Search

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Disorders of the cardiac rhythm may occur in both the fetus and neonate. Because of the immature myocardium, the hemodynamic consequences of either bradyarrhythmias or tachyarrhythmias may be far more significant than in mature physiological states. Treatment options are limited in the fetus and neonate because of limited vascular access, patient size, and the significant risk/benefit ratio of any intervention. In addition, exposure of the fetus or neonate to either persistent arrhythmias or antiarrhythmic medications may have yet-to-be-determined long-term developmental consequences. This scientific statement discusses the mechanism of arrhythmias, pharmacological treatment options, and distinct aspects of pharmacokinetics for the fetus and neonate. From the available current data, subjects of apparent consistency/consensus are presented, as well as future directions for research in terms of aspects of care for which evidence has not been established.

Coagulation factor V (FV) deficiency is a rare bleeding disorder that is usually managed with fresh-frozen plasma. Patients with nonsense mutations may respond to treatment with readthrough agents.

Study design: Cross-sectional comparative study. Objectives: Evaluate prevalence and clinical relevance of an underlying pathology in painful adolescent idiopathic scoliosis (AIS) patients after a non-diagnostic history, physical examination and spinal X-ray using Magnetic Resonance Image (MRI) as diagnostic tool. Summary of background data: Discrepancies regarding indications of routine MRI screening in painful AIS patients are multifactorial. Few studies have investigated relationship and practical importance of painful AIS with an underlying pathology by MRI. Method: A total of 152-consecutive AIS patients complaining of back pain during a 36-month period were enrolled. All patients underwent whole-spine MRI after a non-diagnostic history, physical examination and spinal X-ray. Underlying pathologies were reported as neural and non-neural axis abnormalities based on MRI reports. Variables such as sex, age, constant or intermittent pain, night pain, back pain location (thoracic or lumbar pain), Cobb-angle and follow-up were evaluated as clinical markers to predict presence of underlying MRI pathologies. Results: The presence of an underlying pathology was found by MRI in 54 painful AIS patients (35.5%). Isolated syringomyelia was the only neural axis abnormality found in 6 patients (3.9%). Non-neural axis abnormalities (31.6%) were composed by: 32 herniated nucleus pulposus, 5 vertebral disc desiccation, 4 ovarian cysts, 3 renal cysts, 2 sacral cysts, and 2 vertebral hemangiomas. There was no association with gender, age of presentation, initial coronal Cobb angle and follow up; with presence of an underlying pathology. Lumbar pain location was identified as an adequate clinical marker that correlated with presence of an underlying pathology (p = 0.01). Conclusions: Prevalence of underlying pathologies diagnosed by MRI in painful AIS was found high (35.5%), but it’s clinical relevance and implication are debatable. The use of MRI did not affect orthopedic management of painful AIS patients who showed an underlying pathology. A thorough evaluation must be performed by clinicians; and discussed with patients and family prior to undergo further imaging management. Level of evidence: Level III.

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p< 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

Polarized and wide-field light microscopy has been studied for many years to develop accurate and information-rich images within a focused framework on biophysics and biomedicine. Technological advances and conceptual understanding have recently led to significant results in terms of applications. Simultaneously, developments in label-free methods are opening a new window on molecular imaging at a low dose of illumination. The ability to encode and decode polarized light pixel by pixel, coupled with the computational strength provided by artificial intelligence, is the running perspective of label-free optical microscopy. More specifically, the information-rich content Mueller matrix microscopy through its 16 elements offers multimodal imaging, an original data set to be integrated with other advanced optical methods. This dilates the spectrum of possible and potential applications. Here, we explore the recent advances in basic and applied research towards technological applications tailored for specific questions in biophysics and biomedicine.

In this article, as part of this special issue on biomarkers of early response, we review currently available reports regarding magnetic resonance imaging apparent diffusion coefficient (ADC) changes in hepatocellular carcinoma (HCC) in response to stereotactic body radiation therapy. We compare diffusion image acquisition, ADC analysis, methods for HCC response assessment, and statistical methods for prediction of local tumor progression by ADC metrics. We discuss the pros and cons of these studies. Following detailed analyses of existing investigations, we cannot conclude that ADC is established as an imaging biomarker for stereotactic body radiation therapy assessment in HCC.

During the past 30 years, several advances have been made allowing for safer and more effective treatment of patients with liver cancer. This report reviews recent advances in radiation therapy for primary liver cancers including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. First, studies focusing on liver stereotactic body radiation therapy (SBRT) are reviewed focusing on lessons learned and knowledge gained from early pioneering trials. Then, new technologies to enhance SBRT treatments are explored including adaptive therapy and MRI-guided and biology-guided radiation therapy. Finally, treatment with Y-90 transarterial radioembolization is reviewed with a focus on novel approaches focused on personalized therapy.

By recovering data in an ordered manner and at the right time, clinical decision support systems (CDSSs) are designed to help healthcare professionals make decisions that improve patient care.

The prenatal detection of D‐Transposition of the great arteries (D‐TGA) and tetralogy of Fallot (TOF) has been reported to be less than 50% to as high as 77% when adding the outflow tracts to the four‐chamber screening protocol. Because many examiners still struggle with the outflow tract examination, this study evaluated whether changes in the size and shape of the heart in the 4CV as well as the ventricles occurred in fetuses with D‐TGA and TOF could be used to screen for these malformations. Forty‐four fetuses with the pre‐and post‐natal diagnosis of D‐TGA and 44 with TOF were evaluated between 19 and 36 weeks of gestation in which the 4CV was imaged. Measurements of the end‐diastolic width, length, area, and global sphericity index were measured for the four‐chamber view and the right and left ventricles. Using z‐score computed values, logistic regression was performed between the 88 study and 200 control fetuses using the hierarchical forward selection protocol. Logistic regression identified 10 variables that correctly classified 83/88 of fetuses with TOF and TGA, for a sensitivity of 94%. Six of 200 normal controls were incorrectly classified for a false‐positive rate of 3%. The area under the receiver operator classification curve was 98.1%. The true positive rate for D‐TGA was 93.2%, with a false‐negative rate to 6.8%. The true positive rate for TOF was 95.5%, with a false negative rate of 4.5%. Measurements of the 4CV and of the RV and LV may help identify fetuses at risk for D‐TGA or TOF. Access the CME test hereand search by article title.

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1and XPO1mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3and EGR2aberrations were significant predictors only in U-CLL, and NOTCH1and NFKBIEonly in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

Introduction: The preference for using transradial access (TRA) over transfemoral access (TFA) in patients requiring percutaneous coronary intervention (PCI) is based on evidence suggesting that TRA is associated with less bleeding and fewer vascular complications, shorter hospital stays, improved quality of life, and a potential beneficial effect on mortality. We have limited study data comparing the two access routes in a patient population with atrial fibrillation (AF) undergoing PCI, who have a particular increased risk of bleeding, while AF itself is associated with an increased risk of thromboembolism. Methods: Using data from the RIVA-PCI registry, which includes patients with AF undergoing PCI, we analyzed a high-bleeding-risk (HBR) cohort. These patients were predominantly on oral anticoagulants (OAC) for AF, and the PCI was performed via radial or femoral access. Endpoints examined were in-hospital bleeding (BARC 2–5), cerebral events (TIA, hemorrhagic or ischemic stroke) and coronary events (stent thrombosis and myocardial infarction). Results: Out of 1636 patients, 854 (52.2%) underwent TFA, while 782 (47.8%) underwent the procedure via TRA, including nine patients with brachial artery puncture. The mean age was 75.5 years. Groups were similar in terms of age, sex distribution, AF type, cardiovascular history, risk factors, and comorbidities, except for a higher incidence of previous bypass surgeries, heart failure, hyperlipidemia, and chronic kidney disease (CKD) with a glomerular filtration rate (GFR) &lt; 60 ml/min in the TFA group. No clinically relevant differences in antithrombotic therapy and combinations were present at the time of PCI. However, upon discharge, transradial PCI patients had a higher rate of triple therapy, while dual therapy was preferred after transfemoral procedures. Radial access was more frequently chosen for non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP) cases (NSTEMI 26.6% vs. 17.0%, p&lt; 0.0001; UAP 21.5% vs. 14.5%, p&lt; 0.001), while femoral access was more common for elective PCI (60.3% vs. 44.1%, p&lt; 0.0001). No differences were observed for ST-segment elevation myocardial infarction (STEMI). Both groups had similar rates of cerebral events (TFA 0.2% vs. TRA 0.3%, p= 0.93), but the TFA group had a higher incidence of bleeding (BARC 2–5) (4.2% vs. 1.5%, p&lt; 0.01), mainly driven by BARC 3 bleeding (1.5% vs. 0.4%, p&lt; 0.05). No significant differences were found for stent thrombosis and myocardial infarction (TFA 0.2% vs. TRA 0.3%, p= 0.93; TFA 0.4% vs. TRA 0.1%, p= 0.36). Conclusions: In HBR patients with AF undergoing PCI for acute or chronic coronary syndrome, the use of TRA might be associated with a decrease in in-hospital bleeding, while not increasing the risk of embolic or ischemic events compared to femoral access. Further studies are required to confirm these preliminary findings.

ObjectivesThis study compared the burden of fatigue between treatment-nai¨ve patients with newly diagnosed acute myeloid leukaemia (AML) and the general population and investigated patient factors associated with fatigue severity.MethodsPretreatment patient-reported fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire in a sample of 463 newly diagnosed patients with AML who were enrolled in a clinical trial. Multivariable linear regression models were used to estimate the adjusted mean differences in fatigue between patients with AML and adults from the general population (n=847) by AML disease risk categories. A clinically meaningful difference in fatigue was defined as ≥3 points. Univariable and multivariable linear regression models were used to identify sociodemographic, clinical and molecular correlates of worse fatigue in patients with AML.ResultsPatients with AML reported adjusted mean fatigue scores that were 7.5 points worse than the general population (95% CI −8.6 to −6.4, p<0.001). Across AML disease risk categories, adjusted mean differences in fatigue compared with the general population ranged from 6.7 points worse (patients with favourable risk: 95% CI −8.6 to −4.8, p<0.001) to 8.9 points worse (patients with poor risk, 95% CI −10.5 to −7.2, p<0.001). Overall, 91% of patients with AML reported fatigue that was equal to or worse than the general population’s median fatigue score. Higher pretreatment fatigue was independently associated with female sex, WHO performance status ≥1 and lower platelet levels.ConclusionsPatients with newly diagnosed AML reported worse fatigue than the general population, and mean differences exceeded twice the threshold for clinical significance. Our findings may help to identify patients with AML most likely to benefit from supportive care interventions to reduce fatigue.

Known as pediatric medical traumatic stress (PMTS), posttraumatic stress symptoms from medical experiences have not been explored in children with chronic gastrointestinal diseases. This cross-sectional study of children and adolescents with inflammatory bowel disease, chronic pancreatitis and cystic fibrosis, aimed to (1) estimate the prevalence of medical potentially traumatic events (PTEs) and PMTS, (2) explore potential risk factors for PMTS, and (3) explore potential consequences of PMTS. This cross-sectional study used validated, self-report measures to evaluate PTEs and PMTS. Descriptive statistics and regression analyses were used to achieve study objectives. Over two-thirds of children reported a medical potentially traumatic event (91 of 132, 69%). Forty-eight had PMTS symptoms (36%). PMTS was associated with medication burden, emergency and intensive care visits, and parent posttraumatic stress disorder in multivariate analysis. Potential consequences associated with PMTS included school absenteeism, home opioid use, poor quality of life, and parent missed work. A substantial portion of our cohort reported medical PTEs and PMTS. The exploratory analysis identified potential associations between PMTS and illness factors, parent posttraumatic stress disorder, and functional impairments. Further studies of PMTS detection, prevention and treatment are integral to optimizing these children’s health and quality of life.

Commentaries on literary texts, be they Kāvyas or Nāṭyas, are a prolific though still much understudied genre in South Asia. The stress on the literary text as the achieved and circumscribed “work of art” has undermined studies on the reception history, transmission, and composing and staging of literary texts, where the poem or drama in its entirety is not always the main unit to be considered. Along these lines, literary commentaries are crucial for understanding the relation between theoretical prescriptions and compositional/performative practices, as they often put these two dimensions of literature (the theoretical and the practical) into dialogue. Moreover, a host of knowledge systems (nāṭyaśāstra, alaṃkāraśāstra, vyākaraṇa, mīmāṃsā, etc.), along with their philosophical insights, technical vocabulary, and hermeneutical techniques, are employed, combined, and creatively refunctionalized in literary commentaries, which therefore represent a liminal genre of śāstrathat crosses the seemingly well-established boundaries among disciplines and offers to the modern scholar a unique window into the intellectual life of premodern South Asia.

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107.

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.govas #NCT01641107.

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin’s lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin's lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

Bone is a complex structural composite that features a remarkable combination of mechanical properties, in spite of its rather meager building blocks (i.e., mineral and proteins). The reasons behind these optimal mechanical performances lay in bone hierarchical organization. A crucial role is played by the microscale structure (Haversian), which is formed by a repetition of cylindrical building blocks (osteons) surrounded by a matrix of interstitial tissue. Following a biomimetic approach, mimicking this natural architecture in the design of innovative fiber-reinforced composites appears to be a very promising way to improve the performance of engineering composites. However, it is still an open challenge due to manufacturing-induced limitations. Here we aim to overcome such limitations and implement a bone-like design into novel fiber-reinforced materials. We first focus on the design and manufacturing of osteon-like features by pull-winding technology, to get a continuous and rapid production. We fabricate osteon-inspired multilayer concentric rods by coupling multiple layers of fibers, characterized by different materials and orientations. To study the effect of each layer on the overall mechanical properties and provide guidelines for optimal design, we perform finite element simulations. The simplicity and versality of the production line allow us to manufacture great quantities of these rods at a high production rate. The combination of finite elements analysis and experimental design allow us to find a trade-off between the best and the most feasible configuration. Future works will focus on the manufacturing of a multiscale composite laminate made of these small pull-winded rods, inspired by the osteons.