Neurons and glia are highly polarized cells, whose distal cytoplasmic functional subdomains require specific proteins. Neurons have axonal and dendritic cytoplasmic extensions containing synapses whose plasticity is regulated efficiently by mRNA transport and localized translation. The principles behind these mechanisms are equally attractive for explaining rapid local regulation of distal glial cytoplasmic projections, independent of their cell nucleus. However, in contrast to neurons, mRNA localization has received little experimental attention in glia. Nevertheless, there are many functionally diverse glial subtypes containing extensive networks of long cytoplasmic projections with likely localized regulation that influence neurons and their synapses. Moreover, glia have many other neuron-like properties, including electrical activity, secretion of gliotransmitters and calcium signaling, influencing, for example, synaptic transmission, plasticity and axon pruning. Here, we review previous studies concerning glial transcripts with important roles in influencing synaptic plasticity, focusing on a few cases involving localized translation. We discuss a variety of important questions about mRNA transport and localized translation in glia that remain to be addressed, using cutting-edge tools already available for neurons. Across different living systems, mRNA localization is an important mechanism for achieving functional regionalization and polarization of diverse cell types . Domain Map2  technology has been widely utilized to define the different glial subtypes and highlight the heterogeneity between them. These studies have recently been reviewed . scRNA-sAstrocytes are a glial subtype with an extensive network of cytoplasmic extensions that radiate in all directions from the cell body, leading to their characteristic star-like morphology. They perform crucial roles in synaptic plasticity and blood-brain barrier formation, such as neurotransmitter uptake and release, control of ionic homeostasis and physical interaction with blood vessels which enables the regulation of blood flow and metabolism . MultiplBiochemical signaling is one of the prime ways through which glial cells can modulate neuronal synaptic plasticity, and mRNAs of various signaling molecules have been identified to be localized to astrocytic protrusions. The mRNAs encoding Ras-related protein (Rab13), Plakophilin-4 (Pkp4), Ankyrin Repeat Domain 25 (Ankrd25), and inositol polyphosphate-1-phosphatase (Inpp1) have all been shown to be localized to the protrusions of primary astrocytes but also in a mouse astrocyte cell line, C8-S .All these proteins have been shown to be important for various aspects of synaptic plasticity. Rab13 is known to regulate neurite outgrowth  and to sIt is tempting to speculate that the effects related to synaptic plasticity and neuropsychiatric disorders observed in the studies described above are caused by the functions of astrocytes, as opposed or in addition to neurons. Such distinctions are not well studied, but the presence of those RNAs at the astrocyte periphery suggests that this is a promising avenue for future research.One of the well-known ways in which astrocytes modulate synaptic plasticity is via adhesion molecules and cellular junctions. The extracellular domains of adhesion proteins create structural support to bridge the synaptic cleft, and through their intracellular domains, they directly and indirectly link to the actin cytoskeleton, which in turn allows for the dynamic remodeling of the adhesive contacts . TherefoGFAP is a type III intermediate filament (IF) protein, an element of the cytoskeleton involved in neuron-glia contacts and the formation of the blood-brain barrier. GFAP modulates astrocyte–neuron crosstalk and can affect the efficacy of the CNS synapses; it is suspected to be required for communications between Bergmann glia and Purkinje cells during long-term depression (LTD), a type of synaptic plasticity at excitatory synapses in the cerebellar cortex thought to be a critical cell level mechanism for motor learning .In one of the earliest studies of mRNA localization in glia, GFAP mRNA was shown to be targeted to the processes of Type-II astrocytes in culture . GFAP mRA study of GFAP mutant mice revealed that cerebellar LTD is deficient and eyeblink conditioning are significantly impaired without any detectable deficits in motor coordination tasks .More sophisticated methods were also used to study GFAP mRNA localization in astrocytes, including cell culture in Boyden chambers, allowing the physical separation and sequencing of astrocyte soma from its cytoplasmic projections . These anestin mRNA localizes to the astrocytic protrusions .One of these studies found that transcripts localized to perisynaptic astrocytic processess (PAPs) had an overrepresentation of genes mediating glutamate and GABA metabolism, consistent with PAP functions of glutamate transport and metabolism like and Glul . mRNA coSlc7a5, Slc22a6), calcium ion binding (Spock2), and cell–cell junctions (Gjb2). Another interesting observation made was the demonstration of the presence of smooth and rough endoplasmic reticulum and the Golgi apparatus in astrocyte perivascular processes and endfeet. These observations indicate that local maturation of membrane and secreted proteins is possible in those distal compartments.Similar results were observed for the blood-brain barrier astrocytes, where the examination of translation in the astrocyte distal endfeet resulted in the identification of an astrocyte “endfeetome,” which consists mainly of proteins destined to cell membranes and for secretion . The stuFurther refinement of the PAP-TRAP method showed that some of the most abundant transcripts in peripheral astrocyte processes (PAP) encoded ribosomal proteins, like Rpl4 and Rplp1, pointing to the presence of translation machinery in these compartments . Poly(A)The studies described above suggest an elegant model in which the machinery required for local translation of any relevant mRNAs at the periphery of elongated cytoplasmic projections in any polarized cells, is itself locally translated from mRNAs previously transported to the periphery. Such translation could include de novo assembly of translational complexes or replacement of damaged proteins within the translation complexes, or both, and has been suggested both for astrocytes  and for A recent review summarizes the current knowledge of astrocytic transcriptomes and translatomes, listing additional examples of localized transcripts . HoweverOne of the early observations of localized glial mRNAs was in protrusions of Schwann cells and oligodendrocytes . AlthougIn the early stages of the myelination process, an mRNA binding protein, myelin basic protein (MBP), accumulates near the nucleus. However, as myelination proceeds, MBP mRNA also localizes at distal cytoplasmic processes . SimilarFurther studies of the mechanism by which mRNAs are transported toward the myelinating glial cell periphery in oligodendrocytes showed that the movement of MBP mRNA in oligodendrocytes is on microtubules, not microfilaments . These oThe question of detailed regulation of mRNA localization in oligodendrocyte myelination continues to be explored as it represents an important point of regulation of myelin translation and secretion . The ytoplasm . In factytoplasm .quaking viable (qkv) mice, which are a widely used model for dysmyelination because they exhibit hypomyelination of both the CNS and PNS resulting from spontaneous mutations in the promoter and enhancer regions of the qk gene. Nuclear and perikaryal retention of MBP mRNAs was observed in qkv mice, suggesting that QKI takes part in myelination by regulating the MBP mRNA export and cellular targeting to the periphery  and GABA (Slc6a11) transport and metabolism, membrane dynamics and cell–cell adhesion regulation , a cytoskeletal dynamics regulator (Fam107a), signaling pathways , and neurite outgrowth . Therefore, QKI appears to be highly expressed and highly important both in oligodendrocytes and in other types of glia. Moreover, some of its localized targets participate in the key processes known to affect glia-neuron crosstalk and potential modulation of neuronal synaptic plasticity by those glia. Hence, QKI could be a key player in facilitating or enabling the local control which glia exert on the neighboring neurons.However, MBP is far from being the only mRNA controlled by QKI. A recent study identified 120 targets of QKI in the mouse brain , 24 of wPlekhb1, Bcas1, Trp53inp2, and Ptgds  proteolysis, dendritic spine remodeling and engulfment of dendritic spines and axon terminals . Many ofInterestingly, microglia were found to engulf pre-synaptic terminals in response to neural activity , and it Despite the rising general interest in microglia, particularly in the context of a deadly class of brain tumors called glioblastoma  mRNA locRadial glia are stem cells of the developing nervous system with unique elongated morphology supporting their roles in guiding the radial migration of new-born neurons. They are also known to differentiate into various types of CNS cells, such as neurons, astrocytes, and oligodendrocytes . Radial Radial glia have been a powerful system for investigating mRNA localization, and transcripts localized to their endfeet were also examined . Among tLocal gene regulation in radial glia has been the subject of a recent extensive review, and their similarity to phylogenetically connected cells like neurons and astrocytes has been emphasized . MoreovePerisynaptic Schwann cells (PSCs) are the synapse-associated glia of the PNS and therefore intimately associated with the synaptic activity of neuromuscular junction synapses. The examination of bulk transcriptomes from FACS-sorted PSCs pointed to a high number of transcripts related to glutamate receptor function, axon guidance, and synaptogenesis . By crosSparc, a negative regulator of excitatory synaptogenesis, was also detected locally in PAPs, but no studies were done to prove that excitatory synaptogenesis is impaired or impossible without Sparc mRNA in astrocytic projections  in mice changes after fear conditioning . Althougjections . DespiteGiven that local responses of astrocyte and PSCs are likely to be rapid, it has been hypothesized that mRNA localization and local translation at the astrocyte and PSCs protrusions likely play a role akin to what occurs in neurons. Neuronal studies involving mRNA localization and targeted translation have not only been more numerous than the equivalent glial work but have also involved a more diverse repertoire of advanced technologies. Those studies have made use of modern biochemical and genome-wide approaches, as well as single molecule and super-resolution microscopy methods.Neuronal mRNAs have previously been successfully tagged with the MS2 loops which results in mRNA decorated with fluorescent proteins fused to the MS2 coat protein (MCP) . MS2–MCPAnother prominent technique is single molecule fluorescence in situ hybridization, or smFISH, and its related techniques. smFISH remains a gold standard for visualizing mRNA localization in fixed samples with high sensitivity and resolution. This technique has also begun to be applied to glial cells in intact tissues , 2022. sImportantly, observing localized mRNA is not equivalent to demonstrating its functional significance. To explicitly address the functional significance of the localization of specific mRNAs to the glial periphery for influencing synaptic plasticity, it would be necessary to visualize mRNA translation in living glia, while assaying synaptic plasticity. mRNA translation has been visualized in living neurons using MS2–MCP combined with an orthogonal labeling system . ImagingFinally, there are many tools that automate the quantification of glial mRNA molecules in microscopy images. These include, tools like AstroDot and AstroStat  as well In this review, we describe several examples of mRNA localization and localized translation in a diverse range of glial subtypes, which represent “the tip of the iceberg.” The following is a nonexhaustive list of important and fascinating questions that will no doubt be tackled by the field in the future.Recent research supports the idea that RNA interactions with RBPs, which have the capacity to regulate RNA localization in one cell, can predictably regulate localization in other cell types with vastly different morphologies . It is qDrosophila to humans, so it is probable that localized translation could also be widely conserved. Certainly, the RBPs implicated in localization, such as Imp/ZBP and microtubule associated molecular motors are highly conserved, although it is not clear whether the mRNA localization signals are equally conserved.Basic neuronal mechanisms and functions appear to be well conserved in neurons from What are the molecular mechanisms responsible for activity-regulated gene expression in PSCs? It would be intriguing to know how terminal glia near neuromuscular junctions (NMJ) can differentially localize mRNAs to glial cytoplasmic projections near the NMJ synapses versus other parts of the cell. However, to our knowledge, no publications exist exploring this topic. All these questions are fascinating but will require considerable future work by many labs to answer, especially considering how difficult these glia are to separate from the muscle and from the axon terminal; techniques like FACS slowly start to provide viable solutions to such problems .The prior work in neuronal mRNA localization and RBPs in neurodegenerative and neuropsychiatric disorders raises the question of whether mRNA localization in glia has a similar importance for such diseases . Explori


Recently, it was established that more religious people tend to have less favorable views of vaccination. The aim of this study was to assess the relationship between the religiousness and attitudes towards COVID-19 vaccination and disease, in five Western Balkans countries.Using online questionnaire and convenience sampling procedure, data were obtained from 1605 respondents aged 18-75 years. Perceived COVID-19 vaccine safety and efficacy, and observed danger and susceptibility to disease were assessed by short five-point Likert scales. Religiousness was estimated using single item scale. Multivariate regression analysis was employed.In Serbia, respondents who assessed themselves as more religious considered vaccine against COVID-19 as less safe  and effective , were more prone to the attitude that dangers of COVID-19 are not that serious , and believed to a greater extent that they are less susceptible to the virus . Similarly, in Bosnia and Herzegovina more religious individuals were less convinced that vaccine is effective , less inclined to believe that danger of the virus is serious , and assessed their susceptibility as lower . More religious people in Montenegro  regarded the vaccine as less safe, while in North Macedonia  and Albania  stronger religiosity was associated with more favorable attitudes towards vaccine safety.The relationship between religiosity and attitudes towards COVID-19 vaccination and disease is culturally conditioned. While in some Western Balkans societies religious beliefs render individual with a sense of lack of control triggering worry and anxiety, in some others they work as psychological shield against existential threats.• Religiosity should be considered as a relevant factor in vaccination campaigns implementation.• In the societies where negative attitudes towards vaccination prevail among the believers, religious leaders should be peculiarly educated and encouraged to participate in vaccination campaigns.


Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label” indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future. Sarcoidosis is a systemic inflammatory disease of unknown etiology characterized by the presence of non-caseating granulomas in affected organs . The lunNone of the drugs currently used for sarcoidosis treatment have been rigorously studied in large randomized controlled trials (RCTs) , 17. MosThe recently published European Respiratory Society (ERS) clinical practice guidelines help to address these concerns by outlining tentative treatment approaches for various organ manifestations of sarcoidosis . Very imCurrent advancements in personalized and precision medicine as well as the introduction of compounds developed specifically for sarcoidosis treatment, underscore the imperative of standardized elements of clinical trial design in either collective or organ-specific sarcoidosis. Medications used in sarcoidosis warrant rigorous, methodical studies targeted to the patients for whom their use is intended. Nearly 50% of patients requiring therapy for severe forms of sarcoidosis may experience a therapeutic failure  , making This manuscript will review the current and anticipated drug trials in sarcoidosis with a focus on studies evaluating novel molecules and novel therapeutic pathways. Trials advocating for a “hit hard and early approach”  and re-eThe treatment of sarcoidosis is not clear cut and demands rigorous ongoing attention. As noted above, the ERS guidelines reaffirmed two major reasons to initiate treatment . UnfortuAlthough the guidelines and a previously published consensus study advocate for early introduction of steroid-sparing agents, there is no definition of how “early” these can be added , 7. TherCorticosteroids have historically been the prototypical treatment in sarcoidosis, yet they are associated with a reduced HRQoL and significantly high morbidity and organ-threatening toxicities that are dependent on dose, duration and in some cases, genetic make-up –37. PatiThe ERS guidelines and a recently published Delphi consensus statement from a large group of worldwide sarcoidosis experts advocate an approach to therapy that balances the use of reduced doses of corticosteroids with the (early) stepwise addition of steroid sparing anti-inflammatory non-biologic and biologic agents , 7.The proposed approach to corticosteroid use is to limit continuation to a 3–6 month period to allow for demonstration of therapeutic response . During For patients with symptomatic pulmonary sarcoidosis believed to be at higher risk of future mortality or permanent disability from sarcoidosis who have been treated with glucocorticoids or other IST and have continued disease, the guidelines suggest the addition of infliximab to improve and/or preserve lung function and HRQoL . This waThe main focus of this paper is the implementation and investigation of pharmacologic systemic anti-inflammatory therapy, yet it must be noted that there are various non-systemic and non-pharmacologic therapies that have shown benefit in palliating symptoms. The intended use of systemic anti-inflammatory therapy is to halt or reverse active or partially active sarcoidosis along with remission of associated symptoms and physical impairment. Symptoms and physical impairment arising solely from irreversible tissue damage resulting from previously active disease is usually not amenable to anti-inflammatory treatment. Innumerable combinations of both pharmacological and non-pharmacological palliative measures exist to augment HRQoL by ameliorating organ-specific symptoms and physical impairment related to irreversible tissue damage . These iSystemic medications offer hope for reversing the progression of moderate to severe disease activity and if successful provide the opportunity to re-gain global function as close to a person’s baseline as possible. As stated above, the systemic treatment armamentarium in sarcoidosis is limited, while the likelihood of treatment failure is reported to be fairly high . It is cCommonly, treatment failure is interpreted as a drug being unsuccessful in inducing disease resolution or eliciting disease control. While this is true, there are other causes and, additionally, varying shades of lack of therapeutic responsiveness which must be recognized in order to preserve the use of an effective or partially effective drug. Firstly, an absolute lack of treatment responsiveness must prompt consideration of either wrong diagnosis, inactive sarcoidosis with high damage burden or medication non-adherence (requiring exploration through SDM). If active sarcoidosis is confirmed, there may be genetic influences on bioavailability of a particular medication that require attention , 78. ParTolerability is another cause of “treatment failure” and may have the greatest potential for salvaging efficacious systemic medication. Ongoing query into patient perceptions of side effects, as can be accomplished with patient self-reported measures, may support earlier interventions that effect tolerability. Being clinically inquisitive in gaining knowledge in the many strands of administration  and palliation  to enhance tolerability, is pivotal (in the context of SDM) to preserving systemic medication use.Toxicity accounts for another type of “treatment failure.” This area requires dedicated knowledge to preventing and monitoring for toxic medication effects, as well as an opportunity to re-challenge. Often, once an unanticipated toxicity occurs, a person’s confidence in that medication is shaken.Finally, it is important to note that none of the drugs used in sarcoidosis are “curative” and that relapses occur frequently with treatment interruption, medication holidays or with medication tapers. These relapses should not be interpreted as treatment failure but rather as disease recurrence following early discontinuation of treatment. In cases where a relapse occurs after at first a response was achieved, previously successful therapy should be re-instituted, and a more prolonged treatment course considered .For patients who develop new or worsening symptoms while on therapy, it is critical to consider and evaluate for other causes of these symptoms rather than routinely attributing worsening to failed therapy or to established progressive pulmonary or other organ sarcoidosis manifestation , 81. ComCareful definition of the target cohort, as much as is possible, is critical in clinical trial design. Lack of attention to patient selection and cohort enrichment could generate data that significantly under-represent the efficacy of a good drug. A central premise of selection is establishing active sarcoidosis in the target organ(s) that will be sufficiently responsive to an efficacious treatment. This is accomplished in either or both of two major ways: (a) demonstration of inflammation consistent with sarcoidosis to the exclusion of other causes, which may be accomplished by positron emission tomography (PET)/computerized tomography (CT) scan in non-neurosarcoidosis, cardiac PET/cardiac magnetic resonance imaging (cMRI) in CS or brain MRI changes suggestive of edema/inflammation in neurosarcoidosis –102; (b)Additional challenges with patient recruitment include the need to promote diversity and ensure equitable enrollment of minorities and non-white participants. As much as is possible, trial populations should be reflective of the populations affected by the disease of interest. Sarcoidosis occurs three times more commonly in African Americans and presents with disproportionate severity in patients of a lower socioeconomic status (SES) , 104, yeStudies focused on non-pulmonary manifestations of sarcoidosis face the unique challenge that very few patients (< 2% in one large cohort)  will havBesides RCTs, the use of large global registries with well phenotyped patients is also a critical step to systematically study various forms of high-risk or severe manifestations of sarcoidosis and their optimal treatment regimens. Sarcoidosis is a rare disease with heterogenous manifestations, and a potential marginal benefit of registries compared with RCTs is the ability to include a more heterogenous (and more representative) sarcoidosis population so as to gain large numbers and gain insight into the use of off-label therapeutics and novel therapeutic approaches for uncommon and severe disease manifestations. Several such registries are currently in existence and may begin to yield some much-needed information in this regard , 123–125Another limitation of drug development in sarcoidosis has to do with identifying validated measures that reflect clinically meaningful response to therapy. Identifying and validating outcome measures is one of the greatest tasks at hand in organ-specific or multi-organ trial design in sarcoidosis. Even when considering a prevalent manifestation such as pulmonary sarcoidosis, the most used measures such as FVC can be flawed in capturing clinically meaningful change ; and mayThe selection of outcome measures is predicated upon which outcomes or endpoints  are deemed important in validating the hypothesis while remaining cognizant of the drug’s mechanism of action and anticipated side effects. For example, in clinical trials targeting lung involvement and measuring changes in physiologic function as primary outcome, FVC, FEV1 or DLCO is often selected while changes in physical function may warrant use of 6-min walk distance and other outcome measures assessing dyspnea, cough or HRQoL may be selected from a variety of PROMs intended to measure each of these as secondary or exploratory outcomes. As much as is possible, outcome measures should be authenticated to demonstrate content validity, reliability, discrimination between similar but different situations , and responsiveness to changes over time that correlate with clinically meaningful change in disease state. Measures are more likely to be successful when they demonstrate high precision, easy interpretability, cost effectiveness, accessibility, and are without undue risk regarding patient safety, comfort, and fatigability. Measures that are easy and logical to complete and that provide immediate real time feedback to patients are also more likely to be accepted.As noted, the ERS guidelines stress the two major reasons for treatment: avoid organ loss or death (danger) and/or improve HRQoL. Unfortunately, none of currently available literature has used these as a specific endpoint. Since mortality from sarcoidosis, death alone as an endpoint has not been a practical primary endpoint, the time to clinical worsening (TTCW) which includes a composite of predefined endpoints such as disease-related hospitalization, death, transplantation, or worsening of 6-min walk or FVC of 5–10% have been used as primary endpoints in trials for SAPH and pulmonary fibrosis , 131. HoImproving HRQoL should be a core outcome of all clinical trials in sarcoidosis . UnfortuAnother endpoint accepted as reasonable is the ability to taper steroid dosage (steroid-sparing) . While rA possibly more efficient and patient-centered strategy in non-neurosarcoidosis might be the use of changing PET/CT values over time. The use of PET/CT is likely to shorten trial length, confer greater precision of change , allow fHierarchical composite endpoints (HCE) whereby multiple relevant outcomes or components ranked in order of clinical importance/relevance and combined into a single ordinal outcome may also be considered. These components would have to be adapted to both the organ of interest and the study drug under investigation and should capture both the most favorable and least desirable aspects of a drug or intervention , 140. FoSubject retention relies on principles of patient safety, comfort, anticipating medication tolerability and cost of participation. This necessitates incorporation of preventive measures and management of toxicities related to steroid-tapering studies. Such measures include protocols to ensure gastric, bone, endocrine and cardiovascular protection as well as measures to address psychiatric and sleep disturbance that follows any available published guidelines for prolonged steroid use. On the other hand, investigator protocols to help manage side effects of study drug that are anticipated to be frequent and decrease study drug tolerability, should be carefully developed with supportive communication aids and patient brochures in the event side effects arise.Patients are the most valuable element in clinical trials, and it is their participation that enables science and treatment development to advance. Most patients are motivated to participate in trials. However, “motivation” to benefit self or others is not enough for a patient to be able to participate in a clinical trial, as participation in clinical trials often requires a level of financial stability and job security that allows compliance with complex trial schedules and prolonged time off work for multiple study visits—sometimes at centers far away from home. Consequently, only patients that can afford the financial and other losses associated with clinical trials are able to participate without the support of financial coverage for expenses and collateral costs of participation , 142. Foirect expenses paid by patients to attend visits  and collateral costs to the patient . A potential third category might be procedural burden which might relate to the complexity and potential discomfort of study procedures. While a fourth category might be probability of benefit which relates to foregoing other available treatment to participate in a placebo trial or a trial of a medication without clinical precedent, or as is common in sarcoidosis to remain on prolonged toxic medications such as prednisone. Participation in clinical trials occurs on top of the usual anticipated annual financial losses for patients and family members related to the disease itself  are now accepted as an important element of successful clinical trial design . InclusiThe sarcoid granuloma is the immunohistopathologic hallmark of sarcoidosis , 96, 155As noted above, the inciting “antigenic” stimulus in sarcoidosis is unknown, however, several studies support that an inhaled infectious, organic, or inorganic antigen acquired from various occupational and environmental exposures such as moldy environments, metalworking, firefighting, agricultural employment, and occupational exposures to insecticides and building supplies is implicated in disease etiology , 164. A via TLR) results in activation of effector proteins (such as caspase-1) and cleavage of inactive forms of interleukin (IL)-1β and IL-18 into their active forms (The inflammatory response in sarcoidosis is initiated by the innate immune system through activation of membrane-bound pattern recognition receptors (mbPRRs) on the surface of antigen presenting cells (macrophages and dendritic cells) at the alveolar epithelial surface . These mve forms , 180. Acve forms , 168. Thve forms , 168.The core of the sarcoid granuloma consists predominantly of activated CD4 + T helper (CD4 + Th) lymphocytes with rare scattered CD8 + T cells and B cells in the periphery . The adaAlveolar CD4 + Th lymphocytes may also differentiate down a Th17/Th17.1 effector pathway under the influence of IL-1, IL-6, and TGF-β , 187–189Failure to clear the inciting antigen and persistence of a dysregulated immune response has been associated with the development of chronic disease and progression to fibrosis in sarcoidosis . ActivatOther immune mechanisms associated with persistence of the sarcoid granuloma and thus of the development of chronic progressive fibrotic disease include activation of the JAK-STAT pathway , 186 andClinicalTrials.gov is a publicly available database of all privately and publicly funded clinical trials conducted around the world. It includes all studies conducted within the 50 states and in over 200 countries including Japan and Europe , drug intervention, and early Phase 1 through Phase 4 trials, as well as excluding trials of devices or behavioral interventions, and studies that have been withdrawn, suspended, or terminated resulted in 69 studies. During manual review of these studies, duplicate entries as well as trials evaluating nutritional supplements, non-granulomatous manifestations of sarcoidosis, and diagnostic, radiologic, and non-drug interventions were excluded. We also excluded trials completed before 2018. Trials evaluating the same molecule for different disease manifestations (such as for pulmonary and CS) or where an early phase trial has been completed and late phase trial initiated were acknowledged as independent studies. Twenty-eight trials were identified. Fourteen of these trials are in pulmonary sarcoidosis, four in SAPH and three in CS. There are only two trials each in cutaneous and multi-organ sarcoidosis and one each in hepatic, CNS sarcoidosis and sarcoidosis affecting the calcium and Vitamin D homeostatic balance  of patients with pulmonary sarcoidosis and have been shown to play a significant role in the immunopathogenesis of the sarcoid granuloma formation  216–219219. IL-1This is a randomized double-blind placebo-controlled phase 2 trial with open label extension (OLE) evaluating the safety and efficacy of anti-GM-CSF antibody (Namilumab) in patients with chronic pulmonary sarcoidosis . ParticiNamilumab is a fully human IgG1 monoclonal antibody that binds with high affinity to GM-CSF and neutralizes its function , 226. ItAutoantibodies to GM-CSF (GM-CSFab) have been identified in patients with autoimmune pulmonary alveolar proteinosis (PAP) where they are known to be highly pathogenic –234. PAPThis is the most advanced ongoing drug trial in pulmonary sarcoidosis. It is a multicenter randomized double-blind placebo-controlled phase 3 study evaluating the safety and efficacy of two IV doses of Efzofitimod (3 and 5 mg/kg) given every 4 weeks to patients with pulmonary sarcoidosis receiving stable doses of oral corticosteroids taken with or without additional immunosuppressant therapy . As withThe exact mechanism of action of Efzofitimod in sarcoidosis is unclear. It is a novel immunomodulator that selectively binds the immunoregulatory receptor Neuropilin-2 (NRP2). Neuropilins (NRP) are multifunctional, single pass transmembrane, non-tyrosine kinase surface receptors expressed on all vertebrates , 241. TwEfzofitimod is a fusion protein comprised of an immunomodulatory histidyl-tRNA synthetase (HisRS) domain fused to a human IgG1 Fc fragment. HisRS is an important pathogenic antigen (Jo-1 antigen) in autoimmune myositis –247 and via a home monitoring application. The primary study objective is to investigate the efficacy and tolerability of methotrexate as first-line therapy in patients with pulmonary sarcoidosis compared to prednisone  vs. medium dose prednisone . Participants in both groups will be followed for evidence of disease relapse at the end of 18-months . The stuIt is to be noted that patients enrolled in both the SARCORT  as well There have been several recently completed early phase trials of novel therapeutic agents in sarcoidosis.This randomized double-blind placebo-controlled phase 1b/2a pilot study evaluated the safety, efficacy, and tolerability of transdermal nicotine (vs. placebo) given as a daily 21 mg patch for 24 weeks in patients with active symptomatic pulmonary sarcoidosis receiving a maximum daily dose of 10 mg prednisone  without any concomitant 2nd or 3rd line therapy , 263.via α7 nicotinic cholinergic receptors (α7nAChR) which signal through the JAK-STAT pathway  for 16 weeks (CLEAR regimen)—to patients with chronic progressive pulmonary sarcoidosis (CPPS) . ParticiThe study enrolled 97 patients  across four sites in the U.S. 49 patients were randomized to receive CLEAR regimen and 48 patients to Placebo. Each patient received 8 weeks of four drugs (or matching placebo) followed by 8 weeks of two drugs (or matching placebo) based on individual tolerance and toxicity profile during the first 8 weeks . The priThe results of this study are in complete contradiction with results of prior studies that provided evidence suggestive of a potential benefit of CLEAR therapy in patients with pulmonary  and cutaRegardless of the reason for the results obtained, it is important to note that they do not reflect on all antibiotic trials in sarcoidosis. A recently concluded non-controlled open label phase 1b study of Azithromycin 250 mg taken once daily for 3-months in 21 patients with pulmonary sarcoidosis presenting with chronic cough found that Azithromycin led to improved cough metrics and HRQoL measures . PatientSeveral other studies have been recently completed in patients with pulmonary sarcoidosis. These studies evaluated the role of Canakinumab  (NCT02888080) ; and RCIRCI is a complex mixture of prolonged-release adrenocorticotropic hormone (ACTH) and other pituitary peptides . It has Friedman et al. also recently published results from a recently concluded small phase 1 proof of concept study evaluating the role of Tofacitinib given as a 5 mg oral pill twice daily for 16-weeks in 5 patients with pulmonary sarcoidosis . They foThis is a small single center phase II study that is planned to enroll 15 patients with steroid refractory pulmonary and extra-pulmonary sarcoidosis randomized to Sarilumab vs. placebo . SarilumAll enrolled patients will receive Sarilumab given as a subcutaneous injection every 2 weeks for 16 weeks and will undergo a forced steroid taper. Patients who successfully taper off steroids by week 16, will be randomized to receive continued SQ injections of Sarilumab vs. placebo for an additional 12-weeks. The primary outcome of interest is flare-free survival of Sarilumab treated patients defined as ability to remain off prednisone and other therapies while on Sarilumab. This study targets patients with steroid refractory (prednisone dose 10–60 mg/day) and multi-organ disease. It has a unique study design that incorporates patients with pulmonary sarcoidosis enriched for presence of non-life-threatening multi-organ disease. In addition to patients with pulmonary sarcoidosis, the target population includes patients with active glucocorticoid-dependent sarcoidosis affecting the lymph nodes, liver, kidneys, spleen, bone, soft tissues, skin, and/or eyes while excluding patients with fibrotic pulmonary sarcoidosis (FPS), CNS sarcoidosis, and CS . FurtherTofacitinib is a JAK1/JAK3 inhibitor that is currently approved for the treatment of Rheumatoid arthritis refractory to conventional DMARD therapy , 300. AnDamsky et al.  recentlyThis study conducted in France is focused on patients with extra-pulmonary multi-organ sarcoidosis . It is aper se  had sarcoidosis with evidence of PPF  in patients with FPS enrolled 16 patients and was underpowered to determine pirfenidone efficacy . In thatPatients with FPS present varied radiographic profiles which may correlate with lung function , 323. InThere are several ongoing interventional drug trials evaluating new molecules and therapeutic treatment approaches in patients with CS.RESOLVE-Heart (NCT05351554) is a randomized double-blind placebo-controlled phase 2a study that is planned to evaluate the safety, efficacy, and tolerability of Namilumab in patients with active CS . It is aMAGiC-ART (NCT04017936) is an open label Phase 2 pilot study evaluating the role of IL-1 blockade in patients with CS , 333. StCHASM CS-RCT (NCT03593759) is a large phase 3 non-inferiority multi-center multi-national RCT designed to evaluate the optimal initial treatment strategy for patients with active CS , 341. NePropionibacterium acnes in sarcoid granulomas of myocardial tissue (P. acnes lipoteichoic acid concentration (ACNEX) at 6 and 12 months will also assessed (J-ACNES (UMIN 000025936) is the Japanese Antibacterial Drug management for CS, an ongoing multicenter open-label RCT designed to investigate the effect of antibiotic treatment in addition to standard corticosteroid therapy in patients with CS . The pril tissue . Newly dl tissue . The pril tissue . The ratassessed . A minimassessed .This is an exciting time for therapeutic trials and trials evaluating new treatment approaches in sarcoidosis. For the first time in over two decades, preliminary guidance for the diagnosis and treatment of sarcoidosis have been published and work has begun on defining a set of core outcome measures that can be uniformly applied in clinical trials , 5, 22. The outlook to improve future drug trials in sarcoidosis should look to:–Enhance and diversify subject recruitment and retention by eliminating all real and perceived barriers to trial participation. This includes an active outreach to underserved and minority communities.–Clearly define target cohorts and optimize mechanisms of ascertaining who has active disease prior to trial enrollment. Concomitant with this is the need to clearly define physiologic and clinical endpoints of disease that are consistent with the pathobiology of sarcoidosis and at the same time meaningful to patients.–Determine a core set of organ-specific HRQoL and patient-centered outcome measures that will enable comparison of trial results across studies and minimize redundancy and waste of resources.–Optimize clinical trial designs to enrich study populations of pulmonary sarcoidosis for other organs of interest without detracting from pulmonary specific endpoints.–Build in protocols that address and manage steroid toxicities for studies whose primary outcome is “steroid-sparing”; while at the same time seeking new and safer endpoints that capture clinical deterioration and lack of response to therapy without incurring significant steroid toxicities.–Prioritize studies evaluating the appropriate management of FPS. There is a high morbidity and mortality associated with FPS, yet this group of patients are routinely excluded from clinical trials. Recent findings of the similarities between fibrosis in sarcoidosis and IPF and increasing availability and efficacy of anti-fibrotic therapy should serve as a catalyst for further attention to this severe disease manifestation. The various phenotypes of FPS need to be elucidated and optimal treatment approach for these patients determined.–Finally, while this manuscript was limited to only pharmacologic intervention, it is to be noted that there have been advancements in non-pharmacological management of sarcoidosis, and these will need to be studied alongside the pharmacologic interventions for a more holistic approach to patient care.Having come this far, the sarcoidosis community needs to maintain an unflinching resolve to ensure that large scale well designed RCTs be performed for all future therapeutic interventions and that each subsequent/updated guideline reflect an improved grade of evidence for guideline recommendations.Over 50% of patients with sarcoidosis require treatment for their disease yet none of the medications currently used for sarcoidosis treatment has been rigorously studied in large RCTs  and evidThere are several ongoing RCTs evaluating new therapeutic molecules, novel therapeutic targets and steroid alternative treatment regimens in sarcoidosis with several yielding positive early phase results .While these ongoing trials and future potential trials face significant challenges, it is important to note that these challenges are not insurmountable, and several potential solutions have been proffered in this manuscript.All authors wrote, edited, reviewed, and contributed key concepts to the manuscript. All authors approved the submitted version.


Virtual care use increased during the COVID-19 pandemic. The impact of that shift on patient and provider experiences is unclear.We evaluated patient and provider experiences with virtual visits across an academic, ambulatory hospital in Toronto, Canada and assessed predictors of positive experience with virtual care.Survey data were analyzed from consenting patients who attended at least one virtual visit (video or telephone) and from consenting providers who delivered at least one virtual visit. Distributions for demographic variables and responses to survey questions are reported, with statistical significance assessed using chi-square tests and t tests. Ordinal logistic regression analysis was used to identify any patient predictors of responses.During the study period, 253 patients  completed 517 video visit surveys, and 147 patients  completed 209 telephone visit surveys. A total of 75 and 94 providers completed the survey in June 2020 and June 2021, respectively. On a scale from 1 to 10 regarding likelihood to recommend virtual care to others, fewer providers rated a score of 8 or above compared with patients . Patients of non-White ethnicity had lower odds of rating a high score of 9 or 10 compared with White patients .Patient experiences with virtual care were generally positive, but provider experiences were less so. Findings suggest potential differences in patient experience by ethnicity, warranting further investigation into equity concerns with virtual care. The COVID-19 pandemic has accelerated virtual care use in many jurisdictions, stemming from the need for physical distancing, preservation of personal protective equipment, and the desire to adhere to public health guidance . In the Many studies have been published on patient or provider experiences with virtual care before and during the pandemic -12. SomeAt Women’s College Hospital (WCH), an academic ambulatory hospital in Toronto, Ontario, Canada, virtual care adoption accelerated during the COVID-19 pandemic. In-person ambulatory visits throughout the hospital were largely replaced with video or telephone appointments. In this study, our objective was to use data from WCH during the pandemic to describe patient and provider experiences with virtual care across various clinical areas and to identify demographic characteristics associated with patient experience.WCH is an ambulatory, academic facility in Toronto, Canada and is fully affiliated with the University of Toronto. From an administrative perspective, virtual visits are scheduled almost identically to in-person visits, the only difference being the visit type used. For video visits specifically, the electronic medical record is able to automatically create video encounters with the use of an existing platform  when specific video visit types are used. When booking a phone visit, it is clearly identified to clinicians that the visit is to take place by phone. The hospital provided resources on its website, notifying patients of the option of video virtual care and its availability as well as how to use it, including training videos and guides. Otherwise, patients would have been presented with the option during phone calls with administrative staff or notified of a virtual video or phone visit within the appointment notification letter they received. Clinicians were encouraged to curate their environment prior to conducting virtual visits, especially by video. In many instances, clinicians continued to work within the clinic when conducting virtual care, though several clinics or departments worked mostly or entirely from home. Regardless, creating private space and ensuring the use of appropriate technology were encouraged. Clinicians were also encouraged to collect appropriate identifying information from patients, much as would occur during check-in during an in-person visit. On the patient end, the resources provided to them motivated them to treat virtual encounters much as they would in-person encounters, including ensuring their own private space, being in a well-lit area, and minimizing background distractions.This study received ethics approval from the WCH Research Ethics Board (REB # 2019-0191-E).Data were collected from surveys administered to consenting patients who attended at least one virtual visit (video or telephone) at any clinic within WCH who consented via digital consent to be sent a patient experience survey after their visit. Patients had to be registered in the patient portal to receive the digital consent via the electronic medical record. Patients were offered the opportunity to complete the survey after every virtual visit attended. We analyzed patient experience survey data for video visits from May 2020 to May 2021 (253 patients and 517 responses). As survey deployment for telephone visits was delayed due to staff shortages in the second pandemic wave, we analyzed data for telephone visits since survey launch from October 2020 to May 2021 (147 patients and 209 responses). Provider experience surveys were administered twice, in June 2020 and June 2021, for those who delivered at least one virtual visit at any clinic within the hospital. Both patient and provider surveys included questions regarding demographic characteristics and satisfaction with virtual care, with opportunities for written feedback. Patient and provider survey questions can be found in t tests were performed as applicable to compare demographic characteristics and responses to various questions regarding patient experience  between patients who attended video appointments and patients who attended telephone appointments.Descriptive statistics were used to summarize demographic characteristics and responses to patient experience questions among all patients and new patients  who attended at least one virtual visit at the hospital. The following demographic characteristics were self-identified through survey responses: age, gender, ethnicity, household income, and English-language proficiency. Overall marginalization was determined using the Ontario marginalization index (ON-Marg) , which wThe net promoter score, a metric used to measure a client’s willingness to recommend a company’s product or services , was alsP=.005) and older patients  who completed telephone visit surveys compared with video visit surveys. Among survey respondents who were new patients, telephone users were also older than video users  for video visits and 259 of 358 (72.3%) for phone visits. Among those who consented, 517 of 1057 (48.9%) video visit surveys and 209 of 259 (80.7%) phone visit surveys were completed. Baseline characteristics of all patients who responded to at least one video or telephone survey are reported in . However, the difference in net promoter scores between video and telephone visits was greater for new patients (51.8% for video vs 15.0% for telephone). The majority of patients  preferred to have the option of virtual visits after COVID-19.We report results for the ordinal logistic regression models in A total of 75 providers completed the survey in June 2020, and 94 providers completed the survey in June 2021 . The topResponses to the provider experience surveys are shown in This study describes the patient and provider experiences with virtual visits during the COVID-19 pandemic across an academic ambulatory hospital in Toronto, Canada. Feedback for virtual visits was generally positive among patients. Video visits were the preferred modality over telephone among many patients, particularly for those who were new patients. However, we found that patients of non-White background were less likely to recommend virtual visits compared with those of White background. Provider experiences with virtual visits were less positive compared with those of their patients, but there was a general improvement in provider feedback from 2020 to 2021.Most patients found that their virtual visit was helpful in addressing their health issue and rated a high score when asked to what degree they would recommend virtual visits to a friend. However, a higher proportion of patients reported video visits to be “very helpful” compared with telephone visits. Similarly, the net promoter score was much higher for video visits compared with telephone visits. In our study, patients who completed telephone visit surveys were generally female and older in age compared with patients who completed video visits. In the literature, older patients are less likely to engage in virtual care than in in-person care and even less likely to choose video than telephone ,25.In our study, several patients indicated in the open-ended questions that they would prefer video over telephone due to the ability to see the provider and observe facial expressions and body language. Other studies have also cited the benefit of increased human connection that accompanies video platforms . The difDespite the generally positive feedback for virtual visits, a small proportion of patients did not find the visit helpful or rated a low recommendation score. The open-ended responses suggest that some patients were unhappy with the delay in their appointment start time and the lack of communication from the clinic in such cases. Published studies have cited other patient criticisms of virtual visits such as technical issues with connection and quality of the call , a lack Findings from the regression model indicate that non-White patients were less likely to recommend virtual visits to a friend compared with White patients. Mixed findings are reported in the literature, with several studies showing no significant differences in patient experience with virtual care by ethnicity -34, whilOur findings are consistent with other studies that found lower satisfaction with virtual care among health care providers compared with patients . Our finFrom a provider standpoint, there appeared to be an increase in positive feedback for virtual visits across most survey questions from 2020 to 2021, including quality of virtual visit, time and effort spent on virtual visit, and preference to use virtual care after the pandemic. This may be because, as providers had more experience with virtual care, their self-efficacy may have improved. Another explanation is that the proportion of all visits that were virtual was higher in 2020 than in 2021, so the appropriateness of virtual care for the visit reason was likely also higher in 2021. Several studies have reported that clinicians have a positive outlook on virtual visits , particu. However, our analysis was still able to detect a difference in experience among patients of ethnic minorities. Finally, an electronic survey does not offer a deep understanding of experience, particularly among marginalized groups, as opportunities for feedback is limited and patients may not feel as comfortable sharing their thoughts on the platform due to confidentiality concerns. Future studies of patient experiences with virtual care should include interviews or focus groups with patients from underserved communities. We also surveyed patients seen in specialty clinics within an ambulatory care hospital and did not include primary care patient surveys. Last, these findings reflect the experiences of patients and providers in a single institution within a universal health care system and therefore may not be generalizable to other settings.A strength of this study is that it provides the patient and provider perspectives on virtual care in a large ambulatory hospital setting with responses across many clinical specialties and programs. Our findings also offer insights into both patient and provider experiences and into some of the demographic differences in experience with virtual care to identify potential equity issues. Nonetheless, our study does have several limitations. The overall response rate for demographic questions in the video survey was lower than anticipated due to a technical error in survey deployment. Furthermore, despite our equity focus, there are limitations in the demographic insights that can be gleaned. First, although we captured several important demographic variables in this study, we were unable to assess the association between patient experience and other potentially relevant characteristics, such as education level, employment, and immigration status. The low proportion of patients who consented to receive surveys and the fact that surveys could only be sent to patients who had a valid email address and were registered on the portal system would have limited responses, including from certain marginalized and underserviced groups. We also acknowledge the possibility that patients who have fewer positive experiences with virtual visits may be less inclined to complete the survey, which would potentially bias the findings to be more positiveThis study summarizes the patient and provider experiences with virtual care across an academic ambulatory hospital in Toronto, Canada during the COVID-19 pandemic. Virtual care, comprised of video and telephone visits, was generally well-received among most patients, with many favoring video visits over telephone visits especially for new patients. However, virtual care was less endorsed among many providers. Furthermore, patients with non-White ethnic backgrounds were less likely to recommend virtual visits. These findings provide important contributions regarding understanding overall patient and provider experiences with virtual care as well as predictors of patient experience. Given the prospect of the hybrid modality of care delivery that includes both virtual and in-person options of care delivery post-COVID-19, future work should aim to develop ways to understand factors to improve patient and provider experiences with virtual care and to assess the impact of virtual modalities on patient outcomes and quality of care.


Gastroesophageal reflux disease has long been implicated as a cause for multiple pediatric symptoms ranging from abdominal pain and regurgitation to cough and dental erosions. Diagnostic testing has evolved greatly over the last 20 years; initial testing with pH-metry to measure esophageal acid reflux burden has evolved into measurement of both acid and non-acid reflux and liquid and gas reflux. However, measuring reflux burden alone only tells a small part of the GERD story and many symptoms originally thought to be reflux related are, in fact, related to other disorder which mimic reflux. The current paradigm which involves empiric treatment of symptoms with acid suppression has been replaced with early testing for not only gastroesophageal reflux but also for other diagnostic masqueraders. The focus for interventions has shifted away from acid suppression toward motility interventions and includes a greater recognition of both functional and motility disorders which present with reflux symptoms. Gastroesophageal reflux has been implicated as a cause for wide ranging signs and symptoms in children including regurgitation, epigastric pain, cough, and pneumonias. However, studies using pH probes often fail to show a consistent association with reflux events and signs and symptoms. This lack of association raises the questions that: 1) these signs or symptoms are not acid reflux related or that (2) our current technology lacks the sensitivity to measure esophageal events. With the addition of impedance to pH monitoring (pH-MII), clinicians have gained new insight into the role of non-acid reflux and of gas in the development of pediatric symptoms; up to 89% of reflux episodes in infants and children are non-acidic and up to 2.4% of symptoms are triggered by gas episodes such as supragastric belching  these si.However, beyond just further subtyping reflux categories , clues from standard pH-MII testing can help to identify reflux masqueraders. For example, in patients with a high correlation  between reflux event and typical symptoms such as heartburn, regurgitation, and chest pain, rumination syndrome should be considered. While diagnosed by performing standard high resolution esophageal manometry or 24-h manometry-impedance measurements , where hApart from advances in the interpretation of pH-MII testing, new technologies have provided insight into the risk factors for gastroesophageal reflux and its associated complications. For example, intraprocedural mucosal impedance technology has been used to determine the extent of esophageal inflammation at the time of endoscopy, as a proxy for multiple esophageal biopsies –11; whilA second new technology that provides insight into the mechanisms of reflux is the functional luminal imaging probe (FLIP). FLIP offers additional insight into esophageal motility and distensibility. By inflating a balloon in the esophagus, sensors can measure (1) how distensible the esophagus and esophagogastric junction (EGJ) are and (2) the strength, frequency, and completeness of esophageal contractions seen with secondary peristalsis. Studies of FLIP in patients at risk for reflux have shown that poor peristaltic response to balloon distension predicts abnormal pH-MII testing and this is independent of EGJ distensibility; intact secondary peristalsis  is needeParalleling the development of novel technologies which are aimed at improving the diagnosis of reflux and its associated triggers, novel therapies which move away from acid suppression have been developed to treat reflux symptoms. This move away from acid suppression is grounded in evidence that shows an increased risk of complications from acid suppression combined with a lack of efficacy in certain high risk populations.While proton pump inhibitors (PPIs) are effective in healing esophagitis and improving symptoms in many patients with typical reflux symptoms, new data has emerged about potential risk. While studies of acid suppression have been shown to alter pediatric and adult infection risk by altering the microbiome, new studies have suggested that viral infection risk may also be increased in adults and children taking PPIs –23. MostSince the only therapy to reduce transient relaxations of the lower esophageal sphincter, the main mechanism of reflux, is baclofen which has significant side effects –33, the One of the mainstays of motility therapy in pediatrics has been erythromycin, a motilin agonist, which increases antral contractions to improve gastric emptying. While early studies using pH probes in preterm infants failed to show a benefit in reducing acid reflux burden in preterm infants, studies were limited because pH-MII was not used so non-acid reflux episodes, the most common type of reflux in preterm infants, could not be detected . HoweverRecognizing the disappointing results of macrolides to reduce the total number gastroesophageal reflux events, other motility agents have been studied. One medication with the most promise because of its effects on both esophageal and gastric motility is prucalopride, a 5-HT4 agonist. While approved as a constipation treatment for adults, the medication has shown significant promise to treat upper tract motility. Placebo-controlled studies of prucalopride in adults have shown that the medication not only increased the peristaltic amplitude but it also increases the number of swallows with complete peristalsis , 45. ParAnother promising reflux therapy for pediatrics is intrapyloric Botulinum toxin (BoTox) injections. While studies have shown that BoTox injections may be beneficial in older children with nausea and vomiting, a study of 112 younger children (mean age: 2.9 ± 1.6 year) with symptoms of reflux, vomiting and feeding difficulties showed significant symptom improvement with pyloric injections of 6 units/kg , 50. ResAnother novel medication approach is the use of bile acid sequestrants to reduce the amount of bile reaching the esophagus as bile has been implicated as a cause for esophageal inflammation and, most recently, for more severe extraesophageal symptoms , 52. In Finally, while not novel, neuromodulators have become part of the mainstay of reflux therapy to treat the pain symptoms not responsive to acid suppression (in the case of reflux hypersensitivity) or not associated with reflux events . Selective serotonin reuptake inhibitors , tricyclic antidepressants , and GABA analogs  have been used to modulate both typical and even extraesophageal symptoms and are now part of the algorithms to treat persistent or severe symptoms –59. TheiDietary modification has long been a part of adult reflux guidelines but there is very little data of the impact of diet for symptomatic control. Mediterranean diets, alkaline water diets, high fiber diets, low fat, low calorie, vegetarian, gluten free, low-FODMAP diets have all been studied or proposed in very small trials or in retrospective reviews with varying success in reducing symptoms –64. ReceAnother potential modifier for pediatric gastroesophageal reflux is sleep. Studies in adults have suggested that while acid suppression improved nocturnal sleep quality and reduces symptoms of gastroesophageal reflux disease, poor sleep quality can result in pain amplification making reflux symptoms worse , 71. WhiThe field of gastroesophageal reflux in children has changed dramatically with improved testing which has broadened the differential diagnosis to include motility disorders and functional disorders. With these new technologies, more critical information can be obtained at the index endoscopy. This earlier testing results in a faster time-to-definitive-diagnosis and allows for more precise tailoring of therapies beyond acid suppression. These diagnostic and therapeutic advances have resulted in a reimaging of existing algorithms including a new proposed pediatric algorithm . HoweverRR conceived of the ideas in this manuscript and wrote the draft in its entirety.The author declares 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.


Metabolic reprogramming is an emerging hallmark of breast cancer. A common characteristic of tumor cells is the ability to obtain nutrients from a nutrient-deprived environment and to use them to sustain cancer progression, within crucial metabolic pathways including altered metabolism of glucose, lipids, and amino acids. Also, altered metabolism has been recognized as one of the major mechanisms of resistance to therapies. Important advances have been made to elucidate key mechanisms of metabolic reprogramming which will make possible novel strategies for overcoming breast cancer. However, for metabolic therapy to be effective there is a need to clearly understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the standard-of-care therapies play in targeting the metabolic phenotype.This Research topic consists of three original research articles and three reviews which focus on the major metabolically adapted pathways in breast cancer exploring either potential metabolic targets and corresponding agents for breast cancer treatment or how metabolic adaption influences breast cancer progression and resistance to therapies.Kang et al. cancer cell–derived extracellular vesicles (EVs) can modulate glucose metabolism to induce cell proliferation and an aggressive cancer phenotype. In details, the authors performed proteomic and transcriptomic analyses to investigate the changes in gene expression profiles in the recipient MCF7 cell line and MDA-MB-231 cell-derived EVs. Interestingly, they observed that the uptake of glucose analog [18F]fluorodeoxyglucose by the recipient MCF7 cells significantly increases after coculture with MDA-MB-231 cells. Moreover, MCF7 cells increase the capacity to proliferate and dedifferentiate. These data suggest that cancer cells can induce a transition to an aggressive phenotype to activate glucose metabolism via EVs. This interesting study may serve as a cornerstone for future research on interactions between cancer cells. The increased uptake of glucose and hyperactivated glycolysis, together with the accumulation of lactate, represent the main alterations in glucose metabolism associated with cancer. Several studies also suggest that aberrant lipid metabolism plays an important role in the adaptation of cancer cells to cellular stress induced by treatments. Tokes et al. in their review discussed extensively the changes in glucose and fatty acid pathways induced by routinely applied chemotherapeutic drugs used in neoadjuvant or adjuvant settings of breast cancer. The authors also analyzed the underlying molecular mechanisms together with novel therapeutic strategies.In 1956 Otto Warburg first observed that aerobic glycolysis is a hallmark of glucose metabolism in cancer. As reported by Kiesel et al. hypoxia induces a greater suppression of glutamine to glutamate conversion in murine mammary cancer cell lines (13% in metastatic compared to 7% in nonmetastatic cells). The Authors also suggest that hypoxia increases expression of genes involved in antioxidant response in metastatic compared to nonmetastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Interestingly, hypoxia also increases the transcriptional (4.2-fold) and translational (6.5-fold) expression of activating transcription factor 4 (ATF4) the main effector of the integrated stress response (ISR) pathway. These findings indicate that metastatic cells utilize hypoxia for metabolic reprogramming and induction of antioxidant defense for survival. In the last decade, therapeutic opportunities for targeting vulnerabilities in tumor cells and the immune microenvironment (TIME) are emerging as a key area of research. The review by Kalyanaraman et al. focused on hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle as vulnerable targets for cancer therapy. In particular, mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth whereas MCT inhibitors exert synthetic lethality in combination with metformin in cancer cells. Recently, the TIME was proposed as a vulnerable therapeutic target: an acidic milieu is one of the hallmarks of cancer and approaches to reverse the acidification of the TIME could facilitate chemotherapy and immunotherapy.Solid tumors commonly present regions of hypoxia which increases oxidative stress through the production of mitochondrial reactive oxygen species (ROS) and drives changes in gene expression increasing the risk of cancer metastasis. To improve survival, tumor cells respond by activating genes that modify cell metabolism. In the study by Liu et al. identified 54 different metabolites that discriminate between benign and malignant breast tumors and 17 different metabolites between invasive and non-invasive breast cancer; notably, differential metabolite analysis was able to reduce the missed diagnosis rate of ABVS. Metabolic reprogramming is gaining much attention not only for early diagnosis but also for monitoring drug resistance in breast cancer. In their review, Lv et al. elucidated the relationship between dysregulation of cellular metabolism and resistance to treatment in breast cancer with particular attention to the regulation of glucose, amino acid and fatty acid metabolism, autophagy and OXPHOS, offering promise for novel targeted therapies.New technologies with high sensitivity and specificity for early diagnosis and monitoring of breast cancer are emerging, as automatic breast full volume scanning system (ABVS). Within this contest, metabolic reprogramming may provide potential biomarkers to combine with ABVS with the aim to improve BC diagnosis accuracy. Intriguingly, in serum samples from 70 patients All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.We thank the authors of the articles published as a part of this Research Topic for their valuable contributions.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.


Cardiac surgery carries a high risk of perioperative bleeding and emergency surgery is one of the most significant factors in the determination of this risk. When perioperative bleeding ensues, blood products administration, and surgical re-exploration are generally required, with concomitant increase in perioperative morbidity and mortality . BleedinEmergency cardiac surgery has an inherently higher bleeding risk related to the pathology , the intraoperative strategy (hypothermia) or the context (coronary revascularization after antiplatelet loading dose). Hemostatic balance during cardiac surgery is a rollercoaster ride: initial surgical dissection is best accomplished with a normal coagulation profile, cannulation and cardiopulmonary bypass require complete anticoagulation while final surgical hemostasis and the patient's course in the early post-operative period clearly benefit from complete restoration of hemostatic activity. Guidelines and consensus statements on the laboratory assessment of coagulation profile and optimal pharmacological treatment options have been released , 3. In tKnowledge of the degree of anticoagulation determined by DOACs serum levels is important to decide the most appropriate treatment strategy. Standard coagulation tests like international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) have limited value because of the poor correlation with clinical hemostasis. Thrombin time is extremely sensitive to dabigatran, with significant influence even from subtherapeutic levels of drug. Standard thromboelastography/thromboelastometry assays are not sensitive enough to guide management, although newly developed tests that can detect DOACs are available but need clinical validation . QuantitActivated oral charcoal  can be given if DOAC was last ingested within 2–4 h to reduce residual drug absorption.Different antidotes are available for the thrombin inhibitor and anti-factor Xa inhibitor DOACs. Idarucizumab is an anti-dabigatran monoclonal antibody fragment given as a 5 g initial dose (a second dose may be given if required) that rapidly corrects quantitative assays results even though rebound rise in clotting time after 12–24 h has been reported. Limited use in cardiac surgery before cardiopulmonary bypass has been described with no apparent thromboembolic complications .Non-specific prohemostatic agents, such as four-factor prothrombin concentrate (4F-PCC), are a second line reversal strategy that has been associated with adequate bleeding control in DOACs-related bleeding . The dos® has been reported , while modified ultrafiltration could be effective only for dabigatran that has a low protein-bound fraction  giving falsely low values that do not reflect actual anticoagulation .The strategy of post-operative management should result from an assessment of the hemorragic and thromboembolic risks; as an example, the amount of chest tubes drainage that can be tolerated in the first post-operative hours. This would be a case-by-case assessment to decide how aggressive the correction of coagulopathy must be but also to choose timing and modality of post-operative anticoagulation that needs to be restarted.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.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.


The increasing prevalence of food allergies is a growing public health problem. For children considered high risk of developing food allergy , the evidence for the early introduction of allergenic foods, and in particular peanut and egg, is robust. In such cases, the consensus is clear that not only should such foods not be delayed, but that they should be introduced at approximately 4 to 6 months of age in order to minimize the risk of food allergy development. The early introduction of allergenic foods appears to be an effective strategy for minimizing the public health burden of food allergy, though further studies on the generalizability of this approach in low-risk populations is needed. Although clear epidemiologic data are lacking, food allergies are believed to affect up to 10% of individuals in Westernized countries . Food alSubstantial research has aimed to identify primary prevention strategies for food allergy. Many interventions that have been attempted in pregnant or breastfeeding women and infants appear to have little to no benefit in preventing food allergy, including dietary avoidance of food allergens, vitamin supplements, fish oil, probiotics, prebiotics, and synbiotics—however, it should be noted that the evidence remains uncertain in many cases . OptimalUntil 2008, clinical practice guidelines from the American Academy of Pediatrics (AAP) and other professional societies recommended delaying the introduction of allergenic foods, such as peanut, until 3 years of age. This recommendation was based on the theory that the lack of exposure to allergenic foods during early infancy—which was posited to be a developmental window of high susceptibility—would prevent later development of allergy. Though well-intentioned, it is now clear that these guidelines may have contributed to, rather than prevented, the development of food allergies in children. The dual exposure hypothesis offers one possible explanation as to why this approach failed, proposing that allergen exposure through skin may lead to IgE sensitization unless oral tolerance is first induced through the gastrointestinal tract . ChildreThe landmark Learning Early About Peanut (LEAP) study published in 2015 was the first to suggest that the early introduction of allergenic foods decreases the incidence of food allergy, leading to a paradigm shift away from early food avoidance . LEAP deStaphylococcus aureus colonization [In a follow-up study entitled the Persistence of Oral Tolerance to Peanut (LEAP-On), children who consumed peanuts from infancy through to age five followed by one year of peanut avoidance were 74% less likely to have peanut allergy than children who had consistently avoided peanuts up until age six, suggesting that the tolerance induced by early introduction can persist even in the absence of repeated exposures. Later analysis of the LEAP study cohort showed that early introduction of peanut did not negatively impact growth, nutrition, or duration of breastfeeding . In addinization ,23,24. TTrials examining the early introduction of eggs as a means of reducing egg allergy have yielded mixed results. In 2017, the Prevention of Egg Allergy with Tiny Amount Intake Trial (PETIT) randomized 147 infants with atopic dermatitis to consume either heated egg powder or placebo, in addition to undergoing the aggressive treatment of atopic dermatitis . When coIn contrast to these positive findings, the Solids Timing for Allergy Research (STAR) trial randomized high-risk infants with moderate-to-severe eczema to receive either whole egg powder or rice powder daily from 4 to 8 months of age, followed by cooked egg from 8 months onward . AlthougIn the 2017 Beating Egg Allergy Trial (BEAT), 319 infants with at least one first-degree relative with an allergic disease were randomized to receive whole-egg powder or placebo from 4 to 8 months of age, after which diets were liberalized in both groups . At 12 mIn the Hen’s Egg Allergy Prevention (HEAP) study, 383 infants aged 4 to 6 months with confirmed negative skin prick tests prior to trial initiation were randomized to receive either egg white powder  or placebo three times a week until 12 months of age . No statSeveral studies suggest that early exposure to cow’s milk may prevent later development of cow’s milk protein allergy. In 2010, an observational study of over 13,000 Israeli infants from a population-based birth cohort found that early and regular exposure to cow’s milk-based formula (beginning in the first two weeks of life) was associated with significantly decreased rates of milk allergy by age 3–5 years in comparison to those introduced to formula after 3 months of age .In the HealthNuts Study, an observational longitudinal study of 5276 infants, early exposure to cow’s milk in the first 3 months of life was associated with the decreased risk of cow’s milk sensitization (measured via skin prick testing) and parent-reported cow’s milk allergy at one year of age . No signThe timing of milk introduction appears especially important given the widespread use of supplementary cow’s milk-based formula in the first days and weeks of life. In a 2016 case-control study of 185 infants, the early introduction of cow’s milk formula was associated with a lower incidence of IgE-mediated cow’s milk allergy in comparison to infants who received delayed (after one month of age) or no formula . HoweverSome trials have examined the early introduction of multiple allergenic foods simultaneously. In the 2016 Enquiring About Tolerance (EAT) Study, 1303 infants were randomized to the introduction of six allergenic foods  at either 3 months (early introduction) or 6 months of age (standard) . Althougp = 0.0066) and egg allergies at 18 months of age [In a similar vein, the SEED trial was a randomized controlled trial in which 163 infants aged 3–4 months with atopic dermatitis were randomized to receive either mixed allergenic food powder  or placebo powder . The amos of age . The Tols of age .A question remains regarding the efficacy of the early introduction of allergenic foods for preventing food allergy in a general population with no underlying risk factors for allergy. Some have argued that the evidence supporting the efficacy of early food introduction in the general  population is less compelling given that the intention-to-treat analysis of both HEAP and EAT failed to show a statistically significant decrease in food allergies in a general population . AlthougMultiple barriers may prevent the successful implementation of food allergy prevention programs based on early food introduction . Issues Addressing health disparities based on race and ethnicity is especially important given that Black children are at greater risk of developing food allergies in comparison to other racial groups, and that allergies are increasing in prevalence in this population . Black fPrevotella spp. and butyrate, vaginal seeding, Mediterranean diet in pregnancy, vitamin D supplementation, and intensive restoration of skin barrier function in atopic dermatitis [A number of other strategies are under active investigation for the prevention of food allergy. At this time, there are 14 active clinical trials listed on clinicaltrials.gov investigating probiotics, diet enriched in rmatitis . An overThe increasing prevalence of food allergies around the world is a growing global public health problem. Recent research suggests that while cutaneous or inhalational exposures of allergens may promote IgE-sensitization, ingestion of allergenic foods can result in oral tolerance . As a reIn line with the dual exposure hypothesis, high-dose exposure to ingested food protein promotes development of oral tolerance, whereas low-dose exposure through inflamed skin  or via inhalation is more likely to prime for IgE-sensitization to food proteins. Modified from Nowak-Wegrzyn, Szajewska, and Lack .