Gated communities are the most popular residential pattern in the urban areas of China. However, along with the increasing population density in urban areas, this pattern may have negative influences on people’s daily lives, such as traffic jams. To avoid the negative influences, the government has encouraged residents to open their gated communities; however, few positive actions have been taken. With this background, this study aims to explore the key factors in residents’ willingness to open their gated communities. To start with, a total of 26 potential factors were identified based on a comprehensive literature review. Then, a questionnaire was designed and distributed to collect empirical data. Furthermore, logistic regression was employed to analyze the collected data. Based on the derived results, it was revealed that concerns are different between male and female residents. Male residents regarded “community safety” and “property management” as having a significant impact on their decision to open a gated community, while female residents paid more attention to the factor of “proprietary equity”. The results of this study could provide valuable references that enable the government to better understand residents’ underlying concerns and to make relevant policy decisions. In recent decades, China has been experiencing a rapid urbanization process ,2,3,4. NDuring the long period of China’s history, the gated community has been regarded as the main residential pattern as it has several advantages, such as guaranteeing people’s living safety, privacy and living environment . In the Nevertheless, with the rapid urbanization process and the drastic increasing number of gated communities in recent decade, a number of urban problems has emerged in many cities, such as urban traffic congestion, public facilities division and neighborhood environmental quality ,14,15. IBearing this research question in mind, this study aims to identify the most significant factors that influence residents’ willingness to open their closed communities. A comprehensive review was conducted to collect the suggested advantages and disadvantages of gated communities from the existing literature. Then, follow-up interviews were carried out to further formulate a formal questionnaire. Based on the data collected through questionnaire surveys, the research findings are presented and discussed at the end of this paper.In the existing literature, researchers have explored gated communities from different perspectives. For example, Liao et al.  employedVarious studies have been conducted to discuss the side effects of gated communities. For example, Sun et al.  recordedDifferent community patterns can also have impacts concerning social perspectives. As income inequality has become more and more visible in big cities, Lestari Olivia et al.  argued tResearchers also investigated the barriers to opening the gated communities from different perspectives, such as property law, privacy and employment pressure . HoweverTo identify the potential factors that affect the opening of gated community, a literature review was conducted. Through the literature review, a total of 26 potential factors were identified, as shown in Based on the identified factors listed in In the designed questionnaire, the classical five-point Likert scale was used to measure respondents’ agreement with the identified factors, in which “1” refers to “strongly disagree”, “2” represents “disagree”, “3” means “neutral”, “4” stands for “agree” and “5” is “strongly agree”. The “neutral” option indicates that the respondent does not have an obvious tendency concerning both gated and opened patterns.The questionnaire was distributed and collected through a field investigation method. Several rounds of field investigations were conducted in Shenzhen during the period from 6 January 2019 to 26 March 2019. Respondents were randomly selected on streets based on their willingness to fill out the questionnaires. Finally, a total of 312 questionnaires were collected for further data analysis.SPSS  software was used to test the reliability of the collected data. The coefficient of Cronbach’s α was derived to judge the reliability. Chan et al.  suggesteThe maximum likelihood (ML) method was used to estimate the parameters in the logistic regression models after transforming the dependent variable into a logit variable . As suchp value derived from the Hosmer–Lemeshow test was less than 0.05, which indicated that the model does not adequately fit the data. The respondents were divided into different groups according to personal information. Results reveal that, except for the gender groups, the p values of the Hosmer–Lemeshow tests of other groups were less than 0.05; thus, two independent logistic regression models  were used to test the identified factors. p values of the Hosmer–Lemeshow tests were 2.869 and 8.229, respectively, indicating good data fit in the two models.In this study, logistic regression was employed to investigate the key factors of opening gated communities. Firstly, the collected data of all respondents were analyzed using logistic regression. Results showed that the To test the empirical results, three professionals who are experienced in this field were invited to provide their comments. The three invited interviewees included a government officer, a real estate developer and a scholar. The government officer advocated opening gated communities. From her perspective, the advantages of this measure outweigh the disadvantages; more specifically, the opening of gated communities can effectively solve social problems such as traffic jams. Unlike the government officer, the real estate developer was more concerned about his own economic benefits. In the current situation, gated communities are favored by the public, so the developer believed developing gated communities could attract more customers and improve profits. From the scholar’s point of view, whether to open the gated community should be considered according to the local conditions. This measure only makes sense under the premise that the opening of a gated community could bring more benefits.It is not surprising that community safety is an important factor that influences residents’ willingness to open gated communities. During the process of national development, social stability is an essential prerequisite. Fences and walls can physically isolate a community’s residents from the public; thus, the gated-community pattern can prevent potential crimes to a large extent. In this regard, residents prefer to live in a gated community, and the developer generally adopts the gated-community pattern for new residential buildings to improve sales. However, the governmental officer held the opinion that, with economic and social development, crime rates in urban areas have decreased to a large extent. In these circumstances, the function of guaranteeing safety should not be obvious in the future. However, the officer also agreed that it takes time for the public to become aware of such changes. In previous studies, the relationship between safety and gated communities was investigated; however, the research findings showed some unexpected conclusions. For example, Breetzke et al.  found thIn addition to community safety, proprietary equity is also emphasized when considering opening gated communities. In China, housing is the main asset of the Chinese people. In general, communities with high housing prices have more recreation facilities and prettier garden landscapes. The residents living in such communities are unwilling to open their gated community because they believe that they have paid for these privileges and they do not want to share the facilities and landscapes with the public. In these circumstances, it is understandable that gated communities are preferred. This phenomenon was also observed by the invited academic scholar, and he suggested that this problem may be solved along with the social and economic development which will bring more facilities and more beautiful landscapes to public areas. This research finding is echoed by Salah and Ayad . They coProperty management is another critical aspect when residents consider opening their gated communities. This aspect is mainly focused on the economic perspective. Opening a gated community can reduce property management fees and increase the income channels of property management companies. However, property management is more difficult after a community is opened. Thus, residents are ambivalent to opening their gated communities from this perspective. This is also an important issue which requires a series of comprehensive and thoughtful guarantee measures to remove people’s concerns. Soyeh, et al.  argued tThe social development aspect was found to be insignificant based on the investigation results. From a historical perspective, the gated-community pattern has been there for thousands of years. In the ancient times, gated communities had the function of both guaranteeing residents’ safety and strengthening social control. In addition, China’s traditional culture emphasizes distance and hierarchy among people. In this context, even in modern times, a neighborhood’s impact on housing segregation attracts little attention, and ordinary citizens are more concerned with protecting themselves than with social interaction.This study investigated the key factors of opening gated communities in the urban areas of China. A total of 312 questionnaires were collected and the logistic regression model was used for data analysis. Results showed that community safety, proprietary equity and property management were the three key factors that influence residents’ willingness to open their gated communities. In the meantime, it was found that residents care less about the social development aspect of opening a gated community. From the survey results, the number of residents who are unwilling to open their own communities was much more than the number of residents who are willing to. This result is mainly because the residents have paid too much money for their residence, and they do not want to share the privileges with the public. Based on the above research findings, this study suggested that it may be inappropriate to compulsorily require the gated communities to be opened immediately. In other words, the government should solve the problems that the residents care about the most before the compulsory requirement of opening gated communities.This study has made contributions to the existing knowledge, as there was no such study in Shenzhen; the research findings could aid relevant policy makers in formulating more effective and appropriate measures to design the city better. However, this research also has some limitations. For example, the majority of the respondents was under the age of 40. It is recommended that in future research the questionnaire be distributed to more respondents, covering all age groups. In addition, the vignette approach is suggested as it can be used to deal with sensitive topics and to capture the context of decision making.


TARDBP gene that is involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression. Cytoplasmic inclusion bodies containing phosphorylated and truncated forms of TDP-43 are hallmarks of amyotrophic lateral sclerosis (ALS) and a subset of frontotemporal lobar degeneration (FTLD). Additionally, TDP-43 inclusions have been found in up to 57% of Alzheimer’s disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis. In some cases, TDP-43 deposits are also found in neurons with neurofibrillary tangles. AD patients with TDP-43 pathology have increased severity of cognitive impairment compared to those without TDP-43 pathology. Furthermore, the most common genetic risk factor for AD, apolipoprotein E4 (APOE4), is associated with increased frequency of TDP-43 pathology. These findings provide strong evidence that TDP-43 pathology is an integral part of multiple neurodegenerative conditions, including AD. Here, we review the biology and pathobiology of TDP-43 with a focus on its role in AD. We emphasize the need for studies on the mechanisms that lead to TDP-43 pathology, especially in the setting of age-related disorders such as AD.Transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein encoded by the  Alzheimer’s disease (AD), the leading cause of dementia, is a heterogeneous neurodegenerative disorder in terms of clinical presentations and the density and distribution of the cardinal neuropathologic lesions. The neuropathologic hallmarks of AD are senile plaques composed of extracellular deposits of amyloid-β (Aβ) and neurofibrillary tangles composed of intracellular aggregates of tau protein with multiple post-translational modifications including phosphorylation. Senile plaques are complicated and heterogeneous lesions that contain not only amyloid deposits and tau positive neurites, but also neurites with degenerating pre- and post-synaptic elements , as well as activated microglia and reactive astrocytes . Aβ depoClinically, the two major presentations of AD can be classified as amnestic and non-amnestic. The former is characterized by deficiencies in short-term memory, recall and learning, which are the most common clinical presentations of typical and limbic predominant subtypes of AD. The latter shows impairment in other cognitive domains, such as language, visuospatial skills, or executive functioning. This is often associated with hippocampal sparing AD.In addition to senile plaques and neurofibrillary tangles, many AD brains have other pathological lesions, such as cerebrovascular pathology, Lewy bodies, argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and transactive response DNA binding protein of 43 kDa (TDP-43) pathology , 11. ImpTARDBP gene located on chromosome 1 (1p36.22) [TDP-43 is a 43 kDa heterogeneous nuclear ribonuclear protein (hnRNP) composed of 414 amino acids and is encoded by the The function of TDP-43, much like other hnRNPs, is to regulate gene expression and other aspects of RNA processing including RNA splicing, mRNA turnover, RNA trafficking, and microRNA (miRNA) biogenesis –22. TDP-Additionally, TDP-43 plays a role in the cellular stress response , 26–28. TDP-43 has been reported to regularly shuttle between the cytoplasm and nucleus depending on transcriptional needs . InteresThe structure of TDP-43 is composed of an N-terminal domain, a nuclear localization sequence (NLS), two RNA binding domains RBD1 and RBD2), a nuclear export signal (NES), and a C-terminal glycine rich domain (GRD)  and bvFTD are common clinical phenotypes in Type C, but no genetic association has been reported. Type D is associated with frontotemporal dementia (FTD) and Paget’s disease of bone caused by mutations of VCP gene [Based on the morphology, cell type, and distribution of TDP-43 pathology, FTLD-TDP can be classified into four main subtypes –69 Fig . Type A VCP gene . This clPathological progression of TDP-43 varies depending upon the underlying neurodegenerative disease with different progression patterns proposed for FTLD and ALS by Brettschneider et al , 72. In in vitro [in vitro neuronal cell culture models [Ubiquitination, phosphorylation, and truncation modifies the conformation of TDP-43, as well as its size and charge, contributing to the decreased shuttling into the nucleus –75. Ubiqin vitro . It is pe models , 83. Adde models .in vitro study has indicated that soluble TDP-43 is degraded by the ubiquitin-proteasome system, while insoluble TDP-43 aggregates are degraded via the autophagy system [An impairment in the clearance of TDP-43 may also contribute to the pathogenic process. An y system . Other iy system . Interesy system , suggestIn a non-diseased state, a balance between soluble and insoluble forms of RNA binding proteins (including TDP-43) and cell stress granules is maintained in the cytoplasm primarily due to their reversibility during cellular stress response . In ALS in vitro and in vivo [Neuronal death associated with pathological TDP-43 is thought to be caused by a combination of both a toxic gain of function, as well as a loss of physiological function associated with depletion of TDP-43 from the nucleus . Oligome in vivo –95. Addi in vivo , 96–98.  in vivo , 99, 100C9ORF72-linked FTLD, there is loss of nuclear TDP-43 at pre-symptomatic stages [Loss of function of TDP-43 is another mechanism implicated in neuronal loss in ALS and FTLD. Studies in mouse models rarely detect TDP-43 cytoplasmic inclusion bodies; however, neurodegeneration associated with loss nuclear TDP-43 can be evident . In humac stages . Furtherc stages . This obc stages , 104–111Interestingly, nuclear TDP-43 suppresses splicing of non-conserved cryptic exons, reducing the number of frameshift or nonsense mutations in mRNA transcripts , 112. PaTDP-43 pathology is frequently detected in pathologically confirmed AD brains in up to 57% of AD cases , 115–123TDP-43 has been reported to influence the clinical features of dementia, including cognitive deficits and the likelihood of dementia. Josephs and coworkers sought to determine the frequency of TDP-43 pathology across AD subtypes and its effects on cognition . They foOverall, these results suggest that TDP-43 pathology is common in AD, especially in the limbic predominant subtype. These results also suggest TDP-43 pathology is a risk factor for developing dementia of the Alzheimer type independent of pathological subtypes, and TDP-43 pathology increases the rate of hippocampal atrophy in AD.Interestingly, TDP-43 presenting as a secondary comorbid pathology in AD follows its own distinct pathological distribution pattern compared to that of ALS and FTLD. Josephs et al proposed that the progression of TDP-43 pathology in AD occurs in six stages, with stage 1 being characterized by TDP-43 pathology present within the amygdala  resulted in a decrease in Aβ plaque burden [Another study revealed that the overexpression of TDP-43 in the cortex and hippocampus of an APP/PS1 mouse model , a glycoprotein present within the central nervous system and periphery, is an important lipid transporter, especially for cholesterol . The humonset AD –139. Apoonset AD , 140–144reported , 145. A  APOE3/3 . Using aAD cases . AdditioAD cases . Similarhologies . WennberTARDBP 3′ untranslated region has been reported to increase TARDBP mRNA expression in the motor cortex in ALS [Age-dependent demethylation of the x in ALS . Besidesx in ALS –150. Frox in ALS . Additiox in ALS . These dx in ALS . Similarx in ALS .GRN and TMEM106B are risk factors for FTLD [GRN and TMEM106B genetic associations have also been observed in HS in the setting to Lewy body dementia, most of whom have at least some co-existing Alzheimer type pathology [Hippocampal sclerosis (HS) increases in frequency with age and is a distinct process from AD, even though they both are associated with an amnestic clinical syndrome . About 1for FTLD , 157 andfor FTLD , 159, liathology .Given the fact that HS can be associated with degenerative, toxic, and selective hippocampal neuronal loss associated with anoxic-ischemic injury or epilepsy, the term HS has fallen out of favor. An international group of experts proposed a new name for TDP-43 pathology in the elderly, often associated with HS, “limbic-predominant age-related TDP-43 encephalopathy” (LATE) . LATE neTDP-43 has been reported as a co-pathology in other neurodegenerative disorders besides AD, including Huntington’s disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease, DLB, and multiple system atrophy (MSA) , 164–170n vivo study using transgenic mice expressing human TDP-43 mutants found that administration of an autophagy-inducing drug could ameliorate TDP-43 pathology in the brain and spinal cord of the transgenic animals [An i animals . Given t animals –174, dev animals , but alsAPOE4 gene. The mere presence of TDP-43 pathology increases the likelihood of developing Alzheimer-type dementia. These findings provide strong evidence for TDP-43 being an integral part of multiple neurodegenerative conditions, emphasizing the need to better understand the mechanisms of TDP-43 pathogenesis in AD and other age-related disorders.Significant efforts in the past decade have been placed in finding and testing new treatment methods for AD in hopes to prevent or cure this devastating disease. TDP-43 pathology, commonly found in AD brains, has been shown to influence AD pathology and neurodegeneration, whether it be decreasing senile plaque load through overexpression, or increasing amyloid oligomers and synapse loss through depletion. It also shares an important genetic risk factor with AD, the


Background: The prevalence of parkinsonism in developing countries is largely unknown due to difficulty in ascertainment because access to neurologists is often limited.Objective: Develop and validate a parkinsonism screening tool using objective motor task-based tests that can be administered by non-clinicians.Methods: In a cross-sectional population-based sample from South Africa, we evaluated 315 adults, age >40, from an Mn-exposed (smelter) community, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3), Purdue grooved pegboard, and kinematic-UPDRS3-based motor tasks. In 275 participants (training dataset), we constructed a linear regression model to predict UPDRS3. We selected motor task summary measures independently associated with UPDRS3 (p < 0.05). We validated the model internally in the remaining 40 participants from the manganese-exposed community (test dataset) using the area under the receiver operating characteristic curve (AUC), and externally in another population-based sample of 90 participants from another South African community with only background levels of environmental Mn exposure.Results: The mean UPDRS3 score in participants from the Mn-exposed community was 9.1 in both the training and test datasets . Together, 57 (18.1%) participants in this community had a UPDRS3 ≥ 15, including three with Parkinson's disease. In the non-exposed community, the mean UPDRS3 was 3.9 (standard deviation = 4.3). Three (3.3%) had a UPDRS3 ≥ 15. Grooved pegboard time and mean velocity for hand rotation and finger tapping tasks were strongly associated with UPDRS3. Using these motor task summary measures and age, the UPDRS3 predictive model performed very well. In the test dataset, AUCs were 0.81  and 0.91  for cut points for neurologist-assessed UPDRS3 ≥ 10 and UPDRS3 ≥ 15, respectively. In the external validation dataset, the AUC was 0.85  for UPDRS3 ≥ 10. AUCs were 0.76–0.82 when excluding age.Conclusion: A predictive model based on a series of objective motor tasks performs very well in assessing severity of parkinsonism in both Mn-exposed and non-exposed population-based cohorts. The Global Burden of Disease Study estimates that the number of people affected by Parkinson's disease (PD) more than doubled from 1990 to 2015 with the highest prevalence in high-income regions and lowest in sub-Saharan Africa and Eastern Europe in 2015 . RelativThe Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3) remains the most widely used tool to quantify parkinsonian motor signs in patient and non-patient populations –10. In aThe Washington University School of Medicine Human Research Protection Office  and the University of the Witwatersrand Human Research Ethics Committee  approved this study. All participants provided written informed consent.N = 275, 87%) and test  datasets, respectively. We enrolled the participants in these two groups consecutively (SD = 0.77) from the smelter, and the participants in the test dataset lived a mean of 1.96 Km (SD = 0.74) from the smelter. The participants from Meyerton comprised a subset of participants who were recruited as part of a larger environmental Mn study   smelter in Meyerton, South Africa, we developed and validated a predictive model for UPDRS3, in training (cutively . ParticiMn study . The reclements) . This ish Africa , 12, and N = 40, % dataset2.5-Mn ~20 times lower than at the fixed site in Meyerton (10 ng/m3)  of homes that we visited had at least one age-eligible adult who agreed to participate. Ethembalethu is an industry-free community, with no nearby Mn smelting or mining operations, located ~70 km from Meyerton. Air monitoring in Ethembalethu demonstrated mean concentrations of PM0 ng/m3) . This istivities . We therFor inclusion in the present work, we required participants in both communities to meet the following criteria: (1) be non-ambidextrous (self-report as right-handed or left-handed), (2) complete at least one trial for the dominant and non-dominant hand for each of five motor tasks under the direction of a trained test administrator, (3) have been examined by a movement disorder specialist using the UPDRS3 and had complete UPDRS3 data. Exclusion criteria were: (1) current use of neuroleptic medications, and (2) neurologic co-morbidities that might compromise the accuracy of the UPDRS3, such as stroke or spasticity.In order to include individuals with other conditions that would cause incomplete UPDRS3 data, such as injured/missing limbs or inability to undergo the pull test to assess balance, we used imputation of the respective subscore(s) to obtain complete UPDRS3 data when possible. We included individuals regardless of UPDRS3 score, presence of PD, or occupational Mn exposure, in order to ensure that our original population-based samples remained representative of the respective settlements. The above exclusions, need for imputation, presence of PD, and past or current occupational Mn exposure were all uncommon  in the larger study .All recruitment, testing, and examination occurred in 2016–2020 .TM, Great Lakes NeuroTechnologies, Independence, Ohio)  action tremor—participant alternated touching his/her index finger to his/her nose and to the administrator's finger held an arm's length away from the participant; (3) finger tapping—participant tapped his/her index finger and thumb together while keeping the other fingers stable and the elbow extended; (4) hand rotation—participant rotated his/her hand at the wrist, positioning the arm so that the elbow was flexed and the hand open. Participants were instructed to perform finger tapping and hand rotation tasks with as large an amplitude and as fast, as possible. Participants completed the trials for the right hand first, followed by the left hand, for each of these four tasks. A previous study in PD patients that used a similar Kinesia Motion Sensory device found that in the more parkinsonian hand the test-retest reliability across three 15-s trials, as measured by the intraclass correlation coefficient, was 0.71 for postural tremor and 0.94 for finger tapping speed  and followed published testing procedures . For thee, Ohio) –19 on thng speed .We then developed, validated, and applied comprehensive computer code to process these large datasets . SpecifiOne movement disorder specialist (BR) examined all participants using the UPDRS3 , blindedWe used self-reported handedness to classify UPDRS3 subscores and the five motor tasks as dominant or non-dominant. Participants also provided socio-demographic information, including age, sex, ethnicity, and home language.p < 0.05) and, more importantly, in the expected direction (positive or negative). Greater UPDRS3 scores and subscores indicate greater parkinsonism, which we anticipated would be associated with longer grooved pegboard times, fewer pegs placed, and more pegs dropped. With regard to the kinematic tests, we also anticipated that greater UPDRS3 scores would be associated with lower velocities (or fewer cycles per second) and greater decrement (and hence greater variability as assessed by the coefficient of variation) on the finger tapping and hand rotation tasks. We investigated whether correlations differed according to hand dominance and whether motor task data from only one hand might be sufficient to predict UPDRS3. We also examined the association between summary measures derived from only the first of the three trials to determine if a single trial would be sufficient for UPDRS3 prediction.We performed all data processing and statistical analyses using Stata version MP 14.2  . To helpN = 275). Age and motor task summary measures selected above were our primary a priori predictors of interest, and we initially retained all as continuous measures  and in the independent, external dataset (N = 90), using the receiver operating characteristic (ROC) curve  curve , 23. We C) curve –26, i.e.mination . TherefoSD = 6.3, range 0.0–38.5), but differed markedly between the two communities. Upper limb bradykinesia contributed substantially to UPDRS3 as 16.8% of participants had >6 points in total across the six upper limb bradykinesia subscores, i.e., a subscore of >1 on at least one of these six scores (not shown). In contrast, action/postural tremor was relatively uncommon. Only 20 (4.9%) of the participants had an action/postural tremor subscore of 2, and only three participants had prominent action/postural tremor or only rest tremor (subscore >2). Three participants who had complete kinematic and grooved pegboard data, all from Meyerton, had PD according to this neurological examination.Most (98.5%) of participants were of black/African ethnicity, with a median age of 51 . The meaSeveral summary measures for upper limb bradykinesia correlated with the respective UPDRS3 subscores , with grThe absolute value of the correlation coefficients between the action/postural tremor summary measures and UPDRS3 subscore were all well below 0.20 ; finger tapping kinematic mean velocity; grooved pegboard time; and age, each as linear terms . Finger In our test dataset, performance of the predictive model as measured by the AUC was 0.81  for identifying participants with neurologist-assessed UPDRS3 ≥ 10 . The modWhen we applied our predictive model to the external validation dataset, the AUC was 0.85  when identifying participants with UPDRS3 ≥ 10 . Too fewWhen we explored the effect of using only the motor tasks as predictors, i.e., removing age from the model, AUCs were only modestly attenuated. In our test dataset the AUC was 0.76  for UPDRS3 ≥ 10 and 0.86  for UPDRS3 ≥ 15. In the external validation dataset the AUC was 0.82 .post-hoc exploratory analysis in which we considered how well the predictive model might identify the three individuals with PD in Meyerton (training and test datasets combined), the predicted UPDRS3 scores were 16.3, 17.1, and 21.7, all above the UPDRS3 ≥ 15 cut point.In a In this large study in South Africa we predicted the UPDRS3 score with a limited battery of kinematic and grooved pegboard tests administered by trained non-clinician community members in <10 min per participant. AUCs in two validation datasets demonstrated that performance of this predictive model for identifying individuals with UPDRS3 scores ≥10 or ≥15 was good to excellent. In addition, we confirmed that there was at least a moderate correlation between the predicted UPDRS3 scores and neurologist-assessed UPDRS3. Notably, this UPDRS3 predictive model worked equally well in communities with and without environmental Mn exposure, i.e., in population-based samples with either relatively high or relatively low UPDRS3 scores. Taken together, our findings indicate that this UPDRS3 predictive model likely can be applied to facilitate screening programs or research studies in a wide variety of settings, including under-resourced environments with limited access to PD specialists or other neurologists.In all potential applications of this UPDRS3 predictive model, the first step after administering the three-test battery is to calculate the mean velocities from the two kinematic tests. Of the many kinematic summary measures we assessed, the mean velocities are the easiest to calculate, further ensuring the potential usefulness of our model in many situations. Calculation of these summary measures only requires the isolation of the kinematic data from the relevant axis, i.e., x-axis for finger tapping and y-axis for hand rotations, before taking the mean across all sampled time points with the respective movement. In the second step, these two means from kinematic testing, along with the grooved pegboard time and age, are simply inserted into the equation produced by our predictive model. The resulting UPDRS3 score could be used in an epidemiologic study in which it is not possible for a neurologist to examine any participants. Alternatively, in a third step, one would dichotomize the predicted UPDRS3 score according to a pre-selected cut point to identify individuals with a particular UPDRS3, corresponding to the desired sensitivity and specificity. One likely would dichotomize the predicted UPDRS3 scores at the lowest possible cut point so as to achieve the highest sensitivity that is feasible, given that a specialist would need to examine all individuals with predicted UPDRS3 scores above the selected cut point. As part of a tiered screening protocol, maximizing sensitivity would either facilitate clinical care to the largest percentage of people in a community who might benefit from treatment, or alternatively would minimize misclassification of research study participants in terms of a dichotomous outcome of interest. As evidence of the potential utility of this type of protocol, a similar tiered screening approach was adopted in a previous occupational Mn exposure setting in South Africa .We acknowledge some limitations that could affect usefulness of our predictive model. First, the kinematic methods may not be easily incorporated in all settings. We trained our fieldworkers extensively in the use of kinematic devices, and we view this training as essential. Second, kinematic testing generates large amounts of data, requiring expertise in data handling. In addition, a substantial amount of computer storage and computational power would be required to process these data for many individuals at once, which might be a challenge in under-resourced environments. Third, while we used a common motion capture device, such devices have unique operational principles, instrumentation, and type of data produced  so data The strengths of our study include the use of one movement disorder specialist to obtain gold standard UPDRS3 ratings, the relatively large sample size, and a unique study population at risk for parkinsonism paired with a lower risk population, each representative of their underlying communities. These strengths positioned us well to develop and validate the resulting UPDRS3 predictive model, which also has several strengths. First, we were successful in minimizing the time required to complete the included motor testing without materially affecting performance of the UPDRS3 predictive model. Most notably, we confirmed that it was sufficient to conduct only one trial of the selected tests in one hand. Second, all predictors can be assessed objectively, i.e., without subjective assessments that might require clinical expertise. Although some prior predictive models of UPDRS3 score or “parkinsonism” benefitted from the use of objective motor assessment (either a different fine motor task or gait assessment), some of these models required test administrators to make clinical judgements , 31. ThiRestriction of our model to age and a modest battery of objective motor tasks to avoid the above potential challenges did not come at the expense of performance. Previous occupational or community-based cohorts in which investigators attempted to identify people with parkinsonism achieved AUCs ranging from 0.72 to 0.79 –32. The In summary, using selected accelerometry-based kinematic-UPDRS3 tasks and the grooved pegboard, we developed a UPDRS3 predictive model to identify individuals with potential parkinsonism, which demonstrated good predictive ability. The model performed exceptionally well considering that we applied it in non-patient populations and relied on non-clinicians to administer the tests. These findings have important public health applications in screening for or assessing parkinsonism in clinical or research settings in regions of the world with limited clinical neurologic expertise. The proposed screening tool provides an alternative assessment in these low-resourced environments because of ease of administration.racetteb@wustl.edu, and requestors will need to sign a data use agreement.Individual participant data that underlie the results reported in this article, after de-identification, will be made available upon reasonable request, following article publication. Data will be made available to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose and after approval of the protocol by the University of the Witwatersrand Ethics Committee and the Washington University Human Resource Protection Committee. The analysis performed must be solely to achieve aims in the approved proposal. Proposals should be directed to BR, at The studies involving human participants were reviewed and approved by Washington University School of Medicine Human Research Protection Office  and the University of the Witwatersrand Human Research Ethics Committee . The participants provided their written informed consent to participate in this study.BR, MU, GN, and SN: research project conception, organization, execution, and manuscript preparation review and critique. SN: statistical analysis design. WD and SN: statistical analysis execution. BR, MU, and GN: statistical analysis review and critique. WD: manuscript preparation and writing of the first draft. All authors: approval of final 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.


Recently, working memory (WM) has been conceptualized as a limited resource, distributed flexibly and strategically between an unlimited number of representations. In addition to improving the precision of representations in WM, the allocation of resources may also shape how these representations act as attentional templates to guide visual search. Here, we reviewed recent evidence in favor of this assumption and proposed three main principles that govern the relationship between WM resources and template-guided visual search. First, the allocation of resources to an attentional template has an effect on visual search, as it may improve the guidance of visual attention, facilitate target recognition, and/or protect the attentional template against interference. Second, the allocation of the largest amount of resources to a representation in WM is not sufficient to give this representation the status of attentional template and thus, the ability to guide visual search. Third, the representation obtaining the status of attentional template, whether at encoding or during maintenance, receives an amount of WM resources proportional to its relevance for visual search. Thus defined, the resource hypothesis of visual search constitutes a parsimonious and powerful framework, which provides new perspectives on previous debates and complements existing models of template-guided visual search. We spend a large part of our daily lives searching for known objects in dense visual scenes, such as car keys on a cluttered desk or a child’s jacket in a crowded playground. That is, our visual environment comprises an overwhelming amount of information from which we must select a limited quantity that is of interest. To achieve this complex operation, an accurate representation of the relevant features, for instance the shape of the car keys or the color of the child’s jacket, may give a significant advantage in achieving efficient visual search. This theoretical review examines how these two abilities – looking for goal-relevant objects and remembering their features – interact in a way that optimizes behavior.internal attention  commonly refers to the processes that maintain and manipulate representations most needed for ongoing cognitive operations , an electrophysiological correlate of the number of representations maintained in WM  to specify the target’s features prior to visual search. While both types of cue allow setting up attentional templates, search is consistently less efficient with verbal than pictorial cues, as less visual information is available , a von Mises distribution that reflects the precision of responses to the probed item (PSD), and a von Mises distribution that reflects the proportion of responses to the non-probed item (PSwap). In the theoretical interpretation of these parameters, only PSD is assumed to reflect the continuous allocation of WM resources to the corresponding representations .Hollingworth and Hwang  were thesufficient, the allocation of the largest amount of resources may be necessary for WM representations to act as attentional templates. Using single- and dual-target search, studies provided convincing evidence in favor of this assumption. For instance, Rajsic et al. (Protection from interference). Therefore, it would be more appropriate to conclude that representations obtaining the status of attentional template receive an amount of WM resources proportional to their relevance for visual search. In other words, a single attentional template receives the largest amount of WM resources since it is the only relevant representation for visual search, whereas multiple attentional templates receive an amount of WM resources that depends on their relevance for the search task. In any case, by directly assessing the allocation of resources in WM, this line of research provides converging evidence that the precision of attentional templates may have a functional value in visual search (Bravo & Farid, While not c et al.  asked obc et al. . Resultsc et al.  and its c et al. . Thus, fc et al.  showed tc et al. , observec et al.  was usedc et al. , the allc et al.  suggestsresource hypothesis of visual search comprises a set of three main principles to conceptualize the complex relationships between WM resources and attentional templates. Here, we expose each of the three principles that constitute this hypothesis and discuss their relevance in relation to existing models of template-guided visual search.Based on resource models of WM (Franconeri et al., First, the allocation of resources to an attentional template has an effect on visual search. While appearing trivial, this first principle received considerable amount of support from studies that manipulated the number of features specifying attentional templates and demonstrated clear causal effects on visual search (Bravo & Farid, Second, as laid out above, the allocation of the largest amount of resources to a representation in WM is not sufficient to give this representation the status of attentional template and thus, the ability to guide visual search (Dube & Al-Aidroos, Third, representations that obtain the status of attentional template, whether at encoding or during maintenance, receive an amount of WM resources proportional to their relevance for visual search. Therefore, a single attentional template receives the largest amount of WM resources because it is the only relevant representation (Kerzel & Witzel, So far, we have shown that WM representations receiving the largest amount of resources do not necessarily act as attentional templates. However, single attentional templates inevitably receive the largest amount of resources, which makes them more precise than any other representations in WM. While the increase in resources appears to improve visual search, the exact processes involved are still to be determined. Here, we present three proposals about the role of WM resources in template-guided visual search that may not be mutually exclusive see Fig. . For easAs introduced earlier, attentional templates contribute to two distinct processes in visual search. First, attentional templates allow for the selection of objects with template-matching attributes by converting display-wide enhancement of relevant features into spatially specific enhancement, thus guiding visual attention Eimer, . Second,Recently, Berggren et al.  investigWhile no previous study investigated protection from interference in the context of template-guided visual search, this topic has been particularly fruitful in the WM literature. First, studies investigating individual differences have repeatedly demonstrated that interference impaired memory performance in individuals with low WM capacity, but not in those with high WM capacity Engle, . As inteBehavioral evidence from continuous delayed-estimation tasks indicates that single attentional templates receive the largest amount of WM resources as their recall precision is higher than the recall precision of other WM representations. However, these measures are usually collected after visual search is performed, allowing intervening stimuli to contaminate them. For instance, orienting visual attention toward a distractor disrupts information already stored in WM (Hamblin-Frohman & Becker, Recently, WM has been conceptualized as a limited resource, distributed flexibly and strategically between stored representations. As attentional templates are thought to be represented in WM, we reviewed empirical evidence that the allocation of WM resources has consequences not only on memory, but also on visual search. We have argued that three main principles govern the relationships between WM resources and template-guided visual search. First, the allocation of resources to an attentional template has an effect on visual search, as it may improve the guidance of visual attention, facilitate target recognition, and/or protect attentional templates against interference. Second, the allocation of the largest amount of resources to a representation in WM is not sufficient to give this representation the status of attentional template and thus, the ability to guide visual search. Third, the representation that obtains the status of attentional template, whether at encoding or during maintenance, receives an amount of WM resources proportional to its relevance for visual search. Thus formalized, the resource hypothesis of visual search describes how the internal representation of the target is maintained in WM and how it affects the exploration of visual environments. Moreover, the concept of WM resources gives new insights on previous debates and complements existing models of template-guided visual search.


The immunopathogenesis of sarcoidosis remains unclear. This failure in understanding has been clinically impactful, as it has impeded the accurate diagnosis, treatment, and prevention of this disease. Unraveling the mechanisms of sarcoidosis will require input from basic and translational scientists. In order to reach this goal, scientists must have a firm grasp of the clinical aspects of the disease, including its diagnostic criteria, the immunologic defects, clinical presentations, response to therapy, risk factors, and clinical course. This manuscript will provide an overview of the clinical aspects of sarcoidosis that are particularly relevant for the basic and translational scientist. The variable phenotypic expression of the disease will be described, which may be integral in identifying immunologic disease mechanisms that may be relevant to subgroups of sarcoidosis patients. Data concerning treatment and risk factors may yield important insights concerning germane immunologic pathways involved in the development of disease. It is hoped that this manuscript will stimulate communication between scientists and clinicians that will eventually lead to improved care of sarcoidosis patients. The clinician at the patient’s bedside and the medical scientific researcher in his laboratory often seem lightyears apart. The medical researcher’s world is one of quantification, objectivity, and reproducibility. The clinician’s world is inexact and, although based in science, is overlaid with complex psychosocial and financial issues. Despite this expansive distance in terms of focus, it is imperative that the medical researcher and clinician communicate in order to achieve medical breakthroughs and improve patient care. Understanding the immunopathogenesis of a disease provides the clinician with the rationale for specific therapy and improves his understanding of ineffective therapy and medication side effects. Understanding the clinical aspects of a disease assists the medical researcher in focusing on mechanisms that are clinically relevant. This manuscript will provide an overview of the clinical aspects of sarcoidosis, focusing on issues that are particularly relevant for the basic and translational scientist. Currently, the immunopathogenesis of sarcoidosis is poorly understood, and treatment of this disease is suboptimal. It is hoped that this clinical review will aid medical researchers in their efforts to understand the immune mechanisms of sarcoidosis that are clinically impactful. Furthermore, we believe that the concepts expressed here could be extrapolated to other granulomatous and immunologic diseases.Understanding the clinical aspects of a disease can aid the scientist in focusing on mechanisms that are consistent with the clinical findings, relevant, and impactful. In the case of sarcoidosis, three such clinical aspects are its phenotypic expression, risk factors, and the effects of drug therapy. Each of these is discussed briefly below in general terms and is described specifically in terms of sarcoidosis in the remainder of the manuscript.The importance of clinical phenotyping: The diagnosis of a disease is usually based on the presence of specific historical information, symptoms, laboratory tests, and occasionally, the response to therapy. Although these criteria may be adequate to render a clinical diagnosis, they may correlate poorly with the underlying mechanisms of the disease. A clinical disease may represent a common endpoint for several disparate disease mechanisms. Therefore, a specific mechanism may be responsible for only a fraction of a clinical disease. Clinical phenotyping of a disease may partition patients into cohorts such that a disease mechanism that fails to reveal the cause of a disease may explain the cause of a specific disease phenotype. Disease risk factors: The risk of contracting a disease may be increased or decreased because of numerous clinical factors, including age, race, ethnicity, occupational or environmental exposure, diet, and lifestyle. Knowledge of risk and protective factors for a disease may generate clues concerning previously unconsidered pathways. In addition, evidence supporting a proposed disease mechanism would be enhanced if risk factors were shown to stimulate that mechanism and protective factors were shown to blunt it.The effect of drug therapy: Effective drug therapy may provide important clues concerning disease mechanisms by demonstrating that blocking or stimulating various inflammatory pathways lessens disease activity. In addition, drug therapy and other maneuvers that worsen disease activity may uncover important disease mechanisms. It needs to be emphasized that even when an immunologic pathway involved in a disease has been carefully elucidated, its clinical relevance is unclear without performing a drug trial. The immune system is highly redundant, and pathways that are uniformly associated with a disease may not be causal. This explains why sarcoidosis drug trials that target putative immunopathogenic sarcoidosis pathways [pathways  have sompathways . Organ involvement: Sarcoidosis is a multisystem granulomatous disease of an unknown cause that can affect every organ. The lung is the most common organ involved with sarcoidosis at a frequency of typically over 90 percent of cases [n = 1248) is shown in of cases ,5. The nof cases ,5. The fIt should be noted that the frequency of specific organ involvement is greatly dependent on the method of detection. Rigorous methods of detection may yield much higher frequencies of organ involvement. For example, signs or symptoms of liver sarcoidosis are found in 5–15% of sarcoidosis patients ,7, liverThe diagnosis of sarcoidosis is based on a compatible clinical presentation, usually  a tissue biopsy confirming granulomatous inflammation, and the exclusion of alternative causes of granulomatous disease . Common Non-pulmonary sarcoidosis has been estimated to occur in approximately 8 percent of sarcoidosis patients . Nearly As the lung is the overwhelmingly most common organ to be affected by sarcoidosis and numerous infectious and non-infectious pulmonary granulomatous diseases result from antigens inhaled into the lung, this suggests that pulmonary sarcoidosis develops from an inhaled antigen. The lung may be the “portal of entry” of a putative sarcoidosis antigen that then may “disseminate” into other organs of the body. It is interesting that the skin is second to the lung as a site of isolated organ sarcoidosis. The skin is a particularly conductive site of antigen capture  and adapHLA-DRB1*03, the Vα2.3/Vβ22 T-cell receptor (TCR), and Löfgren’s syndrome [Sarcoidosis is thought to develop similar to other granulomatous diseases of known cause, where an antigen is detected and processed by antigen detecting cells such as macrophages and dendritic cells . These psyndrome ,29. It iAs the diagnosis of sarcoidosis is not standardized, there is a reasonable chance that a patient diagnosed with sarcoidosis actually has an alternative granulomatous disease . This shIn addition, any robust model of sarcoidosis should account not only for multisystem granulomatous involvement but also the aforementioned non-granulomatous evidence of systemic disease. For example, anergy associated with sarcoidosis needs to be explained. Sarcoidosis has been described as demonstrating an “immune paradox” where there is peripheral anergy while exaggerated inflammation develops at sites of disease . ProposeLocation of sarcoidosis within each organ: Sarcoidosis has not only a predilection to involve certain organs but to involve certain portions of each organ. Sarcoidosis more commonly involves the upper portions of the lung [the lung . In the the lung ,38,39, ithe lung . Therefothe lung ,42. Anotthe lung , where sthe lung ,45. Eye the lung ,47, whicthe lung . This cothe lung . Skin sathe lung , granulothe lung . TherefoThe predilection for the upper portions of the lung to be involved with pulmonary sarcoidosis suggests that the antigen(s) that is associated with sarcoidosis is inhaled, similar to what is observed with silica and coal workers pneumoconiosis . There iAcute versus chronic disease: The clinical course of sarcoidosis is highly variable. Patients may present with an acute form of the disease that has a rapid onset and typically resolves in a few months to 1 year [o 1 year . The proo 1 year ,54. Lofgo 1 year ,55. Lofgo 1 year . Other fo 1 year ,57,58. Io 1 year . The numThe granulomatous inflammation of sarcoidosis may be short-lived or chronic. The mechanisms responsible for the lifespan of the sarcoidosis granuloma have not been clearly explained. If the granulomas of sarcoidosis represent a response to a foreign antigen, a chronic granulomatous response may simply be the result of the persistence of the antigen that cannot be adequately cleared. Serum amyloid A (SAA) has been postulated to be involved in the maintenance of the sarcoidosis granuloma by promoting antigen persistence. SAA has been frequently found within the sarcoid granuloma and is rarely observed with other granulomatous diseases ,61. SAA Fibrotic sarcoidosis: In a minority of pulmonary sarcoidosis cases, perhaps up to 20 percent [ percent ,64, sign percent , as well percent . As a la percent ,68, therIt is conjectured that the fibrosis in sarcoidosis is the result of granulomatous inflammation . This coFibrosis seems to stimulate the growth of sarcoidosis granulomas by their common occurrence in scars and tattoos. It is thought that the initial triggers for many interstitial lung diseases involve a repetitive vascular injury that leads to an aberrant reparatory process, activation of and infiltration of myofibroblasts, and excess deposition of collagen fibrils . TherefoVarious single nucleotide polymorphisms (SNPs) are associated with fibrotic pulmonary sarcoidosis; these include SNPS for: (a) GREM 1, which encodes for gremlin, a secreted glycoprotein and member of the bone morphogenic proteins ; (b) CarDemographics: Sarcoidosis occurs all over the world. However, it is more common in certain ethnic groups, races, and locations. The annual incidence of sarcoidosis is more common in African Americans than Caucasian Americans by a ratio of between 2:1 to 3:1 [1 to 3:1 ,80. In a1 to 3:1 . African1 to 3:1 , a great1 to 3:1 , a worse1 to 3:1 , and a g1 to 3:1 . In the 1 to 3:1 . Higher 1 to 3:1 ,83. In a1 to 3:1  and Lofg1 to 3:1 .Although the incidence and prevalence rates of sarcoidosis are uniformly found to be 50–100% higher in women than men across all racial groups in the United States , the genAlthough the literature is rife with statements that age of onset of sarcoidosis peaks between 20 and 45 years , most reSeveral epidemiologic studies have demonstrated that first degree relatives of sarcoidosis patients have an increased risk of having sarcoidosis with odds ratios of 2.5 to 3.8 . A recenThese data concerning racial differences and a propensity for sarcoidosis to aggregate in families suggest that genetic factors are important in the development of sarcoidosis. It is hypothesized that sarcoidosis results from exposure to an environmental antigen in a genetically susceptible individual ,92. As mSarcoidosis is associated with exposure to numerous environmental risk factors. As the exact immunopathogenesis of sarcoidosis is unknown, it is not clear whether these exposures are truly causing sarcoidosis, rendering the immune system more susceptible to developing sarcoidosis, exacerbating subclinical cases of sarcoidosis, or causing a granulomatous disease that is distinct from sarcoidosis . Table 3Infectious agents have also been implicated as a potential cause of sarcoidosis, although the data supporting this conjecture are inconsistent and unconvincing. There is an abundance of indirect evidence that mycobacteria are associated with sarcoidosis. Two meta-analyses of studies evaluating potential infectious diseases that may cause sarcoidosis suggested an etiologic link between mycobacteria and sarcoidosis ,124. MolCigarette smoking has been shown to be protective of sarcoidosis in several sarcoidosis cohorts ,135. A sThe exposure data provides strong evidence that an environmental antigen is an integral factor in the development of the sarcoid granuloma. As most of these exposures are airborne, it is likely that most of these environmental antigens enter the lung initially and lead to a granulomatous lung disease. The fact that numerous environmental exposures are associated with sarcoidosis suggests that either the disease results from the downstream result of many possible causes or that sarcoidosis actually represents a myriad of similar diseases, each with its own specific trigger (“the sarcoidoses” ). It is The different rates and phenotypic expressions of sarcoidosis between the sexes may relate to hormonal or other immunologic differences. However, these differences may also be the result of differing rates of exposure to associated antigens. In a large sarcoidosis mortality study, men who died of sarcoidosis were more likely to have sarcoidosis-related inhalation exposures, whereas women who died of sarcoidosis were more likely to have been in occupations associated with sarcoidosis that had great person-to-person contact  . These fThe decision to treat sarcoidosis is complex because the disease may be self-limited, cause no symptoms or functional impairment, and treatment is associated with significant toxicity. The indications for treatment have been distilled down to two: (a) significant quality of life impairment and (b) significant risk of a dangerous outcome . CorticoThe effectiveness of corticosteroids in sarcoidosis reveals little concerning the inflammatory pathways involved in sarcoidosis, as corticosteroids suppress numerous inflammatory genes that are activated in chronic inflammatory states . The effThe fact that TNF-α antagonists have been useful for the treatment of sarcoidosis is consistent with the belief that this mediator is important in the development of the sarcoidosis granuloma . TNF-α iA drug-induced sarcoidosis-like reaction (DISR) is defined as a systemic granulomatous reaction that is indistinguishable from sarcoidosis that occurs in a temporal relationship with the initiation of an offending drug . The cliAn autoimmune inflammatory syndrome induced by adjuvants (ASIA) is another type of sarcoidosis-like reaction ,165. ASIDISRs may yield important insights into the mechanisms responsible for developing sarcoidosis. ICIs block the immune checkpoint pathway site, including neutralizing the cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and the programmed death ligand 1 (PD-L1). ICIs not only enhance anti-tumor activity but also stimulate the immune system resulting in immune-related adverse events (irAEs) . irAEs iHighly active retroviral therapy (HAART) induced DISRs are immune reconstitution inflammatory syndrome reactions that occur in patients with HIV infection . HAART rSarcoidosis is a disease that is not rigorously defined. It may represent the common pathway of many diseases or, alternatively, represent a collection of distinct diseases. The disease appears to involve a causative exposure in a genetically susceptible individual, and various combinations of exposures and genetic profiles may result in varying phenotypic expression. This makes the elucidation of immunopathogenic mechanisms of sarcoidosis problematic. Scientific exploration of sarcoidosis will require rigorous attention to the clinical aspects of the disease, potential environmental exposures, genetics, and immunology. Given this situation, it seems essential that a collaboration between the clinician and the scientist will be essential in unraveling the cause of sarcoidosis. The clinician’s contribution to this process includes defining clinical phenotypes, identifying risk factors and protective factors, and exploring pharmacologic and other maneuvers that improve or worsen the disease. It is hoped that multidisciplinary collaboration will result in impactful insights that will improve the quality of life of sarcoidosis patients.


Sarcoidosis most commonly affects lungs and intrathoracic lymph nodes, but any other organ can be involved. In epidemiological studies, many occupational and environmental exposures have been linked to sarcoidosis but their relationship with the disease phenotype has barely been studied.To investigate how occupational and environmental exposures prior to diagnosis relate to organ involvement in patients with sarcoidosisWe retrospectively studied patients seen at a sarcoidosis clinic between 2017 and 2020. Patients were included if they had a clinical presentation consistent with sarcoidosis and histologically confirmed epithelioid granulomas or had Löfgren syndrome. In a case–case analysis using multivariable logistic regression we calculated odds ratios (OR) of prespecified exposure categories (based on expert ascertainment) for cases with a given organ involvement versus cases without this organ involvement.We included 238 sarcoidosis patients. Sarcoidosis limited to pulmonary involvement was associated with exposure to inorganic dust prior to diagnosis . Patients with liver involvement had higher odds of contact with livestock  or having jobs with close human contact  than patients without liver involvement. Similar associations were found for splenic involvement . Cardiac sarcoidosis was associated with exposure to reactive chemicals  or livestock . Active smokers had more ocular sarcoidosis .Our study indicates that, in sarcoidosis patients, different exposures might be related to different organ involvements—hereby providing support for the hypothesis that sarcoidosis has more than one cause, each of which may promote a different disease phenotype.The online version contains supplementary material available at 10.1186/s12931-021-01818-5. Cutibacterium acnes) [. It is unclear whether these exposures are truly ‘causing’ the disease, whether they render the immune system more susceptible to the development of sarcoidosis, or whether they exacerbate subclinical cases.Sarcoidosis most commonly affects the lungs and intrathoracic lymph nodes, but any organ can be involved , 2. Sevem acnes) . It is uThe diverse clinical manifestations and the wide range of associated exposures fuel the hypothesis that sarcoidosis has more than one cause, each of which may promote a different disease phenotype . HoweverIn this study, we selected a range of occupational/environmental exposures previously associated with sarcoidosis –8 and asWe retrospectively studied sarcoidosis patients that had visited the outpatient sarcoidosis clinic at the Department of Respiratory Diseases in the University Hospitals Leuven (Belgium) between January 1, 2017 and November 1, 2020 (n = 321) . The cliPatients were included in our study if they had a clinical presentation consistent with sarcoidosis and histologically confirmed epithelioid granulomas (with negative cultures and stains for acid fast bacilli) or had Löfgren syndrome (n = 304) . PatientAn organ was considered affected when involvement was “highly probable” or “probable” according to the WASOG Sarcoidosis Organ Assessment Instrument . Skin inExposure categories were selected based on previously demonstrated associations with sarcoidosis –8. Two eCovariates which could potentially influence the association between exposures and outcomes were extracted from the medical records: sex, race, age at diagnosis, presence of autoimmune or autoinflammatory diseases , genetic disorders , a family history of sarcoidosis, a family history of autoimmune or autoinflammatory disease, having metal prostheses or silicone implants, or taking medication (before diagnosis) that could have potentially triggered sarcoidosis .glmulti [. The best-fit models were selected based on their AIC ranking (Akaike Information Criterion) among all possible models—considering all possible subsets of exposure variables and other covariates . Additionally, tests for interaction were performed using interaction terms in the logistic regression models. Results were expressed as odds ratios (ORs) with 95% confidence intervals (CI). The OR from this analysis represent the odds of having been exposed for cases with a given organ involvement divided by the odds for all other cases without this organ involvement [We did a case–case analysis to examine the association between the studied exposures and organ involvements. A case-case analysis is a special form of a case–control analysis in which cases with different subtypes of the same illness are compared instead of including disease-free controls. This approach can reduce selection and recall bias relative to other case–control formats by ensuring that both case and “control” subjects have all been affected by (a different phenotype of) the same disease and thus underwent a similar selection process. First, univariable logistic regression was performed between each organ involvement and each exposure. Subsequently, for each organ involvement a separate multivariable logistic regression model was constructed to investigate statistical associations with the various exposures. The selection of exposures included in the final model for each organ involvement was done using an automated model selection procedure, implemented by the R package glmulti . The besolvement .The case-case analysis does remain vulnerable to selection bias. Because smoking and respiratory exposures to reactive chemicals, inorganic or organic dust might lead to respiratory health effects independently of the presence of sarcoidosis, exposed patients could potentially seek medical care earlier than unexposed. Respiratory symptoms might therefore be potentially confounding the association between exposure and organ involvement. To assess this potential confounding, we performed a sensitivity analysis by adjusting for the different lung function parameters (at diagnosis) in the regression models.All statistical analyses were performed in statistical computing language R . The STRWe included 238 sarcoidosis patients—84 women and 154 men—who were predominantly Caucasian . Median age was 45 years (interquartile range 37–52 year) for women and 41 years (IQR 35–47 year) for men (Table The majority of the patients had never smoked (62%), and only 18% was an active smoker. Twenty-six patients (11%) had been exposed to reactive chemicals  prior to diagnosis, mostly while having jobs in building industry (working with reactive adhesives or epoxy resins) or in chemical industry . Seventy-four patients (31%) had been exposed to inorganic dust, which included patients with jobs in which they were exposed to metal dust and/or fumes  or jobs with silica exposure (such as road and building construction workers or plumbers). Sixty-three patients (26%) had had organic dust exposure , which included mostly patients working in food production , wood workers, gardeners, farmers and pigeon breeders. Fifteen patients (6.3%) had close contact with mammalian livestock , mainly as animal farmers.Thirty-one patients 13%) had jobs with close human contact, such as health care professionals, educators, and child or elderly care workers. Forty-four patients (18%) had only had administrative jobs. Men were more likely to have had inorganic dust exposure (46% of men versus 3.6% of women), while women were more likely to have jobs with close human contact or administrative jobs  and were possibly more likely to have skin granulomas . No statistically significant associations were found between erythema nodosum and any exposure (model not shown). A sensitivity analysis including adjustment for lung function at diagnosis yielded similar effect size estimates . Also, organic dust exposure—including exposure to plant, animal, or microbial antigens—tended to be related to pulmonary-only sarcoidosis .In the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study, patients exposed to agricultural organic dust  and wood burning  were less likely to have extrapulmonary involvement . World TIn sarcoidosis, epithelioid granulomas are presumably an immunological response to persistent antigens, possibly combined with an adjuvant signal triggering an innate immune response . Dust paA possible explanation for the association between dust exposure and sarcoidosis which is limited to the lungs is that inhaled dust particles do not readily disseminate systemically. Small inhaled particles that deposit in the deep lung can—when not removed by the mucociliary escalator—be transported via the lymphatic system to regional lymph nodes , 23. ParWe found that respiratory exposure to reactive chemicals—including isocyanates, methacrylates, or epoxy resins—was associated with the presence of cardiac sarcoidosis . We should be cautious in interpreting this result as it concerns a limited number of patients . As these chemicals are known to cause asthma , we did not expect an association with any extrapulmonary involvement . It is uOur analysis showed that contact with  livestock  and jobs with close human contact  were independently associated with liver and spleen involvement Table . MoreoveCutibacterium acnes—have been suspected of being involved in the development of sarcoidosis in some patients [C. acnes have been demonstrated in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage fluid of some patients [Infectious agents—such as mycobacteria and patients . This dopatients . Neverthpatients , 28.. demonstrated that sarcoidosis patients whose PBMCs responded to mycobacterial antigens, had more cardiac involvement (3/5 patients) than unresponsive patients  [C. acnes was present in histological samples—confirmed by immunohistochemistry—were more likely to have liver involvement  [Interestingly, Beijer et al= 0.044) . Also, p= 0.057) . Althoug= 0.057) . Indirec= 0.057) , 11.We also found an association between administrative jobs and splenic involvement. Although associations between mould exposure in damp indoor environments and sarcoidosis have been reported , we coulocular sarcoidosis [In our study, smoking was associated with ocular sarcoidosis  and skin granulomas—although not statistically significant . While smokers are less likely to be diagnosed with sarcoidosis in general , smokingdermal exposures.We could not identify other studies investigating the relation between smoking and skin granulomas in sarcoidosis. Although it is possible that this relation is confounded by other unknown exposures, studies have shown that smoking leads to an increased prevalence of various cutaneous disorders characterized by defective permeability, such as eczema and psoriasis . SmokingA concern might be that some included patients represent misdiagnosed cases of hypersensitivity pneumonitis , pneumoconiosis (in those exposed to inorganic dust), or infections. Nevertheless, all included patients had histologically confirmed sarcoid granulomas  or presented with a Löfgren syndrome—highly supportive for a diagnosis of sarcoidosis .. proposed the term “sarcoid-like granulomatous pulmonary disease” since they rarely had extrapulmonary involvement [One could argue that because sarcoidosis is “by definition” a disease of unknown cause, finding a potential cause excludes the diagnosis of sarcoidosis and requires another disease label. For example, for sarcoidosis cases who had been exposed to WTC dust, Izbicki et alolvement . Howeverolvement , this apOur study has several limitations. Since the exposure information available from the medical records was not standardized, exposure misclassification is possible. Nevertheless, thanks to the longstanding presence of an outpatient clinic for environmental and occupational disorders within the hospital’s Department of Respiratory Diseases, there is a tradition of routinely registering occupational and environmental histories in the medical records of new sarcoidosis patients . The expBecause the exposure assessment was done retrospectively, we were unable to reliably estimate the latency period between exposure and disease onset or the precise duration of the exposures. The time relationship between exposure and occurrence of sarcoidosis has barely been studied. Case studies reporting on patients exposed to silica/silicates suggest latency periods from 6 months up to 40 years between exposure and onset of symptoms –39. In aOur recruitment strategy led to selection of patients with pulmonary involvement. In the workup of patients visiting our clinic, screening for extrapulmonary involvement is routinely performed . AlthougSince smoking and exposure to reactive chemicals, inorganic or organic dust might lead to respiratory health effects independently of the presence of sarcoidosis, exposed patients conceivably seek medical care earlier than unexposed. To assess whether respiratory symptoms potentially confound the association between exposure and organ involvement, we performed a sensitivity analysis by adjusting for lung function parameters. This did not substantially alter the effect size estimates for the different exposures, suggesting the absence of substantial confounding (see Additional file Our study indicates that, in susceptible individuals, different exposures might be related to different clinical presentations of sarcoidosis. As this association has hardly been investigated, confirmation in other populations is warranted, preferably including more patients with rare organ manifestations. Future longitudinal studies could clarify whether not only disease presentation but also prognosis is related to exposure and if stopping or reducing these exposures could alter the disease course .Additional file 1: Table S1. Comorbidities and other covariates of the included sarcoidosis patients; Table S2. Results for the univariable analysis of the associations between each organ involvement and each exposure. Table S3. Sensitivity analysis to assess potential confounding by adjusting for different lung function parameters in the best-fit logistic regression models from Table