Transient osteoporosis of the hip, also termed transient bone marrow edema, is a painful condition often occurring after trivial trauma. It can be diagnosed with MRI in patients whose radiographs are negative or inconclusive. In this case report we describe a 39-year-old female patient with this rare entity, who was successfully treated with oral Alendronate, active vitamin D and calcium supplementation combined with avoiding of weight bearing on the affected hip. She improved clinically within three months and on contrast enhanced MRI studies, as performed before and after treatment, complete regression of bone marrow edema was shown already after three months of treatment. The literature was reviewed regarding the pathophysiology of transient osteoporosis of the hip and the beneficial effects of Alendronate in this domain. The report is important because it will increase the awareness among clinicians and radiologists about this entity, as in neglected cases transient regional osteoporosis of the hip may progress to avascular necrosis with complete loss of hip function. T1-weighted magnetic resonance imaging (MRI) but with high signal intensity on T2 MRI or in short tau inversion recovery sequences [Bone marrow edema (BME) is a radiological term describing a region with low signal intensity on Painful conditions of the hip are often difficult to assess clinically, which may lead to a reliance on imaging for diagnosis. The diagnostic imaging pathway for hip pain has evolved considerably with the advent of MRI, supplanting bone scintigraphy as the investigation of choice for the assessment of symptomatic hip joint(s), in patients with acute non-traumatic hip pain whose radiographs are negative or inconclusive TOH, which is also termed transient BME, most commonly seen in middle-aged men and often occurring after trivial trauma or sport related injuries The current case report presents a female patient with TOH and extensive unilateral hip BME pattern that showed almost complete regression on follow-up MRI after 3 months of treatment with oral Alendronate Sodium 70 mg . The case is discussed and the literature is reviewed regarding TOH and potential efficacy of Alendronate as off-label treatment in this domain.A 39-year-old female patient presented with acute right knee pain and contusion after fall. During 2 months, she was treated for a right knee contusion, and an MRI of the right knee showed no signs of internal derangement. The patient started to develop progressive limping and presented in our facility for a second opinion. Careful clinical assessment indicated that the patient has a limping and antalgic gait pattern, as well as an inability to bear weight on the affected side and the right hip was painful on internal and external rotation. Further clinical assessment showed a positive Trendelenburg sign  during a single leg stand on the affected right side). A radiograph of the hip joints showed no evidence of femoroacetabular impingement (FAI).Contrast enhanced MRI of both hip joints revealed extensive BME involving the right femoral head, right femoral neck and extending into the intertrochanteric region with no evidence of MRI signs suggesting AVN,  a, b, c TOH was first described by Curtiss and Kincaid in 1959 Furthermore, histological examination of core biopsy of the hip in patients with BME syndrome of the hip to assess bone metabolism revealed significantly raised levels of bone markers such as bone-specific alkaline phosphatase, osteocalcin, procollagen Type I N-terminal propeptide, and C-terminal cross-linking telopeptide, which were 4-16-fold greater than observed in serum. Taken together, Alendronate efficacy in TOH is linked to inhibiting activated osteoclastic process and as a result preventing bone resorption that can lead to femoral head collapse and eventually AVN. In addition it has a potent analgesic effect on bone which is still an important issue in this domain In general BME syndromes (BMES) often refer to transient clinical conditions with unknown pathogenic mechanisms, including many entities such as TOH, regional migratory osteoporosis, and reflex sympathetic dystrophy. The disorder mainly affects the hip, the knee, and the ankle joints. Many hypotheses have been proposed to explain the pathogenesis of the disorder but unfortunately, the etiology of BMES remains obscure Some other Bisphosphonates showed similar efficacy in treating TOH ,15. IntrTOH is a serious hip disorder with potential progression to AVN and femoral head collapse in case of missed or delayed diagnosis. Treatment with oral once weekly doses of Alendronate appears to be a very effective “off-label” line of treatment for TOH, with extensive BME pattern.All the authors confirm that this work is never published before and currently not considered for publications elsewhere. All the authors have made substantial contributions to all of the following: (1) the conception and design of the report, acquisition of data, analysis and interpretation of data and drafting the article or revising it critically for important intellectual content and all approve this version to be submitted.The patient consent has been obtained.None to report.


Growing human population size and the ongoing climate crisis create an urgent need for new tools for sustainable agriculture. Because microbiomes have profound effects on host health, interest in methods of manipulating agricultural microbiomes is growing rapidly. Currently, the most common method of microbiome manipulation is inoculation of beneficial organisms or engineered communities; however, these methods have been met with limited success due to the difficulty of establishment in complex farm environments. Here we propose genetic manipulation of the host plant as another avenue through which microbiomes could be manipulated. We discuss how domestication and modern breeding have shaped crop microbiomes, as well as the potential for improving plant-microbiome interactions through conventional breeding or genetic engineering. We summarize the current state of knowledge on host genetic control of plant microbiomes, as well as the key challenges that remain. As the human population grows, food production must increase accordingly despite global climate change presenting more challenging conditions for crop production. Conventional agriculture has been largely successful at maintaining yields while adapting to environmental challenges. However, it has also caused environmental degradation, including non-point source pollution, declines in soil productivity, pesticide resistance, and reduced genetic diversity. Recently, plant microbiomes have received growing attention as possible tools for sustainable agriculture. A wide range of microbiome benefits have been reported, including protection against pathogen and pests , increasNext-generation sequencing technologies and culture-dependent methods have advanced the field of microbiome engineering, especially the production of microbial inoculants. The application of microbial inoculants is intended to increase a target function, such as vigor or biocontrol activities; however, their success is highly variable with few inoculants efficiently translated from greenhouse to field . Some caDecades of evidence have established that plants change the abiotic and biotic properties of soils, which in turn impact plant performance and agronomically important traits—a process known as plant-soil feedback PSF; . These fWild plants have selectively assembled microbiomes over their evolutionary histories, which have been disrupted by crop domestication and subsequent breeding . By seleEngineering microbiomes via the host genome has a major advantage over current microbial products in that it does not require changes to infrastructure or management, since plant breeding and genetic improvement is already common practice . In convTo date, most work on host genetic control of the microbiome has demonstrated differences in microbiome composition among cultivars or accessions with no well-defined genetic relationship to each other, often chosen to represent a breadth of diversity within the host species . A minorBecause most microbiome members derive from the host’s immediate surroundings , plant gIn addition to plant morphology defining the available microbial habitat, chemical modification of the host-environment interface also affects recruitment of beneficial microbes. Roots exude a range of molecules, including sugars and signaling compounds, that alter soil chemistry and provide nutrients for resident microbes . These eAfter the initial recruitment, plants are able to regulate their microbiomes through a variety of mechanisms including resource allocation and immune activity. In the well-studied legume-rhizobia mutualism, for example, plants can reduce the amount of carbon that they provide to bacterial strains that have colonized root nodules but do not provide nitrogen in return . ArabidoMicrobial growth and activity is also directly regulated by the plant immune system. The immune response begins with the activation of PRRs, which can detect a variety of highly conserved microbe-associated molecular patterns (MAMPs) such as flagellin and components of fungal and bacterial cell walls  . For thiTogether, these studies demonstrate that modification of just one or a few genes in the host plant can profoundly impact the composition and function of the associated microbiome. These effects on plant-microbiome interactions should therefore be considered when developing new cultivars with desirable traits. However, several key challenges will have to be overcome before genetic modification of crop plants can be used to precisely fine-tune the microbiota for enhanced productivity.per se  can be successfully targeted through conventional breeding. This is particularly true given that selection for microbiome properties would likely reduce the efficiency of breeding for more accessible traits such as yield or disease resistance.The invisibility and immense complexity of plant microbiomes present an immediate challenge for conventional breeding, which requires the ability to measure traits of interest quickly and inexpensively for very large numbers of plants. The current least expensive way to quantify microbiomes is via high-throughput amplicon sequencing; yet this approach quickly becomes cost-prohibitive at the scale needed for conventional breeding. Thus, barring major technological advancements that reduce these costs, it is unlikely that microbiome properties post hoc sequencing or subsequent experimentation. Recently, An alternative approach would be to select on variation in plant responses to microbes, which would not require quantification of the microbiome itself. Indeed, it is plausible that selection on emergent plant traits that are responsive to microbes has already indirectly and unintentionally shaped variation in crop-microbe interactions . HoweverEven if microbiomes could be phenotyped in a cost-effective way for whole breeding populations, translating microbiome composition data into actionable understanding of community function presents its own considerable challenge. The usefulness of amplicon sequencing for understanding microbiome function is limited both by the inability of barcoding genes to resolve taxa at the strain level, and by a lack of information about the metabolic abilities and behaviors of those taxa. Despite tremendous progress in the description of the plant microbiome, more fundamental studies are needed to determine how community composition translates into function. This is particularly important for agriculture, since some microorganisms have been shown to modulate abiotic and biotic stress, but the role of the rest of the community is unknown. Addressing microbiome function is challenging and will require multifaceted approaches, including advancements in experimental design, microbiome characterization, and modeling .One promising experimental approach is the use of synthetic communities of culturable microbes that can be recombined into consortia to observe their interactions and effects on the host . Such stAnother way to learn about microbiome function is to go beyond amplicon sequencing  by incorporating multi-omics methods. Because the same functions can be fulfilled by more than one organism , this fuFinally, improved modeling methods will assist with translating microbiome composition to microbiome function. Often, these involve innovative computational tools to derive new insights from large multi-omics datasets that are not amenable to standard statistical approaches . Recent Although the studies summarized above demonstrate the potential for genetic modification of plants to alter microbiomes in useful ways, most of them report results from experiments performed in laboratory conditions. It is unclear whether the same effects would be observed across the range of complex environments that plants encounter in the field. Most complex plant traits exhibit some degree of interaction between genotype and environment (GxE), reflecting genetic variation for phenotypic plasticity. Because plant phenotypes influence colonization and establishment by different microbes, plant microbiomes also reflect this GxE. However, because plant-associated microbiomes are derived from the environmental pool of potential colonists, they are shaped by an additional source of environmental variation: abiotic factors that influence microbial biogeography, such as soil pH . FinallyIndeed, most studies of microbiome composition in complex environments have observed that GxE effects are at least as strong as any main effect of genotype . Partly GxE is a classic and widespread challenge for plant breeders working to improve almost any trait , and to The improvement of crop microbiomes via genetic manipulation of the host is a promising approach because it has the potential to promote plant-driven enrichment of beneficial microbes from any environment and any soil community. In addition, it requires no additional resources or inputs, and avoids any unforeseen consequences of introducing new organisms into established agroecosystems. However, such methods are likely a long way in the future. A great deal of research is needed to provide the scientific foundation that would enable actionable genetic improvement strategies with predictable outcomes for microbiome function. We are currently limited by our understanding of both (1) how plant genetic variation maps onto microbiome variation, and (2) what features of the microbiome should be modified to make it “beneficial” for a given plant in a given environment. Even when both of these questions are answered in a given system, the immense complexity of natural microbiomes can mask compelling effects that were seen in a laboratory setting . In the KC and MW conducted the literature search and wrote the article. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pinus taeda L.), the most-planted tree species in North America. We describe and discuss the implementation of management and breeding strategies to increase resilience and adaptation, and discuss how new technologies in the areas of engineering and genomics are shaping the future of phenotype-genotype studies. Lessons learned from the study of species important in intensively-managed forest ecosystems may also prove to be of value in helping less-intensively managed forest ecosystems adapt to climate change, thereby increasing the sustainability and resilience of forestlands for the future.Earth’s atmosphere is warming and the effects of climate change are becoming evident. A key observation is that both the average levels and the variability of temperature and precipitation are changing. Information and data from new technologies are developing in parallel to provide multidisciplinary opportunities to address and overcome the consequences of these changes in forest ecosystems. Changes in temperature and water availability impose multidimensional environmental constraints that trigger changes from the molecular to the forest stand level. These can represent a threat for the normal development of the tree from early seedling recruitment to adulthood both through direct mortality, and by increasing susceptibility to pathogens, insect attack, and fire damage. This review summarizes the strengths and shortcomings of previous work in the areas of genetic variation related to cold and drought stress in forest species with particular emphasis on loblolly pine ( Plants experience stress when they receive any type of stimulus that disrupts metabolic homeostasis and affects growth, development, and productivity. During the first phases of the stress event, the plant will use energy to find a new equilibrium by adjusting metabolic pathways, thereby increasing the probability of survival in a process that is usually referred to as acclimation or physiological adaptation.Two general mechanisms of dealing with stress are avoidance and tolerance. Avoidance implies that plants evade the stressful condition by preventing or reducing the exposure to its deleterious effects, whereas tolerance consists of responses that enable plants to endure or withstand the adverse conditions . These mThis is particularly interesting in the case of cultivated forest tree species for which genetic improvement programs exist and provide a significant fraction of planting stock for reforestation. In these species, breeders have typically focused on selection of trees with improved productivity and quality traits under climate conditions that were expected to vary little over time. Unfortunately, climate change is associated with increases in both the variability and the average levels of temperature and water availability, leading to extreme variability of weather events recently called “weather whiplash.” This phenomenon has been highlighted as a major issue that will affect the way plants and animals will mitigate and adapt to future climate conditions . These cManaged agricultural and forest ecosystems can be modified both through changes in management practices and by choice of resilient and well-adapted planting stock, but stress response plasticity and the genetic differences that underline tolerance and resistance are still largely unknown in conifers. The combination of new phenotyping technologies and genomic tools has allowed major advances in understanding of the genetic basis of abiotic stress response in Populus species e.g., , particuPinus taeda L.) is the most-planted forest tree species in North America  compared to eastern sources but that the western sources generally grew slower , had longer root systems and were more prone to xylem cavitation . Another needles , 2016. Odictions .in situ because gases are insoluble in ice (Lauris nobilis L.)  and freeze-thaw cycles (frost drought) . In the e in ice . Despitee in ice , a debate in ice , and theilis L.) , 2015. Tilis L.) . This coconduits . The ideconduits .Picea abies is able to survive winter embolism based on periodic xylem refilling during spring. On the other hand, Evergreen conifers suffer frost drought when the ice in soil, roots and frozen trunk parts prevent water uptake for months, while needles can reach substantially higher temperatures than the air during sunny winter days causing relevant water losses , 2006. RFor loblolly pine plantations, productivity has been the result of years of intensive management and silviculture advancements that have enabled a higher profitably for a variety of uses in very short rotations (8–12 years) . The strPlant carbon starvation is the physiological result of an imbalance that occurs when carbon supply from photosynthesis, non-structural carbohydrates (carbon storage compounds) and metabolites from autophagy are not enough to maintain the carbon demands for respiration, growth and defense . MaintaiPinus echinata), loblolly pine, and their hybrids under limited water conditions. Drought tolerance is linked to survival in the first years of planting and therefore to long-term productivity, and “shortleaf pine is presumed to be more drought tolerant than loblolly pine”  (Picea glauca (white spruce) (Pinus taeda (loblolly pine) (Pinus lambertiana (sugar pine) (Ginkgo biloba (ginkgo) (Pseudotsuga menziesii (Douglas fir) (Gnetum montanum (Larix sibirica (Siberian larch)  (Sequoiadendron giganteum (giant sequoia)  , Picea g spruce) , Pinus tly pine) , Pinus lar pine) , Ginkgo (ginkgo) , Pseudotlas fir) , Gnetum montanum , Larix sn larch) , Abies aver fir) , and Seqsequoia) . The lonsequoia) . A large2O2, nitric oxide and Ca2+ by splicing, and the addition of a 3’ polyA tail by polyadenylation. Plant studies have shown that alternative splicing (AS) and alternative polyadenylation (APA) are important mechanisms involved in the regulation of the proteome, but there is only a limited knowledge of the interaction between these mechanisms and their interplay during transcriptional and post-transcriptional regulation in plants. During AS, multiple messenger RNA (mRNA) isoforms are produced from a single gene enhancing the functional diversity of the proteome during development  and undeed in AS ; identifed in AS  specificed in AS . The poted in AS  and alleed in AS  in transPicea abies (L.) Karst.] were moved to a southern seed orchard location in order to enhance seed production. Bud set in full-sib progeny produced by the cloned northern selections located in the southern orchard (lat. 58° N) environment were delayed up to 3 weeks compared to their half-sibs from the same mother trees growing in the northern (63° N – 66° N) natural stand (Picea glauca) (Pinus sylvestris)  , Scots pvestris) , and Larrix spp. .Pinus echinata Mill.). Ramets of 22 shortleaf pine clones were established in two diverse environments, one located in central Arkansas, United States (34.6° N), near the source of the ortets, and the second site located in south Mississippi (30.5° N) (P = 0.018). The authors concluded that after-effects of reproductive environment do exist in shortleaf pine for growth and adaptive traits but are not as clear-cut nor at the same scale as that reported by It follows that an adaptive epigenetic memory may have important implications for seed production sites in the southeastern United States. According to 30.5° N) . Thirtee30.5° N) . In the The current major goal of biological sciences is to generate functional models that integrate genome and phenome, allowing a multidimensional knowledge of the biology of organisms and the prediction of how they will behave under future scenarios. Several emerging global technologies  are identifying and measuring changes in the molecular components under a broad set of experimental conditions including several abiotic and biotic stresses. On the other hand, next-generation phenomics measures changes in the physical attributes on a genome-wide scale that an organism overcomes during its lifespan. Both data and analytical pipelines have grown exponentially by the application of high-throughput systems. Advances in these areas are creating the next-generation breeding techniques that will reshape the way we have done agriculture until now (revised in The introduction of a number of highly user−friendly (and portable) chlorophyll fluorometers as well as more sophisticated high throughput hyperspectral imaging have enhanced not only the accuracy of chlorophyll measurements but also the implementation of large phenotyping platforms with the automatic control and data analysis system, which allows performing parallel studies of a large amount of plants during long cycles of growth under constant monitoring and different environments . Light eDuring the last 20 years researchers have advanced in the development of high throughput plant phenomics studies in controlled environments like growth chambers and greenhouses by the implementation of imaging systems, pipelines for analysis and interpretation models that would enable the use of genotypic data and novel gene discovery in a more efficient way, moving these systems toward a real optimization of plant breeding. There are limitations for predicting the performance of commercial plant varieties under field conditions based on plant phenotyping in controlled environments, but these systems are particularly useful in studying how plant phenotypes vary among different genotypes in response to controlled stress conditions. Furthermore, the control over different parameters serve to study the interactions between genetic and environmental factors that can produce unanticipated phenotypic responses . PreviouTrifolium stellatum, Lagarus ovatus, and Sisymbrium erysimoides, a legume, a grass, and a forb respectively. Under conditions of limited water availability, the grass and the forb species both produced more biomass when grown in soil from a drier site than in soil from a region with higher average precipitation. Ostrya virginiana (American hop hornbeam) and Betula nigra (river birch), both angiosperm tree species native to eastern North America, in sterilized soil from different regions inoculated with soil microbiome samples from different regions. They found that microbial inoculum from regions with lower precipitation supported greater seedling biomass production under water-limited growth conditions than the inoculum from regions with higher precipitation, regardless of the soil source. Multiple reports have described significant effects on plant drought response of growing plants in soil from a region with less precipitation than is typical of the natural range of the species in question . O’BrienA meta-analysis of data from 126 papers  presenteClimate models suggest that the southeastern United States is likely to show significant changes over the next 50 years in the length of the frost-free growing season and the average late-winter (March) minimum temperature , and in Picea, Pinus, Abies, and Cryptomeria. Several early studies with loblolly pine reported genetic variation both among loblolly pine provenances and among families within provenances (Intra-specific genetic variation for drought tolerance has been observed in many species, including genera such as venances . The obsvenances . This coTwo key questions for breeders are what phenotypes to measure, and which trees to select. The answer will be different for different species, because the sensitivity to drought and the hazard from drought will vary across regions and species. For loblolly pine in the southeastern United States, the initial stage of plantation establishment is particularly important in terms of drought. The first year after seedlings are planted in the field is the most critical time in terms of water availability, because the root systems are still small and unable to reach water in deeper soil horizons. Selection for the ability of pine seedlings to survive a period of limited water availability during the first year could reduce the risk of plantation failure, and should also be a relatively easy trait to measure under controlled conditions. An additional advantage of working with seedlings at this age may be that the physiological or genetic mechanisms of resistance need not be identified in advance, provided that screening methods mimic as closely as possible the kind of drought stress to which resistance is desired. Projections from ensemble climate models  suggest Integrative studies that combine surveys of genetic variation across the natural range with analyses of gene expression, high-throughput phenotyping data, and analyses of replicated test plantings derived either from experimental crosses or from accessions collected from natural populations, have provided new insights into mechanisms of drought tolerance and other complex phenotypes in some non-model species ,b. Some Genomic approaches to understand and improve drought responses in trees have been reviewed , and addMost conifer breeding programs work with families of progeny as the genetic entries in field tests, because inbred lines are typically not available. The most advanced breeding programs in loblolly pine are only five to eight generations from trees selected from wild populations, but pedigree records showing the relationships across multiple generations are available for many individuals in the advanced-generation breeding populations . These fPatterns of linkage disequilibrium in the loblolly pine genome are very different from those found in human populations , so a poRW and LM-R conceived the idea of the review and prepared the initial outline. LM-R contributed KP is Director of the Cooperative Tree Improvement Program at NC State University, a public-private partnership founded in 1956 that receives funding from stakeholders in the forestry sector including landowners, seed producers, seedling nurseries, and timberland management organizations. The remaining 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.


Reading acquisition reorganizes existing brain networks for speech and visual processing to form novel audio-visual language representations. This requires substantial cortical plasticity that is reflected in changes in brain activation and functional as well as structural connectivity between brain areas. The extent to which a child’s brain can accommodate these changes may underlie the high variability in reading outcome in both typical and dyslexic readers. In this review, we focus on reading-induced functional changes of the dorsal speech network in particular and discuss how its reciprocal interactions with the ventral reading network contributes to reading outcome. We discuss how the dynamic and intertwined development of both reading networks may be best captured by approaching reading from a skill learning perspective, using audio-visual learning paradigms and longitudinal designs to follow neuro-behavioral changes while children’s reading skills unfold. Despite standardized curricula and teaching programs at school, children reach very different levels of reading fluency. Proficiency in reading determines personal achievement not only during primary and secondary education but also societal attainment later in life . This esThe acquisition of reading requires years of practice and is accompanied by a gradual re-shaping of existing dorsal spoken language and ventral visual brain networks into an integrated audio-visual reading network. Thus, when a child learns to read, striking changes occur in higher-order visual regions of the (left) ventral occipito-temporal cortex (vOTC) which becomes increasingly responsive to and specialized in written text perception . FurtherDevelopmental dyslexia provides a good model for investigating the role of the dorsal and ventral brain networks in reading development as most dyslexic readers show difficulties in handling the sound structure of spoken language  and in fA major challenge in understanding dyslexia lies in its highly heterogeneous behavioral manifestation. Suggested causes include – but are not limited to – deficits in letter-speech sound integration , poorly By the time children start to learn to read, neural functions for speech perception and production have already gone through several years of functional refinement. Spoken language functions thus form a linguistic basis for reading acquisition both from a phylogenetic and an ontogenetic perspective . Since tFurther support for a key role of the superior temporal cortex in learning to read comes from developmental neuroimaging studies showing that the strength and/or extent of speech evoked responses in this region is associated with children’s reading level , and phoA relation between reading development and morphological characteristics of the superior temporal cortex can be located within a more general pattern of protracted, experience-related changes in pSTC morphology, which have been observed to continue well into the third decade of life, particularly in the left hemisphere . SimilarThe protracted functional and morphological development of the pSTC in the posterior dorsal network may be key to the gradual build-up of neural associations between visual symbols and corresponding spoken language representations and, on a more general level, the strong bi-directional influences between reading and spoken language development . EvidencWhile the pSTC seems to be especially relevant for the processing of already learnt letter-speech sound associations , the infThe anterior part of the dorsal network houses the inferior frontal gyrus (IFG) which is increasingly recruited while beginning readers improve their reading ability and phonological skills . FunctioA core area for developing fluent reading in the ventral reading network is the putative visual word form area (VWFA) within the left vOTC. This area has been shown to become increasingly specialized for text over the course of reading development  and to bOne important open question is the extent to which the commonly observed reduced recruitment of regions within the dorsal and ventral reading networks in dyslexic readers constitute risk and/or protective factors in the etiology of dyslexia, or alternatively reflect consequences of a history of reading problems  genetic  and sociIn line with the idea that the brain’s reading network is formed through the association of written to spoken language representations, our understanding of individual differences in reading development will benefit from a detailed understanding of learning processes underlying the formation of these associations. Studies investigating dyslexia intervention targeting letter-speech sound automatization, have shown improvements in reading outcome and in brain responses associated with letter-speech sound integration following intervention , 2017. HA promising platform to investigate audio-visual learning mechanisms can be found in artificial symbol – (speech) sound training and phonetic recalibration paradigms. Artificial symbol – sound training involves mapping known speech sounds onto novel visual symbols, thus directly targeting reading-related learning skills. Despite the observed association between pre-literate children’s symbol-sound learning performance and their early reading skills , 2018, nAnother paradigm that enables examining perceptual mechanisms associated with short-term audio-visual learning is phonetic recalibration  readers reflect vulnerabilities or risk factors for developing reading problems versus strengths or compensatory factors, or, especially in older children and adults, consequences of a history of reading problems. Promising experimental paradigms to disentangle these different explanatory possibilities are learning paradigms, such as artificial script learning and text-based recalibration that permit to trace children’s actual learning trajectories. Ideally, these types of paradigms should be combined with a longitudinal multi-level approach incorporating developmental dynamics at various levels including genetic, social environmental, cortical and subcortical brain changes as well as cognitive and behavioral factors . This apAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.This review is part of a Ph.D. research project funded by the Netherlands Organization for Scientific Research (Vidi-Grant 452-16-004 to MB).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.


Introduction. The COVID-19 pandemic placed an unprecedented strain on academic healthcare systems necessitating a pause in medical student teaching in clinical care settings, including at Weill Cornell Medicine (WCM). WCM had a preexisting telemedicine curriculum, but limited opportunities for students to apply knowledge and skills related to direct virtual patient care. The authors describe the rapid implementation of real-time interactive telehealth experience (RITE) courses for clerkship students to allow for meaningful engagement in remote patient care and continuation of academic progress during the pause.Methods of Course Development. Medical school administration disseminated a request for proposals for RITE courses conforming to the WCM electives format with rapid turnaround time of 1 week or less. Requirements included remote care activities, goals and objectives, general logistics, supervision methods and standards of achievement. RITE courses were developed in outpatient medicine, inpatient medicine, psychiatry and women’s health. A lottery process was developed to register students for the approved courses.Course Implementation and Evaluation. Using the technical platform and standard course registration process, students were assigned to 74 of 76 available RITE course slots. Students participated in supervised remote direct patient care and also provided critical support for frontline healthcare workers by performing remote clinical tasks. Online teaching and reflection sessions were incorporated into each RITE curricular offering. Student feedback was overall positive ranging from 3.33–4.57 out of 5.Discussion. The COVID-19 pandemic created a need to rapidly incorporate telehealth models in order to continue to deliver patient care and an opportunity to develop innovative remote educational experiences. We developed a framework for structured real-time interactive telehealth experiences to address COVID-19 related curricular needs that will be continued post-COVID-19. This expanded telehealth curriculum for our students will provide standardized training in telehealth logistics, communication techniques, and care delivery now essential for graduating medical students. This surge of patients strained healthcare resources and necessitated increased capacity in intensive care unit beds and redeployment of residents and teaching faculty2. Personal protective equipment (PPE) shortages, limited availability of testing, and multiple residents and faculty out on self-isolation or quarantine further impacted the strain on the system3. Additionally, for the first time in the history of our general medicine services, patients were placed in complete isolation from social support, forced to face the fear of potentially life-threatening diagnoses alone. In light of all of these factors, the clinical care setting was no longer an effective or sustainable teaching and learning environment for medical students.The impact of the COVID-19 pandemic on healthcare systems in the USA has been unprecedented. New York City quickly became an epicenter of disease activity in the late winter and early spring of 2020, leading to a rapidly increasing number of critically ill patients admitted to academic medical centers4. All clerkships underway at the time of the pause quickly transitioned to a remote learning format for the next 2 weeks using recorded lectures, interactive remote cases, and live-streamed discussions and readings to allow students to complete these courses. When these clerkships ended the last week of March 2020, the challenge was to develop an approach to continuous academic progress for the clinical clerks during the pause of in-person clinical training.In early March 2020, in consultation with its primary teaching hospital system, Weill Cornell Medicine (WCM) made the difficult but necessary decision to suspend all medical student teaching in clinical care spaces. This decision was made by multiple other medical schools and supported by a statement from the Association of American Medical CollegesCentral medical education and clinical curriculum leadership agreed that core clerkships could not be continued in the absence of patient contact since the centerpiece of clerkship training in medical school is direct patient care. Additionally, person power for core educational activities was strained as many clerkship teaching faculty and clerkship directors were deployed for COVID-19 related clinical needs. The challenge for second-year clinical clerks was acute since they had only completed a quarter of their core clerkship year. These students were in a position where graduation timelines would be jeopardized without ongoing academic progress.In response to the rapidly evolving COVID-19 pandemic and its impact on the education mission, the Senior Associate Dean of Education convened a COVID-19 response steering committee (CRSC) which met daily throughout the months of March and April 2020. The following guiding principles for the medical education program were established by the CRSC [1]; prioritizing public health imperatives and the safety of students, faculty, staff, and patients [2], continuing delivery of effective content to meet core medical education goals and objectives [3], continuing attention to student academic support, advising, and wellbeing programming, and [4] exercising flexibility of thought and approach, in alignment with any relevant accreditation and state guidelines to allow for adjustments in response to changes in the pandemic and for potential innovation. CRSC members were assigned to individual COVID-19 response committees (CRCs). Each CRC was charged with developing strategic approaches to an assigned area of the medical education program , with adherence to guiding principles.The CRC: Clinical Curriculum was tasked with development of strategies to ensure students would continue making effective academic progress in the clinical curriculum. This CRC recognized that telemedicine was both a necessity during COVID and a well-established area of institutional strength, to which students previously had limited exposure in the patient care setting. Therefore, a recommendation was made to capitalize on this strength and leverage telemedicine to enable academic progress and meaningful student engagement in the clinical care mission during COVID-19.In response to this recommendation, the clinical curriculum office put out a request for proposals to clinical department educational leaders for real-time interactive telehealth experiences (RITE) with a five-day response deadline. The experiences would include supervised and educational task-oriented responsibilities to enhance remote clinical care efforts. The goal was to design a menu of credit-bearing options in which students could enroll over a projected 8-week pause in on-site clinical care activities. Faculty were asked to follow the standard WCM elective format and list goals and objectives, prerequisites, course length, maximum enrollment, general logistics, supervision methods and standards of achievement. In addition to patient care responsibilities, online didactic teaching in addition to debrief and reflection sessions were required. All RITE courses were graded pass/fail, in alignment with all elective offerings at our institution.Four departmental groups responded with RITE proposals. These included faculty from ambulatory and emergency medicine (EM), obstetrics and gynecology, psychiatry and hospitalist medicine . The proSixty students opted to register for RITE program offerings and were entered into the registration lottery. Of the 76 available slots, 74 were filled in the lottery process by 60 unique students. Analysis of the lottery results revealed that 89.7% of students received their top choice, and 100% received 1 or more courses in their top three. The RITE programs that were developed spanned various specialties of medicine. All the offerings incorporated remote patient care experiences, but each had an individualized general structure and learning objectives .Table 2.Patient Care Related ActivitiesThe Frontline Care: Virtual Team Member for COVID Hospital Medicine Teams course was developed to address one of the greatest needs identified within our institution during this unprecedented crisis – providing social support to an increasingly vulnerable COVID-19 suspected and positive patient population. Students were assigned to hospital medicine teams and were responsible for maintaining virtual contact with persons-under-investigation (PUI) and COVID-19 positive patients during a time when no visitors were allowed in the hospital.Students were available to function as virtual team members (VTM) Monday through Friday and assigned up to five patients at a time. Students were directly supervised by a hospitalist attending physician. Patients were excluded if they declined follow-up calls, were unable to engage in conversation due to cognitive impairment or oxygen requirements, or were admitted to the intensive care unit. Students used phone interpreters to communicate with limited English proficiency patients. As the number of post-COVID-19 recovery patients remaining in the hospital increased, students were also assigned to the COVID −19 Recovery Unit teams for the latter portion of the rotations.VTMs were primarily responsible for providing daily updates by phone and video calls to isolated patients and family members emphasizing essential communication skills and tasks related to care coordination. Clinical tasks were performed based on need and included obtaining and updating outpatient medication histories for new admissions, obtaining collateral information from the primary outpatient physician or other source, performing verification of insurance coverage and availability of high-risk discharge medications, providing discharge instructions to both patients and their families regarding post-COVID-19 care and management, and reviewing checklists to help patients prepare for discharge follow-up telehealth visits.Students were also directed to call patients on their hospital room landline or cell phone, including video calls when available, with a goal of twice-daily check-ins arranged at the patient’s convenience as an ‘appointment’ to help orient them to time. Students were clearly instructed to communicate any change in status or new issues raised by the patients or recognized by the students during the daily calls to the primary medical team. Students documented the calls in the electronic medical record and this documentation was routed to their attending supervisor for review and approval.Didactic ActivitiesFaculty experts in infectious disease, mental health, medical ethics, quality improvement and patient safety conducted mandatory weekly didactic teaching sessions through video conferences throughout the course. Students were also divided into two groups of their choice to participate in either a mini-root cause analysis of a medical error they identified during the course or a quality improvement project to improve and standardize patient handoffs during a time of rapid care transfers across settings.Student Feedback and AssessmentDuring weekly debrief sessions, students and attendings shared experiences and discussed challenges and barriers in order to assess and adjust the course content and structure in real time.Students were assessed by faculty and house staff using the standard WCM clinical student performance evaluation form. The form includes questions on medical knowledge, clinical reasoning, history taking, physical exam performance, presentation skills, teamwork skills and overall professional and ethical behavior. Evaluators also provided qualitative comments, which were compiled by the course director to synthesize a narrative evaluation. Students successfully completed the course if the average summary score of their composite evaluations was above the WCM passing threshold. Final grades were reported as Pass/Fail,Patient Care Related ActivitiesThe Telehealth in the Age of COVID-19 course engaged students in the follow-up care of patients with confirmed or suspected COVID-19 after discharge from the emergency department or outpatient clinics. As part of the course, students also participated in longitudinal care of homebound patients with increased mental health needs and isolation in the context of the COVID-19 pandemic. The course was a completely remote and supervised experience, allowing students to be actively involved in clinical care even at the height of the COVID-19 pandemic, doing so in a safe learning environment. Students worked with faculty at two out of the three ‘virtual’ clinical sites: primary care, emergency medicine and the Center on Aging.At the primary care and emergency medicine sites, students contacted recently evaluated confirmed or suspected COVID-19 patients listed in a HIPAA-compliant database. Students were trained in and used a scripted electronic medical record documentation template to facilitate the encounters. They also used a decision tree to help determine the next steps during and after the encounters. Students had site-specific faculty preceptors who discussed cases in real-time if there was any indication that there was a change in patient clinical status, or the patient was doing poorly at home. Students were responsible for documenting and conveying the outcome of each call to the faculty member assigned as their preceptor for the day as well as to the patient’s primary outpatient provider. Faculty preceptors reviewed all phone call notes during each session. The students also had two, 3-hour telehealth attending shadow shifts, where they joined emergency medicine attending physicians doing telehealth encounters via video conferencing software.Students were responsible for counseling patients and providing them with ongoing anticipatory guidance, with connecting them back to their primary providers as they recovered, and in cases where urgent re-evaluation was recommended after discussion with a preceptor, students were also responsible for conveying these plans to patients. In many cases, particularly at the primary care site, this meant that students had a ‘panel’ of patients that they followed for days or even weeks, leading to opportunities for rapport building and continuity with patients and their families.At the Center on Aging site, students collaborated with social workers to create a ‘telephone reassurance’ program where students also followed panels of patients identified by their providers at the practice as vulnerable due to their chronic conditions or social isolation. They utilized a specific telephone script to make follow-up calls anywhere between 1 and 3 times a week to patients, depending on a patient’s needs. They documented all calls and forwarded them to their primary providers at the practice and to the group’s geriatrics social worker. She and one of the course directors discussed cases in real-time if the patient or students had any concerns about a patient’s safety at home. Students were trained to identify and refer patients to the practice’s social worker or directly to community organizations if they discovered issues of food scarcity, social isolation or medication access. Students were trained in and performed telephonic mental health screens and referred many patients to the mental health team at the Center on Aging.Didactic ActivitiesOn orientation day, the students completed ‘Introduction to Telemedicine’, a virtual 1-hour course created for all providers doing telehealth visits at our institution. Course faculty conducted didactic sessions on management of COVID-19 and on telemedicine techniques. Students also participated in observed simulated telephone follow-up calls. In addition, students participated in reflective exercises facilitated by faculty members who highlighted the service-oriented learning innate to the clinical work they undertook during this elective experience. At these sessions, there was also group debriefing on student experiences and feelings as ‘providers’ during the pandemic.Student Feedback and AssessmentEach student received regular real-time feedback from faculty preceptors on their medical knowledge, communication skills and their abilities at clinical reasoning and differential diagnosis based on their clinical presentations and in some cases, direct observation of their telehealth encounters. This included direct observation and feedback on clinical skills through joint phone calls with supervising clinicians.Student performance was assessed by faculty preceptors as well as social work and nursing colleagues using the standardized WCM elective student performance evaluation form. This form included Likert scales to measure core clinical competencies in multiple domains, including professionalism, interprofessional communication and teamwork. Students passed if the average summary score of their composite evaluations was above the WCM passing threshold. Overall grades were pass/fail.Patient Care Related ActivitiesThe Telehealth for Women’s Care course integrated students remotely into the general gynecology, routine and high-risk obstetrical (HROB) and postpartum outpatient clinical care teams. Students were granted access to provider scheduling templates through the electronic medical record system and took part in video visits with all providers. Students were instructed to email the providers to whom they were assigned on the day before each telehealth session. This allowed the students ample time to review the patient charts, ask relevant background questions and prepare for their involvement in the upcoming visits with the provider and patients. As the students’ knowledge base and comfort level with the technology and clinical concepts increased, they became more actively engaged with patient interactions. Students participated in the video visits by eliciting histories and discussing management plans under supervision by faculty, residents and fellows.All students rotated for 1 week with the high-risk obstetrical (HROB) faculty monitoring and caring for pregnant patients, specifically with hypertension and diabetes mellitus. During this week, students learned about the diagnostic criteria for hypertension and diabetes mellitus in pregnancy, the associated adverse outcomes in both, and treatment interventions that may safely be instituted in pregnancy.Students rotated for 2 weeks engaging in postpartum telehealth video visits. During these visits, they addressed patient concerns regarding post-delivery care, including breastfeeding, resumption of sexual activity and use of contraception. Under supervision, they provided postpartum counseling to patients on sensitive issues associated with breastfeeding and family planning. Students also took part in other routine obstetrical and gynecological problem-focused visits as they occurred during these 2 weeks. They had the opportunity to participate in counseling sessions with the social workers as well.Didactic ActivitiesThe HROB week included three hours of interactive live online teaching with the HROB faculty. During the 2 post-partum care and general gynecology weeks, students participated in interactive teaching sessions with the course director on the topics of lactation, contraception, prenatal care and pregnancy during COVID-19. During the last week students participated remotely in educational sessions and in academic debate regarding the administration of infertility treatments during the COVID-19 pandemic. These sessions were led by a faculty member from the reproductive endocrinology and infertility (REI) department. The education sessions covered an overview of assistive reproductive technologies (ART), methods of in-vitro fertilization and specific challenges surrounding ART arising during the COVID-19 pandemic. Students were then divided into two groups, and the groups were assigned to either advocate for or against using ART during COVID-19. Students carried out independent research about the topic and then debated the pros and cons.In addition to the formal didactic curriculum, the course director met with the students daily. These sessions consisted of review of challenging topics the students were seeing, course-specific concerns and feedback, future research and case presentations. Presentation topics were both COVID-19 and non-COVID-19 related. Future research ideas incorporating quality improvement, mental health, healthcare equity and literacy as well as ideas for biomedical innovations were discussed. The opportunity for student involvement in creating research protocols for both group and individual projects was established.Student Feedback and AssessmentStudents were evaluated on their level of participation, knowledge base, patient interaction and communications skills. Each student was required to complete two formal write-ups; either a clinical case of their choice encountered during their high-risk obstetrical week or during their general ob-gyn/postpartum week, as well as one topic associated with infertility. For the clinical write-up of either the high-risk obstetrical or general ob-gyn/postpartum case, students were required to include the following: complete history and physical exam, assessment and plan with a problem list and a 2–3 page discussion of one of the problems with a brief review of the basic science related to the condition with citation of relevant sources from the literature when applicable. A different format for the REI write-up was implemented since this assessment was not based on direct patient interactions. Students were expected to provide an overview of management options in addition to a discussion of ethical concerns and psychosocial issues associated with either providing or withholding IVF treatment during the COVID pandemic. To calculate the overall grade, observed communication and interaction with patients on the phone and during tele-health visits accounted for 50%, each formal case write-up accounted for 20%, and 10% was based on level of preparedness and participation during the group sessions with the course director. Final grade was reported as pass/fail.Patient Care Related ActivitiesThe Telehealth Psychiatry Liaison Elective incorporated students into a newly formed psychiatry liaison service in response to COVID-19. The service assigned liaisons from psychiatry to clinical departments and programs throughout the hospital. Liaisons offered virtual group town hall meetings and debriefing sessions, responsible for developing and implementing tailored interventions. As part of the course, students assisted in conducting the department town halls with primary oversight by an attending psychiatrist or psychologist. To ensure that students were not providing psychiatry liaison services to potential future evaluators, they only participated in town halls for nonacademic staff. They also observed training meetings for liaisons on crisis intervention.This course also included a research component as the students were also required to participate in building and managing an outcomes-focused database for the treatment team. They also assisted the overall effort of the psychiatry liaison service by performing literature reviews in preparation for grant submission on topics such as posttraumatic stress disorder and moral injury as a result of COVID-19.Didactic ActivitiesFor the first few days of the course, students learned the principles of forming a consult psychiatry liaison service. Students then learned how to triage requests from departments to develop group town halls. They were also trained in research database design.Student Feedback and AssessmentStudents were assessed based on a number of equally weighted components. These components included [1] degree of preparation for and participation in the didactic sessions [2], degree of preparation for the town halls [3], overall adherence to WCM student professionalism behaviors, and [4] the quality of their literature reviews and database management. Assessment was performed by faculty members who interacted with the students and the course director collected feedback from faculty about student performance. In order to pass the elective, students were required to meet or exceed minimum expected performance standards in each of the four domains of evaluation.Students were assessed using the standard WCM elective student performance evaluation form. The form was completed for each student by the course director within 4 weeks of the end date of the course. The form includes questions on medical knowledge, clinical reasoning, history taking, physical exam performance, presentation skills, teamwork skills and overall professional and ethical behavior. Course directors were asked to specifically assess how students performed these tasks using a telemedicine approach. Course directors were also asked to include narrative comments, which they collected from the residents and faculty supervisors who worked with the students. RITE course grading was pass/fail, and all students passed the RITE courses.Students were asked to evaluate the RITE programs using the standard WCM course evaluation form, with one custom question added: ‘Rate the added value of this course as a new learning experience, above and beyond what was learned in the required curriculum.’ Students generally rated the RITE programs highly, with a range from 3.33 to 4.67 out of 5 possible points in important categories including course quality, course organization, and amount of patient care responsibilities . The couStudents provided narrative comments related to perceived strengths and areas of improvement for the RITE program courses. Themes that emerged in a summary of program strengths included [1] ability to feel ‘useful’ to both patients and front-line providers despite being on a clinical curriculum pause [2], applied telemedicine experience, and [3] development of longitudinal relationships with patients. Themes that emerged in a summary of areas to improve included [1] challenges inherent in telehealth encounters that occurred only via telephone and [2] experiences that were more observational than experiential in busy clinical settingsThe COVID-19 pandemic created a rapid and unprecedented disruption to the medical education system nationwide, and particularly impacted medical schools in New York City. The clerkship year in medical school has always centered around care of patients. The inability for students to enter the physical clinical environment challenged the core aspect of their clinical training. In response to this challenge, we have demonstrated the successful real-time development and implementation of a program of telehealth experiences for medical students in a healthcare system strained by the pandemic. Importantly, this program ensured student safety but still allowed them to participate in a meaningful and educational way in the care of patients and continue their academic progress.5. Previously, the majority of the training at our institution focused on the mechanics and logistics of telehealth encounters and use of standardized patients for simulated telehealth encounters. Real-time development and implementation of a telehealth program for medical students with more applied application of telehealth skills was borne out of necessity due to COVID-19 and can inform processes at other schools. Even after the COVID-19 crisis has passed, we anticipate that aspects of these interactive telehealth experiences will be formalized into our core clinical curriculum. Medical students will need more structured education in communication techniques, history taking and physical exam strategies and disposition planning done over phone and video-based technology as telehealth becomes part of the ‘new normal’ in health care delivery.Prior to the COVID-19 pandemic, there has been ongoing growth in the use of telehealth models in the practice of medicine, and medical student training in telehealth has been increasing over the yearsDespite the increasing use of telehealth modalities in patient care, and the successful development of the RITE program at WCM, the authors agree that these types of experiences will not or should not replace student experiences in the physical clinical environment. In fact, the RITE experiences were designed to provide students with elective credit, but not academic credit towards clerkship completion. Telehealth education should complement, but not replace, in-person clinical training. As a next step, we will consider whether we should develop a longitudinally integrated telehealth experience as a component of each clerkship, or a separate stand-alone telehealth program for senior medical students.


This essay argues that the illiberal anti-immigrant sentiments which lie behind the success of populist right-wing parties deserve the attention of political theorists working on the ethics of migration, even though such sentiments exceed the boundaries of admissible disagreement on justice in migration. Firstly, populist anti-immigrant sentiments hinder the implementation of liberal democratic immigration policies and thus they represent a feasibility constraint for any liberal ethics of migration, not only the most cosmopolitan ones. Secondly, there are legitimacy reasons why such views should be neither merely dismissed nor simply contained, since they are voiced by populist political parties which are admitted in the electoral competition and even participate in governments. The main upshot of this discussion is a methodological one: the article argues that, since political theory should deal with the feasibility and legitimacy issues raised by populist anti-immigrant sentiments, a realistic approach is needed. The last section shows that such a methodological change offers the opportunity to extend the scope of normative theorising. In particular, it illustrates how a realistic approach encourages theorists to focus on local-level policies, as well as to devote attention to non-governmental actors and to their role in tackling citizens’ hostility towards immigrants. Right-wing populist movements have been gaining prominence in liberal democracies and have become real competitors to mainstream political parties. Normative political theorists have started to consider the challenges that populism  poses to liberal democracy and how to address them  realistic to (extremely) idealistic Carens , p. 169.s Carens , p. 168.A realistic approach, by contrast, takes institutional, political and social reality into account. It tries to identify the agents responsible for bringing about a change and to offer feasible proposals that have a plausible chance of being implemented under the current conditions. Gibney’s method aiming to ‘combine empirical and theoretical elements in an attempt to bring considerations of values and agency together’ Gibney , p. 16 c15Note that a realistic approach to normative political theory is a methodological perspective, which need not be coupled with the endorsement of political realismConcerning the ethics of migration, the morally desirable goal might be either a cosmopolitan goal  or a goal that gives more weight to partialist claims . In both cases, I argue that widespread populist anti-immigrant sentiments represent a feasibility constraint. However, a realistic approach should include an empirically informed understanding of the kind of constraint at stake. I contend that illiberal anti-immigrant sentiments are a contingent rather than permanent feature of human societies, susceptible to amplification or reduction. Therefore, a realistic ethics of migration should examine how such sentiments can be effectively and legitimately addressed, instead of the sentiments simply being acknowledged and normative claims revised accordingly. If there is any realistic chance of persuading some citizens to temper or abandon their illiberal anti-immigrant sentiments, it is worth considering the ethics of the policies and practices that could bring about this change.Obviously, a realistic approach should idealise neither the malleability of public opinion nor the capacity of liberal-minded institutions and non-state actors to persuade the public. Empirical evidence, especially in social psychology, can offer clues as to what theorists can reasonably expect. Loosening the constraints posed by widespread illiberal anti-immigrant sentiments is likely to take time, and there may well be individuals who will not revise their anti-immigrant sentiments. Thus, tackling anti-immigrant sentiments may well be compatible with resistance policies and practices aimed at circumventing unjust immigration policies and practices in the short term.20Taking a realistic approach is also methodologically fruitful for making sense of the legitimacy constraints that limit the admissible ways in which populist anti-immigrant sentiments may be approached. Indeed, a realistic approach is interested not in how a just receiving society for immigrants would look under ideal conditions but in assessing the legitimate ways in which change can be produced and which institutional or non-governmental actors should take action. Populist anti-immigrant sentiments cannot simply be neutralised, regardless of how this happens. A realistic ethics of migration should then discuss which policies would be compatible with the democratic legitimacy principles that require taking citizens’ views into account.21In sum, taking populist anti-immigrant sentiments seriously requires a realistic approach to the ethics of migration that in turn allows theorists to see that such hostile attitudes represent feasibility constraints for any liberal ethics of migration. However, conceiving of populist anti-immigrant sentiments as soft constraints implies that they should not be taken as a given. Rather, such a conception will stimulate theorists to discuss how such hostile sentiments can be addressed. This shows the importance of assessing morally and politically legitimate ways in which populist anti-immigrant sentiments can be tackled, given that such sentiments express the views of a large share of citizens and are voiced by political parties that are admitted in democratic competitions, number among the representatives in parliaments and even participate in governments. The next section shows how a realistic approach that examines how anti-immigrant sentiments are formed and transformed also opens up a new level of theorising, namely, the ethics of local immigration policies, and brings to light the role of local governments and non-state actors.Adopting a realistic approach can lead to a theoretically fruitful methodological change. By attracting theorists’ attention to how such hostile attitudes are formed and how they can legitimately be addressed, a realistic approach encourages theorists to engage with issues that have been underexplored. I will show two ways in which this methodological shift broadens the scope and breadth of normative theorising on migration.status quo.First, this shift affects the level of theorising: once the issue of citizens’ sentiments towards immigrants comes to light, the importance of local-level policies in shaping the perceived impact of immigration emerges. Political theorists usually start with issues of justice in exclusion and inclusion within territorial and citizenship borders, thereby focusing on the admission and integration policies of central governments. By contrast, in adopting a realistic approach they will be encouraged to consider how local narratives and daily interactions affect migrants’ inclusion and the attitudes that citizens have towards them. Second, new actors will emerge alongside local governments: NGOs and other non-state actors either cooperate with local governments or independently carry out local initiatives that affect citizens’ sentiments towards immigrants. Although some authors have, for instance, considered immigrants as subjects with moral obligations  are places where both natives and immigrants live  to tackle populist anti-immigrant sentiments. Clearly, illiberal anti-immigrant sentiments are also widespread at the local level . In addition, local governments are not necessarily hospitable to migrants or eager to counter illiberal anti-immigrant sentiments: right-wing populist parties may well be in power in local governments too. The point is that the local context provides a more favourable environment for those local governments that are not led by right-wing populists to counter illiberal anti-immigrant sentiments in their area. Indeed, local-level policies are better suited than national-level policies to address both the feasibility and legitimacy challenges that populist anti-immigrant sentiments pose to the implementation of any immigration and integration policy consistent with the basic liberal values of freedom and equality. To put it simply, policies aimed at persuading citizens to adopt more liberal attitudes towards migrants have a better chance of being effective and legitimate when carried out locally.First, as feasibility (soft) constraints, such illiberal hostile sentiments may be more effectively counteracted through local-level policies, such as those inspired by contact theory, that foster positive direct interactions between citizens and immigrants. Furthermore, even communication strategies aimed at dispelling anti-immigrant rumours and populist anti-immigrant rhetoric may be more effective if carried out locally.Second, the role of local governments emerges as particularly important in regard to the democratic legitimacy issues that anti-immigrant sentiments raise. As I have argued in ‘For instance, hostility towards immigrants may be connected to forms of misrecognition or marginalisation: some citizens feel that they have been forgotten by political institutions and that their voices are no longer heard or no longer matter. They may also blame immigrants for phenomena such as unemployment, housing shortages or urban blight, which actually have deeper and more complex causes than the  large presence of immigrants. Furthermore, economic anxiety is strictly intertwined with existential cultural anxiety. Some people may feel not only economically but also culturally left behind as their traditional values become increasingly marginalised in public culture. Inglehart and Norris  warn thaIf tackling anti-immigrant sentiments in a legitimate and effective way requires a dialogical attitude, neighbourhoods and towns seem to be appropriate venues through which institutions can act. Local administrations may provide fora where citizens can express their views and concerns about immigration and feel that their perspective is being seriously taken into account by their interlocutors. In fact, given the smaller scale of their constituent population, local governments are well situated to engage in a bidirectional dialogue with their citizens and to publicly discuss immigration and integration policies and their impact on the local community. Even when local governments have to comply with national laws or accept decisions made elsewhere, they can still play a significant role in helping their citizens cope with change and reducing conflict. For instance, in Lewiston, Maine, residents initially felt that their little town would be overwhelmed by the sudden arrival of resettled Somali refugees in 2001. The municipality, however, engaged in ‘dispelling myths about them and explaining the circumstances that prompted their move to the United States’. The efforts of the local government addressed anxiety and resulted in more welcoming attitudes , and these meetings have gathered a wide range of participants, including immigrants and citizens who favour restrictions on immigration. Other programmes have involved one-on-one mentorship for newcomers that is aimed at creating lasting inter-group relationships, in addition to improving immigrants’ English skills  are a contingent feature of contemporary liberal democratic societies. Thus, a realistic approach should not take them as a given and then revise the relevant principles accordingly. To the contrary, such an approach allows theorists to discuss how to address the challenge that populist anti-immigrant sentiments pose to the implementation of any liberal theory of justice in migration. Finally, I have argued that adopting a realistic approach and bringing populist anti-immigrant sentiments into the picture offers the opportunity to extend the scope of normative theorising on the ethics of immigration and integration policies. I have illustrated how being realistic about the psychological and social processes behind the formation and transformation of anti-immigrant sentiments can lead political theorists to discuss the role of local governments and non-governmental actors in addressing their citizens’ hostility towards immigrants.


The crisis of COVID-19 in long-term care services and supports (LTSS) has brought attention to challenges in staffing long-term care organizations, as shortages of direct care workers led to a dramatic inability to provide needed care for many residents in nursing homes and other residential care settings. In this study, we examine unemployment among LTSS direct care workers during the crisis and recovery. This study uses monthly data from January 2019 to December 2020 from the Current Population Survey, a monthly household survey collected by the Bureau of Labor Statistics, and we compare an individual’s 2019 monthly employment patterns to their 2020 monthly employment. Long-term care workers had an unemployment rate of 2.8% in April 2020, when unemployment rates in the US reached a peak; however, new unemployment among long-term care workers has not declined as consistently as in other settings. Female health care workers were significantly more likely to be unemployed compared to their male counterparts, a trend that is consistent with the overall economy, and workers who earned the lowest wages were more likely to have transitioned to unemployment. COVID-19 has added significant complexity to the provision of direct care services, making LTSS a hazardous place to work. Concerns remain about unemployment in long-term care where demand for workers remains high; additional measures need to be taken to ensure that direct care workers have the resources they need to remain employed.


These studies have built on the general assumption that physical and social pain share similar neurological underpinnings  may be a functional way of dealing with exclusion-related pain in the short-term, it could become habit-forming and lead to addiction.primary cause , or it may be a secondary cause; perhaps their initial trauma elicitor was something other than exclusion, and their subsequent substance misuse has led their previous social support network to exclude them. Trauma-informed treatment approaches often focus on social support as a key factor in trauma recovery (Substance Abuse Mental Health Services Administration, When someone seeks treatment for substance misuse or addiction, a therapist taking a trauma-informed approach should identify to what degree social exclusion contributes to their presenting concerns. Social exclusion may be the Unfortunately, not all social support is beneficial. People who misuse substances may surround themselves with others who misuse both to receive validation and satisfy their need for belonging (DeWall and Pond, Additionally, therapists could encourage clients to pursue alternative ways of coping with exclusion Riva, . For exaopportunities for the therapist to address specific trauma-related concerns, but do not explicitly target clients' experiences with social exclusion. Thus, it is incumbent upon the therapist to ensure assessing the specific impact and salience of social exclusion is included in treatment. This can include helping clients repair damage to social relationships resulting from substance misuse, creating new opportunities for substance-free social inclusion outside the therapeutic context, and ensuring alignment with clients' cultural values, identities, and experiences when exploring group counseling as a means of socially inclusive therapy.The degree to which current trauma-informed programs address social exclusion is unclear. Most programs (e.g., Jaycox et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Obstructive sleep apnea (OSA), is a prevalent condition characterized by repeated episodes of pharyngeal airway obstruction resulting in hypopnea and apnea episodes during sleep leading to nightly awakenings. OSA is a major contributor to the healthcare burden worldwide due to its high cardiovascular morbidity and mortality. There is growing evidence to support a pathophysiological link between OSA and venous thromboembolism (VTE). The pro-inflammatory state along with intermittent hypoxia that is invoked in OSA is associated with blood hypercoagulability, venous stasis, and endothelial dysfunction leading to deep vein thrombosis (DVT) and pulmonary embolism (PE). In this systematic review, we aim to analyze and assess the available literature on OSA and VTE (or DVT/PE) to determine whether OSA is an independent risk factor for VTE. Obstructive sleep apnea (OSA) is a highly prevalent form of sleep breathing disorder that affects 9-15% of middle-aged adults worldwide and 24% men and 9% women in the United States (US) ,6. OSA iAlthough the pathophysiology is complex, Virchow’s Triad, first described in 1856 by Rudolf Virchow can be used to elucidate the relationship between OSA and VTE. The triad details three common factors that contribute to the development of thrombosis: hypercoagulation, venous stasis, and vascular endothelial cell damage -14. SincPathophysiologyInflammation and Blood HypercoagulabilityHypercoagulation has been suspected as one of the possible pathophysiological links between OSA and VTE. Hemostatic alterations contribute to the risk of clot formation . The intMany studies have shown that the levels of coagulation factors such as TAT complex are higher in OSA patients ,31. OtheOSA and Altered Blood FlowThe effect of OSA on blood flow is another possible mediator of the pathophysiological link between OSA and VTE. Numerous studies have established an association between OSA and hematocrit levels ,33. ChoiOSA and Vascular Endothelial DysfunctionThe endothelial dysfunction that is seen with intermittent hypoxia and sleep fragmentation is another pathophysiological link between OSA and VTE. Recurrent hypoxic states such as those seen in OSA cause endothelial cells to upregulate the synthesis of tissue factor (TF), a protein that initiates the extrinsic pathway of blood coagulation while suppressing the translation of thrombomodulin, a cofactor required for the activation of protein C in the anticoagulant pathway . The recIp et al. were the first researchers to show that circulating NO levels are reduced in OSA patients and that this finding could be reversed with continuous positive airway pressure (CPAP) therapy . AsymmetOSA influences blood coagulability levels, blood flow patterns, and endothelial function - all three of which contribute to Virchow’s triad, thus accentuating the pathophysiology of VTE. Figure MethodsThis systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines . The seaInclusion CriteriaThe following inclusion criteria were used: studies written in English and conducted on humans, published from 2002 to 2022, studies relevant to our subject of interest, articles that were peer-reviewed, full texts, and articles including case-control, cohort, and observational studies were included.Exclusion CriteriaArticles that were not primary research studies, articles that were not in English, case reports, review articles, systematic reviews, or articles that were published before 2002 were excluded. All non-full text articles and duplicates were also excluded. The inclusion and exclusion process is illustrated in Figure ResultsIn total, 1637 publications were found; 436 from PubMed, 662 from Research4life, 455 from ScienceDirect, and 84 from CINAHL. Among the exclusions were 356 non-English articles that were were found and removed, 176 publications from before 2002 were excluded, and six duplicate articles were removed. This resulted in a total of 538 articles being excluded in the initial automatic screening process, leaving 1099 articles for manual screening. Articles were manually screened on the basis of title, abstract, article type, and availability, leaving 34 articles to be checked for eligibility. Ultimately, 30 articles were included in this review.There is growing evidence to suggest that OSA is a risk factor for the development of subsequent VTE (DVT/PE). Studies have suggested that intermittent hypoxia along with the cytokine-signaling cascade observed in OSA induces a prothrombotic state by increasing blood coagulability. Endothelial dysfunction, along with disruptions in venous flow also contribute to the underlying pathophysiology of OSA and VTE.OSA was found to be a risk factor for the development of VTE (or DVT/PE) in our present review. We looked at 30 peer-reviewed primary research papers and identified a statistically significant link between OSA and subsequent VTE (or DVT/PE). We also discovered evidence to support that blood hypercoagulability plays a major role in the mechanistic pathways that link OSA and VTE, implying that more studies are needed to develop prophylactic therapeutic regimens to minimize adverse PE-related outcomes. A similar review by Alonso Fernández et al. concluded that OSA is highly prevalent in VTE patients and considering it as an independent risk factor would enable clinicians to predict thromboembolic events, thereby preventing adverse outcomes .Chou., et al. found that patients with OSA were 3.113 times more likely to suffer from DVT compared to the pair-matched control group. This study concluded that sleep apnea is an independent risk factor for DVT . SimilarInterestingly, Jiang et al. found that patients with OSA required a higher dose of anticoagulant drugs such as warfarin compared to patients without OSA. They also reported an increased incidence of PE recurrence after warfarin was discontinued, thus supporting that hypercoagulability may be the underlying pathophysiological link between OSA and subsequent PE ,75. SimiObesity is considered the most important risk factor for OSA as the increase in adipose tissue within the pharynx makes it more prone to obstruction, thus causing the clinical manifestations of OSA . ObesityInterestingly, after conducting a gender-stratified multivariate analysis, Dabbagh et al. concluded that OSA is an independent risk factor for VTE among females (odds ratio 2.69) but not among males . This geXie et al. reported that patients with overlap syndrome (coexistence of obstructive sleep apnea and chronic obstructive pulmonary disease) had a higher risk of PE compared to patients with OSA alone . This fiIn conclusion, compelling evidence exists to support that OSA can be considered an independent risk factor for VTE. Current epidemiological data suggest that the incidence of VTE in the setting of OSA is strikingly high. We thoroughly analyzed 30 peer-reviewed, primary research publications and found that all but one reported a statistically significant increase in VTE (or DVT/PE) incidence in patients diagnosed with OSA. Statistical trends also suggested that patients with severe OSA that required CPAP therapy or additional supportive treatments were at a higher risk for developing VTE, further confirming the importance of OSA being an independent risk factor for VTE. The high prevalence and mortality rates of OSA and VTE make it important for more primary research studies to be carried out to clarify the complex interrelationships of both conditions. Since obesity is a major risk factor for both conditions, further research would be useful to determine that the relationship between OSA and VTE is a causal one, rather than due to shared risk factors. Further comprehensive studies would also prove beneficial in determining prophylactic treatment regimens to minimize the risk of VTE in OSA patients. Lastly, more research would also aid in the global understanding of the underlying pathophysiology that interconnects OSA and VTE.


Whole genome metagenomic sequencing is a powerful platform enabling the simultaneous identification of all genes from entirely different kingdoms of organisms in a complex sample. This technology has revolutionised multiple areas from microbiome research to clinical diagnoses. However, one of the major challenges of a metagenomic study is the overwhelming non-microbial DNA present in most of the host-derived specimens, which can inundate the microbial signals and reduce the sensitivity of microorganism detection. Various host DNA depletion methods to facilitate metagenomic sequencing have been developed and have received considerable attention in this context. In this review, we present an overview of current host DNA depletion approaches along with explanations of their underlying principles, advantages and disadvantages. We also discuss their applications in laboratory microbiome research and clinical diagnoses and, finally, we envisage the direction of the further perfection of metagenomic sequencing in samples with overabundant host DNA. High throughput sequencing (HTS) is widely used in microbiology research and its applications have been rapidly moved from basic research to clinical practice. Any specimen yielding a sufficient amount of nucleic acid can be subjected to an HTS analysis. HTS can either be targeted—that is, enriching certain genes or genomic regions—or untargeted as in metagenomic sequencing  Figure . TargeteHowever, metagenomic sequencing is still challenging to apply to samples with a high host nucleic acid background. Fortunately, a series of methods for depleting host DNA has been developed. This review explores numerous strategies to deplete non-microbial DNA in various specimens. We also discuss potential solutions to constraints and obstacles when using these methodologies in research and clinical diagnoses.As microbiome studies have progressed, the scope of investigations has gradually shifted from faeces to microbial communities in various regions of the body and from high biomass samples to samples with a low biomass. A human genome is about a thousand times larger than a microbial genome  and the microorganism, including the cellular structure and genomic variances, have been exploited as strategies for microbial DNA enrichment in samples with mixed nucleic acid populations.By taking advantage of the disparities in size and density between the microorganisms and eukaryotic host cells, they were filtered with a 5 μm filter, differential centrifugation and a flow cytometry assay, and then were tested to remove the buccal epithelial cells in human saliva . HoweverA cell wall can be found in the majority of bacteria and fungi and is substantially harder than the plasma membrane of mammalian cells. For viruses, although they have no cell wall, a protein capsid of a naked virus is sufficient to allow viruses to have a resistance against many disinfectants. In this context, a mild lysis buffer could be used to selectively lyse the plasma membrane of the host cells without damaging the microorganisms. The released DNA from the lysed host cells is then degraded by DNase, leaving intact microorganisms for a downstream extraction .A variety of reagents including sterile water, saponin (a non-ionic detergent belonging to the group of glycosides forms), Triton X-100, Tween 20 and zwitterionic detergent have been assessed for their ability to selectively lyse human cells ,16,17. AOnce the plasma membrane is destroyed by the lysis reagent, the DNA in the host cells is released. DNase I is commonly employed to degrade extracellular DNA ,21, yet TM Basic kit /CRISPR-associated protein 9 (Cas9) system provides opportunities for depleting the targeted nucleic acid sequences in a sample . It workhttps://github.com/skovaka/UNCALLED, accessed on 3 February 2022) has been established that can rapidly match the streaming nanopore current signals to a reference sequence without base-calling. Another recently developed toolkit, Readfish [https://www.github.com/looselab/readfish, accessed on 3 February 2022), requires a sufficiently fast base-caller but can also design and control selective sequencing procedures by removing the need to have complex signal mapping algorithms. To date, selective sequencing has been used in a variety of studies including the depletion of known bacterial genomes within a metagenomic community, the enrichment of certain specific human genes associated with hereditary cancers and the enrichment of low abundance genomes from samples with mixed populations [The Oxford Nanopore MinION is a portable real-time sequencing device that functions by sensing the change in the current flow through a nanopore when DNA passes through. Nanopore sequencing has the significant advantage of providing real-time data and analyses compared with the conventional Illumina platform, thereby allowing a fast turnaround time of clinical results. Another critical advantage of nanopore sequencing is its unique capability of conducting selective sequencing . IndividReadfish  , microbial load, pathogens of interest and budget.Identifying the difference between the host and microbial genome can theoretically broaden possible strategies to achieve a microbial DNA enrichment. Despite the fact that most of these new methods are not commercially available, they are still worth optimising given their promising initial results. A few novel strategies have aimed to eliminate high abundance DNA populations during the library preparation or sequencing steps to achieve a human DNA depletion. Overall, continuous efforts are needed to validate new approaches when using metagenomics to study microbiomes in samples with large amounts of DNA derived from a human host.