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.

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.

Emergency department use following incentives to provide after-hours primary care: a retrospective cohort study.

BACKGROUND: Access to primary care outside of regular working hours is limited in many countries. This study investigates the relation between the after-hours premium, an incentive for primary care physicians to provide services after hours, and less-urgent visits to the emergency department in Ontario, Canada. METHODS: We analyzed a retrospective cohort of a random sample of Ontario residents from April 2002 to March 2006, and a subcohort of patients followed from April 2005 to March 2016. We linked patient and primary care physician data with emergency department visit data. We used fixed-effects regression models to analyze the association between the introduction of the after-hours premium, as well as subsequent increases in the value of the premium, and the number of monthly emergency department visits. RESULTS: The sample consisted of 586 534 patients between 2002 and 2006, and 201 594 patients from 2005 to 2016. After controlling for patient and physician characteristics, seasonality and time-invariant patient confounding factors, introduction of the after-hours premium was associated with a reduction of 1.26 less-urgent visits to the emergency department per 1000 patients per month (95% confidence interval -1.48 to -1.04). Most of this reduction was observed in after-hours visits. Sensitivity analysis showed that the monthly reduction in less-urgent visits to the emergency department was in the range of -1.24 to -1.16 per 1000 patients. Subsequent increases in the after-hours premium were associated with a small reduction in less-urgent visits to the emergency department. INTERPRETATION: Ontario's experience suggests that incentivizing physicians to improve access to after-hours primary care reduces some less-urgent visits to the emergency department. Other jurisdictions may consider incentives to limit less-urgent visits to the emergency department.

Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels.

BACKGROUND: Pruritus is a common symptom that can significantly reduce quality of life through sleep disruption. OBJECTIVE: To examine features of disturbed sleep in patients with chronic pruritic dermatoses and test the hypothesis that systemic inflammation may serve as a biomarker for impaired sleep in these patients. METHODS: Cross-sectional analysis of the National Health and Nutrition Examination Survey investigating systemic inflammation using C-reactive protein (CRP) levels. Logistic regression was used to compare patients with and without sleep disturbances, adjusting for demographics (model 1) and medical comorbidities (model 2). RESULTS: Chronic pruritic dermatoses were associated with multiple sleep disturbances, including nighttime awakenings (model 1: odds ratio [OR], 1.646; 95% confidence interval [CI], 1.031-2.627; model 2: OR, 1.329; 95% CI, 0.888-1.989) and early morning awakening (model 1: OR, 1.669, 95% CI, 1.118-2.493; model 2: OR, 1.582; 95% CI, 1.008-2.481). Mean CRP levels were 52.8% higher among patients with pruritic dermatoses reporting trouble sleeping compared with those who did not (0.663 vs 0.434 mg/dL; P = .034). Trouble sleeping was also positively correlated with CRP levels (ß = 0.142, P = .025). LIMITATIONS: Potential recall bias among participants. CONCLUSIONS: In addition to confirming sleep disturbances with pruritic dermatoses, we found these disturbances are more likely to present with elevated CRP levels. Clinicians should consider the potential risk for sleep-related and cardiac comorbidities in patients diagnosed with itchy skin conditions.

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.

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.

Validation of the RHL30 digital gene expression assay as a prognostic biomarker for relapsed Hodgkin lymphoma.

Despite continuing improvements in the management of classical Hodgkin lymphoma (cHL), relapse remains associated with a risk of lymphoma-related mortality. The biological composition of relapse tumour biopsies shows interpatient variability, which can be leveraged to design prognostic biomarkers. Here, we validated the RHL30 assay, a previously reported gene expression model in an independent cohort of 41 patients with relapsed cHL. Patients classified as high-risk by the RHL30 assay had inferior failure-free survival (FFS) after autologous stem cell transplantation (2-year FFS 41% vs. 92%, P = 0·035). The RHL30 model is a robust biomarker that risk-stratifies patients considered for autologous stem cell transplantation.

Clinical impact of disinvestment in hydroxyethyl starch for patients undergoing coronary artery bypass surgery: a retrospective observational study.

PURPOSE: To examine the effect of discontinuing hydroxyethyl starch (HES) solutions on length of hospital stay, transfusion, risk of death, acute kidney injury (AKI), and dialysis. METHODS: We conducted a historical cohort study of linked administrative and clinical databases in patients undergoing coronary artery bypass surgery (CABG) on cardiopulmonary bypass. We used propensity scores to match patients who did not receive HES (after discontinuation) with patients exposed to HES (before discontinuation) and also controlled for albumin exposure. Hospital length of stay (the primary outcome) was analyzed using Fine-Gray proportional hazard regression, with hospital discharge as the outcome and death as a competing risk. Adverse outcomes were compared between matched patients using conditional logistic regression. RESULTS: We compared 1,085 propensity score-matched pairs (n = 2,170) from a pool of 2,757 patients. Discontinuation of HES was associated with shorter length of hospital stay, as evidenced by an increased probability of discharge (hazard ratio, 1.24; 95% confidence interval [CI], 1.14 to 1.35) and a reduced risk of red blood cell transfusion (odds ratio [OR], 0.68; 95% CI, 0.55 to 0.84), plasma transfusion (OR, 0.48; 95% CI, 0.34 to 0.66), and platelet transfusion (OR, 0.62; 95% CI, 0.44 to 0.87). Discontinuation of HES was not associated with in-hospital mortality (OR, 0.74; 95% CI, 0.36 to 1.54), AKI (OR, 0.84; 95% CI, 0.57 to 1.25), or dialysis (OR, 0.83; 95% CI, 0.25 to 2.73). CONCLUSIONS: For patients undergoing CABG on cardiopulmonary bypass, discontinuation of HES was associated with reduced hospital length of stay and reduced blood product transfusion, without measurable change in renal failure, dialysis rate, or in-hospital mortality. Our results should be interpreted with caution, though we found no evidence of harms associated with discontinuing HES. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02329158); registered 31 December, 2014.

X-Shaped Oligomeric Pyromellitimide Polyradicals.

The synthesis of stable organic polyradicals is important for the development of magnetic materials. Herein we report the synthesis, isolation, and characterization of a series of X-shaped pyromellitimide (PI) oligomers (Xn-R, n = 2-4, R = Hex or Ph) linked together by single C-C bonds between their benzenoid cores. We hypothesize that these oligomers might form high-spin states in their reduced forms because of the nearly orthogonal conformations adopted by their PI units. 1H and 13C nuclear magnetic resonance (NMR) spectroscopies confirmed the isolation of the dimeric, trimeric, and tetrameric homologues. X-ray crystallography shows that X2-Ph crystallizes into a densely packed superstructure, despite the criss-crossed conformations adopted by the molecules. Electrochemical experiments, carried out on the oligomers Xn-Hex, reveal that the reductions of the PI units occur at multiple distinct potentials, highlighting the weak electronic coupling between the adjacent redox centers. Finally, the chemically generated radical anion and polyanion states, Xn-Hex•- and Xn-Hexn(•-), respectively, were probed extensively by UV-vis-NIR absorption, EPR, and electron nuclear double resonance (ENDOR) spectroscopies. The ENDOR spectra of the radical monoanions Xn-Hex•- reveal that the unpaired electron is largely localized on a single PI unit. Further reductions of Xn-Hex•- yield EPR signals (in frozen solutions) that can be assigned to spin-spin interactions in X2-Hex2(•-), X3-Hex3(•-), and X4-Hex4(•-). Taken together, these findings demonstrate that directly linking the benzene rings of PIs with a single C-C bond is a viable method for generating stabilized high-spin organic anionic polyradicals.

Carbon monoxide-releasing molecule-3 protects against ischemic stroke by suppressing neuroinflammation and alleviating blood-brain barrier disruption.

BACKGROUND: At low levels, carbon monoxide (CO) has been shown to have beneficial effects on multiple organs and tissues through its potential anti-inflammatory, anti-apoptotic, and anti-proliferative properties. However, the effect of CO-releasing molecule (CORM)-3, a water-soluble CORM, on ischemic stroke and its mechanism of action are still unclear. METHODS: We investigated the role of CORM-3 in the mouse model of transient middle cerebral artery occlusion (tMCAO). CORM-3 or saline was administered to mice by retro-orbital injection at the time of reperfusion after 1-h tMCAO or at 1 h after sham surgery. We assessed infarct volume and brain water content at 24 and 72 h after ischemia, blood-brain barrier permeability at 6 and 72 h after ischemia, and neurologic deficits on days 1, 3, 7, and 14. RESULTS: Among mice that underwent tMCAO, those that received CORM-3 had significantly smaller infarct volume and greater expression of neuronal nuclear antigen (NeuN) and microtubule-associated protein 2 than did saline-treated mice. CORM-3-treated mice had significantly fewer activated microglia in the peri-infarction zone than did control mice and exhibited downregulated expression of ionized calcium-binding adapter molecule (Iba)-1, tumor necrosis factor-α, and interleukin 1ß. CORM-3-treated mice had significantly lower brain water content and enhanced neurologic outcomes on days 3, 7, and 14 post-tMCAO. Lastly, CORM-3 treatment reduced Evans blue leakage; increased expression of platelet-derived growth factor receptor-ß, tight junction protein ZO-1, and matrix protein laminin; and decreased protein level of matrix metalloproteinase-9. CONCLUSION: CORM-3 treatment at the time of reperfusion reduces ischemia-reperfusion-induced brain injury by suppressing neuroinflammation and alleviating blood-brain barrier disruption. Our data suggest that CORM-3 may provide an effective therapy for ischemic stroke.

Using functional and molecular MRI techniques to detect neuroinflammation and neuroprotection after traumatic brain injury.

This study was designed to investigate whether functional and molecular MRI techniques are sensitive biomarkers for assessment of neuroinflammation and drug efficacy after traumatic brain injury (TBI) in rats. We subjected rats to a controlled cortical impact model and used behavioral tests, histology, and immunofluorescence to assess whether flavonoid pinocembrin provides cerebral protection and improves functional recovery. Most importantly, we used multiple noninvasive structural, functional, and molecular MRI techniques to examine whether the pinocembrin-related neuroprotection and attenuation of neuroinflammation can be detected in vivo. Significant increases in cerebral blood flow (CBF) and amide proton transfer-weighted (APTw) MRI signals were observed in the perilesional areas in untreated TBI rats at 3days and could be attributed to increased glial response. In addition, increased apparent diffusion coefficient and decreased magnetization transfer ratio signals in untreated TBI rats over time were likely due to edema. Post-treatment with pinocembrin decreased microglial/macrophage activation at 3days, consistent with the recovery of CBF and APTw MRI signals in regions of secondary injury. These findings suggest that pinocembrin provides cerebral protection for TBI and that multiple MRI signals, CBF and APTw in particular, are sensitive biomarkers for identification and assessment of neuroinflammation and drug efficacy in the TBI model.

International Variation in Emergency Operation Rates for Acute Diverticulitis: Insights into Healthcare Value.

BACKGROUND: International comparison of outcomes of surgical diseases has become a global focus because of widespread concern over surgical quality, rising costs and the value of healthcare. Acute diverticulitis is a common disease potentially amenable to optimization of strategies for operative intervention. The aim was to compare the emergency operative intervention rates for acute diverticulitis in USA, England and Australia. METHODS: Unplanned admissions for acute diverticulitis were found from an international administrative dataset between 2008 and 2014 for hospitals in USA, England and Australia. The primary outcome measured was emergency operative intervention rate. Secondary outcomes included inpatient mortality and percutaneous drainage rate. Multivariable analysis was performed after development of a weighted comorbidity scoring system. RESULTS: There were 15,150 unplanned admissions for acute diverticulitis. The emergency operative intervention rates were 16, 13 and 10% for USA, England and Australia. The percutaneous drainage rate was highest in USA at 10%, while the mortality rate was highest in England at 2.8%. The propensity for emergency operative intervention was higher in USA (OR 1.45, p < 0.001) and England (OR 1.49, p < 0.001) than in Australia. The risk of 7-day mortality was higher in England than in Australia (OR 2.79, p < 0.001). Percutaneous drainage was associated with reduced 7-day mortality risk. CONCLUSION: Australia has a lower propensity for emergency operative intervention, while England has a greater risk of mortality for acute diverticulitis. International variations raise the issue of healthcare value in terms of differing resource use and outcomes.

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.

Fate of patients with spinal cord ischemia complicating thoracic endovascular aortic repair.

OBJECTIVE: Spinal cord ischemia (SCI) is a potentially devastating complication of thoracic endovascular aortic repair (TEVAR) that can result in varying degrees of short-term and permanent disability. This study was undertaken to describe the clinical outcomes, long-term functional impact, and influence on survival of SCI after TEVAR. METHODS: A retrospective review of all TEVAR patients at the University of Florida from 2000 to 2011 was performed to identify individuals experiencing SCI, defined by any new lower extremity neurologic deficit not attributable to another cause. SCI was dichotomized into immediate or delayed onset, with immediate onset defined as SCI noted upon awakening from anesthesia, and delayed characterized as a period of normal function, followed by development of neurologic injury. Ambulatory status was determined using database query, record review, and phone interviews with patients and/or family. Mortality was estimated using life-table analysis. RESULTS: A total of 607 TEVARs were performed for various indications, with 57 patients (9.4%) noted to have postoperative SCI (4.3% permanent). SCI patients were more likely to be older (63.9 ± 15.6 vs 70.5 ± 11.2 years; P = .002) and have a number of comorbidities, including chronic obstructive pulmonary disease, hypertension, dyslipidemia, and cerebrovascular disease (P < .0001). At some point in their care, a cerebrospinal fluid drain was placed in 54 patients (95%), with 54% placed postoperatively. In-hospital mortality was 8.8% for the entire cohort (SCI vs no SCI; P = .45). SCI developed immediately in 12 patients, delayed onset in 40, and indeterminate in five patients due to indiscriminate timing from postoperative sedation. Three patients (25%) with immediate SCI had measurable functional improvement (FI), whereas 28 (70%) of the delayed-onset patients experienced some degree of neurologic recovery (P = .04). Of the 34 patients with complete data available, 26 (76%) reported quantifiable FI, but only 13 (38%) experienced return to their preoperative baseline. Estimated mean (± standard error) survival for patients with and without SCI was 37.2 ± 4.5 and 71.6 ± 3.9 months (P < .0006), respectively. Patients with FI had a mean survival of 53.9 ± 5.9 months compared with 9.6 ± 3.6 months for those without improvement (P < .0001). Survival and return of neurologic function were not significantly different when patients with preoperative and postoperative cerebrospinal fluid drains were compared. CONCLUSIONS: The minority of patients experience complete return to baseline function after SCI with TEVAR, and outcomes in patients without early functional recovery are particularly dismal. Patients experiencing delayed SCI are more likely to have FI and may anticipate similar life-expectancy with neurologic recovery compared with patients without SCI. Timing of drain placement does not appear to have an impact on postdischarge FI or long-term mortality.

Do practitioners managing mood disorders work to a sub-typing or a 'one size fits all' model?

OBJECTIVE: To assess whether psychiatrists in the community operate to a sub-typing model of mood disorders when choosing psychotropic medications. METHOD: Patients assessed through the Black Dog Institute depression clinic provided information on their previously prescribed and current medications, on how effective they found them and whether they had to be ceased due to side-effects. The prevalence of each medication trialled was analysed according to diagnosis (bipolar I, bipolar II, unipolar melancholic depression or unipolar non-melancholic depression). RESULTS: Analyses indicate that psychiatrists prescribe medications differentially in line with diagnosis. This effect was found in both previously prescribed and currently prescribed medications, and was most distinct for mood stabiliser and antipsychotic medications. Several medications, in contrast, appeared to have been trialled by the majority of patients, regardless of diagnosis. Analyses of effectiveness and cessation due to side-effects were compromised by small sub-sample sizes. CONCLUSIONS: Psychiatrists in the community appear to operate to a sub-typing model of mood disorders, preferentially prescribing many medications according to mood disorder sub-type.

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.

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.

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.