Single gene mutations and prognosis in limited-stage follicular lymphoma treated with radiation therapy.

Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.

Identification of genetic subtypes in follicular lymphoma.

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Primary care services and emergency department visits in blended fee-for-service and blended capitation models: evidence from Ontario, Canada.

INTRODUCTION: It is well-known that the way physicians are remunerated can affect delivery of health care services to the population. Fee-for-service (FFS) generally leads to oversupply of services, while capitation leads to undersupply of services. However, little evidence exists on the link between remuneration and emergency department (ED) visits. We fill this gap using two popular blended models introduced in Ontario, Canada: the Family Health Group (FHG), an enhanced/blended FFS model, and Family Health Organization (FHO), a blended capitation model. We compare primary care services and rates of emergency department ED visits between these two models. We also evaluate whether these outcomes vary by regular- and after-hours, and patient morbidity status. METHODS: Physicians practicing in an FHG or FHO between April 2012 and March 2017 and their enrolled adult patients were included for analyses. The covariate-balancing propensity score weighting method was used to remove the influence of observable confounding and negative-binomial and linear regression models were used to evaluate the rates of primary care services, ED visits, and the dollar value of primary care services delivered between FHGs and FHOs. Visits were stratified as regular- and after-hours. Patients were stratified into three morbidity groups: non-morbid, single-morbid, and multimorbid (two or more chronic conditions). RESULTS: 6184 physicians and their patients were available for analysis. Compared to FHG physicians, FHO physicians delivered 14% (95% CI 13%, 15%) fewer primary care services per patient per year, with 27% fewer services during after-hours (95% CI 25%, 29%). Patients enrolled to FHO physicians made 27% more less-urgent (95% CI 23%, 31%) and 10% more urgent (95% CI 7%, 13%) ED visits per patient per year, with no difference in very-urgent ED visits. Differences in the pattern of ED visits were similar during regular- and after-hours. Although FHO physicians provided fewer services, multimorbid patients in FHOs made fewer very-urgent and urgent ED visits, with no difference in less-urgent ED visits. CONCLUSION: Primary care physicians practicing in Ontario's blended capitation model provide fewer primary care services compared to those practicing in a blended FFS model. Although the overall rate of ED visits was higher among patients enrolled to FHO physicians, multimorbid patients of FHO physicians make fewer urgent and very-urgent ED visits.

TRASH: Tandem Repeat Annotation and Structural Hierarchy.

MOTIVATION: The advent of long-read DNA sequencing is allowing complete assembly of highly repetitive genomic regions for the first time, including the megabase-scale satellite repeat arrays found in many eukaryotic centromeres. The assembly of such repetitive regions creates a need for their de novo annotation, including patterns of higher order repetition. To annotate tandem repeats, methods are required that can be widely applied to diverse genome sequences, without prior knowledge of monomer sequences. RESULTS: Tandem Repeat Annotation and Structural Hierarchy (TRASH) is a tool that identifies and maps tandem repeats in nucleotide sequence, without prior knowledge of repeat composition. TRASH analyses a fasta assembly file, identifies regions occupied by repeats and then precisely maps them and their higher order structures. To demonstrate the applicability and scalability of TRASH for centromere research, we apply our method to the recently published Col-CEN genome of Arabidopsis thaliana and the complete human CHM13 genome. AVAILABILITY AND IMPLEMENTATION: TRASH is freely available at:https://github.com/vlothec/TRASH and supported on Linux.

Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage.

Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1ß and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy.

Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies.

The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various diseases of the central nervous system. TRP is metabolized through two main pathways, the kynurenine pathway and the methoxyindole pathway. First, TRP is metabolized to kynurenine, then kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine, and finally 3-hydroxyanthranilic acid along the kynurenine pathway. Second, TRP is metabolized to serotonin and melatonin along the methoxyindole pathway. In this review, we summarize the biological properties of key metabolites and their pathogenic functions in 12 disorders of the central nervous system: schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, we summarize preclinical and clinical studies, mainly since 2015, that investigated the metabolic pathway of TRP, focusing on changes in biomarkers of these neurologic disorders, their pathogenic implications, and potential therapeutic strategies targeting this metabolic pathway. This critical, comprehensive, and up-to-date review helps identify promising directions for future preclinical, clinical, and translational research on neuropsychiatric disorders.

Inferior Vena Cava Filter Retrieval Rates Associated With Passive and Active Surveillance Strategies Adopted by Implanting Physicians.

Importance: Inferior vena cava filters are commonly implanted and infrequently retrieved. Nonretrieval contributes to significant morbidity, motivating US Food and Drug Administration and multisociety communications emphasizing the need for improved device surveillance. Current guidelines suggest that implanting physicians and referring physicians should be responsible for device follow-up, but it is not known whether shared responsibility contributes to lower retrieval. Objective: To determine if primary responsibility for follow-up care assumed by the implanting physician team is associated with increased device retrieval. Design, Setting, and Participants: This retrospective cohort study examined a prospectively collected registry of patients with inferior vena cava filters implanted from June 2011 to September 2019. Medical record review and data analysis was completed in 2021. The study included 699 patients who underwent implantation of retrievable inferior vena cava filters at an academic quaternary care center. Exposures: Prior to 2016, implanting physicians had a passive surveillance strategy whereby letters highlighting indications for and the need for timely retrieval were mailed to patients and ordering clinicians. Starting in 2016, implanting physicians assumed active responsibility for surveillance, whereby candidacy for device retrieval was assessed periodically via phone calls and retrieval scheduled when appropriate. Main Outcomes and Measures: The main outcome was the odds of inferior vena cava filter nonretrieval. Within regression modeling of the association between the surveillance method and nonretrieval, additional covariates of patient demographics, concomitant malignant neoplasm, and presence of thromboembolic disease were included. Results: Of the 699 patients who received retrievable filter implants, 386 (55.2%) were followed up with passive surveillance, 313 (44.8%) with active surveillance, 346 (49.5%) were female, 100 (14.3%) were Black individuals, and 502 (71.8%) were White individuals. The mean (SD) age at filter implantation was 57.1 (16.0) years. Mean (SD) yearly filter retrieval increased following the adoption of active surveillance, from 190 of 386 (48.7%) to 192 of 313 (61.3%) (P < .001). Fewer filters were deemed permanent in the active group vs passive group (5 of 313 [1.6%] vs 47 of 386 [12.2%]; P < .001). Age at the time of implantation (OR, 1.02; 95% CI, 1.01-1.03), concomitant malignant neoplasm (OR, 2.18; 95% CI, 1.47-3.24), and passive contact method (OR, 1.70; 95% CI, 1.18-2.47) were associated with increased odds of filter nonretrieval. Conclusions and Relevance: The findings of this cohort study suggest that active surveillance by implanting physicians is associated with improved inferior vena cava filter retrieval. These findings support encouraging physicians who implant the filter to take primary responsibility for tracking and retrieval.

Lymphocytic Extracellular Signal-Regulated Kinase Dysregulation in Autism Spectrum Disorder.

OBJECTIVE: Extracellular signal-regulated kinase (ERK1/2) is a conserved central intracellular signaling cascade involved in many aspects of neuronal development and plasticity. Converging evidence support investigation of ERK1/2 activity in autism spectrum disorder (ASD). We previously reported enhanced baseline lymphocytic ERK1/2 activation in autism, and now we extend our work to investigate the early phase kinetics of lymphocytic ERK1/2 activation in idiopathic ASD. METHOD: Study participants included 67 individuals with ASD (3-25 years of age), 65 age- and sex-matched typical developing control (TDC) subjects, and 36 age-, sex-, and IQ-matched developmental disability control (DDC) subjects matched to those with ASD and IQ <90. We completed an additional analysis comparing results from ASD, TDC, and DDC groups with data from 37 individuals with Fragile X syndrome (FXS). All subjects had blood lymphocyte samples analyzed by flow cytometry following stimulation with phorbol ester and sequentially analyzed for ERK1/2 activation (phosphorylation) at several time points. RESULTS: The ASD group (mean = 5.81 minutes; SD = 1.5) had a significantly lower (more rapid) mean ERK1/2 T1/2 activation value than both the DDC group (mean = 6.78 minutes; SD = 1.6; p = .00078) and the TDC group (mean = 6.4 minutes; SD = 1.5; p = .025). More rapid ERK1/2 T1/2 activation times did correlate with increased social impairment across all study groups including the ASD cohort. Differences in ERK1/2 T1/2 activation were more pronounced in younger than in older individuals in the primary analysis. The ASD group additionally had more rapid activation times than the FXS group, and the FXS group activation kinetics did not differ from those of the TDC and DDC groups. CONCLUSION: Our findings indicate that lymphocytic ERK1/2 activation kinetics are dysregulated in persons with ASD, marked by more rapid early phase activation. Group differences in ERK1/2 activation kinetics appear to be driven by findings from the youngest children analyzed. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Clinical significance of clonal hematopoiesis in the setting of autologous stem cell transplantation for lymphoma.

Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival (OS) in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, p = .043) and from the time of ASCT (51.8% vs. 59.3%, p = .018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, p = .445). In terms of specific-gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, p = .011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications.

Serological Biomarkers and Their Detection in Autoimmune Bullous Skin Diseases.

Autoimmune bullous diseases (AIBDs) are a group of skin-related disorders that involve damage to structures maintaining cell-cell adhesion, such as desmosomes and hemidesmosomes. Key AIBDs include pemphigus related diseases, pemphigoid related conditions, acquired epidermolysis bullosa (EBA), and dermatitis herpetiformis (DH). Each group of conditions exhibits characteristic clinical lesion patterns and is associated with specific autoantibodies targeting epidermal and dermal structures involved in cell-cell adhesion and skin integrity. Pemphigus diseases primarily target desmoglein (Dsg) 3 and Dsg1 proteins but several non-Dsg autoantibodies have also been linked to pemphigus. Pemphigoid diseases typically target bullous pemphigoid (BP)180 and BP230; EBA is associated with antibodies directed against anti-type VII collagen and DH by IgA autoantibodies against tissue transglutaminase and deaminated gliadin. Investigation into the serological biomarkers found in AIBDs have allowed the development of diagnostic assessments (i.e. tissue antibody detection and serological testing) based on the unique autoantibody profiles of a particular disease group. The methods for the detection and quantification of disease-associated autoantibodies continue to evolve and improve.

Predictive Effect of Bone Conduction Pattern on Hearing Outcomes of Stapes Surgery.

OBJECTIVE: Examine the effect of preoperative bone conduction pattern on outcomes of stapedotomy/stapedectomy. STUDY DESIGN: Retrospective case series. SETTING: Tertiary-care academic medical center. PATIENTS: Patients who underwent stapedotomy or stapedectomy from 2013 to 2019. INTERVENTIONS: Primary small-fenestra stapedotomy or partial stapedectomy. MAIN OUTCOME MEASURES: Association between preoperative bone conduction patterns and hearing after stapes surgery. RESULTS: Complete audiometric data were available for 137 patients who had surgery. The mean preoperative air-bone gap (ABG) was 26.8 dBHL. The ABG was closed to less than 20 and 10 dBHL in 88.7 and 65.2% of patients, respectively. A notch at 2000 Hz was present in 32.1% of operated ears and was rarely found at other frequencies. There was no statistically significant association between the presence of a notch and hearing outcomes. The slope of the bone conduction line had no association with hearing outcomes, though an increased bone conduction PTA compared with the contralateral ear was associated with ABG closure less than 10 dBHL and overclosure (odds ratio: 2.14, p = 0.027 and odds ratio: 2.20, p = 0.04). CONCLUSION: In properly selected otosclerosis patients, depressions in bone conduction other than near 2000 Hz are rare and hearing outcomes are generally favorable regardless of the preoperative bone conduction pattern. Despite the association with otosclerosis, the presence of a notch at 2000 Hz is not associated with better hearing outcomes with surgery.

Is it worth it? Cost-effectiveness analysis of a commercial physical activity app.

BACKGROUND: Government interest in investing in commercial physical activity apps has increased with little evidence of their cost-effectiveness. This is the first study to our knowledge to examine the cost-effectiveness of a commercial physical activity app (Carrot Rewards) despite there being over 100,000 in the major app stores. METHODS: A cost-effectiveness analysis was performed to calculate the incremental cost-effectiveness ratio (ICER) of the app compared to a no-intervention reference scenario using a five-year time horizon. Primary data was collected between 2016 and 2017. Data synthesis, model creation, and statistical analyses were conducted between 2019 and 2020. An age-, sex-, and geography-dependent Markov model was developed assuming a public healthcare payer perspective. A closed cohort (n = 38,452) representing the population reached by Carrot Rewards in two Canadian provinces (British Columbia, Newfoundland & Labrador) at the time of a 12-month prospective study was used. Costs and effects were both discounted at 1.5% and expressed in 2015 Canadian dollars. Subgroup analyses were conducted to compare ICERs between provinces, sexes, age groups, and engagement levels. RESULTS: Carrot Rewards had an ICER of $11,113 CAD per quality adjusted life year (QALY), well below a $50,000 CAD per QALY willingness-to-pay (WTP) threshold. Subgroup analyses revealed that the app had lower ICERs for British Columbians, females, highly engaged users, and adults aged 35-64 yrs., and was dominant for older adults (65 + yrs). Deterministic sensitivity analyses revealed that the ICER was most influenced by the relative risk of diabetes. Probabilistic sensitivity analyses revealed varying parameter estimates predominantly resulted in ICERs below the WTP threshold. CONCLUSIONS: The Carrot Rewards app was cost-effective, and dominant for older adults. These results provide, for the first time, rigorous health economic evidence for a commercial physical activity app as part of public health programming.

Pit-and-fissure sealants on primary molars are a cost savings.

BACKGROUND: In this study, the authors examine the cost-effectiveness of light-polymerized resin-based fluoride sealants on primary molars in high caries risk children younger than 6 years. METHODS: The authors examined the cost-effectiveness of pit-and-fissure sealant (PFS) treatment on primary molars by comparing sealed and unsealed molars treated in the outpatient clinic or operating room. Using 1,884 primary molars followed over a 5-year period, the authors used a mixed-effects regression model to estimate the probability of caries development. They used restricted means to estimate years free of caries for carious molars. They used a decision tree to address uncertainty due to PFS treatment failure, predict the expected value associated with each strategy, and estimate the incremental cost-effectiveness ratio using a 3% discount rate to adjust future cost and outcomes to present value. RESULTS: Over 5 years, the cost of care was $90 for unsealed molars and $75 for sealed molars. Unsealed molars remained caries free for 4.32 years compared with 4.85 years in sealed molars. The cost-effectiveness of PFS treatment was dominant, leading to a savings of $25 for each caries-free year gained and overall savings of $742 million for the United States dental health system over a 5-year period. CONCLUSIONS: PFS treatment is associated with cost savings and a delay in caries development and should be considered in children with high caries risk. PRACTICAL IMPLICATIONS: Policy makers should consider reimbursement of PFS treatment on primary molars in high caries risk children.

Uterine Artery Embolization for Primary Postpartum Hemorrhage.

Postpartum hemorrhage (PPH) is a common source of morbidity and mortality for delivering mothers worldwide, resulting in greater than 100,000 deaths per annum. Pathologic postpartum hemorrhage is defined as blood loss greater than 500 mL for vaginal deliveries and 1,000 mL for caesarean births, which occurs in up to 10% of deliveries. Severe postpartum hemorrhage can progress to shock, disseminated intravascular coagulation (DIC) and death. PPH is further characterized by time of onset; primary PPH occurs within 24 hours of parturition, and secondary PPH beyond that. Secondary hemorrhage is discussed in a separate article in this issue, this article will exclusively explore primary postpartum hemorrhage. PPH arises from a number of etiologies, including uterine atony, birth canal/perineal lacerations and intrapelvic arterial injuries. PPH is primarily managed by standard medical obstetric maneuvers including uterotonics, fundal massage, intrauterine (Bakri) balloon tamponade and direct control of hemorrhage where applicable. Definitive control with hysterectomy is preserved for hemorrhage refractory to conservative and minimally-invasive management. First described in 1979, angiography and trans-catheter embolization represent valuable tools in the control of postpartum hemorrhage of most etiologies. Embolization is an acceptable, effective alternative to hysterectomy, particularly in patients who desire future fertility. It has high clinical success rates and a body of literature supporting preserved post-embolization fertility.

Comparison of Fracture Strengths among different Commonly Placed Anterior Esthetic Restorations for Primary Dentition: An in vitro study.

The purpose of this study was to determine and compare the shear force (N) required to fracture or dislodge an all-ceramic zirconia-based crown using different luting cement with those of polycarbonate crown and strip crown for the primary anterior teeth in vitro. STUDY DESIGN: Four groups of esthetic restoration for primary anterior teeth were tested for fracture strength: 1) Fifteen all-ceramic zirconia-based crowns cemented with glass ionomer cement, 2) Fifteen all-ceramic zirconia-based crowns bonded with a self-adhesive resin cement, 3) Fifteen polycarbonate crowns cemented with a polymer reinforced zinc-oxide eugenol and 4) Fifteen resin strip crowns. All restorations were placed and cemented on reproductions of dies in an independent laboratory at Delhi, India. All samples underwent loading until fracture or dislodgement with the Universal Testing Machine. The force in Newton (N) required to produce failure was recorded for each sample and the type of failures was also noted and characterized. One-way analysis of variance (ANOVA) test and the Tukey and Scheffe's post hoc comparisons were used for statistical analyses. RESULTS: In this invitro study, results were measured in Newtons (N). Group 1 (410.9±79.5 N) and Group 2 (420.5±57.8 N) had higher fracture strength than Group 3 (330.3±85.6 N) and Group 4 (268.4±28.2 N). These differences were statistically significant at P≤.05 among the sample groups. No significant difference was found between groups 1 and 2 (P = 0.984) nor between groups 3 and 4 (P =0.104). Among type of failures, majority of restoration fractures for zirconia-based crowns and resin strip crowns were due to cohesive failures and polycarbonate crowns had predominantly mixed failures. CONCLUSIONS: Under the limitations of this in vitro study, it could be concluded that all-ceramic zirconia-based crowns attained the highest fracture strength among all restorative samples tested regardless of the type of luting agent employed (P<.01). Cohesive failures were commonly observed in the zirconia crowns and resin strip crowns, whereas polycarbonate crowns revealed predominately mixed failures.