Epidemiology of pediatric spinal trauma with neurological deficits in Catalonia: a 36-year experience.

PURPOSE: Existing literature on pediatric traumatic spinal cord injury (PTSCI) demonstrates large variations in characteristics, incidence, time-periods and etiology, worldwide. Epidemiological studies addressing injuries to the total spine, conducted in Southern European regions are remarkably scarce; therefore we aimed to investigate long-term trends analyzing etiology, fracture location and type, single or multiple fractures, associated lesions and neurological status in Catalonia, Spain. METHODS: We conducted a retrospective observational study. We analyzed post-acute patients after PTSCI, aged 0-17, admitted with neurological deficits between 1986 and 2022 to a specialized hospital in Catalonia. Neurological deficits were assessed using the American Spinal Injury Association Impairment Scale (AIS). RESULTS: Two hundred and forty nine children were included, 174 (69.9%) boys and 75 (30.1%) girls; mean age was 13.9 years (range, 2 months to 17 years). Two hundred and four children (82%) had ≥ 1 spinal fractures, 66 (26.5%) dislocations and 8 (3.2%) SCIWORA. Fractures were multilevel contiguous in 108 (43.4%) cases. Fracture types comprised 81 vertebral compactions (32.5%), 22 burst fractures (8.8%), 7 odontoid (2.8%) and 4 tear-drops (1.6%). There were ≥ 1 associated lesions in 112 cases (45%): in limbs in 23 cases (9.2%), thorax or abdomen in 59 (23.7%) and skull or face in 81 (32.5%). In 44 cases (39% of the 112) there were multiple lesions. Locations comprised cervical spine in 105 cases (42%), thoracic spine in 124 (49%), lumbar spine in 18 (7%), and sacrum in 2 (0.8%). Road traffic accidents (RTAs) were the main etiology (62.2%) over the whole period. However, from 2016 onwards, RTAs dropped below the rate of falls and sports injuries. The most common sites for injury in those aged 9 years or older were in the cervical (41.1%) and thoracic (50.7%) regions. Those aged 8 or under were far more likely to sustain a complete SCI (80.0%) or an accompanying traumatic brain injury (45.0%) likely due to higher numbers of pedestrian versus car RTAs. A significant peak in the occurrence of cases during 2006-2010 (20.1%) was identified with an absolute drop immediately after, during 2011-2015 (8.8%). A marked shift in trend is observed between 2016-2022 regarding age of injuries (an increase in 9 years or older), etiology (increase in falls and sports versus RTA), AIS grade (increase in incomplete lesions AIS B-D versus AIS A), severity (increase in tetraplegia versus paraplegia) and location (increase in cervical versus lumbar and thoracic injuries). CONCLUSIONS: A shift in trend is observed in the past 7 years regarding age of injuries (increase in those older than 9), etiology (increase in falls and sports versus RTA), AIS grade (increase in incomplete lesions AIS B-D versus AIS A), severity (increase in tetraplegia versus paraplegia) and location (increase in cervical). LEVEL OF EVIDENCE: IV.

Towards using 3D cellular cultures to model the activation and diverse functions of macrophages.

The advent of 3D cell culture technology promises to enhance understanding of cell biology within tissue microenvironments. Whilst traditional cell culturing methods have been a reliable tool for decades, they inadequately portray the complex environments in which cells inhabit in vivo. The need for better disease models has pushed the development of effective 3D cell models, providing more accurate drug screening assays. There has been great progress in developing 3D tissue models in fields such as cancer research and regenerative medicine, driven by desires to recreate the tumour microenvironment for the discovery of new chemotherapies, or development of artificial tissues or scaffolds for transplantation. Immunology is one field that lacks optimised 3D models and the biology of tissue resident immune cells such as macrophages has yet to be fully explored. This review aims to highlight the benefits of 3D cell culturing for greater understanding of macrophage biology. We review current knowledge of macrophage interactions with their tissue microenvironment and highlight the potential of 3D macrophage models in the development of more effective treatments for disease.

Testing to sustain hepatitis C elimination targets in people who inject drugs: A network-based model.

Little is known about the level of testing required to sustain elimination of hepatitis C (HCV), once achieved. In this study, we model the testing coverage required to maintain HCV elimination in an injecting network of people who inject drugs (PWID). We test the hypothesis that network-based strategies are a superior approach to deliver testing. We created a dynamic injecting network structure connecting 689 PWID based on empirical data. The primary outcome was the testing coverage required per month to maintain prevalence at the elimination threshold over 5 years. We compared four testing strategies. Without any testing or treatment provision, the prevalence of HCV increased from the elimination threshold (11.68%) to a mean of 25.4% (SD 2.96%) over the 5-year period. To maintain elimination with random testing, on average, 4.96% (SD 0.83%) of the injecting network needs to be tested per month. However, with a 'bring your friends' strategy, this was reduced to 3.79% (SD 0.64%) of the network (p < .001). The addition of contact tracing improved the efficiency of both strategies. In conclusion, we report that network-based approaches to testing such as 'bring a friend' initiatives and contact tracing lower the level of testing coverage required to maintain elimination.

Falls During Inpatient Rehabilitation After Spinal Cord Injury: Characterization, Clock-Hour Visualization, and Time to Event Predictors.

OBJECTIVES: To (1) determine fall characteristics (eg, cause, location, witnesses) of inpatients with spinal cord injury (SCI) and whether they were different for ambulatory persons vs wheelchair users; (2) visualize the total number of daily falls per clock-hour for different inpatients' features (eg, cause of injury, age); (3) compare clinical and demographic characteristics of inpatients who experienced a first fall event vs inpatients who did not experience such event; and (4) identify first fall event predictors. DESIGN: Retrospective observational cohort study. SETTING: Institution for inpatient neurologic rehabilitation. PARTICIPANTS: Persons with SCI (N=1294) admitted to a rehabilitation facility between 2005 and 2022. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional independence measure (FIM), Hospital Anxiety and Depression Scale (HADS), American Spinal Injury Association Impairment Scale (AIS), and Spinal Cord Independence Measure (SCIM) at admission. Kaplan-Meier survival curves and Cox proportional hazards models were used. RESULTS: A total of 502 fall events were experienced by 369 ambulatory inpatients (19.8%) and wheelchair users (80.2%) in 63.9% of cases being alone, with cause, situation, and location significantly different in both groups. Clock-hour visualizations revealed an absolute peak at 12 AM (complete or incomplete injuries, with paraplegia or tetraplegia) but a relative peak at 9 AM mainly including incomplete patients with paraplegia. Of the (n=1294) included patients, 16.8% experienced at least 1 fall. Fallen patients reported higher levels of HADS depression, lower total SCIM, and longer time since injury to admission, with no differences in age, sex, educational level, FIM (quasi-significant), and AIS grade. Multivariable Cox proportional hazards identified time since injury to admission and AIS grade D as significant predictors of first fall event. CONCLUSIONS: Falls identification, characterization, and clock-hour visualization can support decisions for mitigation strategies specifically addressed to inpatients with SCI. Fall predictors were identified as a first step for future research.

Multicentric investigation on the safety, feasibility and usability of the ABLE lower-limb robotic exoskeleton for individuals with spinal cord injury: a framework towards the standardisation of clinical evaluations.

BACKGROUND: Robotic lower-limb exoskeletons have the potential to provide additional clinical benefits for persons with spinal cord injury (SCI). However, high variability between protocols does not allow the comparison of study results on safety and feasibility between different exoskeletons. We therefore incorporated key aspects from previous studies into our study protocol and accordingly conducted a multicentre study investigating the safety, feasibility and usability of the ABLE Exoskeleton in clinical settings. METHODS: In this prospective pretest-posttest quasi-experimental study across two SCI centres in Germany and Spain, in- and outpatients with SCI were recruited into a 12-session training and assessment protocol, utilising the ABLE Exoskeleton. A follow-up visit after 4 weeks was included to assess after-training outcomes. Safety outcomes (device-related adverse events (AEs), number of drop-outs), feasibility and usability measures (level of assistance, donning/doffing-time) were recorded at every session together with changes in gait parameters and function. Patient-reported outcome measures including the rate of perceived exertion (RPE) and the psychosocial impact of the device were performed. Satisfaction with the device was evaluated in both participants and therapists. RESULTS: All 24 participants (45 ± 12 years), with mainly subacute SCI (< 1 year after injury) from C5 to L3, (ASIA Impairment Scale A to D) completed the follow-up. In 242 training sessions, 8 device-related AEs (pain and skin lesions) were reported. Total time for don and doff was 6:50 ± 2:50 min. Improvements in level of assistance and gait parameters (time, steps, distance and speed, p < 0.05) were observed in all participants. Walking function and RPE improved in participants able to complete walking tests with (n = 9) and without (n = 6) the device at study start (p < 0.05). A positive psychosocial impact of the exoskeleton was reported and the satisfaction with the device was good, with best ratings in safety (participants), weight (therapists), durability and dimensions (both). CONCLUSIONS: Our study results prove the feasibility of safe gait training with the ABLE Exoskeleton in hospital settings for persons with SCI, with improved clinical outcomes after training. Our study protocol allowed for consistent comparison of the results with other exoskeleton trials and can serve as a future framework towards the standardisation of early clinical evaluations. Trial Registration https://trialsearch.who.int/ , DRKS00023503, retrospectively registered on November 18, 2020.

Tele-rehabilitation on independence in activities of daily living after stroke: A Matched Case-Control Study.

OBJECTIVES: To compare independence in activities of daily living (ADLs) in post-acute patients with stroke following tele-rehabilitation and matched in-person controls. MATERIALS AND METHODS: Matched case-control study. A total of 35 consecutive patients with stroke who followed tele-rehabilitation were compared to 35 historical in-person patients (controls) matched for age, functional independence at admission and time since injury to rehabilitation admission (<60 days). The tele-rehabilitation group was also compared to the complete cohort of historical controls (n=990). Independence in ADLs was assessed using the Functional Independence Measure (FIM) and the Barthel Index (BI). We formally compared FIM and BI gains calculated as discharge score - admission scores, efficiency measured as gains / length of stay and effectiveness defined as (discharge score-admission score)/ (maximum score-admission score). We analyzed the minimal clinically important difference (MCID) for FIM and BI. RESULTS: The groups showed no significant differences in type of stroke (ischemic or hemorrhagic), location, severity, age at injury, length of stay, body mass index, diabetes, dyslipidemia, hypertension, aphasia, neglect, affected side of the body, dominance or educational level. The groups showed no significant differences in gains, efficiency nor effectiveness either using FIM or Barthel Index. We identified significant differences in two specific BI items (feeding and transfer) in favor of the in-person group. No differences were observed in the proportion of patients who achieved MCID. CONCLUSIONS: No significant differences were seen between total ADL scores for tele-rehabilitation and in-person rehabilitation. Future research studies should analyze a combined rehabilitation approach that utilizes both models.

Inpatient Rehabilitation Falls: Comparing Patients With Traumatic Brain Injury Versus Patients With Stroke.

BACKGROUND: Cognitively impaired neurological rehabilitation inpatients are at an increased risk for falls; yet, little is known regarding fall risk of different groups, such as stroke versus traumatic brain injury. OBJECTIVES: To determine if rehabilitation patients' fall characteristics differ for patients with stroke versus patients with traumatic brain injury. METHODS: This retrospective observational cohort study evaluates inpatients with stroke or traumatic brain injury admitted to a rehabilitation center in Barcelona, Spain, between 2005 and 2021. We assessed independence in daily activities with the Functional Independence Measure. We compared fallen versus nonfallen patients' features and examined the association between time to first fall and risk using Cox proportional hazards models. RESULTS: A total of 1,269 fall events were experienced by 898 different patients with traumatic brain injury ( n = 313; 34.9%) and stroke ( n = 585; 65.1%). A higher proportion of falls for patients with stroke occurred while performing rehabilitation activities (20.2%-9.8%), whereas falls were significantly higher for patients with traumatic brain injury during the night shift. Fall timing revealed completely different behaviors (stroke vs. traumatic brain injury), for example, an absolute peak at 6 a.m. due to young male traumatic patients. Nonfallen patients ( n = 1,363; 78.2%) were younger, with higher independence in daily activities scores, and having a larger time since injury to admission; all three were significant fall predictors. CONCLUSIONS: Patients with traumatic brain injury and stroke showed different fall behaviors. Knowledge of fall patterns and characteristics in the inpatient rehabilitation setting can help design management protocols to mitigate their risk.

Leukocyte Tetraspanin CD53 Restrains α3 Integrin Mobilization and Facilitates Cytoskeletal Remodeling and Transmigration in Mice.

The importance of tetraspanin proteins in regulating migration has been demonstrated in many diverse cellular systems. However, the function of the leukocyte-restricted tetraspanin CD53 remains obscure. We therefore hypothesized that CD53 plays a role in regulating leukocyte recruitment and tested this hypothesis by examining responses of CD53-deficient mice to a range of inflammatory stimuli. Deletion of CD53 significantly reduced neutrophil recruitment to the acutely inflamed peritoneal cavity. Intravital microscopy revealed that in response to several inflammatory and chemotactic stimuli, absence of CD53 had only minor effects on leukocyte rolling and adhesion in postcapillary venules. In contrast, Cd53-/- mice showed a defect in leukocyte transmigration induced by TNF, CXCL1 and CCL2, and a reduced capacity for leukocyte retention on the endothelial surface under shear flow. Comparison of adhesion molecule expression in wild-type and Cd53-/- neutrophils revealed no alteration in expression of ß2 integrins, whereas L-selectin was almost completely absent from Cd53-/- neutrophils. In addition, Cd53-/- neutrophils showed defects in activation-induced cytoskeletal remodeling and translocation to the cell periphery, responses necessary for efficient transendothelial migration, as well as increased α3 integrin expression. These alterations were associated with effects on inflammation, so that in Cd53-/- mice, the onset of neutrophil-dependent serum-induced arthritis was delayed. Together, these findings demonstrate a role for tetraspanin CD53 in promotion of neutrophil transendothelial migration and inflammation, associated with CD53-mediated regulation of L-selectin expression, attachment to the endothelial surface, integrin expression and trafficking, and cytoskeletal function.

Clinical Prediction Rule Validation for Ambulation Outcome After Traumatic Spinal Cord Injury in a Spanish Population.

BACKGROUND: Predicting the ability to walk after traumatic spinal cord injury is of utmost importance in the clinical setting. Nevertheless, only a small fraction of predictive models are evaluated on their performance by other authors using external data. The Dutch Clinical Prediction Rule for long-term walking ability was developed and validated using neurological assessments performed within 15 days postinjury. However, in reality, this assessment is most often performed between 11 and 55 days. When considering a longer time from injury to neurological assessments, the Dutch Clinical Prediction Rule has only been externally validated for patients after non-traumatic spinal cord injury. OBJECTIVE: We aimed to validate the Dutch Clinical Prediction Rule with neurological assessment performed within 3-90 days after traumatic spinal cord injury, using (a) the Dutch Clinical Prediction Rule logistic regression coefficients (Equation 1); (b) the Dutch Clinical Prediction Rule weighted coefficients (Equation 2); and (c) the reestimated (using a Spanish population) weighted coefficients (Equation 3). METHODS: We conducted a retrospective (STROBE-compliant) study involving 298 adults with traumatic spinal cord injury admitted to a hospital between 2010 and 2019 in Spain. The Spinal Cord Independence Measure item-12 was used for walking assessment. RESULTS: Using Equation 1, the model yielded 86.2% overall classification accuracy, 94.5% sensitivity, and 83.4% specificity (area under the curve [AUC] = 0.939, 95% confidence interval [CI]: 0.915-0.965; p < .001).Using Equation 2 yielded 86.2% overall classification accuracy, 93.2% sensitivity, and 83.9% specificity (AUC = 0.9392, 95% CI: 0.914-0.964; p < .001).Using Equation 3 yielded 86.9% overall classification accuracy, 68.9% sensitivity, and 92.8% specificity (AUC = 0.939, 95% CI: 0.914-0.964; p < .001). CONCLUSIONS: This study validates the Dutch Clinical Prediction Rule in a Spanish traumatic spinal cord injury population with assessments performed up to 90 days postinjury with similar performance, using the original coefficients and including a reestimation of the coefficients.

Synbiotics Alter Fecal Microbiomes, But Not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Dysbiosis of the intestinal microbiota has been associated with nonalcoholic fatty liver disease (NAFLD). We investigated whether administration of a synbiotic combination of probiotic and prebiotic agents affected liver fat content, biomarkers of liver fibrosis, and the composition of the fecal microbiome in patients with NAFLD. METHODS: We performed a double-blind phase 2 trial of 104 patients with NAFLD in the United Kingdom. Participants (mean age, 50.8 ± 12.6 years; 65% men; 37% with diabetes) were randomly assigned to groups given the synbiotic agents (fructo-oligosaccharides, 4 g twice per day, plus Bifidobacterium animalis subspecies lactis BB-12; n = 55) or placebo (n = 49) for 10-14 months. Liver fat content was measured at the start and end of the study by magnetic resonance spectroscopy, and liver fibrosis was determined from a validated biomarker scoring system and vibration-controlled transient elastography. Fecal samples were collected at the start and end of the study, the fecal microbiome were analyzed by 16S ribosomal DNA sequencing. RESULTS: Mean baseline and end-of-study magnetic resonance spectroscopy liver fat percentage values were 32.3% ± 24.8% and 28.5% ± 20.1% in the synbiotic group and 31.3% ± 22% and 25.2% ± 17.2% in the placebo group. In the unadjusted intention-to-treat analysis, we found no significant difference in liver fat reduction between groups (ß = 2.8; 95% confidence interval, -2.2 to 7.8; P = .30). In a fully adjusted regression model (adjusted for baseline measurement of the outcome plus age, sex, weight difference, and baseline weight), only weight loss was associated with a significant decrease in liver fat (ß = 2; 95% confidence interval, 1.5-2.6; P = .03). Fecal samples from patients who received the synbiotic had higher proportions of Bifidobacterium and Faecalibacterium species, and reductions in Oscillibacter and Alistipes species, compared with baseline; these changes were not observed in the placebo group. Changes in the composition of fecal microbiota were not associated with liver fat or markers of fibrosis. CONCLUSIONS: In a randomized trial of patients with NAFLD, 1 year of administration of a synbiotic combination (probiotic and prebiotic) altered the fecal microbiome but did not reduce liver fat content or markers of liver fibrosis. (ClinicalTrials.gov, Number: NCT01680640).

Tetraspanin CD53 modulates lymphocyte trafficking but not systemic autoimmunity in Lyn-deficient mice.

The leukocyte-restricted tetraspanin CD53 has been shown to promote lymphocyte homing to lymph nodes (LNs) and myeloid cell recruitment to acutely inflamed peripheral organs, and accelerate the onset of immune-mediated disease. However, its contribution in the setting of chronic systemic autoimmunity has not been investigated. We made use of the Lyn-/- autoimmune model, generating Cd53-/- Lyn-/- mice, and compared trafficking of immune cells into secondary lymphoid organs and systemic autoimmune disease development with mice lacking either gene alone. Consistent with previous observations, absence of CD53 led to reduced LN cellularity via reductions in both B and T cells, a phenotype also observed in Cd53-/- Lyn-/- mice. In some settings, Cd53-/- Lyn-/- lymphocytes showed greater loss of surface L-selectin and CD69 upregulation above that imparted by Lyn deficiency alone, indicating that absence of these two proteins can mediate additive effects in the immune system. Conversely, prototypical effects of Lyn deficiency including splenomegaly, plasma cell expansion, elevated serum immunoglobulin M and anti-nuclear antibodies were unaffected by CD53 deficiency. Furthermore, while Lyn-/- mice developed glomerular injury and showed elevated glomerular neutrophil retention above than that in wild-type mice, absence of CD53 in Lyn-/- mice did not alter these responses. Together, these findings demonstrate that while tetraspanin CD53 promotes lymphocyte trafficking into LNs independent of Lyn, it does not make an important contribution to development of autoimmunity, plasma cell dysfunction or glomerular injury in the Lyn-/- model of systemic autoimmunity.

Injecting network structure determines the most efficient strategy to achieve Hepatitis C elimination in people who inject drugs.

Transmission of Hepatitis C (HCV) continues via sharing of injection equipment between people who inject drugs (PWID). Network-based modelling studies have produced conflicting results about whether random treatment is preferable to targeting treatment at PWID with multiple partners. We hypothesise that differences in the modelled injecting network structure produce this heterogeneity. The study aimed to test how changing network structure affects HCV transmission and treatment effects. We created three dynamic injecting network structures connecting 689 PWID (UK-net, AUS-net and USA-net) based on published empirical data. We modelled HCV in the networks and at 5 years compared prevalence of HCV 1) with no treatment, 2) with randomly targeted treatment and 3) with treatment targeted at PWID with the most injecting partnerships (degree-based treatment). HCV prevalence at 5 years without treatment differed significantly between the three networks (UK-net (42.8%) vs. AUS-net (38.2%), p < 0.0001 and vs. USA-net (54.0%), p < 0.0001). In the treatment scenarios UK-net and AUS-net showed a benefit of degree-based treatment with a 5-year prevalence of 1.0% vs. 9.6% p < 0.0001 and 0.15% vs. 0.44%, p < 0.0001. USA-net showed no significant difference (29.3% vs. 29.2%, p = 0.0681). Degree-based treatment was optimised with low prevalence, moderate treatment coverage conditions whereas random treatment was optimised in low treatment coverage, high prevalence conditions. In conclusion, injecting network structure determines the transmission rate of HCV and the most efficient treatment strategy. In real-world injecting network structures, the benefit of targeting HCV treatment at individuals with multiple injecting partnerships may have been underestimated.

The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments.

The immune system must distinguish viable cells from cells damaged by physical and infective processes. The damaged cell-recognition molecule Clec9A is expressed on the surface of the mouse and human dendritic cell subsets specialized for the uptake and processing of material from dead cells. Clec9A recognizes a conserved component within nucleated and nonnucleated cells, exposed when cell membranes are damaged. We have identified this Clec9A ligand as a filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins. We have determined the crystal structure of the human CLEC9A C-type lectin domain and propose a functional dimeric structure with conserved tryptophans in the ligand recognition site. Mutation of these residues ablated CLEC9A binding to damaged cells and to the isolated ligand complexes. We propose that Clec9A provides targeted recruitment of the adaptive immune system during infection and can also be utilized to enhance immune responses generated by vaccines.

Patient perspectives of target weight management and ultrafiltration in haemodialysis: a multi-center survey.

BACKGROUND: Decisions around planned ultrafiltration volumes are the only part of the haemodialysis prescription decided upon at every session. Removing too much fluid or too little is associated with both acute symptoms and long-term outcomes. The degree to which patients engage with or influence decision-making is not clear. We explored patient perspectives of prescribing ultrafiltration volumes, their understanding of the process and engagement with it. METHODS: A questionnaire developed for this study was administered to 1077 patients across 10 UK Renal Units. Factor analysis reduced the dataset into factors representing common themes. Relationships between survey results and factors were investigated using regression models. ANCOVA was used to explore differences between Renal Units. RESULTS: Patients generally felt in control of their fluid management and that they were given the final say on planned ultrafiltration volumes. Around half of the respondents reported they take an active role in their treatment. However, respondents were largely unable to relate signs and symptoms to fluid management practice and a third said they would not report common signs and symptoms to clinicians. A fifth of patients reported not to know how ultrafiltration volumes were calculated. Patients responded positively to questions relating to healthcare staff, though with significant variation between units, highlighting differences in perception of care. CONCLUSIONS: Despite a lack of formal acknowledgement in fluid management protocols, patients have significant involvement in decisions regarding fluid removal during dialysis. Furthermore, substantial gaps remain in patient knowledge and engagement. Formalizing the role of patients in these decisions, including patient education, may improve prescription and achievement of target weights.

Exploring the Interactions between Non-Medical Methamphetamine Use and Prescribed Buprenorphine or Naltrexone in Opioid Use Disorder Treatment Retention.

OBJECTIVES: Our objectives were to examine the impact of methamphetamine use on opioid use disorder (OUD) treatment retention in patients prescribed either buprenorphine/buprenorphine-naloxone (BUP-NX) or naltrexone/extended-release naltrexone (XR-NTX), while also exploring the role of other risk factors that may modify the impact of methamphetamine use. METHODS: We conducted an exploratory retrospective study examining OUD treatment retention in 127 patients in Ohio (USA). Patients were prescribed either BUP-NX or naltrexone/XR-NTX. Cox proportional hazard regression was used to compare time to dropout of treatment between patients positive and negative on screening for methamphetamines at intake, estimate the association between other risk factors and time to dropout, and test interactions between risk factors and methamphetamine status. RESULTS: Among patients prescribed naltrexone/XR-NTX, those positive for methamphetamines had almost three times the risk of treatment dropout (AHR = 2.89, 95% CI =1.11, 7.07), significantly greater (interaction p = .039) than the methamphetamine effect among those prescribed BUP-NX (AHR = 0.94, 95% CI = 0.51, 1.65). Early in treatment, being prescribed BUP-NX was strongly associated with a greater risk of treatment dropout (at baseline: AHR = 2.90, 95% CI = 1.33, 7.15), regardless of baseline methamphetamine use status. However, this effect decreased with time and shifted to greater risk of dropout among those prescribed naltrexone/XR-NTX (non-proportional hazard; interaction with time AHR = 0.66, 95% CI = 0.49, 0.86), with the shift occurring sooner among those positive for methamphetamine at baseline. CONCLUSIONS: Additional support should be provided to patients who use methamphetamines prior to starting OUD treatment.

Bending the Curve of Global Freshwater Biodiversity Loss: An Emergency Recovery Plan.

Despite their limited spatial extent, freshwater ecosystems host remarkable biodiversity, including one-third of all vertebrate species. This biodiversity is declining dramatically: Globally, wetlands are vanishing three times faster than forests, and freshwater vertebrate populations have fallen more than twice as steeply as terrestrial or marine populations. Threats to freshwater biodiversity are well documented but coordinated action to reverse the decline is lacking. We present an Emergency Recovery Plan to bend the curve of freshwater biodiversity loss. Priority actions include accelerating implementation of environmental flows; improving water quality; protecting and restoring critical habitats; managing the exploitation of freshwater ecosystem resources, especially species and riverine aggregates; preventing and controlling nonnative species invasions; and safeguarding and restoring river connectivity. We recommend adjustments to targets and indicators for the Convention on Biological Diversity and the Sustainable Development Goals and roles for national and international state and nonstate actors.

Prednisolone or pentoxifylline for alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA.

BACKGROUND & AIMS: Infections are common in patients with severe alcoholic hepatitis (SAH), but little information is available on how to predict their development or their effects on patients. Prednisolone is advocated for treatment of SAH, but can increase susceptibility to infection. We compared the effects of infection on clinical outcomes of patients treated with and without prednisolone, and identified risk factors for development of infection in SAH. METHODS: We analyzed data from 1092 patients enrolled in a double-blind placebo-controlled trial to evaluate the efficacy of treatment with prednisolone (40 mg daily) or pentoxifylline (400 mg 3 times each day) in patients with SAH. The 2 × 2 factorial design led to 547 patients receiving prednisolone; 546 were treated with pentoxifylline. The trial was conducted in the United Kingdom from January 2011 through February 2014. Data on development of infection were collected at evaluations performed at screening, baseline, weekly during admission, on discharge, and after 90 days. Patients were diagnosed with infection based on published clinical and microbiologic criteria. Risk factors for development of infection and effects on 90-day mortality were evaluated separately in patients treated with prednisolone (n = 547) and patients not treated with prednisolone (n = 545) using logistic regression. Pretreatment blood levels of bacterial DNA (bDNA) were measured in 731 patients. RESULTS: Of the 1092 patients in the study, 135 had an infection at baseline, 251 developed infections during treatment, and 89 patients developed an infection after treatment. There was no association between pentoxifylline therapy and the risk of serious infection (P = .084), infection during treatment (P = .20), or infection after treatment (P = .27). Infections classified as serious were more frequent in patients treated with prednisolone (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.27-2.92; P = .002). There was no association between prednisolone therapy and infection during treatment (OR, 1.04; 95% CI, 0.78-1.37; P = .80). However, a higher proportion (10%) of patients receiving prednisolone developed an infection after treatment than of patients not given prednisolone (6%) (OR, 1.70; 95% CI, 1.07-2.69; P = .024). Development of infection was associated with increased 90-day mortality in patients with SAH treated with prednisolone, independent of model for end-stage liver disease or Lille score (OR, 2.46; 95% CI, 1.41-4.30; P = .002). High circulating bDNA predicted infection that developed within 7 days of prednisolone therapy, independent of Model for End-Stage Liver Disease and white blood cell count (OR, 4.68; 95% CI, 1.80-12.17; P = .001). In patients who did not receive prednisolone, infection was not independently associated with 90-day mortality (OR, 0.94; 95% CI, 0.54-1.62; P = .82) or levels of bDNA (OR, 0.83; 95% CI, 0.39-1.75; P = .62). CONCLUSIONS: Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125.

Dendritic Cell Migration and Antigen Presentation Are Coordinated by the Opposing Functions of the Tetraspanins CD82 and CD37.

This study supports a new concept where the opposing functions of the tetraspanins CD37 and CD82 may coordinate changes in migration and Ag presentation during dendritic cell (DC) activation. We have previously published that CD37 is downregulated upon monocyte-derived DC activation, promotes migration of both skin and bone marrow-derived dendritic cells (BMDCs), and restrains Ag presentation in splenic and BMDCs. In this article, we show that CD82, the closest phylogenetic relative to CD37, appears to have opposing functions. CD82 is upregulated upon activation of BMDCs and monocyte-derived DCs, restrains migration of skin and BMDCs, supports MHC class II maturation, and promotes stable interactions between T cells and splenic DCs or BMDCs. The underlying mechanism involves the rearrangement of the cytoskeleton via a differential activation of small GTPases. Both CD37(-/-) and CD82(-/-) BMDCs lack cellular projections, but where CD37(-/-) BMDCs spread poorly on fibronectin, CD82(-/-) BMDCs are large and spread to a greater extent than wild-type BMDCs. At the molecular level, CD82 is a negative regulator of RhoA, whereas CD37 promotes activation of Rac-1; both tetraspanins negatively regulate Cdc42. Thus, this study identifies a key aspect of DC biology: an unactivated BMDC is CD37(hi)CD82(lo), resulting in a highly motile cell with a limited ability to activate naive T cells. By contrast, a late activated BMDC is CD37(lo)CD82(hi), and thus has modified its migratory, cytoskeletal, and Ag presentation machinery to become a cell superbly adapted to activating naive T cells.

Supplementing electronic health records through sample collection and patient diaries: A study set within a primary care research database.

PURPOSE: To describe a novel observational study that supplemented primary care electronic health record (EHR) data with sample collection and patient diaries. METHODS: The study was set in primary care in England. A list of 3974 potentially eligible patients was compiled using data from the Clinical Practice Research Datalink. Interested general practices opted into the study then confirmed patient suitability and sent out postal invitations. Participants completed a drug-use diary and provided saliva samples to the research team to combine with EHR data. RESULTS: Of 252 practices contacted to participate, 66 (26%) mailed invitations to patients. Of the 3974 potentially eligible patients, 859 (22%) were at participating practices, and 526 (13%) were sent invitations. Of those invited, 117 (22%) consented to participate of whom 86 (74%) completed the study. CONCLUSIONS: We have confirmed the feasibility of supplementing EHR with data collected directly from patients. Although the present study successfully collected essential data from patients, it also underlined the requirement for improved engagement with both patients and general practitioners to support similar studies.