Clinical Outcome Variables Research Articles

MRI Findings in Osmotic Demyelination Syndrome- A Report of Two Cases

Osmotic demyelination syndrome is a condition seen due to the loss of normal myelin in the central nervous system. Multiple etiologies have been identified as causing this condition, however, the most reported cause is the rapid correction of hyponatremia. Different levels of the central nervous system are involved in the condition. Despite variable etiologies and clinical outcomes of the disease, the Magnetic Resonance Imaging (MRI) findings are well-established and characteristic. Hereby, two cases (45 years and 25 years old males) of Osmotic demyelination syndrome are described, to demonstrate the characteristic magnetic resonance imaging findings of the brain. Both cases were chronic alcoholics with a history of few episodes of vomiting, who later developed neurological symptoms. Their biochemical investigations showed severe hyponatremia. The hyponatremia was corrected rapidly, following which they developed neurological symptoms. Non-contrast MRI brain was done for both patients, which showed abnormal hyperintense T2/Fluid-attenuated Inversion Recovery (FLAIR) signals in central Pons. Both cases showed variable, however characteristics findings of osmotic demyelination syndrome on MRI. Despite, multiple causative factors and clinical outcomes of Osmotic demyelination syndrome, MRI with its characteristic findings plays a key role in diagnosis.

Variations in Time to Recovery from Pediatric Concussion Based on Differing Outcomes of Interest

To quantify variability in pediatric concussion recovery across multiple outcomes of interest. Pediatric concussion studies are hindered by a common significant limitation: lack of agreement on a standard definition of "recovery." A variety of clinical outcomes of interest utilized across studies, including symptom self-report, neurocognitive testing results, self-reported return to activity, and physician clearance for activity, leads to challenges for both research, as well as clinical concussion management. We enrolled concussed youth, ages 11-18 years, from a specialty sports medicine clinic = 28 days of injury. Patients were followed as part of clinical care for concussion for up to 13 weeks. At each visit, participants completed questionnaires and a battery of clinical measures. From these data, we constructed 10 potential definitions of recovery: 3 based on self-reported symptoms (change from pre-injury, no symptoms, below pre-determined thresholds), 2 based on visio-vestibular examination (VVE) deficits (none, = 1), 2 based on physician clearance (for return to school/sport), and 3 based on self-assessment ("back to normal", return to school/exercise). One hundred seventy-four concussed youth were enrolled (median age: 15 years, 54.6% female) with a median time from injury to initial visit of 12 days (IQR: 7, 20). Median number of visits was 2 (range: 1, 5). We observed a wide variation in the proportion of participants recovered across the 10 definitions. Depending on definition, between 4% and 45% were considered recovered within 4 weeks, and between 10% and 80% were considered recovered at the end of follow-up. The VVE-based definition (=1 deficit) consistently had the highest proportion recovered at all time points, while self-reported return to exercise had the lowest proportion. Recovery from concussion is not a single unitary point in time. These results will provide valuable guidance to clinicians in managing concussion and researchers in designing future observational and interventional trials of pediatric concussion.

Specialist Referral and Outcomes in Adolescent Athletes With Prior Concussion History

To examine specialist referral patterns and clinical outcomes in adolescents with differing levels of prior concussion history. Limited evidence exists on healthcare utilization and outcomes in concussed adolescent athletes with and without a history of prior concussion. Data were prospectively collected from participants aged 12-18 diagnosed with a sport-related concussion and documented prior concussion history between August 2015-March 2020. Participants were separated into 3 groups: 0, 1, and 2 + prior concussions. Demographics, medical history, specialist referrals, and clinical outcome variables obtained at 3-months post-concussion were analyzed. One thousand one hundred ninety-seven participants were included: 114 (10.4%) had 2+, 213 (19.4%) had 1, and 770 (70.2%) had 0 prior concussions. There was no difference in sex or time to presentation. A small difference was found across age (15.3 ± 1.6 vs 14.9 ± 1.6 vs 14.5 ± 1.6 years, p < 0.001). Significant differences were also observed between groups in self-reported history of psychological disorders (14.9 vs 15 vs 8.4%, p = 0.01) and headaches/migraines (25.4 vs 20.2 vs 15.5%, p = 0.02). Significant differences between the groups were found in specialist referrals, with more referrals made in the 2 + group to physical therapy (39.6 vs 28.2 vs 23.4%, p = 0.001), neuropsychology (17.1 vs 5.3 vs 7.5%, p = 0.001), and neurology (8.9 vs 2.9 vs 2.2%, p = 0.001). Fewer participants in the 2 + group recovered in = 30 days (53.6 vs 65.6 vs 68.5%, p = 0.04) and reported lower rates of return to activity at 3-months post-concussion (67.9 vs 85.9 vs 87.6%, p < 0.001). No differences were seen in symptom severity, PHQ-8, or GAD-7 scores. All reported as 2 + vs 1 vs 0. Concussed adolescent athletes with a history of 2 or more prior concussions had a higher rate of specialist referrals, were less likely to have returned to prior level of play/activity 3 months following injury, and were less likely to have resolution of symptoms in 30 days or less.

Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results From the CABANA Trial.

Observational data suggest that catheter ablation may be safe and effective to treat younger and older patients with atrial fibrillation. No large, randomized trial has examined this issue. This report describes outcomes according to age at entry in the CABANA trial (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation). Patients with atrial fibrillation ≥65 years of age, or <65 with ≥1 risk factor for stroke, were randomly assigned to catheter ablation versus drug therapy. The primary outcome was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Secondary outcomes included all-cause mortality, the composite of mortality or cardiovascular hospitalization, and recurrence of atrial fibrillation. Treatment effect estimates were adjusted for baseline covariables using proportional hazards regression models. Of 2204 patients randomly assigned in CABANA, 766 (34.8%) were <65 years of age, 1130 (51.3%) were 65 to 74 years of age, and 308 (14.0%) were ≥75 years of age. Catheter ablation was associated with a 43% reduction in the primary outcome for patients <65 years of age (adjusted hazard ratio [aHR], 0.57 [95% CI, 0.30-1.09]), a 21% reduction for 65 to 74 years of age (aHR, 0.79 [95% CI, 0.54-1.16]), and an indeterminate effect for age ≥75 years of age (aHR, 1.39 [95% CI, 0.75-2.58]). Four-year event rates for ablation versus drug therapy across age groups, respectively, were 3.2% versus 7.8%, 7.8% versus 9.6%, and 14.8% versus 9.0%. For every 10-year increase in age, the primary outcome aHR increased (ie, less favorable to ablation) an average of 27% (interaction P value=0.215). A similar pattern was seen with all-cause mortality: for every 10-year increase in age, the aHR increased an average of 46% (interaction P value=0.111). Atrial fibrillation recurrence rates were lower with ablation than with drug therapy across age subgroups (aHR 0.47, 0.58, and 0.49, respectively). Treatment-related complications were infrequent for both arms (<3%) regardless of age. We found age-based variations in clinical outcomes for catheter ablation compared with drug therapy, with the largest relative and absolute benefits of catheter ablation in younger patients. No prognostic benefits for ablation were seen in the oldest patients. No differences were found by age in treatment-related complications or in the relative effectiveness of catheter ablation in preventing recurrent atrial arrhythmias. URL: https://www. gov; Unique identifier: NCT00911508.

HER2-Positive Breast Cancer: Association of MRI and Clinicopathologic Features With Tumor-Infiltrating Lymphocytes.

BACKGROUND. Tumor-infiltrating lymphocytes (TILs) are associated with therapeutic outcomes and prognosis in patients with human epidermal growth factor receptor type 2 (HER2)-positive breast cancer. Identification of TIL levels is clinically relevant. OBJECTIVE. The purpose of our study was to explore associations of clinicopathologic and MRI features with TIL levels in patients with HER2-positive breast cancer. METHODS. A total of 212 consecutive women (mean age, 54.0 years) diagnosed with HER2-positive breast cancer between January 2017 and December 2019 were included in this retrospective study. Patients were divided into low-TIL (< 10%) and high-TIL (≥ 10%) groups. Three breast radiologists independently reviewed images; interreader agreement was assessed, and the first reader's findings were used for further analysis. Associations of clinicopathologic and MRI features with TIL levels were evaluated using multivariable logistic regression analysis. Subanalysis of TIL levels by hormone receptor (HR) status was also performed. RESULTS. A total of 115 (54.2%) patients had low TIL levels, and 97 (45.8%) patients had high TIL levels. A high TIL level was associated (all, p < .05) with histologic grade 3 (odds ratio [OR] = 3.98; frequency, 78.4% vs 52.2% in high- vs low-TIL groups, respectively), high tumor cellularity (OR = 4.59; median cellularity, 60% vs 50%), lower frequency of associated ductal carcinoma in situ (OR = 0.16; frequency, 86.6% vs 94.8%), and higher frequency of peritumoral edema on T2-weighted images (OR = 2.83; 71.1% vs 50.4%). In subgroup analysis by HR status, histologic grade 3 (OR = 5.03, p = .002) was a significant independent predictor of high TIL level in the HR-positive/HER2-positive group, whereas high tumor cellularity (OR = 9.06, p = .002), peritumoral edema (OR = 5.23, p = .03), and low ADC (OR = 11.69, p = .047) were independent predictors of high TIL level in the HR-negative/HER2-positive group. Interreader agreement for peritumoral edema was moderate among the three radiologists (к = 0.432-0.539). CONCLUSION. Peritumoral edema on MRI and the histopathologic feature of tumor aggressiveness help predict high TIL levels in patients with HER2-positive breast cancer. CLINICAL IMPACT. Pretreatment MRI features may serve as a useful tool for assessing TIL levels in patients with HER2-positive breast cancer and for helping to classify patients with variable clinical outcomes related to immune activity and to guide selection among neoadjuvant chemotherapy or HER2-targeted therapy or immunotherapy.

Low BACH2 Expression Predicts Adverse Outcome in Chronic Lymphocytic Leukaemia.

Simple SummaryChronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia with a highly variable presentation, clinical course, and outcome. The overall aim of our study was to determine the clinical and functional significance of two B-cell regulators, BACH2 and BCL6, in CLL. The results showed that CLL patients expressing low levels of BACH2 and BCL6 RNA had a shorter overall survival (OS). Their low RNA expression was associated with a shorter overall survival of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Further, co-immunoprecipitation and mass spectrometry studies from MEC-1 CLL cells showed no direct interaction between BACH2 and BCL6, but shared protein networks that are involved in ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology. Taken together, this study reports BACH2 as a potential prognosticator and indicates the protein networks influenced by BCL6 and BACH2 in CLL.Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6- and BACH2-expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.

Mass-Spectrometry-Based Functional Proteomic and Phosphoproteomic Technologies and Their Application for Analyzing Ex Vivo and In Vitro Models of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease thought to be principally caused by mutations in sarcomeric proteins. Despite extensive genetic analysis, there are no comprehensive molecular frameworks for how single mutations in contractile proteins result in the diverse assortment of cellular, phenotypic, and pathobiological cascades seen in HCM. Molecular profiling and system biology approaches are powerful tools for elucidating, quantifying, and interpreting dynamic signaling pathways and differential macromolecule expression profiles for a wide range of sample types, including cardiomyopathy. Cutting-edge approaches combine high-performance analytical instrumentation (e.g., mass spectrometry) with computational methods (e.g., bioinformatics) to study the comparative activity of biochemical pathways based on relative abundances of functionally linked proteins of interest. Cardiac research is poised to benefit enormously from the application of this toolkit to cardiac tissue models, which recapitulate key aspects of pathogenesis. In this review, we evaluate state-of-the-art mass-spectrometry-based proteomic and phosphoproteomic technologies and their application to in vitro and ex vivo models of HCM for global mapping of macromolecular alterations driving disease progression, emphasizing their potential for defining the components of basic biological systems, the fundamental mechanistic basis of HCM pathogenesis, and treating the ensuing varied clinical outcomes seen among affected patient cohorts.

WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pervasive event in tumorigenesis due to PI3K mutation and dysfunction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Pharmacological inhibition of PI3K has resulted in variable clinical outcomes, however, raising questions regarding the possible mechanisms of unresponsiveness and resistance to treatment. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase frequently amplified and mutated in multiple cancers, as well as in the germ lines of patients predisposed to cancer, and was recently found to activate PI3K signaling through PTEN inactivation. Here, we demonstrate that PTEN dissociated from the plasma membrane upon treatment with PI3K inhibitors through WWP1 activation, whereas WWP1 genetic or pharmacological inhibition restored PTEN membrane localization, synergizing with PI3K inhibitors to suppress tumor growth both in vitro and in vivo. Furthermore, we demonstrate that WWP1 inhibition attenuated hyperglycemia and the consequent insulin feedback, which is a major tumor-promoting side effect of PI3K inhibitors. Mechanistically, we found that AMPKα2 was ubiquitinated and, in turn, inhibited in its activatory phosphorylation by WWP1, whereas WWP1 inhibition facilitated AMPKα2 activity in the muscle to compensate for the reduction in glucose uptake observed upon PI3K inhibition. Thus, our identification of the cell-autonomous and systemic roles of WWP1 inhibition expands the therapeutic potential of PI3K inhibitors and reveals new avenues of combination cancer therapy.

ACL Reconstruction Rehabilitation: Clinical Data, Biologic Healing, and Criterion-Based Milestones to Inform a Return-to-Sport Guideline.

Anterior cruciate ligament (ACL) reconstruction (ACLR) and postoperative rehabilitation continues to be a multidisciplinary focus in both research and clinical environments. Recent research on ACLR warrants a reexamination of clinicians' current rehabilitation practices to optimize the strikingly variable clinical outcomes after ACLR and return to sport. The purpose of the article and updated guidelines is to use contemporary evidence to systematically revisit our practice guidelines and validate our clinical milestones with data from our university-based practice. Using the PubMed search engine, articles that reported on ACLR rehabilitation and protocols, guidelines, graft type, healing and strain, return to sport, psychological considerations, and secondary injury prevention published from 1979 to 2020 were identified using the search terms ACLR protocols, guidelines, ACLR rehabilitation, ACL graft, ACL open kinetic chain (OKC) exercise and closed kinetic chain (CKC) exercise, ACLR return to sport, ACLR psychological factors, and ACL injury prevention. Clinical review. Level 5. Clinical milestones after ACLR were validated using clinical data collected from 2013 to 2017 at a university-based practice. Variables including knee joint range of motion, effusion, Knee Outcome Survey-Activities of Daily Living Scale, and quadriceps strength index were tracked throughout rehabilitation and analyzed to help inform an updated ACLR rehabilitation guideline. Incorporating the latest research, combined with direct clinical data, provides a current, realistic, and clinically benchmarked strategy for ACLR rehabilitation. Commonly held clinical beliefs regarding rehabilitation after ACL injury must be challenged by the latest research to improve patient outcomes and decrease the risk of reinjury. Key updates to the practice guidelines include the use of frequent and accurate quadriceps strength testing, delayed return-to-sport timeline, immediate use of open kinetic chain exercise, criterion-based progressions for running, sprinting, plyometrics, agility, cutting/pivoting, return to competition, and the inclusion of a secondary prevention program after return to sport. B.

Survival Advantage Following TAG-72 Antigen-Directed Cancer Surgery in Patients With Colorectal Carcinoma: Proposed Mechanisms of Action.

Patients with colorectal carcinoma (CRC) continue to have variable clinical outcomes despite undergoing the same surgical procedure with curative intent and having the same pathologic and clinical stage. This problem suggests the need for better techniques to assess the extent of disease during surgery. We began to address this problem 35 years ago by injecting patients with either primary or recurrent CRC with 125I-labeled murine monoclonal antibodies against the tumor-associated glycoprotein-72 (TAG-72) and using a handheld gamma-detecting probe (HGDP) for intraoperative detection and removal of radioactive, i.e., TAG-72-positive, tissue. Data from these studies demonstrated a significant difference in overall survival data (p < 0.005 or better) when no TAG-72-positive tissue remained compared to when TAG-72-positive tissue remained at the completion of surgery. Recent publications indicate that aberrant glycosylation of mucins and their critical role in suppressing tumor-associated immune response help to explain the cellular mechanisms underlying our results. We propose that monoclonal antibodies to TAG-72 recognize and bind to antigenic epitopes on mucins that suppress the tumor-associated immune response in both the tumor and tumor-draining lymph nodes. Complete surgical removal of all TAG-72-positive tissue serves to reverse the escape phase of immunoediting, allowing a resetting of this response that leads to improved overall survival of the patients with either primary or recurrent CRC. Thus, the status of TAG-72 positivity after resection has a significant impact on patient survival.

1243. Eravacycline in Bacteremia: A Case Series

BackgroundEravacycline (ERV) is FDA-approved for the treatment of complicated intra-abdominal infections, but there is limited experience for non-FDA approved indications. MethodsWe present five cases that utilized ERV for treatment of bacteremia.ResultsPatient 1 in septic shock (SS) started on vancomycin (VAN) and ceftazidime-avibactam (CZA). Blood culture (BC) finalized to E. coli and regimen narrowed to CZA. On day 9, gram-positive cocci in chains in BC grew and VAN was added. BC finalized to VRE faecium and regimen was modified to ERV on day 12. Repeat BC on day 15 finalized to no growth with no recurrence of bacteremia until discharged (day 78). Patient 2 treated for MSSA bacteremia with cefazolin and subsequent K. pneumoniae VAP treated with ceftriaxone (CRO) (day 18-26). On day 27, meropenem (MEM) was initiated for gram-negative bacteremia and started on IV trimethoprim/sulfamethoxazole (TMP/SMX) the following day for pneumonia caused by TMP/SMX-susceptible S. maltophila. BC finalized on day 29 to S. maltophila resistant to TMP/SMX, regimen modified to ERV. Repeat BC on day 30 finalized to no growth and ERV was continued until day 42 with no recurrence of bacteremia; however, patient died on day 45. Patient 3 with renal failure and on day 11, CRO started for SBP prophylaxis. On day 13, switched to daptomycin and cefepime (FEP) as patient was febrile and BC repeated. BC finalized to VRE faecium and was started on ERV on day 17 and completed a 7-day course with no recurrence of bacteremia; however, patient died on day 34. Patient 4 initially treated for bacterial superinfection with CRO and azithromycin, and subsequent worsening pneumonia treated with VAN and MEM (day 10-17). On day 19, patient was febrile and treated with VAN and FEP until day 27. Repeat BC on day 29 finalized to VRE species and modified to ERV on day 32. ERV continued for a 7-day course and was discharged with no repeat BC obtained to confirm clearance. Patient 5 in SS started on VAN and MEM. On day 3, BC on admission finalized to VRE faecium and therapy switched to ERV. Repeat BC taken on day 3 after ERV initiation were negative. Discharged to complete two-week course of ERV.ConclusionERV may be an option for bacteremia as demonstrated by clearance in four of five cases. More studies must be conducted as these reports show variable clinical outcomes.Disclosures Joshua R. Rosenberg, MD, Allergan/Abbvie (Consultant)La Jolla/Tetraphase (Consultant)Melinta (Consultant)Merck (Consultant)Paratek (Consultant)Sanofi (Consultant)Shionogi (Consultant)

DIPS (Dystonia Image-based Programming of Stimulation: a prospective, randomized, double-blind crossover trial)

IntroductionDeep brain stimulation of the internal globus pallidus is an effective treatment for dystonia. However, there is a large variability in clinical outcome with up to 25% non-responders even in highly selected primary dystonia patients. In a large cohort of patients we recently demonstrated that the variable clinical outcomes of pallidal DBS for dystonia may result to a large degree by the exact location and stimulation volume within the pallidal region. Here we test a novel approach of programing based on these insights: we first defined probabilistic maps of anti-dystonic effects by aggregating individual electrode locations and volumes of tissue activated of > 80 patients collected in a multicentre effort. We subsequently modified the algorithms to be able to test all possible stimulation settings of de novo patients in silico based on the expected clinical outcome and thus potentially predict the best possible stimulation parameters for the individual patients.MethodsWithin the framework of a BMBF-funded study, this concept of a computer-based prediction of optimal stimulation parameters for patients with dystonia will be tested in a randomized, controlled crossover study. The main parameter for clinical efficacy and primary endpoint is based on the blinded physician rating of dystonia severity reflected by Clinical Dystonia Rating Scales for both interventions (best clinical settings and model predicted settings) after 4 weeks of continuous stimulation. The primary endpoint is defined as “successful treatment with model predicted settings” (yes or no). The value is “yes” if the motor symptoms with model predicted settings are equal or better (tolerance 5% of absolute difference in percentages) to clinical settings. Secondary endpoints will include measures of quality of life, calculated energy consumption of the neurostimulation system and physician time for programming.PerspectiveWe envision, that computer-guided deep brain stimulation programming in silico might provide optimal stimulation settings for patients with dystonia without the burden of months of programming sessions. The study protocol is designed to evaluate which programming method is more effective in controlling motor symptom severity and improving quality of life in dystonia (best clinical settings and model predicted settings).Trial registration Registered with ClinicalTrials.gov on Oct 27, 2021 (NCT05097001).

Subtyping mild cognitive impairment based on imaging and CSF biomarker levels

AbstractBackgroundIndividuals with mild cognitive impairment (MCI) have variable clinical outcomes, with a proportion converting to dementia in a short follow‐up period. Subtyping MCI subjects based on biomarker levels can provide additional insights on why some individuals progress faster, aiding clinical treatment strategy and facilitating cohort enrichment for clinical trials.MethodData included 562 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project with baseline MRI, CSF amyloid beta (Aβ), t‐tau, and p‐tau data and a minimum of one‐year follow‐up information on clinical diagnosis. White matter hyperintensities (WMHs) were segmented using a previously validated random forests classifier (Dadar et al. 2017). SNIPE (Scoring by Nonlocal Image Patch Estimator) was used to measure Alzheimer’s‐disease‐like atrophy patterns in the hippocampi (HC) and entorhinal cortex (EC) (Coupé et al. 2019). CSF Aβ, p‐tau and t‐tau levels were obtained from project files. Agglomerative hierarchical clustering as used to cluster the data based on baseline age, education, APOE4 status, CSF Aβ, p‐tau and t‐tau levels, WMH load, and HC and EC grading scores. We then investigated differences in baseline ADAS13 cognitive scores as well as rate of conversion to dementia between different subtypes.ResultFigure 1 shows the clustering dendrogram, splitting the data into three subtypes of 152, 200, and 210 participants, respectively. Figure 2 compares biomarker values across subtypes. Baseline ADAS13 scores and conversion rates were significantly different across all subtypes (p&lt;0.0001). Subtype 1 had the oldest subjects with largest WMH loads (p&lt;0.0001), with a conversion rate of 30.2%. Subtype 2 had the highest conversion rate (70.0%), with significantly lower CSF Aβ and EC grading scores, and higher CSF p‐tau and t‐tau values (p&lt;0.0001). Subtype 3 had the lowest conversion rate (15.2%), with significantly higher HC and EC grading scores and lower age and WMH loads than the other two subtypes (p&lt;0.0001).ConclusionBiomarker‐based subtyping of MCI subjects led to three distinct groups with significantly different clinical outcomes: 1) older individuals with cerebrovascular pathology and moderate conversion rates, 2) individuals with abnormal CSF biomarker levels, hippocampal and entorhinal atrophy, and high conversion rates, and 3) younger individuals without abnormal biomarker levels and low conversion rates.

Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is a relatively common and severe birth defect with variable clinical outcome and associated malformations in up to 60% of patients. Mortality and morbidity remain high despite advances in pre-, intra-, and postnatal management. We review the current literature and give an overview about the genetics of CDH to provide guidelines for clinicians with respect to genetic diagnostics and counseling for families. Until recently, the common practice was (molecular) karyotyping or chromosome microarray if the CDH diagnosis is made prenatally with a 10% diagnostic yield. Undiagnosed patients can be reflexed to trio exome/genome sequencing with an additional diagnostic yield of 10 to 20%. Even with a genetic diagnosis, there can be a range of clinical outcomes. All families with a child with CDH with or without additional malformations should be offered genetic counseling and testing in a family-based trio approach.

Pure red cell aplasia secondary to rheumatoid arthritis: a case report

BackgroundRheumatoid arthritis is a common autoimmune disease with many extra-articular manifestations. Pure red cell aplasia is a rare manifestation of rheumatoid arthritis and is sparsely documented in the literature, with a variable clinical outcome following immunosuppressive therapy.Case presentationA 63-year-old Sinhalese female presented with transfusion-dependent anemia associated with deforming inflammatory arthritis. She also had leukopenia, right subclavian venous thrombosis, and generalized lymphadenopathy. The diagnosis of rheumatoid arthritis following initial clinical workup and additional blood and bone marrow investigations revealed pure red cell aplasia as a secondary manifestation of rheumatoid arthritis after excluding other secondary causes, such as infections, thymoma, thrombophilic conditions, and hematological malignancy. She responded well to oral prednisolone, cyclosporine A, and hydroxychloroquine, and she attained complete recovery in 2 months.ConclusionPure red cell aplasia is a disabling illness that may lead to transfusion-dependent anemia, which may occur due to rare extrapulmonary manifestation of rheumatoid arthritis. The diagnosis of pure red cell aplasia secondary to rheumatoid arthritis may be challenging where hematological investigations, including bone marrow biopsy, will aid in the diagnosis, and early diagnosis and treatment will bring about a better outcome.

Biomarkers for prognosis in pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) encompass a diverse group of malignancies marked by histological heterogeneity and highly variable clinical outcomes. We performed a systematic review on potential prognostic biomarkers in PNETs by searching the PubMed database. A total of 472 manuscripts were reviewed in detail, of which 52 multivariate studies met the inclusion criteria proposed by the Reporting Recommendations for Tumor Marker Prognostic Studies. These altogether analyzed 53 unique targets, and 36 of them were statistically associated with survival.

User Experience in Remote Surgical Consultation: Survey Study of User Acceptance and Satisfaction in Real-Time Use of a Telemedicine Service.

BackgroundTeleguidance, a promising telemedicine service for intraoperative surgical consultation, was planned to scale up at a major academic hospital in partnership with 5 other hospitals. If the service was adopted and used over time, it was expected to provide educational benefits and improve clinical outcomes during endoscopic retrograde cholangiopancreatography (ERCP), which is a technically advanced procedure for biliary and pancreatic disease. However, it is known that seemingly successful innovations can play out differently in new settings, which might cause variability in clinical outcomes. In addition, few telemedicine services survive long enough to deliver system-level outcomes, the causes of which are not well understood.ObjectiveWe were interested in factors related to usability and user experience of the telemedicine service, which might affect adoption. Therefore, we investigated perceptions and responses to the use and anticipated use of a system. Technology acceptance, a construct referring to how users perceive a technology’s usefulness, is commonly considered to indicate whether a new technology will actually be used in a real-life setting. Satisfaction measures were used to investigate whether user expectations and needs have been met through the use of technology. In this study, we asked surgeons to rate the perceived usefulness of teleguidance, and their satisfaction with the telemedicine service in direct conjunction with real-time use during clinical procedures.MethodsWe designed domain-specific measures for perceived usefulness and satisfaction, based on performance and outcome measures for the clinical procedure. Surgeons were asked to rate their user experience with the telemedicine service in direct conjunction with real-time use during clinical procedures.ResultsIn total, 142 remote intraoperative consultations were conducted during ERCP procedures at 5 hospitals. The demand for teleguidance was more pronounced in cases with higher complexity. Operating surgeons rated teleguidance to have contributed to performance and outcomes to a moderate or large extent in 111 of 140 (79.3%) cases. Specific examples were that teleguidance was rated as having contributed to intervention success and avoiding a repeated ERCP in 23 cases, avoiding 3 PTC, and 11 referrals, and in 11 cases, combinations of these outcomes. Preprocedure beliefs about the usefulness of teleguidance were generally lower than postprocedure satisfaction ratings. The usefulness of teleguidance was mainly experienced through practical advice from the consulting specialist (119/140, 85%) and support with assessment and decision-making (122/140, 87%).ConclusionsUsers’ satisfaction with teleguidance surpassed their initial expectations, mainly through contribution to nontechnical aspects of performance, and through help with general assessment. Teleguidance shows the potential to improve performance and outcomes during ERCP. However, it takes hands-on experience for practitioners to understand how the new telemedicine service contributes to performance and outcomes.

Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency

PurposeWe previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism. MethodsClinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants. ResultsTen newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype–phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein. ConclusionThese studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition.

Rational Development of Liquid Biopsy Analysis in Renal Cell Carcinoma.

Simple SummaryAmong patients affected by renal cell carcinoma (RCC), the most common type of kidney cancer, it remains difficult to identify those who are at high risk for relapse or metastasis. This is in part due to the absence of reliable clinical biomarkers and robust methods to capture them. The aim of our study was to develop an improved assay to capture prognostic genomic biomarkers in circulating tumor DNA (ctDNA) in RCC. For this purpose, we first established a next generation sequencing (NGS) assay, targeting genes that are tailored for RCC and that are largely excluded from commercially available assays. Next, we showed the reliable performance of this assay to detect prognostic gene mutations in tumor DNA isolated from plasma, and from extracellular vesicles. Thus, our study provides a resource to facilitate ctDNA analysis for precision medicine in RCC.Renal cell carcinoma (RCC) is known for its variable clinical behavior and outcome, including heterogeneity in developing relapse or metastasis. Recent data highlighted the potential of somatic mutations as promising biomarkers for risk stratification in RCC. Likewise, the analysis of circulating tumor DNA (ctDNA) for such informative somatic mutations (liquid biopsy) is considered an important advance for precision oncology in RCC, allowing to monitor molecular disease evolution in real time. However, our knowledge about the utility of ctDNA analysis in RCC is limited, in part due to the lack of RCC-appropriate assays for ctDNA analysis. Here, by interrogating different blood compartments in xenograft models, we identified plasma cell-free (cf) DNA and extracellular vesicles (ev) DNA enriched for RCC-associated ctDNA. Additionally, we developed sensitive targeted sequencing and bioinformatics workflows capable of detecting somatic mutations in RCC-relevant genes with allele frequencies ≥ 0.5%. Applying this assay to patient-matched tumor and liquid biopsies, we captured tumor mutations in cf- and ev-DNA fractions isolated from the blood, highlighting the potentials of both fractions for ctDNA analysis. Overall, our study presents an RCC-appropriate sequencing assay and workflow for ctDNA analysis and provides a proof of principle as to the feasibility of detecting tumor-specific mutations in liquid biopsy in RCC patients.

Application of Hans Algorithm for Subcategorization of Diffuse Large B-Cell Lymphoma in Fine-Needle Aspiration Biopsy Cytology

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with remarkably variable clinical presentation and outcome. Hans algorithm subclassified DLBCL into prognostically distinct molecular subtypes by using immunohistochemistry (IHC). Fine-needle aspiration biopsy cytology (FNABC) is a first-line diagnostic modality in lymphadenopathy. The study aims to perform IHC on FNABC cell blocks (CBs) for subclassifying according to the Hans algorithm and correlate with case-matched histopathology. Methods: This was a retrospective study carried out between January 2017 and December 2019. All DLBCL FNABC cases with CBs and smears and which had follow-up histopathology were included in the study. Detailed cytomorphological evaluation and CD10, B-cell lymphoma 6 (BCL6), and multiple myeloma oncogene 1 IHCs were performed on CBs. The cases are divided into 3 distinct molecular subtypes based on the Hans algorithm as germinal centre B-cell (GCB), activated B-cell (ABC), and unclassified subtypes. The results were compared with the final histopathology. Results: A total of 44 cases were diagnosed as DLBCL, and 33 cases with sufficient material for further IHC were included in the study. Twelve cases were of the GCB type, 19 were of the ABC type, and 2 remained unclassified. Follow-up histopathology was available in 20 cases. Overall, histopathological concordance was found in 95% of cases (19/20). The single discordant case was classified as GCB on FNABC and was ABC on histopathology. Conclusion: FNABC with CBs is an acceptable alternative to biopsy for providing a complete diagnosis of DLBCL as per the current WHO classification.