SPI index reveals the greater presence of various wet classes during the investigated period. Geological substrate has been found to be highly susceptible to erosion and landsliding when climatological conditions are suitable. Accelerated urbanization and reduced vegetation cover intensified slope instability. The authors implemented adequate remote-sensing techniques in order to monitor and assess the temporal changes in landslide events at local level. Potential solutions for preventative actions are given in order to introduce and conduct qualitative mitigation strategies for shaping sustainable urban environments. Results from this study could have implications for mitigation strategies at national, regional, county, and municipality levels, providing knowledge for the enhancement of geohazard prevention and appropriate response plans.Romania is one of the countries severely affected by numerous natural hazards, where landslides constitute a very common geomorphic hazard with strong economic and social impacts. The analyzed area, known as the “Ciuperca Hill”, is located in Oradea (NW part of Romania) and it has experienced a number of landsliding events in previous years, which have endangered anthropogenic systems. Our investigation, focused on the main causal factors, determined that landslide events have rather complex components, reflected in the joint climatological characteristics, properties of the geological substrate, and human activity that further contributed to the intensive change of landscape and acceleration of slope instability. Analysis of daily precipitation displays the occurrence and intensive distribution between May and September. Higher values of rainfall erosivity (observed for the 2014–2017 period), are occurring between April and August. Erosivity density follows this pattern and indicates high intensity events from April until October.  Europe is a network of a majority of highly populated urban areas . Cities Although natural disasters occur worldwide, their impact has been observed to be greater in developing countries. These events are mostly perceived as uncontrollable events in which a society undergoes severe danger, disrupting all or some of the essential functions of the society. Their occurrence is due to the two main factors: geographical location and geological/geomorphological settings of the given area. Among these factors, historical development represents an important factor which is mostly influenced by the changing economic, social, political and cultural conditions. These consequently act as factors creating high vulnerability to natural disasters, reflecting on economic, social, political and cultural vulnerability e.g., ,16)..16]).On the other hand, natural hazards  like landslides involve publicly observed and monitored state-controlled interventions requiring special financial conditions. The redevelopment processes are determined by several factors, but information is considered one of the most important in the process . During As pointed out by , slope iThe objective of this study is to analyze the relationship between selected meteorological parameters, their occurrence and temporal distribution in an environment susceptible to landslides due to the specific sedimentological and human land-use characteristics. In doing so, the authors identify and outline causal factors related to climate variability, geology, and human activity reflected via land use. This approach is found to be rather effective in neighboring countries , which are trying to implement sustainable approaches for effective mitigation of the hydro-meteorological factors influencing slope instability in urban environments. Therefore, results from this study could facilitate the promotion of adequate mitigation strategies and risk education, leading to vulnerability reduction and increased resilience respectively. The manuscript is organized as follows: 1. Introduction; 2. Study area; 3. Data collection and processing; 4. Results and discussion; 5. Management implications and mitigation measures, and 6. Concluding remarks.The city of Oradea   . It is tThe Oradea surroundings are located on the upper Holocene lower level of a floodplain. The plain is constituted of gravel and sands. There are also five higher positioned fluvial terraces and glacial deposits located on the slopes of the Apuseni Mountains. Sands in alternation with sandy clays crop out from the terraces. The glacial deposits are constituted of gravel and sands of the Upper Pleistocene. The fluvial plain is characterized by a dense network of abandoned river beds, with E–W and SE–NW directions, which can be clearly recognized in remote sensed images , as well as in the field, and can be easily mapped .In a geological sense, the analyzed area is located at the contact of two main units: the Pannonian Basin (having the base dislocated into numerous fragments), and eastwards the orogen area represented by the Apuseni Mountains (part of Western Charpatians). The Crişurilor Plain, subunit of the Romanian Western Plain, was formed in the conditions of the continuous subsidence of the Pannonian Depression, and in the context of withdrawal and filling of the Panonnian Lake. The plain is composed of alternative Tertiary and Quaternary deposits up to 600 m depth , overlapping the crystalline base ,43. The The climate of the investigated area is continental-temperate with oceanic influences in the central and western parts. The rainfall regime displays yearly, seasonal and monthly variability, directly influencing slope stability. The highest quantities of precipitation are recorded during the warm season, characterized by increased thermal convection (mainly in the plains and hilly regions) as well as during the years in which cyclonic and frontal activity prevails . In the The Ciuperca (Mushroom) is an iconic part of recent and historical times in Oradea. The hill is a symbol of the city, as its elevation gives a perfect spot for a lookout over the settlement. At the same time, the area was used for multiple purposes throughout history : agriculFor several decades this was one of the main attraction sites of the city because of its beautiful perspective over the settlement and the Crişul Repede valley, but after 2000 the hill’s recreational use was abandoned. For many years the site was neglected, the park area was underused, the tourist potential was not exploited, Ciuperca as a facility was not sufficiently attractive, and the view was not integrated in the local touristic offer. Even so, Ciuperca Hill represented one of the most important natural green areas of the city of Oradea, being a fragile environment, vulnerable and very sensitive to urban expansion. The local urban regulatory framework supports the rehabilitation and regeneration of the abandoned and degraded green areas, in an effort to increase the surface of the green areas in the city of Oradea .The local strategical documents ,53, togePublic garden on Ciuperca Hill-Development of natural habitats of protected tree species and spontaneous flora  [2 park from Ciuperca Hill was expanded to 38,759 m2, after the Greek Catholic Church, which owned most of the land, transferred it to the Oradea City Hall. The site was a degraded green area, occupied by uncontrolled vegetation of trees and shrubs, with visiting trails and platforms ruined because of lack of maintenance and land instability [In this context the rehabilitation of the abandoned and under-used green area of the Ciuperca Hill became inevitable, therefore it was made a priority of the project titled 07–2013) ). The prtability .According to the local authorities  the workAs pointed out, Romania is one of the European countries most affected by landslides, that have a major impact on human activity ,49,61. M2 on the recently rehabilitated Ciuperca Hill in Oradea  and documentation were used to demonstrate the landscape susceptibility to landslides and prior occurrences. A geological map for the surrounding area  was used for the aggregation of the lithostratigraphic data. These geological maps were produced by the Romanian Institute of Geology . The RomTime series surface deformation was assessed using remote sensing techniques. In this research, Google Earth Satellite Recordings (GESR) were used. Satellite recordings were downloaded from an open-source server ,40. WithDaily values of temperature and precipitation were obtained for the Oradea meteorological station  from the National Meteorological Service of Romania for the 2003–2017 period. Meteorological observations are in accordance with World Meteorological Organization (WMO) standards. Daily values of precipitation and air temperature were used to aggregate monthly and annual values.PCI), modified Fournier index (MFI), rainfall erosivity (RE) and erosivity density (ED), as well as factors affecting them at local scales [PCI characterizes rainfall variability through space and time, and has previously been used to identify potential patterns of climatic interaction with geological substrate that may trigger landslide events . The erosivity density (ED) is highly reliant on rainfall intensity and influences event sediment concentration . As a pluvial parameter (expressed as MJ *ha−1h−1), it shows the ratio of rainfall erosivity to precipitation and measures the erosivity per rainfall unit (in mm). The calculation of PCI and MFI have been performed following the approach of Oliver [RE and ED were calculated by following the approach of Li and Ye [SPI, is a multi-scalar in time and space, and it is a rather good parameter for comparing indices between different locations, and the frequencies of comparable extreme events [SPI, as a meteorological drought indicator was included in this study since it is based on wide use and regional relevance. The SPI was calculated and classified according to the approach provided by McKee et al. [R statistical analysis software  was used for the calculation of the indices and data visualization.Although there are many factors that influence the occurrence of landslides besides the precipitation factor , the authors of this study focused on selected pluvial and drought parameters in order to fully describe the variability and occurrence of the main agent of wet mass movement events. Selected meteorological parameters were used in order to calculate rainfall erosivity indices such as precipitation concentration index . The MFI based on monthly mean values yields diversity in terms of erosion classes: 13.3% of very low, 33.3% of low and 33.3% of moderate aggressiveness, with several extreme values , indicating very high erosivity classes for 2010, 2015 and 2016. Analysis of daily precipitation displays the occurrence and intense distribution between May and September. Higher RE is observed for 2014–2017, occurring between April and August. ED follows the pattern of RE and indicates high-intensity events from April until October. SPI index reveals the greater presence of various wet classes, especially during the month of June in 2015 and 2016, where index values of 2.2 indicate the occurrence of extremely wet conditions. The majority of drought index classes vary from moderately to extremely wet  (Obtained results of the October) a–d.MFI values for 2015 and 2016 (133 and 132 index units respectively) fall within a very high erosivity class. These suggest that the high precipitation recorded in 2016 occurred in a few torrential events over a short period of time, thus increasing the susceptibility of the geological substrate to erosion and landslides. It is important to note that activation of the landslide event in 2016 was additionally backed up by mishandled activities preformed on the hill (2). In regard to spatial analysis units, 0.7% of the area has high values of slide and flow susceptibility, which are outlined and addressed in the presented study  [As previously pointed out, the geological substrate predominantly comprises sandy clays on more compact marl with a high degree of plasticity and hence highly susceptible to erosion and landsliding when climatological conditions are suitable. Bălteanu et al.  show thaCF)  of this CF) , requestCF) ,69).Groundwater drainage—three drains (depth ditches with a width of approximately one meter) are to be constructed along the hill, so that the bottom of the drains is at the boundary between the stable land and the land susceptible to sliding;Surface drainage—drains are required on the support walls and on the access roads area that collect the water and transport it downstream for discharge into the emissary.Strengthening restaurant and tourist information point buildings. This involves two categories of work:Stabilization of the slope—at the bottom of the area, drilling of pilots will be accomplished, constituting a support area.Rehabilitation works: architectural , structural , landscaping  occur in 2019–2020 within the framework of the project “Redevelopment of the Public Garden Ciuperca Hill ” ,90.According to Gori et al. , qualitaBeside these stages, a slope information system is needed to create public awareness concerning potential hazards related to wet mass movements, and to cultivate a responsibility towards maintaining slope safety within own property boundaries. A future approach should include landslide susceptibility mapping by using the Landslide Susceptibility Mapping Tool Pack  as proposed by Sahin et al. . Public Rehabilitation of the abandoned and under-used green area of Ciuperca Hill, a cultural symbol of Oradea city, was thoroughly addressed in this paper from the standpoint of sustainability and interplay between natural and anthropogenic processes that occurs in the given case study. Urban, cultural and environmental values have been put into danger by the complex of factors that caused the landslide. The slope stability, being a very complex phenomenon, requires a multidisciplinary approach to survey and mitigation strategies. The approach to solve problems associated with landslides is one of the most challenging, but it is also the most suitable issue for a good implementation of spatial planning strategies along with valid land use. A detailed analysis of climatic and geological/geomorphological factors is of great importance when identifying the causal factors of landslide events. To reduce future infrastructure damage and prevent the development of landslide events in the Oradea area, it is necessary to introduce and conduct qualitative mitigation strategies by implementing a long-term slope reinforcement program. A successful strategy is dependent on a combined scientific and engineering approach and management of environmental resources at both local and national levels. In this way, urban environments that are highly susceptible to hydro-meteorological factors can achieve a satisfying level of sustainability. The results presented in this case study can, furthermore, contribute to creating suitable mitigation strategies in order to avoid or reduce the impacts of landslide hazard occurrence not only in the investigated area, but in the surrounding regions  as well.


The inference of ancestry has become a part of the services many forensic genetic laboratories provide. Interest in ancestry may be to provide investigative leads or identify the region of origin in cases of unidentified missing persons. There exist many biostatistical methods developed for the study of population structure in the area of population genetics. However, the challenges and questions are slightly different in the context of forensic genetics, where the origin of a specific sample is of interest compared to the understanding of population histories and genealogies. In this paper, the methodologies for modelling population admixture and inferring ancestral populations are reviewed with a focus on their strengths and weaknesses in relation to ancestry inference in the forensic context. The increased availability of whole human genome sequences in the public domain is an invaluable data resource in many genomics, biomedical, and anthropological research areas. In particular, the data repositories focusing on the genomic diversity among human populations  and genetic polymorphisms are closely related ,10,11,12In forensic genetics, STRs are presently the standard markers used for identification and relationship testing. Furthermore, variation in allele frequencies may be used to infer an individual’s ancestry ,16. OtheThe study of population structure from genomic data has a long history within the genetic and statistical literature. The increasing complexity and availability of data from ancestry informative markers on multiple populations have required the development of appropriate methodologies to model and capture the subtle genetic structures in the data: from the first studies of a few hundred markers and individuals to more recent studies with thousands of individuals genotyped on highly dense assays or from whole genome sequences.This progress, driven by biotechnological advances, has been challenging not only from a methodological point of view but increasingly so from a computational perspective. Where independence between the markers was ensured by their genetic distance, the closer proximity of genetic markers results in statistical dependence . This increases the complexity of the analysis since such dependencies must be adequately modelled and their dependence structure learned from the data. Some methods incorporate the structure into their modelling framework, either by identifying stretches supposedly inherited as a complete block  or atteThe most widely used methodologies for analysing genetic structure can broadly be divided into four different groups: principal components analysis, model-based clustering, classification and likelihood-based, and hypothesis test-based methods. In addition, tree-based and distance/dissimilarity clustering methods are used but not included in this review. Most of the development in the study of population structures is driven by interests in medical genetics or population genetics, where controlling for population stratification may be vital for some applications or where the study of population dynamics on its own is the main purpose. Hence, few methods have been developed with the applications of forensic genetics in mind. In the subsequent sections, the various methodologies are discussed with references to key publications in their domain.To demonstrate and visualise the results from the various methods, data from  are usedormation . Both thlines between its parental populations. More recent PCA-based methods for inference include SMARTPCA [triangle spanned by Sub-Saharan Africa, Europe, and East Asia is cleary visible in the plot of PC1 and PC2.Principal components analysis (PCA) has a long history of application in the study of population structure. The usage of PCA in the analysis of population structure was pioneered by , as an eSMARTPCA  and EIGESMARTPCA . These mSMARTPCA , there aloss function, this implies that in the estimation of the unknown quantities  emphasis is given to the majority groups in the data [K . Another property shared by several methods and statistical models is that they provide a compression of the data, in the sense that the methods are trying to retrieve as much information from the data as possible and discard a nonsignal as noise. Taken a bit further, one may interpret the model output and parameter estimates as data summaries . Consequently, some of these summaries  are similar or even identical for different population genealogies [Besides being an efficient tool for visualising high-dimensional (genetic) data, PCA also yields the best linear low-dimensional approximation of the data in terms of Euclidean distance. This, together with the orthogonality of the principal components (PCs), implies that population substructures can be detected by the discriminant analysis of the PCs, DAPC . Primarithe data ,31. The The seminal STRUCTURE paper  introduccorrect) value for K, the number of population clusters, is not a well-defined problem, i.e., only heuristic methods exist for guiding the specification of K [K may result in rather different results and interpretations of the population stratification and history.Despite the many successful applications of STRUCTURE  may readily deal with partial profiles, whereas in particular regression, models are susceptible to missing data.In this case, the assignment of nonadmixed individuals can be conducted by a Bayes classifier, where the individual is assigned to the most probable population among the ones included in the reference database. As such, the population assignment problem can be solved by several types of classification algorithms known from the machine learning literature . Common to most of these methods is their ability to account for interaction effects between the explanatory variables on the outcome . Furthermore, similar to the methods of http://frog.med.yale.edu/FrogKB/, accessed on 13 December 2021) [http://mathgene.usc.es/snipper, accessed on 13 December 2021) [From a forensic perspective evaluating the weight of the evidence is typically conducted using the likelihood ratio principle. For multiple propositions , this approach generalises to several ratios assessing the pairwise agreement between data and the alleged populations of origin. The predicted population of origin is the population where the profile is most probable. The likelihood function typically assumes a specific population genetic model, e.g., within each population assuming Hardy–Weinberg equilibrium and independent genetic markers. This corresponds to a naïve Bayes classifier assuming a Binomial distribution for each marker given the population specific allele frequencies. Two forensically relevant implementations including several reference populations and AIMs panels are freely available online (FROG-kb (er 2021) ,50 and Ser 2021) ). Other er 2021) . These mer 2021) ,54.exhaustive populations. This means that for clustering the admixture components must sum to one, indicating that all the genetic admixture of an individual can be explained by contributions from the K clusters. However, the Ghost admixture example of  sexactly one class . Hence, this forced classification means that even when all the possible classes are (highly) unlikely, the DNA profile under classification must be assigned to precisely one of the populations .For classifications, an underlying assumption is that an observation belongs to This issue was the main motivation for the derivation of the GenoGeographer methodology ,56. Rathj.For each reference sample l and referece metapopulation j, the more likely it is to assume l to originate from metapopulation j. However, how (dis)similar should these admixture components be to declare l (not) to originate from j? Moreover, how should this similarity be measured? One possible measure of proximity could be to use a Brier-like score, l and reference metapopulation j:As for the training samples STRUCTURE admixture components l to metapopulation j in terms of STRUCTURE admixture components . The maad hoc defined thresholds for dissimilarity  are not required. The conclusions are based solely on a hypothesis test and a predefined significance level.The Brier scores, The model formulation of STRUCTURE implies that any spurious and complex type of admixture can be modelled. For the GenoGeographer framework, however, only specific admixtures can be assessed. Currently, first-order admixtures can be accounted for , but theK biallelic SNPs, there exist K. By exploiting the conditional independence structures, the framework of graphical models provides a more data efficient modelling of the microhaplotype frequencies and thus requires fewer samples.One solution to this may be to use linked markers as these typically are more informative for pedigree analyses . In ordeSTRUCTURE remains to be a valuable methodology and approach for analysing population structure in forensic genetics. There exist several guides and tutorials for how to prepare the population data and choosing parameter settings for STRUCTURE  and warnings about misspecification of origin may be detected by visual inspections of the results. From a forensic point of view, the results from both PCA and STRUCTURE are hard to report in terms of a weight of evidence calculation. The similarity (or dissimilarity) between the sample and reference materials can be reported but typically only in terms of their visual appearance. By contrast, classification and likelihood-based methods are able to give weight to the evidence. This may be in terms of a posterior probability or likelihood ratio, where the assignment would be to the most probable population. However, none of these methods take into account the risk of assigning the profile to the least unlikely population in the case where none of the populations are representative for the true population of origin.However, STRUCTURE’s popularity in the field of population genetics to study population structure is well deserved. It complemented PCA with a quantitative method that assigns sample specific weights to each of the Inferring a DNA profile’s geographic region or population of origin has been an active field of research in forensic genetics for several years. The vast collections of publicly available databases of whole-genome sequences provide a unique resource for researchers. Rather than spending time and consumables on collecting samples, these DNA profiles can now be harvested online. However, in doing so, one relies on the quality of the data provided by others, which includes the genetic typing and base calling but also the metadata regarding sampling location and ethnic information.In the case of forensic genetics, the finer resolutions are often of interest. In order to increase the specificity, it may be necessary to supplement the selected AIMs with more locally informative markers, specific to separating the local and often related populations of interest. In the search for such markers, the publicly available datasets are of immense importance as they can be used to screen for candidate AIMs. In particular, the samples from regions close to the specific populations of interest are essential for selecting potential markers.population specific patterns . The typical forensic use case focuses on a specific individual (or human remains), for which the most likely population of origin needs to be identified. In such cases, likelihood ratio or classification methods can be used. However, the fundamental assumption of the existence of an appropriate population in the reference material may very often be violated. Hence, DNA profiles are assigned to the population that is most similar to the sample, which due to human evolution and history may geographically and culturally be very far away from the true population. The GenoGeographer methodology attempts to overcomes this logical problem by using statistically based outlier tests.Combining the flexibility of STRUCTURE with the appealing visual features of PCA  is essential in the exploratory phase of ancestry inference. However, the forensic questions related to ancestry is typically different from those of population genetics, where the focus may be on


Primary immunodeficiencies (PIs) are a set of heterogeneous chronic disorders characterized by immune dysfunction. They are diagnostically challenging because of their clinical heterogeneity, knowledge gaps among primary care physicians, and continuing shortages of clinically trained immunologists. As a result, patients with undiagnosed PIs are at increased risk for recurrent infections, cancers, and autoimmune diseases.The aim of this research is to develop and implement a clinical decision support (CDS) tool for the identification of underlying PIs.We will develop and implement a CDS tool for the identification of underlying PIs among patients who receive primary care through a health care provider at the University of Iowa Hospitals and Clinics. The CDS tool will function through an algorithm that is based on the Immune Deficiency Foundation’s 10 Warning Signs for Primary Immunodeficiency. Over the course of a year, we will use Lean Six Sigma principles and the Define, Measure, Analyze, Improve, and Control (DMAIC) framework to guide the project. The primary measure is the number of newly diagnosed PI patients per month. Secondary measures include the following: (1) the number of new patients identified by the CDS as being at high risk for PI, (2) the number of new PI cases in which immunoglobulin replacement or rotating antibiotics are started, (3) the cost of evaluation of each patient identified by the CDS tool as being at high risk for PIs, (4) the number of new consults not diagnosed with a PI, and (5) patient satisfaction with the process of referral to the Immunology Clinic.This study was determined to not be Human Subjects Research by the Institutional Review Board at the University of Iowa. Data collection will begin in August 2021.The development and implementation of a CDS tool is a promising approach to identifying patients with underlying PI. This protocol assesses whether such an approach will be able to achieve its objective of reducing diagnostic delays. The disciplined approach, using Lean Six Sigma and the DMAIC framework, will guide implementation to maximize opportunities for a successful intervention that meets the study’s goals and objectives as well as to allow for replication and adaptation of these methods at other sites.PRR1-10.2196/32635 Primary immunodeficiencies (PIs) are diagnostically challenging chronic disorders involving the immune system that lead to recurrent infections, increased risk for cancer, and autoimmune disease . PIs mayDiagnoses of PIs are frequently delayed because of this clinical heterogeneity, knowledge gaps among primary care physicians, and continuing shortages of clinically trained immunologists -5. ThesePI diagnostic delays also cost a calculated $85,882 per patient  and contTo permit more appropriate management of the underlying condition. Immune globulin replacement and immunomodulators have demonstrated efficacy in reducing the frequency and severity of infections ,13.To enable more appropriate preventative health measures. Guidelines from the Advisory Committee on Immunization Practices (ACIP) and Infectious Disease Society of America (IDSA) state that immunocompromised patients, including those with PIs, have different requirements for vaccinations ,15. IdenTo prevent downstream diagnostic errors. Patients with a PI are more likely to present with atypical manifestations of infections that are less likely to be identified early on. Local infections are also more likely to become systemic, leading to increased morbidity and mortality . RecogniTo uncover diagnoses of family members. PIs are inherited conditions . IdentifTo empower patients about chronic illness. A diagnosis of PI is empowering to patients and enables them to reach out to support systems. Studies have demonstrated that early detection and diagnosis improves patient satisfaction and quality of life .To address health disparities. PIs are more likely to affect patients in particular ethnic populations, including those of Middle Eastern descent . ExpertsThe objective of this study is to develop and implement a clinical decision support (CDS) tool for identifying patients with an underlying PI. The Jeffrey Modell Foundation has published a set of 10 warning signs for PIs for both adults and children . We willToward that end, there are two specific aims:Identify the total number of patients who present to the University of Iowa General Internal Medicine, Pediatrics, or Family Medicine clinics with two or more warning signs of a PI over a 12-month period.Refer at least 10% of these identified patients to a University of Iowa clinical immunologist for evaluation within 12 months of their initial presentation.CDS tools for PIs have not yet been developed and assessed in peer-reviewed literature. This intervention would represent the first attempt to address this critical need. However, we build upon several lines of evidence that bolster the rationale that a CDS tool is needed to identify PI patients:A 2019 study of a large pediatric cohort of 185,892 patients revealed 2188 patients (1.26%) at medium to high risk for PIs . The autCDS tools for identifying secondary immunodeficiencies, including HIV, have been developed. Although these methods are different and guidelines for implementation vary considerably, they add to the evidence of the feasibility of immunodeficiency screening of large populations .Several CDS tools have been developed for tracking antibiotic usage, including at the University of Iowa . The purUniversity of Iowa Hospitals and Clinics (UIHC) represents the only comprehensive academic medical center within the state of Iowa. Between July 1, 2019, and June 30, 2020, there were 1,039,681 clinic visits, 32,872 inpatient admissions, and 50,468 emergency department visits. In the UIHC system, there are 77,779 patients that have a primary care provider in Family Medicine, General Internal Medicine, and General Pediatrics.Patients with suspected immunodeficiencies are evaluated at the Allergy and Immunology Clinic located at the University of Iowa’s clinics in Iowa City. If patients are determined to have an immunodeficiency, then they return to the Allergy and Immunology Clinic to obtain specialized care. Per year, there are 1863 half-day clinics staffed by 12 physicians serving 8963 patients. There are approximately 1684 patients with a diagnosis of a PI whose management is overseen by physicians and other practitioners in the Immunology Clinic. The average wait time to a new appointment is 5.46 weeks for adults and 13.16 weeks for pediatric patients.Inclusion criteria include patients who receive their care from one of the General Internal Medicine, Pediatrics, or Family Medicine clinics through the UIHC system. Exclusion criteria include patients with an established secondary or acquired immunodeficiency, and patients with an established PI diagnosis.We will use Lean Six Sigma principles and the Define, Measure, Analyze, Improve, and Control (DMAIC) framework to implement this intervention. The Lean Six Sigma approach has been previously described in health services research literature as a methodology to improve health care delivery . It combIn line with the DMAIC framework , we haveAdditionally, to understand the needs of the customers, we are using Voice of the Customer to clarify experiences, expectations, and needs. We are currently conducting semistructured interviews with 20 patients with PIs to understand their experiences. EK, a core member of the team, is a patient with PI and is helping to formulate questions and analyze data.During the Measure phase, we anticipate collection of data regarding our primary and secondary outcomes. The primary measure, as articulated in the project charter, is the number of newly diagnosed PI patients per month. We will measure the rate over the past 24 months to obtain a baseline, and then monitor it throughout the course of the protocol.We will also measure the following five secondary measures:Number of new patients identified by the CDS tool as being at high risk for PI.Number of new PI cases in which immunoglobulin replacement or rotating antibiotics are started.Cost of evaluation of each patient identified by CDS tool as being at high risk for PIs.Number of new consults not diagnosed with a PI.Patient satisfaction with the process of referral to the Immunology Clinic.Administrative data will be used for the primary measure and secondary measures 1-4. For secondary measure 5, we will conduct semistructured interviews and surveys to obtain the Voice of the Customer.Throughout the analyze phase, we will use the data being obtained as part of the Measure phase to assess the efficacy of the intervention and to guide modifications as necessary.For quantitative data, we will construct both run and control charts. The specific type of chart will be dependent on the number of evaluated patients and specific outcome measures. For example, if the CDS tool is unable to find many patients with PI, then a T-chart may be more appropriate than an X-bar chart.For qualitative data, we will continue to use Voice of the Customer. Once the CDS tool is implemented, we will conduct semistructured interviews with primary care providers to better understand their perspectives and opportunities for further refinement so that the CDS tool is more user-friendly.For individual cases of newly diagnosed PI, we will perform more detailed analysis to recognize causes of diagnostic delays. We will use value-added analysis to calculate the costs of diagnosis and identify causes of inefficiency in diagnosis. Additionally, we will use time analysis to chronologically map out opportunities for earlier diagnosis. Both of these analyses will then be used to further refine the CDS tool.During the Improve phase, we will employ sequential Plan-Do-Study-Act (PDSA) cycles to refine the CDS tool to different settings, starting with Internal Medicine, then Pediatrics, and finally Family Medicine. The investigators will continue to use Voice of the Customer as a key Lean Six Sigma tool to guide these PDSA cycles.Additionally, as we begin to finalize the CDS tool, we will use failure mode and effect analysis to proactively determine how the newly established process for identifying PIs may create inefficiencies and result in failures in diagnosis.Toward the end of the quality improvement project, we will develop a monitoring and proactive response plan to sustain the improvement plan. Using those measures, we will establish a trigger level to ensure that new cases of suspected PIs are screened through the CDS tool. Additionally, with advances in the diagnosis of PIs, such as genetic testing, we will incorporate newer modes of evaluation into the CDS tool.Finally, we intend on publishing our findings and presenting them at national meetings. Thorough documentation of the process, including this protocol, will be essential for transfer of knowledge to other settings and implementation in different settings.This study protocol was submitted to the University of Iowa Institutional Review Board and determined not to be Human Subjects Research.As of July 31, 2021, this protocol has been funded by the Society to Improve Diagnosis in Medicine as a DxQI Grant. It has been determined to not be Human Subjects Research by the University of Iowa Institutional Research Board on July 13, 2021. Data collection will begin on August 15, 2021, and end on July 31, 2022. We intend on publishing results in winter 2022.While there have been tremendous advances in the modalities used to diagnose PIs, evidence of real-world interventions to better identify PI are largely lacking. To fill that evidence gap, this study protocol outlines a quality improvement initiative to help reduce delays in diagnosing PIs. To bolster the likelihood of success, we have designed our initiative in line with the principles of Lean Six Sigma and have structured it via the DMAIC framework.We anticipate a series of challenges and have a comprehensive strategy to address these challenges as they arise. First, we have a screening algorithm  that hasSecond, we have a plan to accommodate increased volumes of patients who would need evaluation. Currently, there are 1863 half-day immunology clinics among 12 faculty members serving 8963 unique patients. The average wait time to a new appointment is 5.46 weeks for adults and 13.16 weeks for pediatric patients. The division has plans to expand with the hiring of 1-2 new faculty members over the coming academic year. Additionally, as allergy/immunology faculty are certified to see both adult and pediatric patients, flexibility can be arranged to accommodate incoming evaluations.Third, the CDS tool will be implemented in a stepwise pattern through the clinics to assess its ability to achieve our stated specific aims. Therefore, we have the capacity to revise the tool accordingly as we recognize the specificity and sensitivity of elements within the algorithm in detecting cases of PI.


Most interventions for mental health and psychosocial support (MHPSS) have been developed in contexts and with populations that differ significantly from the realities of migration. There is an urgent need for MHPSS in transit; however, transit-specific aspects of MHPSS provision are often neglected due to the inherent challenges transit poses to traditional conceptualizations of practice. The Delphi method, which consisted of three iterative rounds of surveys, was applied with the goal of identifying challenges to and adaptations of MHPSS in the transit context. Twenty-six MHPSS providers working with refugees in 10 European transit countries participated; 69% of participants completed all three survey rounds. There was consensus that a flexible model of MHPSS, which can balance low intensity interventions and specialized care, is needed. Agreement was high for practice-related and sociopolitical factors impacting MHPSS in transit; however, the mandate of MHPSS providers working in the transit context achieved the lowest consensus and is yet to be defined. There is a need to rethink MHPSS in the refugee transit context. Providing MHPSS to refugees on the move has specificities, most of which are related to the instability and uncertainty of the context. Future directions for improving mental health protection for refugees, asylum seekers, and migrants in transit are highlighted. According to UNHCR reports, by the end of 2020, the number of people who were forced to leave their home countries in order to escape war, persecution, and human rights violations and to search for safety reached 82.4 million . The curIt is important to note that, while crisis language is often used to frame refugee movements, for refugees, each decision to move is part of a much longer journey . After lThe situation of protracted transit, in addition to bringing numerous risks for refugees, also leads to various challenges for countries along transit routes who are obliged to provide protection and care to people currently residing in their territories. These responsibilities include ensuring protection of rights, access to adequate shelter, food, and other basic living necessities, and access to healthcare and social services, as well as to the asylum procedure for those seeking international protection. The provision of these protections and services is even more difficult for countries that are already struggling with limited resources, particularly when it comes to health and social protection systems, which is often the case in countries along transit routes. For many state systems, the current refugee crisis has highlighted preexisting gaps in social services and infrastructure as well as the need to rethink existing practices and policies. This is not only due to limited resources, but also stems from specific characteristics that are inherent in the transit context and the population of concern, which may call into question if and how some traditionally conceptualized services respond to the needs of refugees on the move.Most interventions for mental health and psychosocial support (MHPSS) have been developed and tested in contexts that differ significantly from the realities of refugee life on the move. Namely, the unpredictability of circumstances in the transit context presents challenges for informed treatment planning and, accordingly, deciding which interventions should be applied. In addition, health care systems in most transit countries are often under-resourced and provide limited access to MHPSS services, while services funded by international agencies and civil society usually lack continuity and sustainability. Therefore, the standard frequency and duration of treatment may not be achievable. Typically, there is a shortage of trained interpreters and cultural mediators, as well as MHPSS practitioners sensitized for work in the context of migration. Furthermore, refugees’ short duration of stay in one country and the lack of cross-country cooperation mean that it is not possible to ensure continuity of care. All of these factors pose challenges to the way MHPSS practice has traditionally been conceptualized in the stable and well-resourced contexts of European and North American destination countries.Additional challenges to traditional MHPSS practice stem from other characteristics of the transit context and the population in question, including the high prevalence of mental health difficulties that have been identified in refugee populations ,20,21,22The aim of the current study was to identify challenges and areas requiring adaptation within MHPSS in the refugee transit context. Additionally, the study aimed to provide essential evidence to inform the adaptation of MHPSS guidance to the transit context in order to improve future research and practice.The Delphi method  is commoFor the purpose of the present study, a group of experts convened to develop the initial statements. This group consisted of members of the Research Working Group of the Consortium on Refugees’ and Migrants’ Mental Health (CoReMH). The Consortium on Refugees’ and Migrants’ Mental Health was established in 2020 with the goal of facilitating international cooperation between mental health experts and practitioners working on the ground with refugees in the transit context. The CoReMH is devoted to identifying and addressing prominent issues in mental health protection for refugees, asylum seekers, and migrants, through evidence-based practice, research, and advocacy work. The authors are members of the CoReMH. In total, eleven experts from Serbia, Croatia, Turkey, Italy, Bulgaria, and Kosovo, 91% of whom were female, participated in the statement development process. Initially, open-ended questions and general topics were developed during the first online meeting. Subsequently, the initial set of statements was collaboratively produced, and the subsections of the survey as well as methodological details such as the inclusion criteria and sampling method were discussed and defined. The resulting initial survey draft was sent to all experts who participated in statement development as a Google form. They were asked to provide their opinion on the inclusion and wording of each statement by choosing between “include as is”, “remove completely”, or “reword/change”. If they chose the third option, they were asked to include their reasoning or suggested changes. Further, space for additional comments, questions, ideas, or concerns was provided at the end of each section, as well as at the end of the survey to allow the experts to express their opinions and provide suggestions. The resulting data were used to inform a new draft of the survey and a second experts’ meeting was convened. At this meeting, the final version of the Initial Survey was completed.Ultimately, the Initial Survey consisted of 12 sections. At the beginning of the survey, key terms were defined, and demographic questions were asked. Section 1 of the Initial Survey focused on understanding the mandate of mental health practitioners in the transit context and how they define their job. Sections 2–4 asked participants to consider the impact of the transit context on MHPSS interventions, identify contextual challenges to MHPSS, and consider what does and does not work in this context. Section 5 explored how the professional roles, settings, and boundaries in transit are similar to or different from those in a standard context. Sections 6–8 delved into evidence-based practice in the transit context, as well as ethical and methodological challenges that are inherent when working with refugees, and realistic measures of assessing effectiveness. Sections 9–11 focused on the mental health of practitioners themselves; specifically, they examined the impact this work has on them, the way that they perceive the value and efficacy of their interventions, and their cooperation with other providers. Section 12 consisted of two open-ended general conclusion questions regarding what else people should know about MHPSS provision in the transit context and why rethinking MHPSS of that context may be plausible.The surveys were administered using Google Forms.n = 22) described their professional and educational background as related to psychology, including clinical psychology, psychological rehabilitation, psychological counseling, psychiatry, psychotherapy, and having a master’s degree in psychology. Other professions included workshop management, social work, child protection, academia, and nonprofit leadership. During Round 2, 24 of the original participants completed the survey with an acceptable attrition rate of 7.69%. Eighteen of the original participants completed the Round 3  Survey with an overall attrition rate of 30.77% from Round 1.The inclusion criterion for participants was defined as having a minimum of one year of experience working in the provision of MHPSS services to refugees in the transit context. Participants were recruited through the CoReMH, as well as other providers in members’ networks, using a snowballing sampling strategy. During Round 1, 26 participants completed the survey of which 3 self-identified as male (11.5%) and 23 identified as female (88.5%). Participants’ ages ranged from 24 to 70 years  and they were from 10 countries . Years of experience ranged from 1 to 29 . The vast majority of the participants , a measure that takes into account both mean and standard deviation . The CV RStudio Cloud  ,39,40,41The first round of the Delphi study indicated a fairly high overall level of agreement with the contents of the initial 92 statements: the average rating across all participants and statements was 7.71 points on the 10-point scale. A high level of consensus was achieved for 27 statements.Out of the remaining statements, based on statistics and suggestions from the participants, 34 were reformulated, 16 were deleted, and 13 were kept in their original form. Based on the qualitative data collected in the survey, one new section (Section 13) consisting of 28 statements was introduced, entitled “Impact of Sociopolitical Context on MHPSS in the Transit Context,” which focused on policies and other structural characteristics of the transit context.As in the first round, there was a high overall level of agreement with the contents of the statements included in the second-round survey. Of the 87 statements panelists were asked to rate, 46 met requirements for high consensus.Of the remaining statements, 5 were reformulated, 12 were dropped, and 26 were kept in their original form.In Round 3, high consensus was reached for 20 statements. Ten statements failed to achieve a high level of consensus.In total, 93 statements reached consensus. These statements are listed by theme in The highest overall average score was observed for the importance for close cooperation between MHPSS practitioners from different countries on the route (M = 9.39). Of all the statements that reached consensus, only two had average scores below 7, indicating an attribution of lower importance to these particular aspects of MHPSS. The first focused on whether the ethical, practical, and methodological concerns limit possibilities for conducting research in transit (M = 5.89); the second addressed whether the transit context decreases clients’ motivation to engage with MHPSS services (M = 6.61).Three main themes emerged from our findings. First, the failure to reach consensus on certain statements related to the mandate of MHPSS providers working in the transit context revealed that this professional role and identity remain unclear and require further definition. For example, when considering which types of interventions make sense in the transit context, panelists showed the highest support for occupational workshops and activities being an important part of MHPSS for people on the move (M = 9.31) but failed to agree upon two typically central tenets of MHPSS providers’ jobs: providing specialized services for diagnosed mental health disorders (CV = 0.34) and helping people process potentially ongoing traumatic and stressful experiences (CV = 0.30). Despite the lack of consensus on these two statements, study results show that there is considerable agreement on certain aspects of providers’ mandate. The most strongly agreed upon aspects were raising awareness of the importance of MHPSS for people on the move (M = 9.00), recognizing and validating clients’ existing capacities and strengths (M = 9.13), and connecting clients with other resources (M = 9.19). These high-agreement statements can provide insights into how practitioners think about their role in transit and can serve as a starting point for future discussions on the mandate of MHPSS providers in transit that seek to explore and address the identified areas of disagreement.Second, a trend in the data across several sections was that many features inherent in the transit context present challenges to the ways in which both practice and research are usually carried out. Of the statements in Section 2, which focused on the impact of transit on MHPSS interventions, the importance of a flexible model of care that could meet clients’ needs wherever they are reached the highest level of agreement (M = 8.83). When considering challenges to MHPSS in transit, participants most strongly agreed that MHPSS interventions should be adapted to consider the impact of circumstantial factors in transit (M = 8.96). This complicates and presents both ethical and practical challenges for the application of methods for treatment and data collection in transit that were originally developed for use in contexts with different resources and were likely tested on populations with different needs and backgrounds. Nevertheless, there was a high level of agreement regarding the need for more evidence on the effectiveness of MHPSS intervention implementation in transit (M = 8.42), which highlights that, despite the numerous challenges identified, providers agree that more transit-specific research, which could enable evidence-based practice, is urgently needed.Third, a high level of agreement was exhibited for most statements from Section 13 on the impact of the sociopolitical context on MHPSS in transit. Specifically, border-related violence (M = 8.78), the high level of uncertainty (M = 8.70), the undesired extension of time spent in transit (M = 8.70), stress surrounding the asylum procedure and the low likelihood of obtaining asylum (M = 8.39), and the present political context (M = 8.22) were all identified by providers as stressors, which negatively impact the mental health of people on the move. These findings highlight the importance of considering social determinants of mental health, including environmental conditions created or reinforced by migration governance policies, in the design and provision of MHPSS services in transit.The main aim of the current study was to identify challenges to and areas for adaptation within MHPSS services in the refugee transit context as well as to provide the evidence needed to guide that adaptation. The study findings fall into three broad themes.This study showed there is a common understanding of the importance of some aspects of MHPSS providers’ mandate. Namely, the panelists overwhelmingly assessed as important and agreed that their mandate involves maintaining clients’ mental health and wellbeing, helping people survive and cope in healthy ways, raising awareness of the importance of MHPSS, and bolstering extant resilience capacities. Interestingly, the highest level of agreement in the mandate section corresponded to connecting people on the move to other resources, highlighting the multiplicity of roles that MHPSS providers are expected to play in the transit context.Surprisingly, the experts did not agree that the job of MHPSS practitioners working with refugees in transit should include treating diagnosed mental health disorders. Upon reviewing the qualitative data linked to this topic, it was found that those who agreed with the statement mainly argued that this was a central part of their work, as it is essential to prevent deterioration of mental health, especially for those presenting with severe symptoms , but if this is not the job of MHPSS practitioners providing MHPSS support to people on the move, I do not understand whose it should be”). Conversely, those who did not agree with the statement expressed concern about limited resources, potentially inadequate training and competencies, ethical issues in medicalizing symptoms, and the lack of continuity of care. It is important to highlight that these factors have also been identified as legitimate concerns by past research, which has found harmful effects linked to these factors for both providers and clients. Low resources are often linked to increased caseloads for providers, which has been shown to be associated with emotional exhaustion and burnout in community mental health care providers . InadequIn addition, there was a lack of consensus around the importance of helping refugees to process potentially ongoing trauma. As with the previous statement, those who agreed expressed that this was a large part of their job and that it was their responsibility to provide such support (“This is probably the primary job and it’s the job that takes up the most time in this kind of setting.”). Those who were opposed argued that it is more appropriate to help the refugees process trauma when people have settled in a destination country and achieved a basic state of safety and stability . Whether providers considered this an important aspect of their mandate or not in the transit context, they emphasized the need to acknowledge individual preferences across clients and the beneficiary’s perspective . The unanticipated contentiousness of these statements demonstrates how, in the transit context, even the most basic functions of mental health care provision are called into question.There are several potential causes for these findings. It is possible that the lack of universal standards on required qualifications for MHPSS care providers poses a concern regarding the expertise needed to ensure the required quality of care for refugees who have experienced several traumatic events. This could explain why some providers are hesitant when it comes to the more sensitive aspects of MHPSS work, such as providing treatment to persons with mental health disorders or processing traumatic experiences. In addition, it seems there are dilemmas among care providers about whether certain types of MHPSS interventions, primarily specialized care, should be applied before refugees arrive at their destination and achieve some form of life stability. However, the importance of providing an opportunity to process ongoing trauma whenever it is introduced by the client was highlighted . Interestingly, there is agreement, both within and outside of our study, on the provision of mental health services in the post-migration context. Healthcare professionals have stressed the importance of mental health care provision for newly arriving refugees as well as strengthening continuity of care . A qualiThe short time refugees tend to spend in transit countries could also account for the avoidance of the aforementioned interventions. However, previous studies have shown that time spent in transit varies from several months to several years , so it iFurthermore, the methods that are currently promoted by most international bodies and donors supporting MHPSS services, particularly in low- and middle-income countries, mainly include basic psychosocial support. Individual specialized care is rarely funded by international donors and is consequently rarely part of project-based MHPSS care providers’ mandates. This, in the long run, may influence the way MHPSS care providers conceptualize their professional identity and, accordingly, the way they orient their practice towards or away from treating mental health disorders and trauma . Overall, this study showed polarization among care providers, which highlights the urgent importance of rethinking core aspects of MHPSS care providers’ identity and their understanding of their mandate.When it comes to other aspects of MHPSS practitioners’ mandate, including setting, roles, and boundaries, there was agreement that the transit context differs from that of standard work in several ways. These include lack of proper premises for delivering MHPSS services, working with interpreters, and MHPSS practitioners balancing multiple roles in relation to their clients, all of which make maintaining boundaries more difficult than in the standard context. Furthermore, this study revealed that advocacy work is conceptualized as one of the core aspects of MHPSS work in the transit context. This includes working in multidisciplinary teams, advocating for clients’ rights, informing policy development, and striving to achieve a political impact that will be protective for the mental health of refugees. Thus, MHPSS providers’ responsibility for education on human rights violations and for supporting clients in knowing their rights and reporting any violations in order to avoid perpetuating an inhumane system was highlighted . Therefore, the study revealed an evolving aspect of MHPSS providers’ mandate, which emerged as a response to job requirements in such precarious and dynamic circumstances and confirmed the need to rethink and adjust definitions of the role of MHPSS providers in the transit context.The study revealed a need to define suitable MHPSS interventions for the transit context. There was support for developing a more flexible model of care ranging from community-based to specialized care, in accordance with past research on meeting mental health needs in the transit context . This moIt was also pointed out that trust, which is foundational for successful MHPSS interventions, is much more difficult to establish in the transit context given the uncertainty created by sociopolitical factors. Our qualitative data offers an example of how some providers conceptualize the impact of transit-related factors on the establishment of trust  are met”).Other researchers have highlighted the importance of strengths, values, and action-based intervention approaches in the transit context , an apprThese contextual factors were also seen as impacting care providers’ mental health and creating feelings of hopelessness, guilt, and anger .Furthermore, the need to conduct more research within the transit context to inform practice as well as for additional training for MHPSS practitioners on research methodology, in order to support future evidence-based practice in transit, was recognized. Moreover, the panelists agreed that there is a need to define what can be considered “evidence” when discussing evidence-based practice in the transit context.However, despite the numerous contextual limitations, there was a high level of agreement on the perceived value and effectiveness of MHPSS in the transit context, which can be attributed to a belief that MHPSS in the transit context can make a difference, regardless of the myriad obstacles inherent in transit.Another insight from this study is the importance of considering the impact of the sociopolitical context on MHPSS in the transit context. Sociopolitical context and European migration and border governance policies were recognized as risk factors that impact refugees’ mental health and the effectiveness of MHPSS interventions. Moreover, numerous factors introduced by the sociopolitical context represent under-researched areas and are typically not accounted for in MHPSS. These include, but are not limited to, border-related violence, pushbacks, the undesired extension of time spent in transit, high level of uncertainty, lack of legal and safe pathways for refugees, unpredictability and unfairness of migration procedures, police violence and exposure to violence from criminal groups, and stress surrounding the asylum procedure, including potential retraumatization  and the This study also highlighted that the stressful and traumatic experiences refugees go through during transit constitute another round of trauma, sometimes consisting of more traumatic events than were experienced in the country of origin, whose negative effects on refugees’ mental health have been demonstrated in previous studies . In addiOur study findings on the asylum process as a stressor are supported by past research, which has both found that the asylum procedure is a source of stress and recognized policies related to migration as having shaped many social determinants of health for migrant populations ,55,57. PThe study points out that mental health protection for refugees on the move cannot be ensured by interventions at the individual level alone, without addressing wider systemic and sociopolitical factors, as it would be hard to speak about the long-term effectiveness of MHPSS interventions .The Delphi method included 26 panelists, of which 18 assessed the statements in all three rounds. The retention rate of 69.23% of the initial pool of panelists throughout the three iterations and over a two-month data collection period probably reflects more dedicated and perhaps more experienced providers. The uneven representation of female and male panelists, although a possible source of bias, in fact broadly corresponds to the situation in the MHPSS field in countries on the refugee route to Western European destination countries, where most often the providers are female. The panelists had a variety of professional backgrounds and many of them had an activist history. This may have impacted the lack of consensus on statements regarding specialized care provision, given that some panelists did not have competencies in this area. The uneven number of statements across sections of the Delphi survey reflects the possible bias of the group of experts who identified the initial areas of MHPSS provision in the transit context to be assessed and their concern with the vague definition of the mandate and job of providers under these circumstances. However, during the three Delphi iterations, the panelists had the opportunity to influence the formulation of statements, their rejection, and even the inclusion of new sections.Ultimately, this study reinforces the importance of recognizing how the transit context impacts the standard view of MHPSS that is typically provided in much more stable and well-resourced conditions.The study highlights several important aspects of the current state of the field that need to be reconsidered. First, there is a need for a clearer understanding of the versatile and multidimensional mandate of MHPSS practitioners in the refugee transit context. Second, the importance of considering specificities of the transit context when designing and implementing MHPSS services is highlighted. To this end, providers advocated for a more flexible model of MHPSS that can adapt to the changing needs of refugees on the move and meet them where they are at. This model should be neither so ‘zoomed-in’ on specialized care that it loses sight of the vast number of people needing other kinds of support, nor so ‘zoomed-out’ that it loses sight of the individual needs of each person within the range of MHPSS possibilities. Third, the study reveals the importance of addressing both individual and systemic risk factors for mental health in order to ensure sustainable and comprehensive mental health protection for people on the move. Finally, the study pointed to several key future directions for improving MHPSS in the transit context. These include a need for closer cooperation between MHPSS practitioners from different countries along the route to enable continuity of care, as well as to exchange knowledge, experiences, and lessons learned. The need for collaboration is also evidenced by calls for the production of guiding documents, which could inform research, practice, and advocacy work in the transit context, thus enabling appropriate mental health protection and care for refugees on the move.


Hearing loss is one of the most common disabilities affecting both children and adults worldwide. However, traditional treatment of hearing loss has some limitations, particularly in terms of drug delivery system as well as diagnosis of ear imaging. The blood–labyrinth barrier (BLB), the barrier between the vasculature and fluids of the inner ear, restricts entry of most blood-borne compounds into inner ear tissues. Nanoparticles (NPs) have been demonstrated to have high biocompatibility, good degradation, and simple synthesis in the process of diagnosis and treatment, which are promising for medical applications in hearing loss. Although previous studies have shown that NPs have promising applications in the field of inner ear diseases, there is still a gap between biological research and clinical application. In this paper, we aim to summarize developments and challenges of NPs in diagnostics and treatment of hearing loss in recent years. This review may be useful to raise otology researchers’ awareness of effect of NPs on hearing diagnosis and treatment. Hearing loss is one of the most common disabilities affecting the quality of life. Nowadays, people’s lifestyle has been changed with longer life expectancy, and the prevalence and the severity of hearing loss have increased . AccordiAttention to the treatment of hearing loss has varied, which is influenced by social status, education, and race. For example, nearly two-thirds of United States adults aged 70 years and older are affected by hearing loss, and only 15% of older people use hearing aids . At presin vivo, but also carry drugs to specific parts of the cochlea  to guinea pig round window, which provides sustained release of drugs, increases the total concentration of peripheral blood lymphocytes by about 1.6-fold, and increases the residence time of drugs by about 24-fold. The initial peak concentration of dexamethasone injection before clearance from the lymphatic vessels was within 12 h, while the mDex hydrogel sustained release for 10 days . This stAs a new medical application of nanomaterials, the nano drug delivery system not only has a wide application in drug transportation of inner ear hearing loss, but also plays a role in clinical diagnosis and treatment of inner ear hearing loss diseases because of its specific penetration, good biocompatibility, and editability . Due to 3O4) or magnetite (γ-Fe2O3) nucleus, with a molecular diameter of 100–300 nm and with a certain biocompatibility (in vivo (3) NPs and lipid NPs that are designed to combine with traditional contrast agents to form chelates that can reflect the distribution of these contrast agents in the cochlea and form visual images (Superparamagnetic nanoparticles (SPIONs) with good physical properties are characterized by nanocrystalline iron oxide (Fetibility . Therefo(in vivo . Besidesl images ,b. Some l images . Interesl images . These fThere are more than 324,000 CI users in the world. CI has greatly improved the quality of hearing life of patients with hearing loss. The mechanism of CI in the treatment of hearing loss is related to the connection between the CI electrode array and auditory neurons . CI direThe application of nanomaterials, such as graphene and MXene, can also promote the proliferation and differentiation of neural stem cells in the inner ear, and many ultrastructures can be produced by 3D printing technology or other novel methods, so as to obtain more satisfactory biological characteristics that can be applied in hair cells . These nWhat is more exciting is that there are also nanomaterials in the cochlea that can be used for a longer time by spontaneous power supply. Some studies have investigated the silver NP microcoil with the micro size by aerosol jet printing. It has been demonstrated that the electromagnetic field generated by this material is not affected by cochlear environment . The eddThese studies may have paved the way for the development of self-powered nanofibrous implantable auditory sensors, which suggests that more and more nanomaterials may be used in the construction of cochlear materials and cochlear signal transduction technology in the future.in vivo. These substances act on the cells or tissues of the inner ear, which may also have ototoxicity, thus affecting the biological activity of hair cells and the activity of auditory neurons. Although some studies have found that NPs may have ototoxicity in vivo, there is no clear report on the ototoxicity of nanomaterials to humans (Nanomaterials and related technology products may not only provide diagnosis and treatment strategies for specific and efficient treatment of hearing loss, but also other inner ear diseases, such as otology tumors and ear inflammation. Furthermore, we can foresee that some types of nanomaterials or nanoproducts may be routinely used in the treatment of hearing loss and other inner ear diseases in the future . Among to humans .Previous studies have reported that positively charged NPs can enter the inner ear more easily through RWM, as drug carriers for inner ear diseases or CI materials, but they will produce certain ototoxicity in the process of biodegradation with cell membrane damage, production of reactive oxygen species, hair cell apoptosis, etc. . The timMoreover, the cost of developing and manufacturing NPs for clinical application in the field of inner ear diseases is significantly higher than traditional treatments . Many pain vivo with nanomaterials, and promising results have also been reported. However, we do not know the specific effect of nanomaterials applied in human inner ear. There is still a big gap between basic research and clinical application of nanomaterials, so it is necessary to study the safety and effectiveness of nanomaterials. With the emergence of new biomaterials and the realization of a deeper understanding of inner ear physiology, nanomaterials will have a clearer understanding of the diagnosis and treatment of hearing loss.The application of nanomaterials in the diagnosis and treatment of hearing loss diseases is novel and promising. In the future, ideal nanomaterials should be more universal, able to load more therapeutic drugs with various functions, such as preventing rapid degradation, retaining targeting effects, and prolonging the action time in the inner ear. This kind of materials should not only have better efficacy in various diseases of inner ear hearing loss, but also have stronger ear permeability, and ensure no impact or side effects on the human body. Many studies have attempted to deliver drugs, genes, and growth factors to the inner ear ZLH, SL, and QX wrote the first draft of the manuscript. YZ and ZHH polished the language. KL searched the literatures. XC, PS, and MLY conceived the idea and revised the manuscript. All authors read and approved the final manuscript.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Efficient water allocation in a transboundary river basin is a complex issue in water resources management. This work develops a framework for the allocation of transboundary river water between the countries located in the river basin to evaluate the characteristics of allocation approaches. The allocation of river water is obtained based on initial-water conditions, cooperative, and non-cooperative game-theoretic approaches. The initial-conditions water allocation approach assigns 34, 40, and 26% of the Harirud River flow to Afghanistan, Iran, and Turkmenistan, respectively. The game-theoretic cooperative approach assigns 36, 42, and 22% of the river flow to Afghanistan, Iran, and Turkmenistan, respectively. The non-cooperative game-theoretic approach establishes that the most stable water allocation was 42, 38, and 20% of the Harirud River flow for Afghanistan, Iran, and Turkmenistan, respectively. Human and agricultural water-stress criteria are used to evaluate the water allocations in the Harirud River basin. The criterion of human water stress has the largest influence in Iran, and the criterion of agricultural water stress has the smallest influence in Afghanistan. This work’s results indicate the initial-conditions water allocation approach favors Turkmenistan, whereas the cooperative and the non-cooperative game-theoretic approaches favors Iran and Afghanistan, respectively. The results show that the priorities of each country governs water allocation, and cooperation is shown to be necessary to achieve sustainable development. Management of transboundary river basins requires adaptive management which means the countries can adapt to changes and stresses of water resources and reduce their effect on sustainability (Wolf2).Water management in transboundary river basins involves technical and scientific assessments, and legal, economic, cultural, social, and historical factors that cross political and cultural boundaries. Transboundary river management can improve food security, economic growth, adaptation to climate change, international trade, public health, and international cooperation . The challenges of the water crisis increase in shared water regions, and water managers must cooperate to manage water in a beneficial manner. Determining the benefits from the cooperation between countries and how they are distributed among the stakeholders is a nontrivial task in transboundary river basin management (Wolf2). To this end, it is necessary to increase the institutional capacity so that beneficial water management and water use can be established at all levels of society, and to ensure that governance organizations become active and effective in decision-making.Sustainable development is an effort to balance between economic evolutions, environmental issues, and social and welfare needs of a region in the present without damaging the future generations’ resources . The most common solutions for water allocation are optimization methods and game theory approaches . As an example, Kazemi et al.6 reported a multi-objective optimization model for the allocation of water resources in the Sefidrood River Basin, Iran. The objectives of their model were to maximize revenue and minimize the Gini index. The results showed that the Gini index increases (an increase of injustice) with the increasing number of dams.The allocation of water resources among transboundary stakeholders has been approached from various perspectives . Many decision-making situations involving the allocation of scarce resources under cooperative or non-cooperative behaviors can be solved with game theory (Harrison and List10), as done in this work for the allocation of a transboundary river’s water. Degefu et al.11 proposed a framework in which the theory of bargaining was combined with the allocation of resources and bankruptcy games to allocate water and improve welfare in the transboundary river basin. The Euphrates River was selected as the study area that encompasses parts of Turkey, Syria, and Iraq, and a framework was created for the economic redistribution of water and maximizing overall welfare. Arfanuzzaman and Abu Syed12 examined the relationship between ecosystem and water needs in the Teesta River Basin between India and Bangladesh using game theory. Their results showed that the zero-sum game perspective can be used to develop transboundary water policies. Zeng et al.13 applied a cooperative game theory method to solve transboundary water problems between two cities in the Guanting basin of northern China. The results demonstrated that full cooperation leads to the greatest total benefit to each stakeholder. Qin et al.14 proposed an integrated decision support framework combining multi-criteria decision making, bankruptcy theory, and the power index in the Dongjiang River Basin in China. The results showed that the proposed method is reliable for simultaneously considering the criteria of fairness and sustainability in the management of transboundary rivers.The genesis of game theory is traced to von Neumann and Morgenstern15). HBV stands for the Swedish title Hydrologiska Byråns Vattenbalansavdelning which was developed in 1976. The model is a popular rainfall-runoff model in simulating gauged and ungauged basins  that has been applied in different climate regions .The HBV model is a lumped conceptual catchment model that has relatively few model parameters and minimal forcing input requirements, usually the daily temperature and the daily precipitation (Bergström and Göran1). Yet, riparian countries, especially upstream ones in transboundary basins, are sometimes hesitant to be cooperative, and they tend to pursue self-serving use of river water. In this context, it seems necessary to consider strategies for water allocation according to realistic conditions within transboundary basins and to examine the effect of the strategies on transboundary countries. Past studies of water allocation lack a consistent framework to assess water allocation in transboundary basins.Cooperative management of transboundary rivers contributes to sustainable water management and improves the chances of rendering benefits for all riparian countries  of countries in water allocation and show the effect of these behaviors in meeting the water needs of countries that are not presented before in past studies. First is the allocation of water among competing users according to an initial-conditions water allocation of water that is made based on geographic location, economic development, and historical water use. The second approach involves game theory, wherein several coalitions of water users (or players in the game-theory jargon) are formed in which the players have specific functions. Coalition revenues are distributed among the players of a coalition based on inter-player cooperation and their agricultural, urban, industrial, and environmental water requirements. The third approach for transboundary water allocation is based on non-cooperative game theory. Finally, three approaches are evaluated based on the riparian countries’ characteristics.20). The GA and its variants mimic evolutionary processes in nature  to improve an initially, randomly, generated population of possible solutions iteratively until it converges to a near-global solution. The reader is referred to Bozorg-Haddad et al.21 for a description of the GA and some of its variants with codes available for their programming.The GA is a pioneering evolutionary algorithm for optimization  at location t is calculated with Eq.  of crop j at location k, respectively. The revenue to country k = r, , is calculated with Eq. .Each player is in this instance is primarily interested in the magnitude of his or her revenue from participating in a cooperative game rather than in increasing the total income of the cooperative game compared to what could be obtained by participating in a non-cooperative game. In a cooperative game players interact with each other before the game and they may sign contracts with each other and form alliances. The revenue from all possible strategies is expressed in the form of characteristic functions, such as revenue received from a game. A fair revenue sharing by cooperative players can be obtained with the Shapley value method . This study considers the human water stress and the agricultural water stress criteria, which are defined next.Various political, social, economic, and environmental criteria are defined to determine the status of transboundary water resources. The United Nations Environment Programme (UNEP) has set out specific criteria for assessing the management of transboundary basins in the form of a codified approach  of the simulated flows equaled 0.821, which indicated acceptable predictive skill or accuracy. The river water was allocated in this study based on the water demands within the Harirud River basin for the period 2000–2014.There was lack of data in the Harirud Basin outside Iran and minimal data sharing between the transboundary countries. It was therefore necessary to apply rainfall-runoff simulation to make up for the data shortages. Rainfall-runoff simulations for the Harirud River basin were performed using the HBV conceptual model. Data on precipitation, temperature, potential evapotranspiration, and river flow for a 10-year (1969 through 1978) were implemented for model calibration. The observational time series of monthly river flow corresponded to the Robat Akhund gaging station in Afghanistan. The calibrated HBV model simulated monthly river flow from 1979 through 2014. The correlation coefficient . The contributions are listed in Table The mathematical programming problem of water allocation maximizes the agricultural revenue. The priority of water withdrawal by the upstream country (Afghanistan) is considered because of its geographically advantageous position. The players in the coalition of cooperators must agree on revenue sharing. This sharing was obtained with the Shapley value method that establishes the relative contribution of each player to the revenue of the coalition (Shapley24). The calculated Gately index is shown in Table A key issue in a cooperative game concerns the stability of a coalition, which can be evaluated with the Gately index. This index measures a player’s ability to harm other players if it leaves the coalition Gately4. The caThe water allocations obtained with the cooperative approach are displayed in Fig. Each country devises strategies for interacting with the other countries. Afghanistan occupies the upstream portion of the Harirud Basin, and it may pursue a compromise strategy and allow larger flow to the downstream countries, resulting in larger revenue for Iran and Turkmenistan. Afghanistan, on the other hand, may use more water and reduce the downstream revenue. The downstream countries have two strategies: (1) they can choose a strategy of compromise with Afghanistan’s strategy seeking to improve basin management, or (2) they can adopt a strategy of opposition to Afghanistan’s strategy and seek to undermine it.The formulation of the non-cooperative game is adjusted by incentives from the downstream countries to the upstream county, and the optimization is implemented to maximize agricultural revenue. The incentive is structured such that Iran and Turkmenistan would give Afghanistan $1.5 million and $0.5 million, respectively, for each additional million cubic meters of water that Afghanistan releases to the downstream countries.The combinations of strategies of the three countries are listed in the payoff matrix of Table The annual water allocation calculated with the non-cooperative approach when Afghanistan is oppositional and Iran–Turkmenistan compromise is depicted in Fig. The combined annual revenues of the countries corresponding to the three allocation approaches are depicted in Fig. The individual countries’ revenues are displayed in Fig. Figure Figure It is concluded from the data presented in Figs. This study developed a mathematical programming model for water allocation to maximize the interests of the countries in a transboundary river basin and apply restrictions on their uses of the transboundary river water. The river system features one upstream country and two downstream countries. The volumes of water available to meet the countries’ urban and agricultural water demands are considered in this study.The GA was applied to allocate the transboundary river water. The initial-conditions water allocation was performed by maximizing water supply reliability. The percentages of the Harirud River’s flow allocated to Afghanistan, Iran, and Turkmenistan equalled 34, 40, and 26, respectively.Water allocation was carried out with a cooperative game theory approach to maximize agricultural revenue. The shares of river flow allocated to Afghanistan, Iran, and Turkmenistan were 36, 42, and 22%, respectively. Turkmenistan was the most likely country to leave the coalition. Iran's Shapley value was higher than those of the other countries in the coalition because its contribution to the coalition’s revenue profits is the largest by virtue of its large agricultural output.River water allocation was also calculated with a non-cooperative game theory approach. Countries could choose to be compromising or oppositional. Afghanistan releases more water downstream when taking the compromise strategy, and increases the amount of water withdrawn for itself when it chooses to be oppositional. Iran and Turkmenistan pay incentives to lure Afghanistan to be compromising and deprive Afghanistan of this benefit if it chooses to be oppositional.The Nash equilibrium outcome of each country was determined by entering the results obtained from the combination of the countries’ strategies in the payoff matrix. The Nash equilibrium in this matrix occurs when Afghanistan is oppositional and the other two countries are compromising. This situation gives rise to a Nash equilibrium under non-cooperation in which the water allocations to Afghanistan, Iran, and Turkmenistan are 42, 38, and 20% of the river’s flow, respectively.The allocations were evaluated using stress criteria. The human water-stress criterion indicates that Iran, due to having the largest population in the Harirud River basin, endures stress. Instead, Turkmenistan endures the least stress. The agricultural stress criterion was also calculated by the three water-allocation approaches, and the results showed that the amount of water allocated per unit of agricultural land in Afghanistan is the largest. Iran and Turkmenistan face relatively similar agricultural stress. The results concerning the evaluation criteria indicate the best revenues for Turkmenistan, Iran, and Afghanistan are obtained with the initial-conditions water allocation, the cooperative, and the non-cooperative approaches respectively.This study’s results demonstrate that transboundary river water must consider all probable strategies and all possible approaches. In this manner, countries can strategize based on the benefits and costs associated with probable strategies. The results obtained for the Harirud Basin explain the strategies followed by Afghanistan, Iran, and Turkmenistan in recent years. Afghanistan earns the most revenues from water use dictated by a non-cooperative approach. Iran attempts to meet its water needs with a cooperative approach. Turkmenistan is satisfied with the current situation and cooperates with Iran because it currently receives 50% of the water downstream (more than the share it would receive if it follows different strategies).This study showed that the allocation results for water allocation of a transboundary river basin will change depending on the variable behavior of countries and the uncertainty in the decisions of countries located in the basin. Results denoted that the upstream country is not willing to cooperate because of the benefits of maximum consumption. Also, the downstream country, which is larger in terms of agricultural economy and number of inhabitants in the region and irrigable land area, tends to cooperate with the upstream country in order to meet the needs of its region. In other words, for further research, it is necessary to add other parameters that are benefits other than the benefits of water consumption to the issue of allocation so that all countries may become cooperative. In the current situation, the Harirud basin does not have sustainable management of water resources and the environment, and probably will face more serious problems in the future for all riparian countries. Cooperative management of the transboundary river basin would produce the best long-term outcomes for the transboundary countries. This would require the countries to make some concessions in exchange for achieving sustainable water management that would produce benefits for all of them indefinitely.