Functional Physical Analysis and Quality of Life in the Preoperative and Early Postoperative Periods of Cardiac Surgery and 30 Days After Hospital Discharge.

INTRODUCTION: The analysis of patients submitted to heart surgery at three assessment times has been insufficiently described in the literature. OBJECTIVE: To analyze chest expansion, maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), distance traveled on the six-minute walk test (6MWT), and quality of life in the preoperative period, fourth postoperative day (4th PO), and 30th day after hospital discharge (30th-day HD) in individuals submitted to elective heart surgery. METHODS: A descriptive, analytical, cross-sectional study was conducted with 15 individuals submitted to elective heart surgery between 2016 and 2020 who did not undergo any type of physiotherapeutic intervention in Phase II of cardiac rehabilitation. The outcome variables were difference in chest expansion (axillary, nipple, and xiphoid), MIP, MEP, distance on 6MWT, and quality of life. The assessment times were preoperative period, 4th PO, and 30th-day HD. RESULTS: Chest expansion diminished between the preoperative period and 4th PO, followed by an increase at 30th-day HD. MIP, MEP, and distance traveled on the 6MWT diminished between the preoperative period and 4th PO, with a return to preoperative values at 30th-day HD. General quality of life improved between the preoperative period and 4th PO and 30th-day HD. An improvement was found in the social domain between the preoperative period and the 30th-day HD. CONCLUSION: Heart surgery causes immediate physical deficit, but physical functioning can be recovered 30 days after hospital discharge, resulting in an improvement in quality of life one month after surgery.

Functional Physical Analysis and Quality of Life in the Preoperative and Early Postoperative Periods of Cardiac Surgery and 30 Days After Hospital Discharge

ABSTRACT Introduction: The analysis of patients submitted to heart surgery at three assessment times has been insufficiently described in the literature. Objective: To analyze chest expansion, maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), distance traveled on the six-minute walk test (6MWT), and quality of life in the preoperative period, fourth postoperative day (4th PO), and 30th day after hospital discharge (30th-day HD) in individuals submitted to elective heart surgery. Methods: A descriptive, analytical, cross-sectional study was conducted with 15 individuals submitted to elective heart surgery between 2016 and 2020 who did not undergo any type of physiotherapeutic intervention in Phase II of cardiac rehabilitation. The outcome variables were difference in chest expansion (axillary, nipple, and xiphoid), MIP, MEP, distance on 6MWT, and quality of life. The assessment times were preoperative period, 4th PO, and 30th-day HD. Results: Chest expansion diminished between the preoperative period and 4th PO, followed by an increase at 30th-day HD. MIP, MEP, and distance traveled on the 6MWT diminished between the preoperative period and 4th PO, with a return to preoperative values at 30th-day HD. General quality of life improved between the preoperative period and 4th PO and 30th-day HD. An improvement was found in the social domain between the preoperative period and the 30th-day HD. Conclusion: Heart surgery causes immediate physical deficit, but physical functioning can be recovered 30 days after hospital discharge, resulting in an improvement in quality of life one month after surgery.

ANCA-negative EGPA: only eosinophils without vasculitis? Insights from anti-T2 biologics.

The pathogenic role of p-ANCA in eosinophilic granulomatosis with polyangiitis (EGPA) is a long-standing matter of debate. In this work, we report our real-life experience with EGPA patients, treated with biologics targeting type 2 (T2)-eosinophilic inflammation (Mepolizumab, Benralizumab, Dupilumab). Interestingly, we observed EGPA extrarespiratory relapses only in p-ANCA-positive patients (2/5 cutaneous vasculitis, 3/5 constitutional symptoms), with new rise of p-ANCA and normal eosinophil blood count. Notably, revising our cohort with the new ACR 2022 criteria, these five patients were the only ones to satisfy the entry criterion of vasculitis' defined diagnosis at disease onset. These observations may suggest that biologics, selectively turning off T2 inflammation, may have unmasked p-ANCA exclusive role in the pathogenesis of vasculitis in EGPA. Therefore, we raise the question whether EGPA vasculitis exists only in p-ANCA-positive patients, and whether p-ANCA-negative disease is "only eosinophils without vasculitis".

Machine learning application in autoimmune diseases: State of art and future prospectives.

Autoimmune diseases are a group of disorders resulting from an alteration of immune tolerance, characterized by the formation of autoantibodies and the consequent development of heterogeneous clinical manifestations. Diagnosing autoimmune diseases is often complicated, and the available prognostic tools are limited. Machine learning allows us to analyze large amounts of data and carry out complex calculations quickly and with minimal effort. In this work, we examine the literature focusing on the use of machine learning in the field of the main systemic (systemic lupus erythematosus and rheumatoid arthritis) and organ-specific autoimmune diseases (type 1 diabetes mellitus, autoimmune thyroid, gastrointestinal, and skin diseases). From our analysis, interesting applications of machine learning emerged for developing algorithms useful in the early diagnosis of disease or prognostic models (risk of complications, therapeutic response). Subsequent studies and the creation of increasingly rich databases to be supplied to the algorithms will eventually guide the clinician in the diagnosis, allowing intervention when the pathology is still in an early stage and immediately directing towards a correct therapeutic approach.

Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: Results from the MYONET registry.

OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

Low-dose intravenous immunoglobulin (IVIg) in different immune-mediated conditions.

IVIg has been used for a long time as a replacement therapy for primary and secondary immunodeficiencies. Beside this supplementary role, when used at higher doses (i.e., 2 g/kg/monthly) it exerts an immunomodulatory role able to control multiple autoimmune and systemic inflammatory diseases. Several mechanisms of action have been described and hypothesized, nonetheless a synergistic action on the different component of the immune response seems to be crucial. The other side of the coin are the costs which showed an increase during the years due to the production of highly purified preparations which limit side reactions. This renders the product not easily accessible especially for low-income countries. Moreover, it is based on plasma donations that experienced a significant shrinkage after the COVID-19 pandemic and the consequences are still impactful. Due to the above-mentioned problems different authors tried to find out if a lower dosage of IVIg (< 2 g/kg/monthly) might exert an immunoregulatory role. In this review we aimed to summarize the current literature about a possible beneficial effect of a lower dosage of IVIg in multiple conditions that would help to treat a vast majority of patients. Even though in some cases (e.g., Kawasaki disease and immune thrombocytopenia) results are promising, for other conditions more research is needed.

Pathological and radiological response following neoadjuvant treatments in primary localized resectable myxofibrosarcoma and undifferentiated pleomorphic sarcoma of the extremities and trunk wall.

BACKGROUND: To explore the correlation between pathological and radiological response to preoperative treatments and outcome in surgically treated patients with myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). METHODS: All consecutive patients with primary localized MFS and UPS of the extremities and trunk wall surgically treated with curative intent at our center (2005-2021) were included. Clinical data including residual visible tumor (VT%) on surgical specimen and Response Evaluation Criteria in Solid Tumor (RECIST) were retrieved. Kaplan-Meier curves for overall survival and disease-free survival, and cumulative incidence of local relapse and distant metastasis were estimated in a competing risk framework according to RECIST and VT%, overall and by treatment group. Cox and Fine and Gray multivariable models were performed. RESULTS: Of 693 patients affected by primary MFS and UPS, 233 (66 MFS and 167 UPS) were treated by neoadjuvant chemotherapy (naChT), radiotherapy (naRT), or both (naChT-RT). VT% was ≤5% in 13/46 (28.2%), 24/99 (24.2%), and 40/88 (45.4%) patients, respectively. There were 11/46 (29.7%), 22/99 (22.7%), and 23/88 (26.1%) RECIST partial responses and 18/46 (48.6%), 59/99 (60.8%), and 60/88 (68.2%) RECIST stable disease, respectively. In naChT, a trend for a better survival was observed when VT% ≤5% (p = .09), whereas RECIST partial responses and stable disease had the same outcome. VT% was not associated with outcome in naRT or naChT-RT, whereas RECIST response was. CONCLUSION: In primary localized MFS and UPS treated with neoadjuvant therapies, VT% seems more relevant than size reduction after naChT, whereas the opposite is true when naRT is administered alone or concurrent to ChT.

Staging Systems and Nomograms for Soft Tissue Sarcoma.

Reliable tools for prognosis prediction are crucially needed by oncologists so they can tailor individual treatments. However, the wide spectrum of histologies and prognostic behaviors of sarcomas challenges their development. In this field, nomograms could definitely better account for their granularity compared to the more widely used AJCC/UICC TNM staging system. Nomograms are predictive tools that incorporate multiple risk factors and return a numerical probability of a clinical event. Since the development of the first nomogram in 2002, several other nomograms have been built, either general, site-specific, histology-specific, or both. Recently, some new "dynamic" nomograms and prognostic tools have been developed, allowing doctors to "recalculate" a patient's prognosis by taking into account the time since primary surgery, the event history, and the potential time-dependent effect of covariates. Due to these new tools, prognosis prediction is no longer limited to the time of the first computation but can be adapted and recalculated based on the occurrence (or not) of any event as time passes from the first computation. In this review, we aimed to give an overview of the available nomograms for STS and to help clinicians in the process of selecting the best tool for each patient.

A machine learning analysis to evaluate the outcome measures in inflammatory myopathies.

OBJECTIVE: To assess the long-term outcome in patients with Idiopathic Inflammatory Myopathies (IIM), focusing on damage and activity disease indexes using artificial intelligence (AI). BACKGROUND: IIM are a group of rare diseases characterized by involvement of different organs in addition to the musculoskeletal. Machine Learning analyses large amounts of information, using different algorithms, decision-making processes and self-learning neural networks. METHODS: We evaluate the long-term outcome of 103 patients with IIM, diagnosed on 2017 EULAR/ACR criteria. We considered different parameters, including clinical manifestations and organ involvement, number and type of treatments, serum creatine kinase levels, muscle strength (MMT8 score), disease activity (MITAX score), disability (HAQ-DI score), disease damage (MDI score), and physician and patient global assessment (PGA). The data collected were analysed, applying, with R, supervised ML algorithms such as lasso, ridge, elastic net, classification, and regression trees (CART), random forest and support vector machines (SVM) to find the factors that best predict disease outcome. RESULTS AND CONCLUSION: Using artificial intelligence algorithms we identified the parameters that best correlate with the disease outcome in IIM. The best result was on MMT8 at follow-up, predicted by a CART regression tree algorithm. MITAX was predicted based on clinical features such as the presence of RP-ILD and skin involvement. A good predictive capacity was also demonstrated on damage scores: MDI and HAQ-DI. In the future Machine Learning will allow us to identify the strengths or weaknesses of the composite disease activity and damage scores, to validate new criteria or to implement classification criteria.

Oxidative stress, mitochondrial dysfunction, and respiratory chain enzyme defects in inflammatory myopathies.

We investigated the relationship between oxidative stress and inflammatory myopathies. We searched in the current literature the role of mitochondria and respiratory chain defects as sources of oxidative stress and reactive oxygen species production that led to muscle weakness and fatigue. Different molecules and pathways contribute to redox milieu, reactive oxygen species generation, accumulation of misfolded and carbonylated proteins that lose their ability to fulfil cellular activities. Small peptides and physical techniques proved, in mice models, to reduce oxidative stress. We focused on inclusion body myositis, as a major expression of myopathy related to oxidative stress, where mitochondrial abnormalities are causative agents as well. We described the effect of physical exercise in inclusion body myositis that showed to increase strength and to reduce beta amyloid accumulation with subsequent improvement of the mitochondrial functions. We illustrated the influence of epigenetic control on the immune system by non-coding genetic material in the interaction between oxidative stress and inflammatory myopathies.

How to treat liposarcomas located in retroperitoneum.

Almost half of retroperitoneal (RP) sarcomas are liposarcomas (LPS). The large majority of RP LPS are either well-differentiated LPS (WDLPS) or dedifferentiated LPS (DDLPS), these latter further classified according to grading in G2 and G3 DDLPS. Surgery is the only potentially curative treatment to achieve local control and possibly cure in primary localized disease. Over the last decade, a better delineation of the different histology-specific patterns of failure and the development of nomograms predictors of outcome has led to a better management of these rare tumors, with a special focus on non-surgical treatments. Available evidences - although far from exhaustive - show that radiation therapy might have a role, if any, as neoadjuvant treatment in locally aggressive histologies (i.e. WDLPS and G2 DDLPS), while it does not seem beneficial for histologies with a higher metastatic risk (i.e. G3 DDLPS and leiomyosarcoma). Neoadjuvant chemotherapy, instead, can be considered to reduce the risk of distant metastasis while waiting for the results of an ongoing RCT (STRASS-2) evaluating its effect in these tumors. However, given the rarity of these diseases and the subsequent lack of strong evidences to guide treatment, outcome improvement in these patients remains a challenge. Patients' referral to a sarcoma center where a dedicated specialized multidisciplinary team tailor optimal treatment on a case-by-case basis is crucial to ensure these patients the best outcome. Refining available nomograms - e.g including molecular variables - and identifying predictors of response/toxicity to chemotherapy and immunotherapy might be significantly helpful in tailoring treatments to the patient's characteristics. Also, new systemic agents are eagerly awaited for improving the management further.

Hymenoptera Venom Allergy and Anaphylaxis.

Hymenoptera stings can induce allergic and occasionally fatal reactions, and are responsible for significant morbidity and deterioration in health-related quality of life. The diagnostic work-up must consider the medical history of patients, in the context of venom allergy epidemiology and Hymenoptera taxonomy, and the clinical manifestations of the reactions, to channel the available in vivo and in vitro tests towards the most accurate diagnosis and the consequent appropriate management, also considering the risk profile of the patients on a precision-medicine approach. All these aspects are covered by this work that aims at providing an up-to-date review to increase the awareness of this topic among interested stakeholders, like healthcare professionals and political decision makers, who can contribute to the proper immediate and long-term management of venom allergy and anaphylaxis.

Alarmins in autoimmune diseases.

Alarmins are endogenous, constitutively expressed, chemotacting and immune activating proteins or peptides released because of non-programmed cell death (i.e. infections, trauma, etc). They are considered endogenous damage-associated molecular patterns (DAMPs), able to induce a sterile inflammation. In the last years, several studies highlighted a possible role of different alarmins in the pathogenesis of various autoimmune and immune-mediated diseases. We reviewed the relevant literature about this topic, for about 160 articles. Particularly, we focused on systemic autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, idiopathic inflammatory myopathies, ANCA-associated vasculitides, Behçet's disease) and cutaneous organ-specific autoimmune diseases (vitiligo, psoriasis, alopecia, pemphigo). Finally, we discussed about future perspectives and potential therapeutic implications of alarmins in autoimmune diseases. In fact, identification of receptors and downstream signal transducers of alarmins may lead to the identification of antagonistic inhibitors and agonists, with the capacity to modulate alarmins-related pathways and potential therapeutic applicability.

Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.

A machine learning analysis to predict the response to intravenous and subcutaneous immunoglobulin in inflammatory myopathies. A proposal for a future multi-omics approach in autoimmune diseases.

OBJECTIVE: To evaluate the response to treatment with intravenous (IVIg) and subcutaneous (20%SCIg) immunoglobulin in our series of patients with Inflammatory idiopathic myopathies (IIM) by the means of artificial intelligence. BACKGROUND: IIM are rare diseases mainly involving the skeletal muscle with particular clinical, laboratory and radiological characteristics. Artificial intelligence (AI) represents computer processes which allows to perform complex calculations and data analyses, with the least human intervention. Recently, the use an AI in medicine significantly expanded, especially through machine learning (ML) which analyses huge amounts of information and accordingly makes decisions, and deep learning (DL) which uses artificial neural networks to analyse data and automatically learn. METHODS: In this study, we employed AI in the evaluation of the response to treatment with IVIg and 20%SCIg in our series of patients with IIM. The diagnoses were determined on the established EULAR/ACR criteria. The treatment response was evaluated employing the following: serum creatine kinase levels, muscle strength (MMT8 score), disease activity (MITAX score) and disability (HAQ-DI score). We evaluated all the above parameters, applying, with R, different supervised ML algorithms, including Least Absolute Shrinkage and Selection Operator, Ridge, Elastic Net, Classification and Regression Trees and Random Forest to estimate the most important predictors for a good response to IVIg and 20%SCIg treatment. RESULTS AND CONCLUSION: By the means of AI we have been able to identify the scores that best predict a good response to IVIg and 20%SCIg treatment. The muscle strength as evaluated by MMT8 score at the follow-up is predicted by the presence of dysphagia and of skin disorders, and the myositis activity index (MITAX) at the beginning of the treatment. The relationship between muscle strength and MITAX indicates a better action of IVIg therapy in patients with more active systemic disease. Considering our results, Elastic Net and similar approaches were seen to be the most viable, efficient, and effective ML methods for predicting the clinical outcome (MMT8 and MITAX at most) in myositis.

The Impact of SARS-CoV-2 Infection in Patients with Inborn Errors of Immunity: the Experience of the Italian Primary Immunodeficiencies Network (IPINet).

COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50-60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life.

The iGreenGO Study: The Clinical Role of Indocyanine Green Imaging Fluorescence in Modifying the Surgeon's Conduct During the Surgical Treatment of Advanced Gastric Cancer-Study Protocol for an International Multicenter Prospective Study.

Background: The near-infrared/indocyanine green imaging fluorescence (NIR/ICG) technology is showing promising results in several fields of surgical oncology. The clinical value of NIR/ICG technology in the surgical treatment of advanced gastric cancer (AGC) is not clearly established. Methods: This is the protocol of the "iGreenGO" (indocyanine Green Gastric Observation) Study, a national prospective multicenter study. Western patients who undergo curative-intent gastrectomy with D2 lymphadenectomy for AGC constitute the study cohort. All the patients undergo preoperative upper gastrointestinal endoscopy for submucosal peritumoral ICG injection at the most 20 h before surgery. Intraoperative endoscopic injection before starting surgical dissection is also allowed. The primary endpoint is the "change in the surgical conduct" (CSC), i.e., the need to perform further dissection after intraoperative NIR/ICG technology activation at the end of D2 lymphadenectomy. Secondary endpoints include the pattern of abdominal fluorescence distribution according to tumor and patient characteristics, the preoperative clinical variables potentially associated with CSC, and the incidence of stage migration due to NIR/ICG application. Discussion: The iGreenGO Study is the first study to investigate the clinical role of NIR/ICG technology for the surgical treatment of AGC in a large cohort of Western patients. Results from the present study can further clarify the role of NIR/ICG technology in surgical lymphadenectomy for AGC.

Common Variable Immunodeficiency in Elderly Patients: A Long-Term Clinical Experience.

Background: Common variable immunodeficiency (CVID) is a complex, predominantly antibody deficiency usually diagnosed between 20−40 years. Few data about elderly patients are reported in the literature. Our aim was to evaluate the clinical phenotypes of elderly patients with CVID. Method: A retrospective analysis of adult patients with CVID was performed in our Referral Centre, focusing on the main differences between "older" patients (≥65 years at the diagnosis) and "younger" patients (<65 years). Results: The data from 65 younger and 13 older patients followed up for a median period of 8.5 years were available. At diagnosis, recurrent infections represented the only clinical manifestation in 61% and 69% of younger and older patients, respectively. The incidence of autoimmune diseases was higher in elderly patients compared with younger ones (30 vs. 18%, respectively). During the follow-up, the incidence of autoimmune disorders and enteropathy increased in the younger patients whereas neoplasia became the most prevalent complication in the elderly (38%). All patients received a replacement therapy with immunoglobulin, with good compliance. Conclusion: CVID occurrence in elderly patients is rarely described; therefore, the clinical characteristics are not completely known. In our series, neoplasia became the most prevalent complication in the elderly during the follow-up. In elderly patients, 20% SCIg was as safe as in the younger ones, with good compliance. A genetic analysis is important to confirm the diagnosis, identify specific presentations in the different ages, clarify the prognosis and guide the treatment. Future clinical research in this field may potentially help to guide their care.