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OBJECTIVES: To assess the feasibility of a multifaceted strategy to translate evidence-based guidelines for treating nursing home-acquired pneumonia (NHAP) into practice using a small intervention trial. DESIGN: Pre-posttest with untreated control group. SETTING: Two Colorado State Veterans Homes (SVHs) during two influenza seasons. PARTICIPANTS: Eighty-six residents with two or more signs of lower respiratory tract infection. INTERVENTION: Multifaceted, including a formative phase to modify the intervention, institutional-level change emphasizing immunization, and availability of appropriate antibiotics; interactive educational sessions for nurses; and academic detailing. MEASUREMENTS: Subjects' SVH medical records were reviewed for guideline compliance retrospectively for the influenza season before the intervention and prospectively during the intervention. Bivariate comparisons-of-care processes between the intervention and control facility before and after the intervention were made using the Fischer exact test. RESULTS: At the intervention facility, compliance with five of the guidelines improved: influenza vaccination, timely physician response to illness onset, x-ray for patients not being hospitalized, use of appropriate antibiotics, and timely antibiotic initiation for unstable patients. Chest x-ray and appropriate and timely antibiotics were significantly better at the intervention than at the control facility during the intervention year but not during the control year. CONCLUSION: Multifaceted, evidence-based, NHAP guideline implementation improved care processes in a SVH. Guideline implementation should be studied in a national sample of nursing homes to determine whether it improves quality of life and functional outcomes of this debilitating illness for long-term care residents. [ABSTRACT FROM AUTHOR]

Background: Despite an epidemic of obesity among adults, the effect of excess body weight on outcome from critical illness is not well studied.Objective: To examine the association between excess body weight and outcome in mechanically ventilated patients with acute lung injury.Design: Secondary analysis of participants in trials of therapy for acute lung injury.Setting: 10 U.S. medical centers that participate in the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network.Patients: 902 mechanically ventilated patients who were enrolled in randomized, controlled trials of therapy for acute lung injury.Intervention: Assignment to higher (12 mL/kg of predicted weight) or lower (6 mL/kg of predicted weight) tidal volume ventilation strategies with specified weaning protocols. Some patients also received ketoconazole, lisofylline, or placebo by factorial design.Measurements: Mortality rate, rate of unassisted ventilation by day 28, and number of ventilator-free days.Results: Indirect causes of lung injury, including trauma, were more common in obese patients. Overweight and obese patients had higher peak and plateau airway pressures before enrollment because of higher set tidal volumes. After risk adjustment, excess body weight was not associated with death, achievement of unassisted ventilation, or number of ventilator-free days. This lack of effect persisted with categorical or continuous measures of body mass index (BMI). We found no significant interaction between ventilator protocol assignment and BMI category.Conclusions: After risk adjustment, overweight and obese patients with acute lung injury have outcomes similar to those of patients with normal BMI. The lack of interaction between ventilator protocol assignment and BMI suggests that patients with normal, overweight, or obese BMI benefit from lower tidal volume ventilation for acute lung injury. [ABSTRACT FROM AUTHOR]

During an episode of illness, older patients may receive care in multiple settings; often resulting in fragmented care and poorly-executed care transitions. The negative consequences of fragmented care include duplication of services; inappropriate or conflicting care recommendations, medication errors, patient/caregiver distress, and higher costs of care. Despite the critical need to reduce fragmented care in this population, few interventions have been developed to assist older patients and their family members in making smooth transitions. This article introduces a patient-centered interdisciplinary team intervention designed to improve transitions across sites of geriatric care. [ABSTRACT FROM AUTHOR]

Objective: To assess whether outcomes and costs differ for elderly patients admitted to rehabilitation hospitals, subacute nursing homes, and traditional nursing homes.Design: Inception cohort stratified by provider type and followed prospectively for 6 months.Setting: A total of 92 hospital-based units and freestanding facilities from 17 states.Patients: A total of 518 randomly selected patients with hip fracture and 485 stroke patients admitted from November 1991 to February 1994.Main Outcome Measures: At 6 months comparing community residence, recovery to premorbid levels in 5 activities of daily living (ADLs), Medicare costs, and the number of therapy and physician visits. Outcomes were adjusted for premorbid residence and function, caregiver availability, comorbid illness, admission function, cognition, depression, sensory deficits, and mobility impairments.Results: On admission, rehabilitation hospital patients were more likely (P<.001) to have caregivers and better cognitive and physical function. Hip fracture patients admitted to rehabilitation hospitals did not differ from patients admitted to nursing homes in returning to the community (adjusted odds ratio [OR], 1.3; 95% confidence interval [CI], 0.6-2.6) or in the number of ADLs recovered to premorbid level (difference, 0.09 ADL; 95% CI, -0.27-0.44), but stroke patients admitted to rehabilitation hospitals were more likely to return to the community (adjusted OR, 3.3; 95% CI, 1.5-7.2) and recover ADLs (difference, 0.63 ADL; 95% CI, 0.20-1.07). Subacute nursing home patients with stroke were more likely than traditional nursing home patients to return to the community (adjusted OR, 6.8; 95% CI, 2.2-21.4), there was no difference in return to the community for patients with hip fracture (adjusted OR, 1.6; 95% CI, 0.7-3.6), and there were no differences in recovery of ADLs for either condition. Medicare costs were greater (P<.001) for rehabilitation hospital patients than for subacute nursing home patients, and the costs for subacute nursing home patients were greater (P=.03 for stroke and .009 for hip fracture) than for traditional nursing home patients.Conclusions: Study findings are consistent with enhanced outcomes for elderly patients with stroke treated in rehabilitation hospitals but not for patients with hip fracture. Subacute nursing homes were more effective than traditional nursing homes in returning patients with stroke to the community, despite comparable functional outcomes. [ABSTRACT FROM AUTHOR]

This project assessed case mix differences between 299 hospital-based and 354 freestanding clients randomly selected from 20 home health agencies in nine states in 1982. Similarities between hospital-based and freestanding clients outweighed their differences, suggesting that no reimbursement differential is warranted for the two types of providers at this time. Medicare's prospective payment system for hospitals may result in more pronounced case mix differences between the two modalities in the future. Basing payment on case mix is therefore appropriate in order [ABSTRACT FROM AUTHOR]

Cochlear implant users with residual hearing benefit synergistically from combined electrical stimulation via the cochlear implant and preserved residual hearing after surgery. However, direct mechanical trauma and subsequent inflammation may deteriorate hearing function. AC102, a novel otoprotective pyridoindole with anti-apoptotic and anti-oxidative properties significantly improved hearing recovery following cochlear implantation when administered intratympanically prior to surgery. Additionally, AC102 exerts neurotrophic effects, possibly aiding in the preservation of auditory nerve fibers and spiral ganglion neurons. Rapid clearance of the drug, however, might be a limiting factor to further attenuate the inflammatory response and maintain neuronal health. The aim of the current study was to design an AC102-loaded electrode array for sustained drug delivery and investigate its effects in hearing preservation cochlear implantation. First, the release-kinetics of AC102 were investigated in vitro and modelled by the Higuchi equation of drug release. An electrode array coated with 10 % AC102 was manufactured, its release kinetics evaluated, and subsequently tested in vivo. 20 normal hearing Mongolian gerbils were unilaterally implanted with an AC102-loaded or an unloaded control electrode. Compound action potentials were measured prior to cochlear implantation and serially over 28 days. Hair cells, inner hair cell synapses, and auditory nerve fibers were quantified in cochlear whole-mounts by immunofluorescence staining. AC102 release from silicone coating could be predictably modelled by the Higuchi equation of drug release. The electrode array with an AC102-silicone depot enabled non-linear sustained drug release with initially higher release concentrations. In vivo, the AC102-loaded electrode array significantly recovered auditory threshold shifts near the maximum insertion depth over 28 days. In the apical region, a significant recovery was noticed only until day 14, after which threshold shifts aligned between groups. Histologically, AC102-loaded electrodes significantly preserved outer hair cells apical of the maximum insertion depth and inner hair cells and neuronal structures at the tip of the inserted electrode. In conclusion, the drug-loaded electrode arrays could predictably release AC102 over a period of 28 days. AC102 enabled the restoration of auditory thresholds near the area of maximum insertion, which is the desired region to be preserved in cochlear implant recipients with residual hearing., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Although chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease-negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study., Methods: In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment., Findings: From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome., Interpretation: This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach., Funding: National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association., Competing Interests: Declaration of interests ARR received research support from Pharmacyclics and AbbVie; one-time ad hoc scientific advisory board work for Nohla Therapeutics and Kaleido; and expert witness work for the US Department of Justice. CLM is the founder, has equity in, consults for, and is a Director of Cargo Therapeutics and Link Cell Therapies; has equity in Lyell Immunopharma; and receives royalties from the National Institutes of Health for CAR22 consulting for Immatics, Ensoma, Mammoth, Adaptimmune, and Bristol Myers Squibb. DBM consults for Kite Pharma-Gilead, Juno Therapeutics-Celgene, Novartis, Janssen, and Pharmacyclics; and receives research support from Kite Pharma-Gilead, Allogene, Cargo Therapeutics, Pharmacyclics, Miltenyi Biotec, and Adaptive Biotechnologies. JHB consults for Kite Pharma-Gilead; and receives research support from Kite Pharma-Gilead, Genentech-Roche, Regeneron Pharmaceuticals, and Cellular Biomedicine Group. MJF consults for Kite Pharma-Gilead, Adaptative Biotechnologies, and Cargo Therapeutics; receives research support from Kite-Pharma-Gilead, Allogene Therapeutics, Cargo Therapeutics, and Adaptative Biotechnologies; and is on the data safety monitoring board for Fate Therapeutics. LM receives research support from Adaptive Biotechnologies and Servier Laboratories; and consults for Amgen and Pfizer. JYS consults for Kite Pharma-Gilead and ImmPACT Bio. PS receives research support from Kite Pharma-Gilead. SS consults for Janssen. SAF consults for Lonza PerMed, Gradalis, Obsidian, and Samsara BioCapital. MPH is on the Kite Pharma-Gilead advisory board. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102's effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions., (© 2024. The Author(s).)

Purpose: The purpose of this study was to describe the clinical features, management, outcomes, and diagnostic pitfalls in a large series of patients with ocular neuromyotonia., Design: Retrospective cohort., Methods: Patients diagnosed with ocular neuromyotonia from January 1, 2004, through January 1, 2023, seen at one of the 3 Mayo Clinic sites in Rochester, MN, Scottsdale, AZ, and Jacksonville, FL, comprised the study population. We ascertained patients with ocular neuromyotonia through a search using the medical records database. Only patients with an observed episode of ocular neuromyotonia were included and the medical records were reviewed. The main outcome measures were clinical features and outcomes of patients with ocular neuromyotonia., Results: Forty-two patients who were diagnosed with ocular neuromyotonia were included. The median age was 58 years (range, 16-80 years). A history of cranial radiation therapy was present in 39 patients (93%). The sixth cranial nerve was involved in 31 patients (74%). Bilateral disease was found in 2 patients (5%). The median time from onset of diplopia to diagnosis was 8 months (range, 1 month-25 years), with a high rate of initial misdiagnosis in 52%. Twenty of 42 patients (48%) were treated with oral medication, of whom 95% had significant improvement or resolution of symptoms., Conclusion: Prior cranial irradiation is the most common cause for ocular neuromyotonia, affecting the sixth cranial nerve most often. Although delayed and initial misdiagnosis is common, most patients show improved symptoms on medical treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: We recently introduced a frameless, navigated, robot-driven laser tool for depth electrode implantation as an alternative to frame-based procedures. This method has only been used in cadaver and non-recovery studies. This is the first study to test the robot-driven laser tool in an in vivo recovery animal study. Methods: A preoperative computed tomography (CT) scan was conducted to plan trajectories in sheep specimens. Burr hole craniotomies were performed using a frameless, navigated, robot-driven laser tool. Depth electrodes were implanted after cut-through detection was confirmed. The electrodes were cut at the skin level postoperatively. Postoperative imaging was performed to verify accuracy. Histopathological analysis was performed on the bone, dura, and cortex samples. Results: Fourteen depth electrodes were implanted in two sheep specimens. Anesthetic protocols did not show any intraoperative irregularities. One sheep was euthanized on the same day of the procedure while the other sheep remained alive for 1 week without neurological deficits. Postoperative MRI and CT showed no intracerebral bleeding, infarction, or unintended damage. The average bone thickness was 6.2 mm (range 4.1-8.0 mm). The angulation of the planned trajectories varied from 65.5° to 87.4°. The deviation of the entry point performed by the frameless laser beam ranged from 0.27 mm to 2.24 mm. The histopathological analysis did not reveal any damage associated with the laser beam. Conclusion: The novel robot-driven laser craniotomy tool showed promising results in this first in vivo recovery study. These findings indicate that laser craniotomies can be performed safely and that cut-through detection is reliable., Competing Interests: DB, PG, and MM were employed by AOT, which is the company that provided the laser. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Winter, Pilz, Kramer, Beer, Gono, Morawska, Hainfellner, Klotz, Tomschik, Pataraia, Hangel, Dorfer and Roessler.)

Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22 + malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Competing Interests: The authors report no conflicts of interest.

Purpose : Although dissociated vertical deviation (DVD) is reported to occur rarely in children with intermittent exotropia (IXT), little is known regarding the clinical features of these children. The purpose of this study was to compare the demographic and clinical characteristics of children with intermittent exotropia and DVD to those without DVD. Methods : The medical records of all children diagnosed with intermittent exotropia at our institution from 1 January 2002, through 31 December 2018, who had 2 or more exams with 3 or more assessments of control, were retrospectively reviewed. Exotropic children with DVD were compared to those without DVD. Results : During the 17-year study period, 115 children met the inclusion criteria, of which 25 (21.7%) had DVD. Compared to the 90 exotropic children without DVD, children with IXT and DVD were more likely to have a motility disorder ( p  = .021), a worse mean distance control score (2.8 vs 2.4; p  = .09), a larger mean angle of deviation (27.8 prism diopters [PD] vs 25.1 PD; p  = .04), and a lower median stereopsis (200 secs vs 100 secs; p  = .08). The children with DVD were more likely to have undergone surgery ( p  = .17) although there was no difference in the mean age at initial surgery between the two groups. Conclusions : The presence of dissociated vertical deviation in children with intermittent exotropia is associated with more motility disorders and worse binocular function compared to those without DVD. These children will likely require closer observation and earlier intervention.

Phylogenetics has been foundational to SARS-CoV-2 research and public health policy, assisting in genomic surveillance, contact tracing, and assessing emergence and spread of new variants. However, phylogenetic analyses of SARS-CoV-2 have often relied on tools designed for de novo phylogenetic inference, in which all data are collected before any analysis is performed and the phylogeny is inferred once from scratch. SARS-CoV-2 data sets do not fit this mold. There are currently over 14 million sequenced SARS-CoV-2 genomes in online databases, with tens of thousands of new genomes added every day. Continuous data collection, combined with the public health relevance of SARS-CoV-2, invites an "online" approach to phylogenetics, in which new samples are added to existing phylogenetic trees every day. The extremely dense sampling of SARS-CoV-2 genomes also invites a comparison between likelihood and parsimony approaches to phylogenetic inference. Maximum likelihood (ML) and pseudo-ML methods may be more accurate when there are multiple changes at a single site on a single branch, but this accuracy comes at a large computational cost, and the dense sampling of SARS-CoV-2 genomes means that these instances will be extremely rare because each internal branch is expected to be extremely short. Therefore, it may be that approaches based on maximum parsimony (MP) are sufficiently accurate for reconstructing phylogenies of SARS-CoV-2, and their simplicity means that they can be applied to much larger data sets. Here, we evaluate the performance of de novo and online phylogenetic approaches, as well as ML, pseudo-ML, and MP frameworks for inferring large and dense SARS-CoV-2 phylogenies. Overall, we find that online phylogenetics produces similar phylogenetic trees to de novo analyses for SARS-CoV-2, and that MP optimization with UShER and matOptimize produces equivalent SARS-CoV-2 phylogenies to some of the most popular ML and pseudo-ML inference tools. MP optimization with UShER and matOptimize is thousands of times faster than presently available implementations of ML and online phylogenetics is faster than de novo inference. Our results therefore suggest that parsimony-based methods like UShER and matOptimize represent an accurate and more practical alternative to established ML implementations for large SARS-CoV-2 phylogenies and could be successfully applied to other similar data sets with particularly dense sampling and short branch lengths., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Systematic Biologists.)

Background/objective: Guidelines on obesity management reinforce regular exercise to reduce body fat. Exercise modalities, including high-intensity interval training (HIIT), appear to produce a similar effect to continuous aerobic training (CAT) on body fat. However, they have not addressed the chronic effect of HIIT vs. CAT on body fat assessed by dual energy X-ray absorptiometry (DEXA). Thus, we compared the effectiveness of CAT vs. HIIT protocols on body fat (absolute or relative) (%BF) and abdominal visceral fat reduction, assessed by DEXA, in adults with overweight and obesity., Methods: We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) including both female or male adults with excess body weight. We performed searches in the databases MEDLINE (PubMed), EMBASE, Scopus, LILACS, Web of Science and Cochrane., Results: In our analysis (11 RCTs), we found no greater benefit on %BF of HIIT vs. CAT (MD -0.55%, 95% CI -1.42 to 0.31; p = 0.209). As for abdominal visceral fat, no training modality was superior (SMD: -0.05, 95% CI -0.29 to 0.19; p = 0.997). Regarding secondary outcomes (body weight, BMI, VO 2 max, glycemic and lipid profiles), HIIT shows greater benefit than CAT in increasing VO 2 max and fasting blood glucose and reducing total cholesterol., Conclusion: HIIT is not superior to CAT in reducing %BF or abdominal visceral fat in individuals characterized by excess weight. However, HIIT showed beneficial effects on cardiorespiratory fitness, total cholesterol and fasting blood glucose when compared to CAT., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Society of Chinese Scholars on Exercise Physiology and Fitness. Published by Elsevier (Singapore) Pte Ltd.)

Both single- and double-outflow cavopulmonary assist devices (CPADs) were recently proposed for the Fontan population, whereas single-outflow configurations were evaluated in large animal trials and double-outflow concepts are lacking an equivalent in vivo assessment. The aim of this study was to test the hemodynamic properties of a double-outflow CPAD device in an acute sheep model. The two inflow cannulae of a CPAD were anastomosed to the caval veins. Outflow graft connection was performed via end-to-side anastomosis to the right (RPA) and main pulmonary artery (MPA). Speed ramp protocols were conducted, and hemodynamic effects were monitored in terms of caval flows, cardiac output (CO), central venous pressure (CVP), pulmonary artery pressure (PAP), and left atrial pressure (LAP). Six experiments were conducted (53.35 ± 5.1 kg). In three experiments, the animal model was established, the CPAD was examined, and restoration of biventricular equivalency in terms of venous return was achieved. Venous pressures (CVP) declined linearly with increasing pump speed (r > 0.879), whereas caval flow (r > 0.973), CO (r > 0.993), PAP (r > 0.973), and LAP (r > 0.408) increased. Despite the considerable complexity of the sheep model caused by the sheep pulmonary arterial anatomy that requires substantial graft bending, the CPAD was evaluated in three acute experiments and showed the potential to completely substitute a subpulmonary ventricle., Competing Interests: Disclosure: M.G. received personal fees and research grants from BerlinHeart GmbH and research grants from 4Fontan AG; T.S. received personal fees and grants from Abbott, Medtronic, CorWave. U.K. received grants from Berlin Heart GmbH; D.Z. received personal fees from Abbott, Medtronic, Abiomed, Edwards, Daiichi Sankyo and research grants from Abbott, Medtronic, Berlin Heart, Edwards, Corcym. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Wetlands provide essential ecosystem services, including nutrient cycling, flood protection, and biodiversity support, that are sensitive to changes in wetland hydrology. Wetland hydrological inputs come from precipitation, groundwater discharge, and surface run-off. Changes to these inputs via climate variation, groundwater extraction, and land development may alter the timing and magnitude of wetland inundation. Here, we use a long-term (14-year) comparative study of 152 depressional wetlands in west-central Florida to identify sources of variation in wetland inundation during two key time periods, 2005-2009 and 2010-2018. These time periods are separated by the enactment of water conservation policies in 2009, which included regional reductions in groundwater extraction. We investigated the response of wetland inundation to the interactive effects of precipitation, groundwater extraction, surrounding land development, basin geomorphology, and wetland vegetation class. Results show that water levels were lower and hydroperiods were shorter in wetlands of all vegetation classes during the first (2005-2009) time period, which corresponded with low rainfall conditions and high rates of groundwater extraction. Under water conservation policies enacted in the second (2010-2018) time period, median wetland water depths increased 1.35 m and median hydroperiods increased from 46 % to 83 %. Water-level variation was additionally less sensitive to groundwater extraction. The increase in inundation differed among vegetation classes with some wetlands not displaying signs of hydrological recovery. After accounting for effects of several explanatory factors, inundation still varied considerably among wetlands, suggesting a diversity of hydrological regimes, and thus ecological function, among individual wetlands across the landscape. Policies seeking to balance human water demand with the preservation of depressional wetlands would benefit by recognizing the heightened sensitivity of wetland inundation to groundwater extraction during periods of low precipitation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cisplatin is among the most effective antineoplastic agents and has revolutionized the treatment of many cancer diseases. However, one of its serious side effects is a progressive and irreversible hearing loss, occurring in both adults and children. For the development of otoprotective therapies that prevent this side effect, cisplatin-induced hearing loss animal models are indispensable. Due to the high toxicity of cisplatin, the establishment of such animal models is a difficult and time-consuming task. Here we introduce the detailed protocol of a sophisticated guinea pig model with a sufficient and permanent hearing loss induced by cisplatin. This manuscript is intended to provide guidance in the development of future cisplatin guinea pig models which may reduce the mortality rate of the animals and help to gain more reproducible results., Methods: Pigmented and unpigmented guineapigs were treated with an intravenous single application of 8 mg/kg cisplatin under general anesthesia. An extensive and long-term intensive care protocol consisting of scheduled application of fluids, antiemetics, analgesics, glucose and supportive feeding among others, was used to ensure wellbeing of the animals. Hearing tests were performed prior to and 5 days after cisplatin application. Animals were then euthanized., Results: The ABR audiometry 5 days after cisplatin application revealed a hearing threshold ranging from 70 dB to 90 dB in the frequencies from 1 kHz to 32 kHz respectively.All animals presented a good health condition despite the treatment with cisplatin., Discussion: The introduced care protocol in this manuscript is intended to serve as a guidance for the establishment of a stable guinea pig model for short- and long-term investigation regarding the inner ear and its protection in the frame work of cisplatin-induced damage., Competing Interests: CA and CH received funding from MED-EL Corporation, Innsbruck, Austria. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ahmadi, Saidov, Gausterer, Kramer, Honeder and Arnoldner.)

The cardiac responses to vagus nerve stimulation (VNS) are still not fully understood, partly due to uncontrollable confounders in the in-vivo experimental condition. Therefore, an ex-vivo Langendorff-perfused rabbit heart with intact vagal innervation is proposed to study VNS in absence of cofounding anesthetic or autonomic influences. The feasibility to evoke chronotropic responses through electrical stimulation ex-vivo was studied in innervated isolated rabbit hearts (n = 6). The general nerve excitability was assessed through the ability to evoke a heart rate (HR) reduction of at least 5 bpm (physiological threshold). The excitability was quantified as the charge needed for a 10-bpm HR reduction. The results were compared to a series of in-vivo experiments rabbits (n = 5). In the ex-vivo isolated heart, the baseline HR was about 20 bpm lower than in-vivo (158 ± 11 bpm vs 181 ± 19 bpm). Overall, the nerve remained excitable for about 5 h ex-vivo. The charges required to reduce HR by 5 bpm were 9 ± 6 µC and 549 ± 370 µC, ex-vivo and in-vivo, respectively. The charges needed for a 10-bpm HR reduction, normalized to the physiological threshold were 1.78 ± 0.8 and 1.22 ± 0.1, in-vivo and ex-vivo, respectively. Overall, the viability of this ex-vivo model to study the acute cardiac effects of VNS was demonstrated., (© 2023. The Author(s).)

Summary: Treenome Browser is a web browser tool to interactively visualize millions of genomes alongside huge phylogenetic trees., Availability and Implementation: Treenome Browser for SARS-CoV-2 can be accessed at cov2tree.org, or at taxonium.org for user-provided trees. Source code and documentation are available at github.com/theosanderson/taxonium and docs.taxonium.org/en/latest/treenome.html., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC., Competing Interests: Conflicts of Interest and Source of Funding: Supported by a research grant from the National Institutes of Health (NCI, CA124633 to C.A.F.) and Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748 (R.A.G and B.X.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Various animal models have been established and applied in hearing research. In the exploration of novel cochlear implant developments, mainly rodents have been used. Despite their important contribution to the understanding of auditory function, translation of experimental observations from rodents to humans is limited due to the size differences and genetic variability. Large animal models with better representation of the human cochlea are sparse. For this reason, we evaluated domestic piglets and Aachen minipigs for the suitability as a cochlear implantation animal model with commercially available cochlear implants., Methods: Four domestic piglets (two male and two female) and six Aachen minipigs were implanted with either MED-EL Flex24 or Flex20 cochlear implants respectively, after a step-by-step surgical approach was trained with pig cadavers. Electrophysiological measurements were performed before, during and after implantation for as long as 56 days after surgery. Auditory brainstem responses, electrocochleography as well as electrically and acoustically evoked compound action potentials were recorded. Selected cochleae were further analyzed histologically or with micro-CT imaging., Results: A surgical approach was established using a retroauricular single incision. Baseline auditory thresholds were 27 ± 3 dB sound pressure level (SPL; auditory brainstem click responses, mean ± standard error of the mean) and ranged between 30 and 80 dB SPL in frequency-specific responses (0.5 - 32 kHz). Follow-up measurements revealed deafness within the first two weeks after surgery, but some animals partially recovered to a hearing threshold of 80 dB SPL in certain frequencies as well as in click responses. Electrically evoked compound action potential thresholds increased within the first week after surgery, which led to lower stimulation responses or increase of necessary charge input. Immune reactions and consecutive scalar fibrosis following implantation were confirmed with histological analysis of implanted cochleae and may result in increased impedances. A three-dimensional minipig micro-CT segmentation revealed cochlear volumetric data similar to human inner ear dimensions., Conclusions: This study underlines the feasibility of cochlear implantation with clinically used cochlear implants in a large animal model with representative inner ear dimensions comparable to humans. To bridge the gap between small animal models and humans in translational research and to account for the structural and size differences, we recommend the minipig as a valuable animal model for hearing research. First insights into the induced trauma in minipigs after cochlear implant surgery and a partial hearing recovery present important data of the cochlear health changes in large animal cochleae., Competing Interests: Declaration of Competing Interest The other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Persistent sinus tachycardia substantially increases the risk of cardiac death. Vagus nerve stimulation (VNS) is known to reduce the heart rate, and hence may be a non-pharmacological alternative for the management of persistent sinus tachycardia. To precisely regulate the heart rate using VNS, closed-loop control strategies are needed. Therefore, in this work, we developed two closed-loop VNS strategies using an in-silico model of the cardiovascular system. Both strategies employ a proportional-integral controller that operates on the current amplitude. While one control strategy continuously delivers stimulation pulses to the vagus nerve, the other applies bursts of stimuli in synchronization with the cardiac cycle. Both were evaluated in Langendorff-perfused rabbit hearts (n = 6) with intact vagal innervation. The controller performance was quantified by rise time (T r ), steady-state error (SSE), and percentual overshoot amplitude (%OS). In the ex-vivo setting, the cardiac-synchronized variant resulted in T r  = 10.7 ± 4.5 s, SSE = 12.7 ± 9.9 bpm and %OS = 5.1 ± 3.6% while continuous stimulation led to T r  = 10.2 ± 5.6 s, SSE = 10 ± 6.7 bpm and %OS = 3.2 ± 1.9%. Overall, both strategies produced a satisfying and reproducible performance, highlighting their potential use in persistent sinus tachycardia., (© 2022. The Author(s).)

Background: Vagus nerve stimulation (VNS) has gained great importance as a promising therapy for a myriad of diseases. Of particular interest is the therapy of cardiovascular diseases, such as heart failure or atrial fibrillation using selective cardiac VNS. However, there is still a lack of organ-specific anatomical knowledge about the fascicular anatomy and topography of the cardiac branch (CB), which diminishes the therapeutic possibilities for selective cardiac neuromodulation. Here, we established a topographical and anatomical map of the superior cardiac VN in two animal species to dissect cervical and cardiac VN morphology. Methods: Autonomic nerves including superior CBs were harvested from domestic pigs and New Zeeland rabbits followed by imaging with microcomputed tomography (µCT) and 3D rendering. The data were analyzed in terms of relevant topographical and anatomical parameters. Results: Our data showed that cardiac vagal fascicles remained separated from other VN fascicles up to 22.19 mm (IQR 14.02-41.30 mm) in pigs and 7.68 mm (IQR 4.06-12.77 mm) in rabbits from the CB point and then started merging with other fascicles. Exchanges of nerve fascicles between sympathetic trunk (ST) and VN were observed in 3 out of 11 nerves, which might cause additional unwanted effects in unselective VNS. Our 3D rendered digital model of the cardiac fascicles was generated showing that CB first remained on the medial side where it branched off the VN, as also shown in the µCT data of 11 pig nerves, and then migrated towards the ventromedial site the further it was traced cranially. Conclusion: Our data provided an anatomical map of the cardiac vagal branches including cervical VN and ST for future approaches of selective cardiac neurostimulation, indicating the best position of selective cardiac VNS just above the CB point., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kronsteiner, Zopf, Heimel, Oberoi, Kramer, Slezak, Weninger, Podesser, Kiss and Moscato.)

Invasive alien species (IAS) are a major driver of global biodiversity loss, hampering conservation efforts and disrupting ecosystem functions and services. While accumulating evidence documented ecological impacts of IAS across major geographic regions, habitat types and taxonomic groups, appraisals for economic costs remained relatively sparse. This has hindered effective cost-benefit analyses that inform expenditure on management interventions to prevent, control, and eradicate IAS. Terrestrial invertebrates are a particularly pervasive and damaging group of invaders, with many species compromising primary economic sectors such as forestry, agriculture and health. The present study provides synthesised quantifications of economic costs caused by invasive terrestrial invertebrates on the global scale and across a range of descriptors, using the InvaCost database. Invasive terrestrial invertebrates cost the global economy US$ 712.44 billion over the investigated period (up to 2020), considering only high-reliability source reports. Overall, costs were not equally distributed geographically, with North America (73%) reporting the greatest costs, with far lower costs reported in Europe (7%), Oceania (6%), Africa (5%), Asia (3%), and South America (< 1%). These costs were mostly due to invasive insects (88%) and mostly resulted from direct resource damages and losses (75%), particularly in agriculture and forestry; relatively little (8%) was invested in management. A minority of monetary costs was directly observed (17%). Economic costs displayed an increasing trend with time, with an average annual cost of US$ 11.40 billion since 1960, but as much as US$ 165.01 billion in 2020, but reporting lags reduced costs in recent years. The massive global economic costs of invasive terrestrial invertebrates require urgent consideration and investment by policymakers and managers, in order to prevent and remediate the economic and ecological impacts of these and other IAS groups., Competing Interests: Declaration of competing interest The authors declare that there are no conflicting or competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We have previously demonstrated beneficial cardiac protection with hypothermic polarizing cardioplegia compared to a hyperkalemic depolarizing cardioplegia. In this study, a porcine model of cardiopulmonary bypass was used to compare the protective effects of normothermic blood-based polarizing and depolarizing cardioplegia during cardiac arrest., Methods: Thirteen pigs were randomized to receive either normothermic polarizing (n = 8) or depolarizing (n = 5) blood-based cardioplegia. After initiation of cardiopulmonary bypass, normothermic arrest (34°C, 60 min) was followed by 60 min of on-pump and 90 min of off-pump reperfusion. Primary outcome was myocardial injury measured as arterial myocardial creatine kinase concentration. Secondary outcome was haemodynamic function and the energy state of the hearts., Results: During reperfusion, release of myocardial creatine kinase was comparable between groups (P = 0.36). In addition, most haemodynamic parameters showed comparable results between groups, but stroke volume (P = 0.03) was significantly lower in the polarizing group. Adenosine triphosphate levels were significantly (18.41 ± 3.86 vs 22.97 ± 2.73 nmol/mg; P = 0.03) lower in polarizing hearts, and the requirement for noradrenaline administration (P = 0.002) and temporary pacing (6 vs 0; P = 0.02) during reperfusion were significantly higher in polarizing hearts., Conclusions: Under normothermic conditions, polarizing blood cardioplegia was associated with similar myocardial injury to depolarizing blood cardioplegia. Reduced haemodynamic and metabolic outcome and a higher need for temporary pacing with polarized arrest may be associated with the blood-based dilution of this solution., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Deforestation alters wildlife communities and modifies human-wildlife interactions, often increasing zoonotic spillover potential. When deforested land reverts to forest, species composition differences between primary and regenerating (secondary) forest could alter spillover risk trajectory. We develop a mathematical model of land-use change, where habitats differ in their relative spillover risk, to understand how land reversion influences spillover risk. We apply this framework to scenarios where spillover risk is higher in deforested land than mature forest, reflecting higher relative abundance of highly competent species and/or increased human-wildlife encounters, and where regenerating forest has either very low or high spillover risk. We find the forest regeneration rate, the spillover risk of regenerating forest relative to deforested land, and how rapidly regenerating forest regains attributes of mature forest determine landscape-level spillover risk. When regenerating forest has a much lower spillover risk than deforested land, reversion lowers cumulative spillover risk, but instaneous spillover risk peaks earlier. However, when spillover risk is high in regenerating and cleared habitats, landscape-level spillover risk remains high, especially when cleared land is rapidly abandoned then slowly regenerates to mature forest. These results suggest that proactive wildlife management and awareness of human exposure risk in regenerating forests could be important tools for spillover mitigation., (© 2022 The Authors.)

The global increase in biological invasions is placing growing pressure on the management of ecological and economic systems. However, the effectiveness of current management expenditure is difficult to assess due to a lack of standardised measurement across spatial, taxonomic and temporal scales. Furthermore, there is no quantification of the spending difference between pre-invasion (e.g. prevention) and post-invasion (e.g. control) stages, although preventative measures are considered to be the most cost-effective. Here, we use a comprehensive database of invasive alien species economic costs (InvaCost) to synthesise and model the global management costs of biological invasions, in order to provide a better understanding of the stage at which these expenditures occur. Since 1960, reported management expenditures have totalled at least US$95.3 billion (in 2017 values), considering only highly reliable and actually observed costs - 12-times less than damage costs from invasions ($1130.6 billion). Pre-invasion management spending ($2.8 billion) was over 25-times lower than post-invasion expenditure ($72.7 billion). Management costs were heavily geographically skewed towards North America (54%) and Oceania (30%). The largest shares of expenditures were directed towards invasive alien invertebrates in terrestrial environments. Spending on invasive alien species management has grown by two orders of magnitude since 1960, reaching an estimated $4.2 billion per year globally (in 2017 values) in the 2010s, but remains 1-2 orders of magnitude lower than damages. National management spending increased with incurred damage costs, with management actions delayed on average by 11 years globally following damage reporting. These management delays on the global level have caused an additional invasion cost of approximately $1.2 trillion, compared to scenarios with immediate management. Our results indicate insufficient management - particularly pre-invasion - and urge better investment to prevent future invasions and to control established alien species. Recommendations to improve reported management cost comprehensiveness, resolution and terminology are also made., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Populations and communities fluctuate in their overall numbers through time, and the magnitude of fluctuations in individual species may scale to communities. However, the composite variability at the community scale is expected to be tempered by opposing fluctuations in individual populations, a phenomenon often called the portfolio effect. Understanding population variability, how it scales to community variability, and the spatial scaling in this variability are pressing needs given shifting environmental conditions and community composition. We explore evidence for portfolio effects using null community simulations and a large collection of empirical community time series from the BioTIME database. Additionally, we explore the relative roles of habitat type and geographic location on population and community temporal variability. We find strong portfolio effects in our theoretical community model, but weak effects in empirical data, suggesting a role for shared environmental responses, interspecific competition, or a litany of other factors. Furthermore, we observe a clear latitudinal signal - and differences among habitat types - in population and community variability. Together, this highlights the need to develop realistic models of community dynamics, and hints at spatial, and underlying environmental, gradients in variability in both population and community dynamics., (© 2021 by the Ecological Society of America.)

The United States has thousands of invasive species, representing a sizable, but unknown burden to the national economy. Given the potential economic repercussions of invasive species, quantifying these costs is of paramount importance both for national economies and invasion management. Here, we used a novel global database of invasion costs (InvaCost) to quantify the overall costs of invasive species in the United States across spatiotemporal, taxonomic, and socioeconomic scales. From 1960 to 2020, reported invasion costs totaled $4.52 trillion (USD 2017). Considering only observed, highly reliable costs, this total cost reached $1.22 trillion with an average annual cost of $19.94 billion/year. These costs increased from $2.00 billion annually between 1960 and 1969 to $21.08 billion annually between 2010 and 2020. Most costs (73%) were related to resource damages and losses ($896.22 billion), as opposed to management expenditures ($46.54 billion). Moreover, the majority of costs were reported from invaders from terrestrial habitats ($643.51 billion, 53%) and agriculture was the most impacted sector ($509.55 billion). From a taxonomic perspective, mammals ($234.71 billion) and insects ($126.42 billion) were the taxonomic groups responsible for the greatest costs. Considering the apparent rising costs of invasions, coupled with increasing numbers of invasive species and the current lack of cost information for most known invaders, our findings provide critical information for policymakers and managers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Invasive alien fishes have had pernicious ecological and economic impacts on both aquatic ecosystems and human societies. However, a comprehensive and collective assessment of their monetary costs is still lacking. In this study, we collected and reviewed reported data on the economic impacts of invasive alien fishes using InvaCost, the most comprehensive global database of invasion costs. We analysed how total (i.e. both observed and potential/predicted) and observed (i.e. empirically incurred only) costs of fish invasions are distributed geographically and temporally and assessed which socioeconomic sectors are most affected. Fish invasions have potentially caused the economic loss of at least US$37.08 billion (US2017 value) globally, from just 27 reported species. North America reported the highest costs (>85% of the total economic loss), followed by Europe, Oceania and Asia, with no costs yet reported from Africa or South America. Only 6.6% of the total reported costs were from invasive alien marine fish. The costs that were observed amounted to US$2.28 billion (6.1% of total costs), indicating that the costs of damage caused by invasive alien fishes are often extrapolated and/or difficult to quantify. Most of the observed costs were related to damage and resource losses (89%). Observed costs mainly affected public and social welfare (63%), with the remainder borne by fisheries, authorities and stakeholders through management actions, environmental, and mixed sectors. Total costs related to fish invasions have increased significantly over time, from

A high number of trauma patients are under the influence of alcohol. Since many of them need immediate surgical procedures, it is imperative to be aware of the interaction of alcohol with general anesthesia. To counter challenges that arise from clinical studies, we designed an animal experiment in which 48 adult Wistar rats either received 1 g · kg -1 ethanol, 2 g · kg -1 ethanol or placebo via intraperitoneal application. Subsequently, they were anesthetized with an individual concentration of sevoflurane. The minimum alveolar concentration (MAC) of the different groups was assessed using Dixon's up-and-down design and isotonic regression methods. The bootstrap estimate of the MAC of sevoflurane in the placebo group was 2.24 vol% (95% CI 1.97-2.94 vol%). In the low dose ethanol group, the bootstrap estimate was 1.65 vol% (95% CI 1.40-1.98 vol%), and in the high dose ethanol group, it was 1.08 vol% (95% CI 0.73-1.42 vol%). We therefore report that intraperitoneal application of 1 g · kg -1 or 2 g · kg -1 ethanol both resulted in a significant reduction of the MAC of sevoflurane in adult Wistar rats: by 26.3% and 51.8% respectively as compared to placebo., (© 2022. The Author(s).)

Dissociated vertical deviation (DVD) is generally associated with early-onset esotropic strabismus and poor stereopsis. It is infrequently observed among patients with intermittent exotropia. In this cohort of 242 consecutive children with intermittent exotropia examined over a 17-year period, 25 (10.3%) were found to have DVD, 13 (52%) of whom had normal stereopsis. In the children with both intermittent exotropia and DVD, disease severity appears to depend more on the quality of stereopsis than on the presence of DVD., (Copyright © 2021 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Much research effort has been invested in understanding ecological impacts of invasive alien species (IAS) across ecosystems and taxonomic groups, but empirical studies about economic effects lack synthesis. Using a comprehensive global database, we determine patterns and trends in economic costs of aquatic IAS by examining: (i) the distribution of these costs across taxa, geographic regions and cost types; (ii) the temporal dynamics of global costs; and (iii) knowledge gaps, especially compared to terrestrial IAS. Based on the costs recorded from the existing literature, the global cost of aquatic IAS conservatively summed to US$345 billion, with the majority attributed to invertebrates (62%), followed by vertebrates (28%), then plants (6%). The largest costs were reported in North America (48%) and Asia (13%), and were principally a result of resource damages (74%); only 6% of recorded costs were from management. The magnitude and number of reported costs were highest in the United States of America and for semi-aquatic taxa. Many countries and known aquatic alien species had no reported costs, especially in Africa and Asia. Accordingly, a network analysis revealed limited connectivity among countries, indicating disparate cost reporting. Aquatic IAS costs have increased in recent decades by several orders of magnitude, reaching at least US$23 billion in 2020. Costs are likely considerably underrepresented compared to terrestrial IAS; only 5% of reported costs were from aquatic species, despite 26% of known invaders being aquatic. Additionally, only 1% of aquatic invasion costs were from marine species. Costs of aquatic IAS are thus substantial, but likely underreported. Costs have increased over time and are expected to continue rising with future invasions. We urge increased and improved cost reporting by managers, practitioners and researchers to reduce knowledge gaps. Few costs are proactive investments; increased management spending is urgently needed to prevent and limit current and future aquatic IAS damages., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

For large avians such as vultures, limb loss leads to loss of ambulation and eventually death from malnutrition. Prosthetic devices may replace the limb, however, conventional prosthetic sockets are not feasible in feathered limbs and the extreme stress and strain of unreflected daily use in animals. Osseointegration is a novel technique, where external prosthetic parts are connected directly to a bone anchor to provide a solid skeletal-attachment. This concept provides a high degree of embodiment since osseoperception will provide direct intuitive feedback allowing natural use of the limb in gait and feeding. Here we demonstrate for the first time an osseointegrated bionic reconstruction of a limb in a vulture after a tarsometatarsal amputation with a longterm follow-up.

Purpose: To compare the double-Maddox rod test with other methods of measuring cyclodeviation DESIGN: Retrospective cohort study., Methods: We retrospectively identified 153 adults in a clinical practice with cyclodeviation assessed using double-Maddox rods, of whom 105 were also assessed using fusible synoptophore targets, 73 using nonfusible synoptophore targets, 118 using single-Maddox rod, and 43 using fundus photography. Relationships between double-Maddox rod and other tests were evaluated by calculating mean differences with 95% confidence intervals (CI), intraclass correlation coefficients (ICC), and Bland-Altman plots with linear regression., Results: Synoptophore cross-in-circle targets and the largest (of right or left) single-Maddox rod values were similar to double-Maddox values (mean differences: -1.2° and 0.1°, respectively; ICC: 0.79 and 0.82, respectively). Synoptophore house targets measured less excyclodeviation (mean difference: -2.7°; ICC: 0.71). Mean summed single-Maddox rod values were somewhat similar to double-Maddox values (mean difference: 1.5°; ICC: 0.85), but differences increased with greater cyclodeviation (r 2  = 0.2678; P < .001). Fundus photographs showed large, uncorrelated differences compared with double-Maddox rod test, when summing right and left eyes and when using the largest of right or left (mean differences: 12.2° and 6.2°; ICC: -0.02 and 0.21, respectively), and differences increased with greater cyclodeviation (r 2  = 0.4094; P < .001 and r 2 = .1143; P= .03, respectively)., Conclusions: There was good agreement between double-Maddox and the largest single- Maddox test values and synoptophore cross-in-circle targets but poorer agreement with other tests. Further study is needed to understand which measurements best reflect true cyclodeviation and relationships with symptoms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Iron deficiency (ID) is globally prevalent, and apart from anemia is associated with thrombocytosis. While considered benign, studies linking thrombotic events with prior ID anemia suggest otherwise. Herein we used animal models to assess the influence of ID on thrombotic tendency. Sprague-Dawley rats were fed control or iron deficient diets and ferric carboxymaltose was used to reverse ID. Thrombosis was induced via stenosis of the inferior vena cava or damage to the right carotid artery using ferric chloride. Thrombi were evaluated histologically and via high frequency ultrasound in the venous model. ID consistently induced thrombocytosis alongside anemia. Venous thrombus growth and final dimensions in both arterial and venous thrombi were largest in ID. In both models, platelet numbers correlated with the final thrombus size, with ID thrombi having the largest platelet areas. Platelet function was also evaluated in surgically naive rats. Coagulability on thromboelastography and hemostasis on tail transection were augmented in ID. Platelet and plasma P-selectin expression were both higher in ID. Platelet adhesion and aggregation in ID was impaired under shear flow but was intact on static assays. Iron replacement therapy reversed all ID-related changes in hematological parameters, thrombus dimensions, and platelet assays. In summary, ID alone increases thrombotic tendency. Iron replacement therapy reverses these changes, making it a viable strategy for prevention of ID-related thrombotic disease. This may be of importance in patients with chronic illnesses which may already be at increased risk for thrombosis such as inflammatory bowel disease, chronic kidney disease, or cancer.