Chronic ocular graft-versus-host disease (oGVHD) is an ocular comorbidity of graft-versus-host disease (GVHD) that usually occurs concurrently with systemic manifestations. Failure to detect and treat oGVHD in its early stages may lead to progression of ocular signs and symptoms leading to oGVHD that is refractory to conventional treatment.We report the clinical course of a 19-year-old male and a 59-year-old female with severe and progressive chronic oGVHD without concurrent systemic signs of chronic graft-versus-host disease (cGVHD). Although their systemic conditions had been stable, both suffered from severe oGVHD and were referred to our clinic. Both cases exhibited marked improvement in conjunctival inflammation and fibrotic changes after amniotic membrane transplantation (AMT). Both cases underwent keratoplasty eventually to stabilize ocular surface conditions and to improve visual function.We reported the clinical outcomes of 2 cases of chronic oGVHD without concurrent systemic comorbidities that were treated with AMT. The clinician should be aware that cGVHD may persist in target organs even in the absence of concurrent systemic comorbidities following seemingly successful systemic treatment. A multidisciplinary team approach is essential in the early detection and therapeutic intervention for chronic oGVHD. Dry eye disease (DED) is the most frequent ocular manifestation after haematopoietic stem cell transplantation (HSCT) , 2, and The human amniotic membrane (AM) is reported to exert anti-inflammatory and anti-scarring actions –9, and aIn this article, we report the clinical outcomes of 2 cases of refractory chronic oGVHD without long-term systemic comorbidities, both of which were treated with AMT and keratoplasty to achieve clinical improvement.A 19-year-old Japanese male with a history of acute myelogenous leukaemia (AML) who underwent reduced intensity allogeneic HSCT (mini-transplantation) in March 2005 was referred to the Keio University Dry Eye outpatient clinic in October 2005 complaining of severe ocular pain, difficulty opening his eyes and foreign body sensations after acute and chronic skin GVHD were completely stabilized. Prior to mini-transplantation, no ocular surface abnormality was noted at the previous hospital, and he started to suffer from newly developed symptoms of DED in May 2005, after alleviation of acute skin GVHD. Systemic prednisolone (PSL) had been tapered from 40 to 20 mg/day in July and was discontinued in August 2005. Just after cessation of PSL, bilateral lid swelling and severe ocular pain had emerged. PSL (15 mg/day) was restarted to treat skin chronic GVHD in October 2005. Skin chronic GVHD was well controlled by this treatment. At the first visit to Keio University Dry Eye outpatient clinic in October 2005, severe DED, extensive trichiasis, corneal conjunctivalization, corneal ulcer, spontaneous lacrimal punctal occlusion, and active corneal neovascularization were observed in both eyes  who underwent allogeneic bone marrow transplantation (BMT) without irradiation in May 2010 was referred to the Keio University Dry Eye outpatient clinic in September 2013 as she developed refractory chronic oGVHD. After BMT, she developed acute skin GVHD and was successfully treated with systemic tacrolimus (2 mg/day) and PSL (30 mg/day), which was tapered over almost 1 year. In early 2011, just after tapering of treatment for acute skin GVHD, she developed DED and transient difficulty opening her mouth, which was diagnosed as chronic ocular and oral GVHD. She had been suffering from symblepharon, LSCD and conjunctivalization in her right eye, and she had been previously treated with contact lenses, commercially available eye drops, autologous serum and topical cyclosporine and tacrolimus, yet her ocular surface condition had not improved. At the first visit to Keio University Hospital in 2013, severe conjunctival fibrosis of the upper conjunctiva and fornix shortening, partial LSCD and conjunctivalization of the upper cornea on her right eye were observed (Fig. Chronic oGVHD is an immune-mediated fibrotic disease that usually occurs concurrently with systemic comorbidities, and its aetiologies are multifactorial and still largely unknown. Currently available treatments such as eye drops, oral medications or punctal plugs are often insufficient to control severe ocular surface inflammation and excessive fibrosis, and additional therapeutic interventions such as AMT, corneal transplantations, and COMET are indicated for this intractable disease. The availability of such surgical interventions is limited, and the indications for these interventions should be considered carefully. Therefore, it is vital to detect oGVHD in the early phase to prevent severe ocular complications.AMT has been reported to be effective in treating refractory ocular surface diseases, including Stevens-Johnson syndrome and ocular cicatricial pemphigoid , 10. CliIn both cases the fornix was successfully reconstructed and long-term maintenance was achieved after AMT. However, a minor recurrence of corneal conjunctivalization in case 2 and corneal perforation in case 1 were observed after AMT, and both were treated with corneal keratoplasty.Although acute skin GVHD in cases 1 and 2 and transient chronic oral GVHD in case 2 were observed, oGVHD continued to progress rapidly even after stabilization of systemic conditions. Both cases resulted in severe oGVHD during or after tapering of systemic corticosteroids or immunosuppressants and AMT was required to reconstruct the fornix and to prevent corneal conjunctivalization due to LSCD.The limbal stem cell region has been reported to be infiltrated by inflammatory cells based on confocal microscopy observations in chronic oGVHD . FurthercGVHD patients are immunocompromised, and monitoring for ocular surface infections as well as systemic conditions is imperative. However, ocular manifestations may become apparent even after stabilization of systemic GVHD, as we experienced in the two cases reported herein. We suspect that these patients had hidden or latent mucosal or exocrine gland GVHD involving several mucosal surface barrier regions. The clinician therefore should be aware of the possibility of subclinical mucosal inflammation in cGVHD and the possibility of exacerbation of such inflammation especially at cessation or tapering of systemic anti-inflammatory medication. A multidisciplinary team approach is essential in determining the optimal timing for tapering of systemic anti-inflammatory medication in order to minimize the risk of chronic oGVHD.


To report pooled prevalence of all mental disorders among the general prison population in the United Kingdom (UK). This includes individuals in Young Offender Institutions (YOI), youth custody and adult prisons across all categories. A secondary aim explores possible sources of heterogeneity by performing subgroup and meta-regression analysis across certain covariates (e.g. sex of prisoner). We hypothesise that contemporary estimates of mental disorders are higher than the general population.Prevalence of mental health problems among prisoners are considerably higher than the general population; this poses an important public health concern. Individuals who require diversion to appropriate psychiatric services are becoming embroiled in the revolving door of the criminal justice system. However, there are no up-to-date reviews assessing prevalence of mental disorders across the general prison population in the UK. This study aims to address this gap.We conducted a systematic search of PsycINFO (1923 – October 2019), MEDLINE (1946 – October 2019), EMBASE (1947 – October 2019) and Web of Science  of articles reporting prevalence of mental disorders in UK prison populations (PROSPERO registration number: CRD42019132685). The Joanna Briggs Institute (JBI) Appraisal Checklist for Studies Reporting Prevalence Data assessed study quality and bias. Pooled prevalence of each mental disorder was calculated using Stata statistical software 16.0 via the metaprop command. Forest plots present prevalence estimates with study weights and associated 95% confidence intervals (CI). Overall, 20 studies satisfied inclusion criteria, comprising of 12,335 prisoners across England, Wales and Scotland.We identified higher rates of neurotic disorders , personality disorders , alcohol  and drug dependence . The lowest prevalence rates included schizophrenia , panic disorders , adjustment disorders  and intellectual disability . Meta-regressions for psychotic disorder and personality disorder revealed no significant differences across study year, sample size and gender.Our prevalence estimates of mental disorders in prisons are higher than the general English population. However, we should acknowledge the influence of considerable heterogeneity. These findings demonstrate the need to quantify current prevalence of mental disorders amongst prisoners in the UK. We recommend for the government to consider performing an up-to-date census of psychiatric morbidity to facilitate service provision.


ABSTRACT IMPACT: This project seeks to identify unique host responses that are biomarkers for specific urethral pathogens, and which can be used in the development of point-of-care (POC) STI diagnostics. OBJECTIVES/GOALS: How Chlamydia trachomatis (CT) and other common STIs, e.g. Neisseria gonorrhoeae, evade immunity and elicit pathology in the male urethra is poorly understood. Our objective is to determine how STI-infected urethral epithelial cells, as well as the uninfected ‘bystander’ cells with which infected cells communicate, respond to CT and other STIs. METHODS/STUDY POPULATION: We evaluated how immortalized urethral cell lines - including transduced human urethral epithelial cells (THUECs) - respond to increasing doses of CT infectious particles using in vitro one-step progeny assays performed in the presence or absence of cycloheximide, a drug that inhibits eukaryotic protein synthesis. We will perform concurrent single-cell RNA sequencing (scRNA-seq) and multiplex cytokine analyses to determine how different CT doses impact the transcriptomes of infected and bystander urethral epithelial cells and modulate cytokine production of the overall monolayer. Results of these experiments will inform the feasibility of performing similar analyses in situ using urethral swabs from men with clinically diagnosed urethritis. RESULTS/ANTICIPATED RESULTS: Our results demonstrate that immune-competent urethral cell monolayers strongly resist CT infection, unless most of the cells are simultaneously infected. This suggests that uninfected bystander cells sense CT-infected cells and secrete soluble factors that may act to limit CT proliferation in infected cells and to inform remaining uninfected cells that a potential pathogen is present. We anticipate that our scRNA-seq and cytokine analyses will identify both specific effector pathways that protect against CT and intracellular signals that modulate them. We speculate that these pathways and signals may differ during infection with CT and other STIs. Importantly, we anticipate that our in vitro model of CT infection will be highly representative of in situ immune responses observed in urethras of infected men. DISCUSSION/SIGNIFICANCE OF FINDINGS: In men, common STIs including CT are usually managed syndromically due to a lack of POC diagnostics. By determining how STIs elicit urethral inflammation and identifying countermeasures that STIs use to evade urethral immunity, we can identify host responses that serve as biomarkers for urethritis, generally, and for specific urethral pathogens.


Understanding the neurobiological underpinnings of pedophilic behavior may contribute to a more comprehensive characterization of these individuals on a clinical ground, a pivotal step forward for the development of more efficient therapeutic rehabilitation strategies.Pedophilia is a disorder of public concern because of its association with child sexual offense and recidivism. Previous neuroimaging studies of potential brain abnormalities underlying pedophilic behavior, either in idiopathic or acquired  pedophilia, led to inconsistent results. This study sought to explore the neural underpinnings of pedophilic behavior and to determine the extent to which brain alterations may be related to distinct psychopathological features in pedophilia. To this aim, we run a coordinate based meta-analysis on previously published papers reporting whole brain analysis and a lesion network analysis, using brain lesions as seeds in a resting state connectivity analysis. The behavioral profiling approach was applied to link identified regions with the corresponding psychological processes. While no consistent neuroanatomical alterations were identified in idiopathic pedophilia, the current results support that all the lesions causing acquired pedophilia are localized within a shared resting state network that included posterior midlines structures, right inferior temporal gyrus and bilateral orbitofrontal cortex. These regions are associated with action inhibition and social cognition, abilities that are consistently and severely impaired in acquired pedophiles. This study suggests that idiopathic and acquired pedophilia may be two distinct disorders, in line with their distinctive clinical features, including age of onset, reversibility and The online version contains supplementary material available at 10.1007/s11682-020-00442-z. Pedophilia is a paraphilic disorder included within the Diagnostic and Statistic Manual of Mental Disorder  identify the brain regions consistently impaired in idiopathic and acquired pedophilia; (ii) determine whether the two forms of pedophilia are associated with overlapping or distinct brain networks; (iii) link topographically defined regions with corresponding psychological processes, testing which kind of experiments are most likely to activate a given region, to give a cognitive/psychological meaning to the detected alterations.In order to identify brain regions consistently impaired in idiopathic pedophilia, a coordinate based meta-analysis using the Activation Likelihood Estimation (ALE) method was performed  AND . A search for studies in review and meta-analysis articles and a reference tracing were also performed.To be included in the analysis, studies had to meet the following criteria: (i) use structural (sMRI) or functional (fMRI) MRI; (ii) perform a whole brain analysis  analysis were excluded); (iii) be original peer-reviewed data; (iv) include both pedophilic individuals and a healthy control group (HC) or pedophilic individuals who committed and who did not commit sexual abuse; (v) have a sample size of at least five individuals per group; (vi) report results in a standardized coordinate space .Literature screening and selection was performed according with the PRISMA guidelines  method  version 3.0.2. This algorithm treats activated foci of brain regions as three-dimensional Gaussian probability distributions centered at the given coordinates  ; therefore, they did not present a spatially defined lesion that could be outlined. In order to identify the neural structures consistently impaired in bvFTD, a coordinate based meta-analysis was run on papers presenting structural or functional abnormalities in patients with bvFTD vs. healthy controls  on the axial image of a standardized template using the MRIcron software  of patients with lesions functionally connected to each individual voxel. A stability analysis was performed by replicating the analyses using three different control groups, each with 25 healthy subjects . Analyses were performed using SPM-CONN (2018b) adopting standard preprocessing and denoising steps.Second, traced lesions were used as individual seeds in a seed based connectivity analysis, using resting state fMRI data from one hundred healthy subjects randomly selected from a freely available dataset: http://www.brainmap.org/), to reveal the Behavioral Domain and Paradigm Classes consistently associated with these regions.To link topographically defined brain regions with the corresponding psychological process, we ran a behavioral profiling approach across databases of aggregation from activations experiments  was impaired in nine patients, spared in four, while no data were available for the remaining six cases.Lesion localization was very heterogeneous, as reported in Table Though the individual lesions had different locations, the lesion network mapping analysis revealed that 95% of them were part of a single brain network defined by functional connectivity with posterior midline structures , including the posterior cingulate cortex (PCC) and precuneus; the bilateral OFC ); the right inferior temporal gyrus , the left calcarine gyrus  and the left fusiform gyrys   identify consistent alterations associated with acquired and idiopathic pedophilia; (ii) understand whether and to what extent the two forms of pedophilia may share the same biological substrate; (iii) investigate whether consistent brain abnormalities may explain psychopathological features typically detected in pedophiles.Of relevance, the lesion network mapping technique revealed that the neural bases of acquired pedophilia localize to a common resting state network, despite the high spatial heterogeneity of the individual lesions. Overall, these data support a shared neurobiological substrate in acquired pedophilia, as they reveal that the lesions chronologically associated with acquired pedophilic behavior are all functionally connected with a network involving the OFC areas, the posterior midline structures, the right inferior temporal gyrus and the left fusiform gyrus.On the contrary, the ALE meta-analysis of whole brain neuroimaging studies in idiopathic pedophilia revealed no spatially convergent findings across studies, suggesting that idiopathic pedophilia does not have consistent brain alterations that may be detected by structural or functional neuroimaging investigations. However, when lowering the statistical threshold, a few clusters of spatial convergence emerged in the superior frontal gyrus, middle cingulate and middle occipital gyrus. The different findings obtained from the analyses in idiopathic and acquired pedophilia may suggest that the two conditions may not rely on a shared neural base. Of note, the amygdala, which had been reported to be consistently impaired in pedophilia , specifically theory of mind (posterior midline structures), emotion recognition (right OFC), impulse control (right OFC), semantic interpretation of cues . It is noteworthy that these results match well with the aberrant behavior pattern described in acquired pedophiles. The observation of altered activity in a key region for impulse inhibition fits perfectly with previous evidence from single case description of patients with acquired pedophilia, in whom dis-inhibition is invariably present  model of causation . Results of neuroimaging analyses, however, strongly reflect cognitive/behavioral deficits observed in those patients, corroborating the plausibility of our analysis. Second, the lesion network analysis was run using only a relatively small sample of healthy controls (one hundred subjects). The additional analyses we run, however, corroborated the robustness of the results, which remained stable using different control groups of 25 healthy controls. Finally, in the lesion network mapping analysis we could not take into account potential medication effects in the individual patients. However, the original papers indicate that drugs were usually administered after symptoms insurgence, thus the impact of pharmacotherapy for the purposes of the current study is limited. Future studies should assess potential effects of pharmacotherapy.In summary, the results of this study pinpoint aberrant brain activity related to acquired but not to idiopathic pedophilia. All the lesions causing acquired pedophilia localized to a shared resting state network including the posterior midlines structures, the right inferior temporal gyrus and the bilateral OFC, regions consistently involved in social cognition, theory of mind, emotion recognition and action inhibition. Alterations of these neuropsychological functions have been consistently described in individual reports of acquired pedophiles, in line with the observed results. Interpreting these findings in light of the INUS model of causation is relevant to better characterize these patients and to develop novel therapeutic and rehabilitative strategies ESM 2(PDF 370 KB)ESM 3(DOC 92.5 KB)ESM 4(PDF 486 KB)ESM 5(DOC 47.0 KB)


The optimal blood pressure (BP) management in acute ischaemic stroke (AIS) and acute intracerebral haemorrhage (ICH) remains controversial. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions regarding BP management in acute stroke.The guidelines were developed according to the ESO standard operating procedure and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations based on the GRADE approach. Despite several large randomised-controlled clinical trials, quality of evidence is generally low due to inconsistent results of the effect of blood pressure lowering in AIS. We recommend early and modest blood pressure control (avoiding blood pressure levels >180/105 mm Hg) in AIS patients undergoing reperfusion therapies. There is more high-quality randomised evidence for BP lowering in acute ICH, where intensive blood pressure lowering is recommended rapidly after hospital presentation with the intent to improve recovery by reducing haematoma expansion. These guidelines provide further recommendations on blood pressure thresholds and for specific patient subgroups.There is ongoing uncertainty regarding the most appropriate blood pressure management in AIS and ICH. Future randomised-controlled clinical trials are needed to inform decision making on thresholds, timing and strategy of blood pressure lowering in different acute stroke patient subgroups.


Social support exchanges are an integral part of older adults’ well-being. Yet, we know little about how older adults' marital status may influence their support exchanges with different social partners in everyday life, and whether the effect of support exchanges on daily well-being vary by marital status. Adults aged 65+ (N = 278) completed an initial interview about their background and close social networks; then, participants reported whether they provided or received support from their close social partners and rated their psychological well-being for 5 to 6 days. Multilevel logistic models revealed that married older adults were more likely to provide or receive daily support from their close partners than widowed or divorced older adults. However, with respect to specific non-spousal ties, married older adults were less likely to provide support to siblings, friends or others  compared to divorced older adults. Although married older adults were more likely to receive support from children than divorced older adults, they were less likely to receive support from siblings and friends compared to widowed or divorced older adults. Furthermore, receiving support from other familial ties  was associated with reduced daily well-being for widowed older adults whereas married older adults were able to maintain their daily well-being in such situation. Findings highlight the central role siblings and friends play in unmarried older adults' daily support networks and suggest that receiving support could have differential impact on daily well-being depending on older adults’ marital status.


As prevalence decreases in pre-elimination settings, identifying the spatial distribution of remaining infections to target control measures becomes increasingly challenging. By measuring multiple antibody responses indicative of past exposure to different pathogens, integrated serological surveys enable simultaneous characterisation of residual transmission of multiple pathogens.Here, we combine integrated serological surveys with geostatistical modelling and remote sensing-derived environmental data to estimate the spatial distribution of exposure to multiple diseases in children in Northern Ghana. The study utilised the trachoma surveillance survey platform  to collect information on additional identified diseases at different stages of elimination with minimal additional cost. Geostatistical modelling of serological data allowed identification of areas with high probabilities of recent exposure to diseases of interest, including areas previously unknown to control programmes. We additionally demonstrate how serological surveys can be used to identify areas with exposure to multiple diseases and to prioritise areas with high uncertainty for future surveys. Modelled estimates of cluster-level prevalence were strongly correlated with more operationally feasible metrics of antibody responses.This study demonstrates the potential of integrated serological surveillance to characterise spatial distributions of exposure to multiple pathogens in low transmission and elimination settings when the probability of detecting infections is low. Following implementation of successful interventions, one of the primary challenges for neglected tropical disease programmes is identifying areas with remaining disease transmission. As disease prevalence decreases, these infections become increasingly rare and hard to detect. Serological assays measure long-lived disease-specific antibody responses indicating past exposure to pathogens and increase the probability of detecting disease transmission. Here, we integrate serological assays with environmental and spatial data to map priority areas for surveillance for multiple neglected tropical diseases in Northern Ghana using the two-stage cluster-based survey platform established for trachoma surveillance. The use of multiplex bead assays measuring exposure to multiple pathogens allows integrated surveillance of diseases of interest to the national control programme. We identify areas with high risks of transmission to selected diseases as well as areas with high uncertainty which are priorities for future control and surveillance efforts. Together, this highlights the utility of multiplex serological platforms as a tool for integrated surveillance and mapping of neglected tropical diseases. Neglected tropical diseases (NTDs), such as trachoma, schistosomiasis, onchocerciasis, lymphatic filariasis and soil-transmitted helminthiases, cause substantial public health burdens globally. With increasing investment in NTD control, elimination and eradication programmes, community-based surveys are used to monitor impacts of interventions, identify residual transmission and target high-risk populations ,2. TheseAs transmission of infectious diseases decrease, the probability of detecting infections becomes correspondingly low and requires prohibitively large sample sizes to identify infections. For many diseases, this also corresponds with more pronounced spatial heterogeneity, with transmission concentrated in specific geographic areas or sub-populations –9. SerolThe development of multiplex serological assays increases the operational feasibility of serological techniques by enabling measurement of a broad range of responses with high repeatability from limited blood samples. Multiplex bead assays (MBA) are a well-validated method to measure population-level serological responses to a wide panel of NTDs, malaria, vaccine preventable diseases and other infections . These aDespite increasing collection of serological data, challenges remain in translating these data into actionable programmatic information . SpatialHere, we adapt a commonly used Gaussian mixture model and binomial geostatistical models to describe the spatial distribution of antibody responses to multiple diseases in a population-based survey of children in Northern Ghana. Conducted as part of routine surveillance for trachoma elimination, this survey utilised a two-stage cluster-sampling population-based survey design and identified very low levels of the sign “trachomatous inflammation—follicular”, a finding supported by estimates of seroconversion rates –29. AlthThis study was approved by the Ghana Health Service Ethics Review Committee (GHS-ERC: 03/07/15) and the London School of Hygiene & Tropical Medicine (10285). Written informed consent was sought from parents or guardians of all participating children. Verbal assent was additionally obtained from children who were able to provide this. The CDC investigators were not considered to be engaged in human subjects research.www.getodk.org).This study was conducted in the Northern, North East, Savanna and Upper West regions of Ghana in a predominantly rural agricultural population . The cliChlamydia trachomatis), Wb123 lymphatic filariasis (Wucheria bancrofti), Ov16 onchocerciasis (Onchocerca volvulus), NIE strongyloidiasis , soluble egg antigen (SEA) schistosomiasis (Schistosoma mansoni), rp17 and TmpA yaws , VSP3 giardiasis (Giardia lamblia). Glutathione s-transferase (GST) was used as a negative control. MBA were conducted using standard methods )Within this setting, serological data support other estimates of NTD burdens and associated environmental risk factors within Northern Ghana. These results are consistent with previous findings of very low prevalence of trachoma and additionally demonstrate how serology may be employed to identify areas for post-elimination surveillance for potential recrudescence ,28. AddiO. volvulus transmission. However, lymphatic filariasis MDA ceased in 2014, and these serological data indicate an increase in onchocerciasis previously unknown to GHS and as a direct result of the integrated surveillance approach, GHS decided to start MDA specifically for onchocerciasis in this focus . While further work is required to confirm transmission and disease burdens may have changed since 2015, this identifies a priority area for surveillance.Geostatistical modelling of serological data representing exposure to multiple pathogens has important implications for survey design. The systematic and random population-based sampling strategy used for trachoma mapping enabled assessment of the distribution of other NTDs; this approach would not have been feasible with purposive sampling. For example, this study identified a focus of onchocerciasis with a significant prevalence of anti-Ov16 antibodies in children aged 1–9 years in Saboba-Cherepon. Previous mapping of onchocerciasis in this area through the Rapid Epidemiological Mapping of Onchocerciasis (REMO) in 2009 determined this to be an area of hypo-endemicity, not requiring onchocerciasis specific MDA at that time. Since then, the area has been treated for lymphatic filariasis, which includes the delivery of ivermectin  and the expectation had been this would also impact on For control and elimination programmes needing to make operational decisions quickly without access to technical expertise needed to develop geostatistical models, very simple metrics can be applied to identify locations at high risk of transmission. While the relationship between arithmetic mean MFI values and estimated seroprevalence is not linear, prioritising control activities at clusters with the highest mean MFI values would likely ensure that interventions are reaching communities with the highest seroprevalence. This agrees with previous studies showing high correlation between mean quantitative antibody levels and other infection-based metrics of NTD transmission ,24. As sDespite the value of this approach, this study had several important limitations. As this study does not include adults, further validation of these methods may be required in settings with very high historical transmission and exposure in older age groups. While serological surveys of children are likely to be a better marker of recent rather than historical exposure, the utility of this approach will vary for specific diseases and associated risk factors. For trachoma, young children under 9 are believed to be the primary source of infection. In contrast, children aged under 5 years have lower risks of onchocerciasis and schistosomiasis, which predominantly impact school-aged children and adults with high-risk occupational activities. This highlights a key methodological challenge of integrated surveys targeting multiple diseases with different risk groups and transmission mechanisms. Additionally, this analysis relied on a single dataset collected over one time point. These diseases may additionally have differing immune responses, antibody kinetics and infection periods and longitudinal data may be able to more accurately identify recent infections or characterise transmission . The uncDespite these limitations, this study demonstrates how integrated serological surveillance can characterise the spatial distribution of exposure to multiple pathogens. An adaptable framework is provided to understand the spatial and environmental factors driving transmission in elimination settings when infection data are rare. As countries approach elimination, this study additionally highlights the need for innovative surveillance approaches utilising population representative sampling to maximising efficiency by collecting data across multiple diseases. Applying these techniques can provide valuable information for control programmes needing to identify and target remaining foci of infection.S1 TextTable A. Priors used for proportions in three component mixture models. Table B. Spatial and environmental covariates. Fig A. Disease-specific antibody responses for all included children, i. Density plots of log-transformed MFI values, ii. Age distributed antibody responses. Fig B. Antibody densities by age categories. Fig C. Relationships between mean posterior estimates of seroprevalence and arithmetic mean MFI per cluster for: A) Trachoma; B) Filariasis; C) Onchocerciasis; D) Strongyloides; E) Schistosomiasis; F) Giardiasis.(DOCX)Click here for additional data file.


Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks . Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC.


Suicide rates increase over the life-span, necessitating concern in older adults. Recent studies suggest that anxiety disorders are associated with suicidal thoughts and behavior. The present study examined the association between anxiety symptoms  and suicide risk (Suicide Behaviors Questionnaire-Revised), testing whether the association differs between younger and older adults. Depression symptoms  were controlled for in the analyses. In a sample of 944 participants (46% 60+ years), anxiety symptoms, depression symptoms, and suicide risk were lower among older adults (60+ years) than younger adults . Age moderated the significant association between anxiety symptoms and suicide risk . Results indicate that an increase in anxiety is associated with a smaller increase in suicide risk for older adults than younger adults. The need for suicide risk screening among individuals with elevated anxiety symptoms is critical, especially for younger adults.


This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation.


Although numerous risk factors are reported in the literature, many are non-modifiable and management of the injury remains difficult. Lower leg muscle structure and function are modifiable characteristics that influence tibial loading during foot-ground contact. Therefore, this study aimed to determine whether long-distance runners with MTSS displayed differences in n = 20) and matched asymptomatic controls (n = 20). Means, standard deviations, 95 % confidence intervals, mean differences and Cohen’s d values were calculated for each variable for the MTSS symptomatic and control limbs.Lower leg structure was assessed using ultrasound and a measure of lower leg circumference to quantify muscle cross-sectional area, thickness and lean lower leg girth. Lower leg function was assessed using a hand-held dynamometer to quantify maximal voluntary isometric contraction strength and a single leg heel raise protocol was used to measure ankle plantar flexor endurance. Outcome variables were compared between the limbs of long-distance runners suffering MTSS (MTSS symptomatic limbs displayed a significantly smaller flexor hallucis longus cross-sectional area, a smaller soleus thickness but a larger lateral gastrocnemius thickness than the control limbs. However, there was no statistical difference in lean lower leg girth. Compared to the matched control limbs, MTSS symptomatic limbs displayed deficits in maximal voluntary isometric contraction strength of the flexor hallucis longus, soleus, tibialis anterior and peroneal muscles, and reduced ankle plantar flexor endurance capacity.Differences in lower leg muscle structure and function likely render MTSS symptomatic individuals less able to withstand the negative tibial bending moment generated during midstance, potentially contributing to the development of MTSS. The clinical implications of these findings suggest that rehabilitation protocols for MTSS symptomatic individuals should aim to improve strength of the flexor hallucis longus, soleus, tibialis anterior and peroneal muscles along with ankle plantar flexor endurance. However, the cross-sectional study design prevents us determining whether between group differences were a cause or effect of MTSS. Therefore, future prospective studies are required to substantiate the study findings. Medial tibial stress syndrome (MTSS), more commonly known as shin splints, is one of the most common forms of exercise induced lower leg pain . ResearcTwo risk factors for MTSS that could easily be modified is structure and function of the lower leg muscles that contribute to the changes in lower leg girth seen in individuals who develop MTSS. Authors have previously reported that compared to asymptomatic controls, MTSS symptomatic individuals displayed less lean lower leg girth , reducedin vivo lower leg muscle cross-sectional area (CSA) or thickness to determine whether reduced lean lower leg girth associated with MTSS is due to atrophy of specific lower leg muscles or a uniform reduction in lower leg muscle size. A better understanding of how lower leg muscle composition differs between MTSS symptomatic and asymptomatic controls will provide evidence to develop future intervention studies that target specific lower leg muscles to treat or prevent MTSS.Lean lower leg girth is a circumferential measure of lower leg muscle bulk measured while a participant is standing and then corrected for adipose tissue thickness. Lean lower leg girth, however, does not provide information regarding how individual lower leg muscle composition affects the overall circumference measurement. To date, no study could be located that has assessed in vivo structural composition measurements. Researchers have previously reported that when matched to asymptomatic controls, MTSS symptomatic individuals display less ankle plantar flexor endurance, increased flexor hallucis longus plantar flexion torque and a greater isokinetic evertor strength compared to invertor muscle strength  measured the lower leg muscle thickness and CSA, lean lower leg girth and lower leg MVIC strength of a convenience sample of two females and four males on two separate occasions. Intraclass correlation coefficients for lower leg muscle thickness all > 0.671) and CSA , lean lower leg girth (0.992) and lower leg MVIC strength  confirmed the measurements were moderate to highly reliable. The ankle plantar flexor endurance protocol has previously been shown to have excellent test-retest reliability [71 and CSp < 0.05) differences in the outcome variables between the 20 MTSS symptomatic and 20 matched control limbs. The effect size was calculated using Cohen’s d where 0.2, 0.5 and 0.8 were considered small, moderate and large, respectively [Descriptive statistics  were calculated for each variable for the MTSS symptomatic and control limbs. Nine of the eleven MTSS symptomatic participants experienced bilateral symptoms. Therefore, a mixed-model linear regression design was used to determine whether there were any significant  at the middle and distal thirds of the medial margin of the tibia, which coincides with the site of MTSS pain. Given the findings of Naderi et al. [A thinner SOL and lower SOL MVIC strength, combined with a thicker GL, could be compensatory strategies by MTSS symptomatic participants to reduce SOL traction on the tibia. Naderi et al.  prospecti et al.  and thati et al. . FurtherMTSS symptomatic limbs in the current study also displayed a significant deficit in ankle plantar flexor endurance capacity compared to control limbs. This is unsurprising given the significantly lower ankle plantar flexor muscle strength, notably reduced SOL strength, considering its endurance capacity associated with postural tasks . These fThe FHL and TA help control medial longitudinal arch (MLA) height and attenuate ground reaction forces during the stance phase of gait. Naderi et al.  concludeAnother possible explanation for the lower strength of FHL, P, SOL and TA in MTSS symptomatic participants could be due to pain and associated neuromuscular adaptations. Although the mechanics are not entirely understood, individuals who experience pain (e.g. lower back pain) display altered muscle activation patterns and morphological muscle changes . FurtherIt is acknowledged that, as a cross-sectional study, we cannot determine whether the between group differences identified in this study were a cause or effect of MTSS development. Furthermore, the small sample size prevents definitive conclusions from being made. We were also not able to assess the structure of tibialis posterior due to constraints of our ultrasound probe. Tibialis posterior contributes to ankle plantar flexion and foot inversion and, therefore, assists in reducing the negative tibial bending moment during the stance phase of gait. Future research should be prospective in design and assess the structure and function of tibialis posterior to determine its role in resisting negative tibial bending moments.Compared to well-matched control participants, runners suffering MTSS symptoms displayed less FHL CSA and SOL thickness but greater GL thickness, as well as lower FHL, SOL, P and TA MVIC strength and ankle plantar flexor endurance capacity. These differences may contribute to the slow recovery time typically seen by MTSS patients because they might be less able to withstand the negative tibial bending moment generated during midstance, which can cause greater tibial strains. Furthermore, future investigation of asymptomatic runners using a prospective design is required to determine whether the between group differences identified in this study are consistent in runners who develop MTSS.


ABSTRACT IMPACT: Access to intracranial recording in our epileptic sample provides a unique opportunity to characterize neurological activation patterns associated with attention and implicit learning; this foundational physiological understanding will serve to better guide cognitive rehabilitation techniques in TBI patients that aim to improve functioning across these cognitive domains. OBJECTIVES/GOALS: 1) Investigate the network level interactions of attention and learning during an attention network task (ANT) and an implicit learning contextual cueing (CC) task. 2) Assess the effect that attention rehabilitation strategies have on behavioral and neural responses pre/post-attentional intervention. METHODS/STUDY POPULATION: This study involves refractory epilepsy patients (rEP) with implanted intracranial electrodes and moderate-to-severe traumatic brain injury (m/sTBI) survivors. In rEP, we are identifying network level modulations of cortical regions via the ANT, which probes components of attention  and a CC task that probes implicit learning. We hypothesize that modulation of attention and learning can be seen at the neuronal level. In TBI we will assess improvement following two behavioral attention rehabilitation paradigms; and use our results from epileptic patients to guide measurement of treatment-related neuroplastic change via scalp electroencephalography. RESULTS/ANTICIPATED RESULTS: Preliminary behavioral results from the rEP cohort are in line with previous studies and the intracranial data is suggestive of region- and task-specific modulations in memory and attention related systems. Following completion of recruitment, we expect to more concretely identify regions and networks that exhibit modulatory effects associated with attention and implicit learning. Additionally, we anticipate that deficits in attention will be mitigated following training and hypothesize that implicit learning rate will improve in TBI patients as a result of both attentional rehabilitation paradigms. DISCUSSION/SIGNIFICANCE OF FINDINGS: Characterizing intracranial activity in epilepsy patients will give electrophysiology data unattainable in TBI patients. This intracranial perspective will enable us to propose mechanisms of action that may result from our interventions and enable critique of current rehabilitation treatments.


Fifteen Veterans Administration Medical Centers (VAMCs) offer geriatric specialty care telehealth services through a hub and spoke model to patients at affiliated community-based outpatient clinics (CBOCs). These services are not used to the extent they could be. Through interviews with 50 staff and providers at rural CBOCs we identified several implementation facilitators and barriers. CBOC-level barriers included space constraints, low staffing, internet connection issues, and limited knowledge of services available and referral processes. Patient-level barriers included discomfort with technology, cognitive decline, and inability to travel to the CBOC. We found that champions within the CBOC and iterative, targeted outreach from the hub helped facilitate uptake of services. We entered the identified barriers into the CFIR-ERIC (Consolidated Framework for Implementation Research-Expert Recommendations for Implementing Change) Implementation Strategy Matching Tool to help generate targeted strategies that will be used to refine each hub’s implementation approach.


Relationship research has suggested that health among spouses is interdependent and should be considered jointly. Using data from the 2008/2010 and 2016/2018 waves of the Health and Retirement Study , we investigated the joint influence of married partners’ individual and shared cumulative biological risk on future health outcomes. Two risk indicators were constructed to indicate biological health in different domains. Individual grip strength, walk speed, lung function, and cystatin-C were biomarkers selected to construct frailty risk whereas blood pressure, pulse, waist circumference, C-reactive protein, glycohemoglobin, high-density lipoprotein cholesterol, and total cholesterol were biomarkers used to construct cardiometabolic risk. Shared risk was calculated as the number of risks the partners shared. We employed multilevel Poisson regression models to nest partners within couples and examine the effects of individual and shared cumulative risks on future functional limitations. Heckman correction was performed to correct potential selection bias. Our unadjusted models showed individual  and shared  risks are associated with greater future functional limitations. Further, shared cardiometabolic risk moderated the effect of individual risk . In the adjusted models, the direct associations between shared risks and future functional limitations were explained by indicators of partner selection and shared experiences. In the fully adjusted model, the cross-level interaction for frailty risk became statistically significant. The unique set of dynamics shown in our study offered new insights into understanding how couples influence one another in the context of multisystem biological health.


Most prior research on caregivers’ mental health focused on individual or household factors, we know much less about the influence of neighborhood factors on mental health of spousal caregivers. The current study fills the gap in our knowledge by examining the association of neighborhood characteristics  and depressive symptoms among spousal caregivers. We used data from 2006 to 2016 waves of the Health and Retirement Study, which includes 2,362 spousal caregivers. Negative binomial regression models were estimated to examine the association of perceived neighborhood disorder and neighborhood social cohesion with depressive symptoms. A greater perceived neighborhood disorder was associated with higher CES-D scores, which indicates more depressive symptoms. On the other hand, a higher level of neighborhood social cohesion was associated with lower CES-D scores. When they were included in the same model, the association between neighborhood disorder and depression disappeared, while respondents who reported higher levels of neighborhood social cohesion continue to exhibit lower CES-D scores than those lived in less cohesive neighborhoods. This study highlights the importance of neighborhood contexts in understanding caregivers’ well-being. Findings of this study suggest that neighborhood social cohesion may attenuate the negative effects of neighborhood disorder. Therefore, enhancing positive characteristics of the neighborhood may promote well-being of spousal caregivers.


Research on professional burnout during the pandemic has focused on hospital-based health care workers. This study examined the psychological impact of the pandemic on home-based primary care (HBPC) providers. We interviewed 13 participants from six HBPC practices in the New York including medical/clinical directors, program managers, nurse practitioners, and social workers and analyzed the transcripts using inductive qualitative analysis approach. HBPC providers experienced emotional exhaustion and a sense of reduced personal accomplishment. They reported experiencing grief of losing many patients at once and pressure to adapt to changing circumstances quickly. They also reported feeling guilty for failing to protect their patients and reduced confidence in their professional expertise. Strategies to combat burnout included shorter on-call, regular condolence meetings to acknowledge patient deaths, and peer support calls. Our study identifies potential resources to improve the well-being and reduce the risk of burnout among HBPC providers.


Despite successful defect coverage by means of complex skin or muscle flaps, particularly large and deep problematic wounds with exposed bradytrophic tissues after soft tissue loss are very susceptible to surgical revision.A dermal matrix, consisting of native collagen  supplemented by an elastin hydolyzate was first used for the treatment of burns, predominantly those that were full-thickness. Subsequently, its use was extended to defect coverage especially after soft tissue loss caused by degloving injuries.52 patients with exposed bradytrophic tissues caused by severe burn or degloving injuries were treated the same way.In all patients operative debridement showed soft tissue loss with free bone or free periostal structures, exposed tendons or joint capsules.In all patients after accurate wound bed preparation defect coverage was performed with collagen-elastin matrix and unmeshed split skin grafts in combination with negative pressure wound therapy for fixation of dermal matrix and split skin grafts.Two-years follow up of these collagen-elastin matrix procedures in defect coverage showed an excellent functional outcome:Up until now, no areas with unstable scars have occurred, no surgical scar revisions were required. The patients were still able to wear normal footwear, clinical gait analysis showed perfect functional outcome.The application of collagen-elastin matrix in patients with exposed bradytrophic tissues after severe burn or degloving injury treated so far represents an excellent reconstruction method, from initial coverage to scar development.


Whether slowing disease progression or combatting the ills of advancing age, the extensive utility of exercise training has contributed to the outright declaration by the American College of Sports Medicine that ‘exercise is medicine’. Consistent with general framework of adaptation, the advantages of exercise training are indiscriminate—benefitting even the most susceptible clinical populations. Still, the benefit of exercise training presupposes healthy adaptation wherein progressive overload matches sufficient recovery. Indeed, a difference exists between healthy adaptation and non-functional over-reaching —a difference that may be blurred by cancer treatment and/or comorbidity. Recent advances in smartwatches make them ideally suited to non-invasively monitor the physiological stresses to exercise training. Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance. While behaviour-change research aims to identify positive constructs of exercise adherence, further attention is needed to uncover how to optimise exercise prescription among cancer populations. Herein, we briefly discuss the constituents of exercise load monitoring, present examples of internal and external load and consider how such practices can be applied to cancer populations. The systemic benefits of exercise training are irrefutable.A difference exists between healthy adaptation and non-functional over-reaching —a difference that may be blurred by cancer treatment and/or comorbidity.Smartwatches are ideally suited to non-invasively monitor the physiological stresses to exercise training.Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance.The benefit of exercise training presupposes healthy adaptation wherein progressive overload matches sufficient recovery. However, one of the most challenging barriers of exercise prescription is knowing how and when to modulate frequency, intensity and duration for continued improvement .et al were some of the concerns surrounding exercise training in cancer patients assuaged.In the last 20 years, considerable momentum has been achieved within in the field of exercise oncology—now recognised as subdiscipline of oncology research.10.1136/bmjsem-2021-001134.supp1Supplementary dataFrom a practical perspective, recent advances in smartwatches make them ideally suited to non-invasively monitor the physiological stresses to exercise training. Such an approach extends the reach beyond laboratory settings and the need for expensive instruments to evaluate progress. Given the current challenges attributed to the COVID-19 pandemic, having remote access to individual exercise training responses is an attractive option to strengthen home-based exercise. Resolving the nuances of healthy adaptation and recovery will assuredly influence exercise prescription with related effects on injury risk and exercise adherence as well. The exercise training dose–response relationship is akin to a pharmacological investigation evaluating the efficacy of a medication. Indeed, a difference exists between healthy adaptation and non-functional over-reaching Though the absolute workload is appreciably higher among athletic populations, the same principles of training, recovery and adaptation apply to cancer populations. While the implementation of exercise load monitoring may vary, the importance of individualising such an approach cannot be overstated. Since age, cardiorespiratory fitness and non-exercise stressors all contribute to the rate of recovery, it is unsurprising to observe large within-person/between-person differences emerge regarding exercise tolerance and subsequent adaptations. Therefore, to promote further sophistication in the field of exercise oncology, the present viewpoint briefly discusses the constituents of exercise load monitoring, presents examples of internal and external load and considers how such practices can be applied to cancer populations.It is customary to delineate the quantification of exercise training load into internal and external constructs. Internal training load reflects physiological ) and psychological ) stressors, whereas external training load represents metrics of work performed such as distance travelled, steps per day or repetition counts. Consensus indicates a combined approach yields a clearer perspective about the inherent oscillations involving exercise adaptation and recovery.2) share a linear relationship at submaximal intensities. Given the combined effects of blood volume expansion, increased stroke volume and heightened parasympathetic outflow, one of the most prominent phenotypic attributes of exercise training is a lowered HR at rest and during exercise. Since HR fluctuates daily, a single measurement provides little useful interpretive information such that repeated measurements and consideration for adequate hydration are essential. Unlike the transient changes in HR over the course of a day, resting HR when measured under standardised conditions is thought to reflect global cardiovascular health. Thus, changes in resting HR over days may be indicative of physiologic or psychologic stressors, whereas alterations over weeks may represent increased (or decreased) cardiorespiratory fitness.7Wearable health monitoring technologies including smartwatches have become a familiar sight. Owing to the non-invasive capabilities of photoplethysmography, infrared light is used to measure the volumetric variations of blood circulation—making it possible to measure and record HR in real time. At the onset of exercise, sympathetic activity rises to produce an intensity-dependent increase in HR. As such, HR and oxygen uptake  modification. This common shortcoming is thought to interfere with study reproducibility, interpretation and cross-study integrationAccess to wearables can expedite the collection of internal and external load data, however, having a system in place to make meaningful inferences about adaptive responses can be challenging. Numerous research publications have endeavoured to extract the most from exercise training in elite athletes—yet such efforts are still gaining traction in cancer populations.Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance. While behaviour-change research aims to identify positive constructs of exercise adherence, further attention is needed to uncover how to optimise exercise prescription among cancer populations. Consideration for measurement error notwithstanding, there is need to identify early signs of maladaptation, including the smallest worthwhile change,


While existing microbots display effective propulsion, their functionalities decrease dramatically upon decreasing the robot size. Accordingly, it is desired to customize microscale robots for their specific mission and body location. Selecting the microbot constituents with task-specific tailored functionalities will enhance their practicality in performing their primary mission. A myriad of synthetic microbots, based on various propulsion mechanisms and different designs and materials, have thus been developed7. New functionalities and capabilities have been added to these tiny machines, including fast motion in complex biological media, large cargo-towing force, collective behavior and excellent biocompatibility for use in living systems. These attractive capabilities have paved the way to sophisticated microscale robotic devices capable of performing complex tasks and have motivated researchers to explore exciting new important in vivo biomedical applications ranging from targeted drug delivery to precise surgery and intracellular biosensing10. While the scaling down of robotic platforms has tremendous potential for advancing the treatment and diagnosis of patients, it also brings fundamental engineering challenges such as power sourcing, motion control and tracking, integration of multifunctionality, safety and related recovery and degradation capabilities11. Unlike large robots, the tiny footprint of microbots greatly hampers the ability to integrate multiple functions (without compromising their dimensions). For example, important microbot operations, such as drug delivery and cleaning out clogged arteries, have completely different requirements and hence rely on largely incompatible functions, which are extremely challenging to combine with a single microscale robot.Over the past 15 years the field of microbots has exploded with many teams from around the globe contributing to major innovationsConsidering the major challenges of fabricating multifunctional microscale robots, a key question arises: is the future hold for general-purpose universal microbots capable of performing a wide range of tasks or to simple microbots tailored to meet the demands of specific applications and target locations Fig. ? Big rob2, but these fabrication methods also face critical miniaturization constraints, which limit their functional capabilities to few basic functions. Instead, future multifunctional microscale robots could rely on smart multi-responsive materials capable of imparting several mission-specific functions into a single portion of such a microbot for executing multiple tasks. Such bio-inspired responsive materials can enable programmable, reconfigurable mobile microscale robots and increase the adaptability of such microbots for complex operations without scaling up the robot’s footprint12. For example, smart biomarker responsive materials can lead to theranostic microbots, performing “sense and release” functions by detecting disease-specific marker to trigger autonomous release of their embedded therapeutic payload13. Such route can enable diabetes theranostic applications based on autonomous closed-loop glucose-responsive insulin-delivery gated acoustic vehicles14.In contrast, the preparation of multifunctional microscale robots requires a paradigm shift from the traditional mechanical assembly fabrication route used for preparing larger (millimeter) scale robots, e.g., ingestible capsules. While these larger robots commonly rely on different sections to obtain their different functions, microbots are too small to be prepared by such mechanical assembly fabrication route. Some efforts have been devoted to advanced rolled-up and template deposition techniques for fabricating microbots with several functional unitsAdvanced robotics fabrication and functionalization technologies are paving the way to new robotic capabilities which are attractive for a wide range of biomedical applications. However, despite of these tremendous technological advances, it is extremely challenging to design and efficiently manufacture multifunctional microbots capable of performing diverse tasks. Considering the tiny dimensions of microbots and the largely different operational requirements of different microbot applications and body locations, the design of small-scale multi-purpose robots faces distinct challenges. Typical strategies for preparing large multi-purpose robots cannot be adapted to the microscale.11. Despite the major progress towards developing such bio-inspired microbots there is still a long way for the performance of synthetic microbots to compete with the sophistication of nature’s biomotors. A multidisciplinary collaboration in science, engineering and medicine and researchers trained with cross-disciplinary research skills are vital for addressing critical barriers for translating microbots into the clinical practice toward establishing a new era in the treatment of diseases.The efficiency of microbots to perform their main mission will be greatly improved by using simple robot design custom-made specifically to this mission. Designing the microscale robots with task-specific tailored materials and functionalities will allow customization of microbots for their primary biomedical mission and will enhance their practicality and efficiency in performing this mission. Incorporating additional features that are not essential for this specific biomedical operation can greatly compromise their effectiveness to perform their main task. Complex biomedical operations, requiring multiple tasks, will require multifunctional microbots based on new advanced fabrication techniques. In particular, bio-inspired responsive materials offer tremendous promise for designing theranostic microbots, integrating the sense and release functions. Alternately, it may be possible to combine different single-function microbots in swarms for performing different operational tasks


Growing evidence shows that the thalamus, beyond serving as an information relaying center, has key roles in motivated behaviors  contribute to both normal  and abnormal  salience processing.The hypothesis-and-theory by Quiñones-Laracuente et al. examined the time-dependent recruitment of pre-limbic (PL) prefrontal inputs onto PVT following auditory fear learning. The authors showed that PL to PVT projections are activated by conditioned stimuli (CS) 7 d, but not 2 h, following learning. In contrast, the PL-amygdala circuit is preferentially recruited 2 h following learning. In addition, unit recordings of Layer VI PL neurons, the origin of projections to PVT, exhibit increased cue-induced inhibition at later, but not earlier, time points. Together, these results suggest that PL signaling of simple fear associations shifts with time toward inhibitory modulation of PVT, which may underlie disinhibition of PVT neurons  and subsequently enhanced central amygdala output.In our collection, five articles exclusively focus on PVT. The original research article by Matzeu and Martin-Fardon reported that posterior PVT injections of orexin-A peptide promotes reinstatement of extinguished cocaine seeking after intermediate (2–3 weeks), but not protracted (4–5 weeks), abstinence. Intermediate but not protracted abstinence is associated with an upregulation of orexin 2 receptor expression in PVT, while orexin cell numbers increase after both intermediate and protracted abstinence. This work extends previous work on the role of hypothalamic orexin (hypocretin) neurons in PVT in addiction-related behavior  but not reward value (incentive information). In contrast, activity of PVT neurons that fire immediately before reward delivery is correlated with reward value but not predictive information. Together, these data capture the heterogeneity of PVT responses to discrete processes involved in cue-induced motivated behaviors.Rowson and Pliel provide a timely review on the sex-dependent effects of acute vs. chronic stress on PVT, and outline the implications of this dimorphism for motivated behaviors. Consistent with the idea of PVT as a complex integrator of varied physiological signals, Petrovich elegantly discusses the role of PVT in controling feeding behavior. Petrovich describes a framework whereby PVT integrates homeostatic and hedonic needs to feed with physiological and environmental stress signals, ultimately guiding the balance between food seeking and consumption.PVT is also a regulator of stress  in action selection. Further discussion of afferents of each structure leads to the hypothesis that Pf and OFC together contribute to internal state representation during action selection either through direct Pf to OFC projections or convergence of their respective inputs onto striatal cholinergic interneurons.Two reviews focus on ILN, recently implicated in goal-direct behaviors  and individual central thalamic nuclei  in delayed conditional discrimination tasks through lesion studies in rodents. The authors review electrophysiological findings in MD and mPFC during adaptive goal-directed behaviors, which suggest that MD affects both action and outcome-related neuronal responses in mPFC.Finally, We appreciate these excellent contributions. These articles not only summarize the current findings on the role of individual thalamic nuclei mediating motivated behavior, but also raise intriguing questions about how thalamus exerts these effects. We hope that this issue gives impetus to ongoing work in the field to better characterize the role of thalamus in motivated behaviors and related disorders.XL and MJ took the lead in writing this editorial. GM contributed to its finalization. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Purpose: The purpose of this study was to assess whether there was an association between care-recipient relationship type and the QoL of older adults and their informal caregivers, and whether this association pertained to older adults’ cognitive function. Methods: This was a secondary data analysis. Older adults (n=1230) and their informal caregivers (n=1871) were identified from participants in the National Health and Aging Trends Study (NHATS) Round 5 and the National Study of Caregiving (NSOC) II. A series of bivariate and multivariable regression models examined the associations among the care-recipient relationship type and QoL in older adults and their informal caregivers, adjusted for socio-demographic variables as well as cognitive functioning. Results: Both older adults and caregivers’ QoL outcomes varied by the type of relationship. Recipients cared for by adult-child caregivers or multiple caregivers experienced higher functional limitation than those cared by spousal caregivers . “Other” caregivers, such as siblings, friends, etc., had lower odds of experiencing negative emotional burden than spousal caregivers . "Other" caregivers were also 51% less likely to experience social strain than spousal caregivers. Lower odds of experiencing negative emotional burdens were also found with multiple caregivers. The association between adult-child caregivers and social strain was explained by the recipients’ cognitive function. Conclusions: Care-recipient relationship type impacts the QoL in both recipients and their informal caregivers. This association appears to be affected by care recipients' cognitive function level.


Most clinical studies supporting procalcitonin (PCT)-guided management of lower respiratory tract infections have been performed in adults. There is a paucity of studies evaluating the clinical impact of PCT use in children and limited data informing age-appropriate PCT cut-offs; diagnostic accuracy in immunocompromised children; patient subgroups most likely to benefit from PCT testing; whether PCT adds value beyond available rapid molecular viral diagnostics; and optimal implementation strategies for PCT-guided treatment. At the present time there is little evidence to support routine use of PCT to aid management of paediatric pneumonia. Procalcitonin (PCT) is a biomarker that shows promise in identifying bacterial infection and is increasingly used in patients of all ages. Several PCT assays are approved by the US FDA for prediction of mortality and to guide antimicrobial management in sepsis and lower respiratory tract infection (LRTI). However, the vast majority of clinical studies supporting PCT-guided management have been done in adults. Few rigorous, interventional studies have evaluated the impact of PCT use in children, in whom its clinical utility is unclear. At the present time there is little evidence to support routine use of PCT to aid management of paediatric pneumonia.et al.P < 0.001). However, more recently, the ProACT trial enrolled 1656 adults with LRTIs from 14 US emergency departments and randomized them to management using a PCT testing and treatment algorithm versus usual care. The primary outcome was antibiotic days by 30 days after enrolment.Despite extensive evaluation in adults, it is still not clear whether use of PCT provides benefit for management of adult LRTI. Schuetz P = 0.039). In another RCT, Esposito et al.P < 0.05), and fewer antibiotic days . Both the above trials enrolled subjects before 2010, prior to widespread use of molecular viral diagnostics; had a small sample size; did not include many subjects with severe CAP; and did not report compliance with the PCT algorithm, so the applicability of these studies to current practice is unclear.In contrast to the numerous published adult LRTI PCT trials, there are only two paediatric RCTs evaluating PCT use in paediatric pneumonia. The ProPAED trial enrolled 337 subjects <18 years old with LRTIs in two emergency departments in Switzerland and randomized them to receive either PCT-guided antibiotic management or usual care.,et al.Several observational studies highlight the limitations of PCT as a diagnostic aid for management of paediatric pneumonia. Twenty years ago a study of 72 children hospitalized with CAP found greater positive and negative predictive values of PCT than other biomarkers, including C-reactive protein and WBC count, for differentiating bacterial and viral causes of pneumonia.Additional paediatric-specific evaluations of PCT in LRTI are clearly needed to address numerous questions about PCT, including determining appropriate age-based PCT cut-offs, diagnostic accuracy in immunocompromised children, and patient subgroups most likely to benefit from PCT testing. In some studies of paediatric sepsis and LRTI, low PCT values may reduce antibiotic use among patients with low acuity illness and low likelihood of having bacterial infection; thus, PCT may be most promising for ruling out rather than ruling in bacterial disease, but further studies are needed to confirm this.In conclusion, the clinical utility of PCT to guide diagnosis and antibiotic management of paediatric pneumonia is unproven due to a paucity of paediatric studies. Even in adult populations, where numerous evaluations of PCT have been conducted, results are conflicting regarding whether use of PCT provides clinical benefit. There are several questions around PCT implementation and impact in paediatrics that are promising areas for future research. The existing body of evidence is not convincing that PCT adds anything beyond what other, cheaper biomarkers (like C-reactive protein) or clinical assessment can provide for management of paediatric pneumonia.None to declare.


The COVID-19 pandemic caused significant disruptions for people and institutions across healthcare settings. Clinical trials are an important research tool to test interventions in real-world healthcare settings and provide high quality evidence that supports older adults’ longevity and wellness. Clinical trialists must consider how to account for unpredictable and ever-changing environmental contexts. The COVID-19 pandemic is a specific example of a changing context that impacted all stages of the clinical trials process from planning, to administration, and outcomes. Reflecting on ways clinical trialists navigated their studies during the COVID-19 pandemic may unlock opportunities to design flexible clinical trials that meet the needs of older adults in real-world environments. This symposium highlights five clinical trials for older adults that occurred during the COVID-19 pandemic. Dr. Carpenter will discuss lessons learned in implementing a palliative care intervention in nursing homes. Brianna Morgan will describe the pivots needed to complete a clinical trial testing an advance care planning website for nursing home residents with dementia. Dr. Nuckols will describe obstacles and opportunities to implementing a randomized controlled trial on hospital nursing units, including implications for medication safety. Dr. Pevnick will highlight barriers and facilitators to implementing a pharmacist-led intervention to reduce hospital readmissions. Dr. Stark will share novel procedures for conducting clinical trials in the community that reduce burden for older adult participants while maintaining fidelity. Presenters will address practice transformations that researchers can bring forward to design flexible clinical trials that meet the needs of older adults in different healthcare contexts.


The medial prefrontal cortex (mPFC) has robust afferent and efferent connections with multiple nuclei clustered in the central thalamus. These nuclei are elements in large-scale networks linking mPFC with the hippocampus, basal ganglia, amygdala, other cortical areas, and visceral and arousal systems in the brainstem that give rise to adaptive goal-directed behavior. Lesions of the mediodorsal nucleus (MD), the main source of thalamic input to middle layers of PFC, have limited effects on delayed conditional discriminations, like DMTP and DNMTP, that depend on mPFC. Recent evidence suggests that MD sustains and amplifies neuronal responses in mPFC that represent salient task-related information and is important for detecting and encoding contingencies between actions and their consequences. Lesions of rostral intralaminar (rIL) and ventromedial (VM) nuclei produce delay-independent impairments of egocentric DMTP and DNMTP that resemble effects of mPFC lesions on response speed and accuracy: results consistent with projections of rIL to striatum and VM to motor cortices. The ventral midline and anterior thalamic nuclei affect allocentric spatial cognition and memory consistent with their connections to mPFC and hippocampus. The dorsal midline nuclei spare DMTP and DNMTP. They have been implicated in behavioral-state control and response to salient stimuli in associative learning. mPFC functions are served during DNMTP by discrete populations of neurons with responses related to motor preparation, movements, lever press responses, reinforcement anticipation, reinforcement delivery, and memory delay. Population analyses show that different responses are timed so that they effectively tile the temporal interval from when DNMTP trials are initiated until the end. Event-related responses of MD neurons during DNMTP are predominantly related to movement and reinforcement, information important for DNMTP choice. These responses closely mirror the activity of mPFC neurons with similar responses. Pharmacological inactivation of MD and adjacent rIL affects the expression of diverse action- and outcome-related responses of mPFC neurons. Lesions of MD before training are associated with a shift away from movement-related responses in mPFC important for DNMTP choice. These results suggest that MD has short-term effects on the expression of event-related activity in mPFC and long-term effects that tune mPFC neurons to respond to task-specific information. To survive in a dynamic environment organisms must be able to adapt efficiently to changes in conditions, responding in ways that optimize favorable consequences. Behavioral ecologists have demonstrated that foraging animals select among food patches of different quality in a way that maximizes food intake while reducing energy costs  plays a critical role in adaptive goal-directed behavior  has dense reciprocal connections with the agranular medial cortex and adjacent motor and cingulate areas. Afferent inputs to VM include branches of axons that also innervate MD and GABAergic projections from the basal ganglia. Thalamocortical neurons in VM have dense widespread projections to layer 1 in agranular medial and adjacent motor and cingulate cortices and less dense projections in parietal and occipital cortices that appear organized to control integrative motor responses Vertes, . The antAnatomical analyses indicate that rodent mPFC is homologous to primate anterior cingulate and premotor cortices and lacks an area homologous to primate dlPFC Preuss, . Here weEarly studies of delayed response deficits in monkeys  designed around the octagonal hub used for radial DNMTP tasks . In VSRTIt has been argued that mPFC is important for evaluating actions and outcomes along multiple dimensions  and rhomboid (Rh) nuclei in the ventral midline thalamus are important sources of thalamic input to the hippocampus and mPFC that appear organized to modulate mPFC—hippocampal interactions , and hippocampal lesions had no significant effect on RT or accuracy  and others that were directionally specific and fired during movements from the base to the sample and from the base to the choice levers . Lever press-related responses included neurons firing during all four lever presses  and others that fired only during base lever presses .Of 1,335 isolated neurons recorded with moveable tetrode arrays, 458 (34.3%) exhibited criterion event-related activity of which 445 (33.3%) exhibited temporal patterns of activity related to actions or outcomes that were characterized as normalized population peri-event time histograms PETH; , 8. ThesN = 191) included reinforcement anticipation  that fired beginning 0.7 s before predictable times of reward and persisted for an average of 2.7 s throughout reward delivery; reinforcement excitation  that fired within 0.2 s after reward delivery and remained elevated for an average of 3.0 s; error responses  that fired within 0.2 s of when the expected reward was not delivered; delay (D) responses (n = 58) that started firing within 0.4 s of when sample rewards were delivered and continued until the delay lever press; and post-reinforcement (PR) responses (n = 16) that began after reward delivery ended when rats disengaged from drinking spouts where rewards were delivered.Outcome related responses  along with single examples for base lever press , reinforcement excitation , and reinforcement anticipation . Although the data were insufficient for vector or decoding analyses , lever presses (both LPE and BLP), and preparatory responses . VentralEach of the response types observed in rodent mPFC during dDNMTP represents task-specific aspects of goal-directed behavior that are consistent with mPFC functions identified by behavioral analyses of lesion effects. PFC relies on working memory to temporarily maintain information not available to the senses to support adaptive goal-directed responding. This is thought to be represented by persistent neuronal firing during delay intervals , day 2 , and day 3  aligned with reinforced sample  and correct choice  and unreinforced incorrect choice . Event-related responses observed on day 1 largely disappeared with thalamic inhibition on day 2 and recovered substantially on day 3. Averaged across all neurons studied, day 2 thalamic inhibition reduced normalized activity during critical response windows to 46.9% of the day 1 response and this recovered to an average of 79.5% during day 3 recovery. Mixed model ANOVAs revealed significant effects of inactivation on day 2 and significant recovery on day 3 based on normalized activity during critical response windows. These effects did not interact with response type, the effect of thalamic inhibition on average firing rate , location of neuron in dorsal vs. ventral mPFC, or muscimol dose. These results show that dDNMTP event-related responses are reduced nonspecifically in mPFC with behaviorally-significant inactivation of MD and IL.Francoeur et al.  examinedOptogenetic studies have provided evidence that MD amplifies and sustains behaviorally-relevant information in PFC  supports multiple functions required for adaptive goal-directed behavior: working memory, flexible trial-by-trial response selection, attending to task-relevant information, encoding relationships between actions and their consequences, and organizing and executing action sequences. mPFC lesions produce delay-independent impairments of egocentric (response-related) DMTP and DNMTP tasks that affect RT and accuracy of responding. They spare comparable allocentric tasks.2.During the dDNMTP task, mPFC functions are served by discrete populations of neurons with responses related to preparation to respond, movements between levers, lever press responses, reinforcement anticipation, delivery of or lack of expected reinforcement, and memory delay following reinforcement. Population analyses show that these different response types effectively tile the temporal interval from when dDNMTP trials are initiated until they end.3.No individual thalamic nucleus can fully account for the broad effects of mPFC lesions on adaptive goal-directed behavior. Lesions of specific nuclei have distinct effects on behavior consistent with their anatomical connections.(a)MD has very limited effects on egocentric DMTP or DNMTP tasks that depend on mPFC. While some reports find no significant effect of MD lesions on these tasks, others have described delay-dependent deficits that spare RT or impaired acquisition that disappears with training. The reports of delay-dependent deficits are consistent with evidence that MD sustains and amplifies neuronal responses that represent behaviorally-relevant information in mPFC. Impairments in the acquisition are consistent with evidence that MD interacts with PFC to detect and encode action-outcome contingencies that are the basis of goal-directed learning.(b)Rostral intralaminar and VM nuclei affect speed and accuracy of responding based on learned conditional rules, effects consistent with their prominent connections with striatum and motor cortices, respectively. Like mPFC lesions rostral intralaminar and VM lesions produce delay-independent impairments affecting response speed and accuracy for egocentric DMTP and DNMTP tasks while sparing allocentric DNMTP.(c)Anterior thalamic and ventral midline Re and Rh nuclei affect allocentric spatial function, consistent with their prominent connections with the hippocampal system. Anterior thalamic lesions spare egocentric DMTP and DNMTP tasks affected by mPFC lesions. ReRh lesions affect tasks that depend on both mPFC and hippocampus.(d)Dorsal midline nuclei integrate inputs from visceral-, arousal-, and emotion-related areas of the brain and influence cortical and subcortical circuits related to mPFC function. They are important for behavioral-state control of adaptive responding and response to salient stimuli in associative learning. Dorsal midline lesions spare DMTP and DNMTP tasks that depend on mPFC.4.During the dDNMTP task, most MD neurons with criterion event-related responses (237/254) exhibit temporal patterns of firing that closely match response types in mPFC. A preponderance of these are movement and reinforcement-related responses critical for dDNMTP choice. MD lesions made before initial training selectively decrease the number of movement-related responses in mPFC.5.Drug inactivation of MD and adjacent intralaminar nuclei broadly suppresses the expression of event-related activity in mPFC during the dDNMTP task. Optogenetic studies suggest that MD amplifies and sustains behaviorally-relevant information in the PFC, a process that might help tune mPFC neurons to respond to task-relevant information during goal-directed behavior or suppress the expression of event-related activity during more prolonged drug inactivation.RM was primarily responsible for writing the article. MF and BG contributed to writing and discussion of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.