UCTD is an autoimmune disorder that does not fulfill the classification criteria necessary for diagnosis of a specific CTD.It has been proven that 1/3 of patients with UCTD will develop fully symptomatic CTD within 5 years from the onset of the first manifestations. Therefore the search for serological markers that will help exclude the diagnosis of UCTD with a high risk of progression to CTD has been undertaken. Anti‐DFS70 antibodies are thought to have this function.Based on available economic analyses, it can be concluded that the use of anti‐DFS70 antibody assay in the standard management of patients with suspected UCTD is economically beneficial, as it reduces expenses related to unnecessary laboratory and imaging diagnostics.Controversial clinical data do not fully support the validity of anti‐DFS70 assay for the diagnosis of UCTD. The coexistence of other autoantibodies may suggest a risk of developing CTD in the future.9Previous studies indicate that anti‐DFS70 antibodies occurring in the blood serum in high concentrations, and as the only ones, are a reliable marker for excluding CTDs. They constitute a differentiating factor between healthy people and CTD patients among ANA‐positive patients. Accordingly, anti‐DFS70 screening tests should be included in ANA detection algorithms.Aleksandra Fijałkowska: Conceptualization; investigation; methodology; writing—original draft; writing—review and editing. Robert A. Schwartz: Conceptualization; project administration; supervision; writing—original draft; writing—review and editing. Anna Woźniacka: Conceptualization; methodology; project administration; supervision; writing—original draft; writing—review and editing.The authors declare no conflict of interest.


According to the WHO, people are absent from work for 11 days on average per year due to illness.Anyone can easily relate to absence from work due to a transient infection such as influenza. A typical full‐time employee could expect to lose about 3½ of their 5 work days in a given week due to absenteeism and presenteeism from an influenza infection.Yet there is something less recognizable that substantially affects work productivity: disorders of the gut‐brain interaction (DGBIs), formerly referred to as functional gastrointestinal disorders. This group of disorders includes common conditions such as irritable bowel syndrome (IBS) and functional dyspepsia. In this issue, Frändemark et al.These findings are very much in line with previous studies investigating IBS. Three previous cohort studies, from Sweden,Any chronic health condition impacts one's life and this extends to their work environment. This is surely true for IBS and other DGBIs. However, the lack of recognition of IBS as a legitimate disorder among the general public, and more specifically employers, contributes to the negative influence of IBS symptoms on job performance. Not being aware of the potential impact of these conditions can put additional strain on employee‐employer relations.As far as healthcare of IBS patients is concerned, it therefore does not suffice to assume that therapies or interventions aimed at decreasing IBS symptoms in general will necessarily lead to equivalently relevant decreases in work impairment. Healthcare professionals should therefore actively engage in exploring the specific work‐related impact of symptoms. Additional effort from employers and occupational healthcare specialists is also required to ensure necessary adjustments to the working environment and conditions when appropriate, for instance, proper access to clean toilet facilities.Further, elements of specific work‐related aspects should be integrated into treatment programs for IBS and other DGBIs. For example, it has previously been shown that cognitive behavioral therapy‐based comprehensive self‐management for IBS was superior to usual care in improving overall work productivity loss and activity impairment with sustained effects up to 12 months. Such intervention was found to be particularly beneficial for IBS patients with greater baseline work and activity impairments.The author has no conflicts of interest to declare.


Implantable cardioverter defibrillators (ICD) are indicated for primary and secondary prevention of sudden cardiac arrest. Despite enhancements in design and technologies, the ICD lead is the most vulnerable component of the ICD system and failure of ICD leads remains a significant clinical problem. A novel, small‐diameter, lumenless, catheter‐delivered, defibrillator lead was developed with the aim to improve long‐term reliability.The Lead Evaluation for Defibrillation and Reliability (LEADR) study is a multi‐center, single‐arm, Bayesian, adaptive design, pre‐market interventional pivotal clinical study. Up to 60 study sites from around the world will participate in the study. Patients indicated for a de novo ICD will undergo defibrillation testing at implantation and clinical assessments at baseline, implant, pre‐hospital discharge, 3 months, 6 months, and every 6 months thereafter until official study closure. Patients may be participating for a minimum of 18 months to approximately 3 years. Fracture‐free survival will be evaluated using a Bayesian statistical method that incorporates both virtual patient data (combination of bench testing to failure with in‐vivo use condition data) with clinical patients. The clinical subject sample size will be determined using decision rules for number of subject enrollments and follow‐up time based upon the observed number of fractures at certain time points in the study. The adaptive study design will therefore result in a minimum of 500 and a maximum of 900 patients enrolled.The LEADR Clinical Study was designed to efficiently provide evidence for short‐ and long‐term safety and efficacy of a novel lead design using Bayesian methods including a novel virtual patient approach. The design of the LEADR study is presented. This studies a novel ICD lead that is built on the robust design of the existing Medtronic Model 3830 lead. Both have a flexible central conductor which is designed to make the lead more reliable. Current market‐approved ICD leads have a diameter that varies from 6.8 to 8.6 Fr. (2.27–2.87 mm). Presently available leads use stylet delivery for implantation; necessitating an internal lumen. Previous efforts to decrease ICD lead diameter to allow for ease of implantation and to reduce likelihood of venous obstruction and tricuspid valve regurgitation have resulted in two Food and Drug Administration (FDA)‐mediated recalls. The Medtronic Sprint Fidelis (6.6 Fr) was recalled in 2007 due to its high incidence of conductor fracture and the St. Jude Medical Riata leads (6.3–7.6 Fr) were recalled in 2011 due to insulation failure resulting in externalization of conductor cables.The purpose of the LEADR Clinical Study is to demonstrate safety and efficacy of The Model 093000 lead (further referenced as the “LEADR ICD lead”). The performance goals for the primary safety objective and primary efficacy objective (defibrillation testing) are chosen based on the known performance of market‐approved leads or historical study data,1.2ClinicalTrials.govNCT00266682). The SelectSecure Model 3830  pacing lead has long‐term reliability data out to 10 years supporting the design of the LEADR ICD.The LEADR ICD lead was developed to address the needs for long‐term reliability and reduced defibrillation lead diameter. This new lead is based on the SelectSecure Model 3830  pacing lead Figure  which re(Deleted)The SelectSecure Model 3830 lead is catheter delivered, as opposed to other pacing and defibrillation leads that are delivered using a stylet. The absence of a stylet lumen allows the use of a flexible cable from the connector to the tip, enabling a smaller overall diameter and potential for improved fracture performance due to lower stresses during bending Figure .The LEADR ICD lead is a 4.7 Fr, steroid‐eluting, catheter delivered, active fixation, polyurethane insulated, integrated bipolar single coil defibrillation lead. The lead is designed for pacing, sensing, cardioversion, and defibrillation therapies. The right ventricular (RV) coil delivers cardioversion and defibrillation therapies. Pacing and sensing occur between the helix and RV coil electrode. The materials in the LEADR ICD lead have been used for more than 10 years in other lead designs with acceptable field performance Figure .13Current ICD lead designs incorporate multiple lumens and conductors to enable both dual and single coil defibrillation therapy as well as integrated and true bipolar sensing. Additionally, current active fixation ICD leads have helices that extend and retract when the conductor coil to the helix is rotated. Although these designs may provide options for physicians, they introduce constraints that can limit durability and increase size.The LEADR ICD lead architecture is dedicated for single coil defibrillation, integrated bipolar pacing and sensing, and catheter delivery. This eliminates several design constraints that are present in current ICD leads. The single coil defibrillation and integrated bipolar design require only two conductor circuits instead of up to four in traditional designs. Catheter delivery allows the central axis placement of a thin, flexible cable to the tip helix instead of a relatively stiff torque coil that may be more susceptible to fatigue fracture. The cable to the tip helix is placed in the location normally reserved for a stylet lumen, which gives advantages of both low bending stress and size reduction. The conductor to the defibrillation electrode is a coiled helix surrounding the tip conductor, and is also on the central axis, reducing stress compared to coiled helices in traditional ICD leads. Because the outer conductor is coiled around the inner conductor, the cable externalization failure mode seen in other ICD leads is not possible. The LEADR ICD lead design enables improved fatigue strength compared to previous ICD lead designs.1.3The LEADR study has two primary objectives. The primary safety objective is to demonstrate that the freedom from major complications related to the LEADR ICD lead at 6 months post‐implant exceeds a pre‐specified threshold of 90%. The endpoint is defined as a subject's first occurrence of a major complication related to the LEADR ICD lead, as determined by an independent Clinical Events Committee (CEC), that occurs on or before 6 months 182 days) post‐implant. Major complications are those complications resulting in death, lead fracture, hospitalization, prolongation of an existing hospitalization by at least 48 h, and/or system revision . The primary efficacy objective is to demonstrate that defibrillation efficacy exceeds a threshold of 88% in a subset of patients. The defibrillation endpoint will be met if a single 18 Joule shock terminates an induced sustained shockable ventricular arrhythmia (SSVA) or if two consecutive induced SSVAs are terminated with 25 J shocks . The study is expected to be conducted at up to approximately 60 study sites worldwide . At the time of manuscript submission, 19 sites have been activated and 70 patients have been enrolled.The LEADR Clinical Study is a pre‐market, prospective, multi‐center, single‐arm, Bayesian, adaptive, interventional pivotal clinical study approved by local regulatory and ethics committees that adheres to the Declaration of Helsinki to evaluate efficacy and safety of the LEADR ICD lead , sustained shockable ventricular arrhythmia (SSVA) induction and defibrillation testing is required at implant for at least the first 95 consecutive implanted patients. Only a subset of patients is required to undergo defibrillation testing so as to reduce risk and burden to the patients Figure . Additio2.4The LEADR Clinical Study design is adaptive with regard to both sample size and follow‐up duration Figure . It featThe first decision point occurs after 500 subject implant attempts Table . If no fThe second decision point will be when the first 500 patients with an implant attempt have had the opportunity to have a 6‐month visit. If at that time point, no more than one fracture has been observed in the study, the data will be analyzed when the first 500 patients with an implant attempt have had the opportunity to be followed for 12 months. If instead more than one fracture has been observed by this time point, the data will be analyzed once the last  implanted subject has had the opportunity to reach a 12‐month follow‐up.For analyzing the primary safety objective, a piecewise exponential survival model employing Gamma priors which yield a skeptical prior distribution for a 6‐month freedom rate (median of 56.2%) is used. The posterior distribution will be computed using the conjugate distribution for the Gamma priors. Information about simulations to study the statistical operating characteristics of the adaptive design and details about sample size calculations for the primary efficacy objective can be found in the supplementary information.r-project.org) were performed to study the statistical operating characteristics of the adaptive design. For all simulations, an attrition rate of 4% at 1 month and 10% 1‐year post‐implant were assumed. Power for the primary safety objective was estimated by assuming a major complication‐free rate of 95.5% and 94.5% at 1 and 6 months, respectively. Simulation results showed that the adaptive study design has good frequentist operating characteristics, such as power >90% and Type I error <2.5% for the primary safety objective  a high‐performing scenario where the LEADR ICD lead has an expected fracture‐free rate of 99.9% at 12 months, and (2) a poor‐performing scenario where the lead has a 98.4% fracture‐free rate at 12 months. In the high‐performance scenario, there is a 94% chance of observing 1 or fewer fractures within 6 months after the 500th implant attempt, compared to 1.4% chance for the poor‐performing scenario.The primary efficacy objective will be analyzed using a Beta‐Binomial Bayesian model with a skeptical Beta before ensure good Frequentist operating characteristics. To determine the sample size for the primary efficacy objective, a defibrillation success rate of 97% was assumed to study statistical power. To assess the Type I error, a success rate of 88% was assumed. Simulation studies determined that at least 95 patients completing the defibrillation testing protocol will provide a power >90% with a Type I error <2.5%.2.5The secondary objective of fracture‐free survival will be evaluated using a novel Bayesian statistical method that incorporates modeled and clinical data Figure .16 To 2.6Bayesian analysis methods will be used for all objectives.For the primary safety objective, the null hypothesis is that the 6‐month freedom from major RV lead‐related complications is equal to or below 90%. For the safety objective to be successfully met, the 95% two‐sided credible interval for the 6‐month RV lead‐related major complication rate must have a lower bound exceeding 90%.The primary safety objective addresses the entire safety profile of the LEADR ICD lead as fractures are included in major complications. The determination of the pre‐specified performance goal of 90% for the lead‐related major complication endpoint aligns with previous ICD and CRT‐D studies: Block HF, Reverse, Evera MRI, and PainFREE SST.For the primary safety objective, all patients undergoing an implant attempt of the LEADR ICD lead will be included in the analysis. The objective will be analyzed using a time‐to‐event analysis. The time to event will be defined as a subject's time to first LEADR ICD lead‐related major complication. In the case of no event, patients will be censored at the time point of their last exposure to the LEADR ICD lead.For inferential analyses, a piecewise exponential model will be assumed with two intervals of interest: 0‐1‐month post‐implant, and 1 month and beyond post‐implant, as it is possible the rate of lead‐related major complications may differ in the acute (first 30 days) compared to more chronic time points Figure .Bayesian Prior Gamma distributions will be combined with the prospective event/follow‐up data to generate posterior distributions for each event rate. These posterior distributions will be used to construct the 95% two‐sided credible interval for the freedom from major complication at 6‐months as described above. Further details about the specification of the Bayesian priors can be found in the supplementary methods.For the primary efficacy objective, the null hypothesis is that the implant defibrillation success rate is equal to or below 88%. For the objective to be successfully met, the 95% two‐sided credible interval must have a lower bound that exceeds 88%. The analysis cohort will be defined as patients who complete the implant defibrillation testing protocol.Defibrillation implant success for transvenous devices, though no longer routinely performed, has historically been shown to be as low as 88%.The primary efficacy objective will be analyzed using a Beta‐Binomial Bayesian model as described above in the sample size section from which a 95% two‐sided credible interval for defibrillation success will be constructed. Details can be found in the supplementary methods.For the secondary objective analyses, time‐to‐event analyses will be performed. Time to event will be set as the interval from the time of implant to the time of the first LEADR ICD lead fracture. Patients without fractures during the time period of interest will be censored at their time point of last exposure to the LEADR ICD lead. All patients undergoing an implant attempt of the LEADR ICD lead will be included in the analysis. More information about the analysis for the secondary objective can be found in the supplementary information.For the secondary objective analyses, time‐to‐event analyses will be performed. Time to event will be set as the interval from the time of implant to the time of first LEADR ICD lead fracture. Patients without fractures during the time period of interest will be censored at their time point of last exposure to the LEADR ICD lead. All patients undergoing an implant attempt of the LEADR ICD lead will be included in the analysis. More information about the analysis for the secondary objective can be found in the supplementary information.2.7The sponsor will manage data collection and monitoring. An independent CEC will be utilized to regularly review and adjudicate reported system, procedure‐related adverse events, and deaths. An Episode Review Committee containing independent reviewers will be utilized to review and adjudicate device‐treated episodes to determine appropriateness of therapy (shocks and anti‐tachycardia pacing) delivered to patients. Overall oversight will be provided by an independent Data Monitoring Committee to review accumulating data, help safeguard the interests of study patients and monitor the overall conduct of the study.3Prior efforts to design a small‐diameter defibrillation lead have been met with unexpected challenges that have led to failure based upon the mechanical properties of the leads.In addition to assessing the safety, and fracture survival of the LEADR ICD lead, defibrillation efficacy will also be analyzed. As defibrillation testing is no longer routine at many centers,4The LEADR Clinical Study was designed to efficiently provide evidence for short and long‐term safety and efficacy using Bayesian methods including a novel virtual patient approach. A positive study, meeting our endpoints, would demonstrate the clinical safety and efficacy of this technology to provide physicians an option for a smaller diameter lead in treating patients indicated for an ICD or CRT‐D.This study is funded by Medtronic, Inc.Supplementary information.Click here for additional data file.