Oxidative DNA damage contributes to usnic acid-induced toxicity in human induced pluripotent stem cell-derived hepatocytes.

Dietary supplements containing usnic acid have been increasingly marketed for weight loss over the past decades, even though incidences of severe hepatotoxicity and acute liver failure due to their overuse have been reported. To date, the toxic mechanism of usnic acid-induced liver injury at the molecular level still remains to be fully elucidated. Here, we conducted a transcriptomic study on usnic acid using a novel in vitro hepatotoxicity model employing human induced pluripotent stem cell (iPSC)-derived hepatocytes. Treatment with 20 µM usnic acid for 24 h caused 4272 differentially expressed genes (DEGs) in the cells. Ingenuity Pathway Analysis (IPA) based on the DEGs and gene set enrichment analysis (GSEA) using the whole transcriptome expression data concordantly revealed several signaling pathways and biological processes that, when taken together, suggest that usnic acid caused oxidative stress and DNA damage in the cells, which further led to cell cycle arrest and eventually resulted in cell death through apoptosis. These transcriptomic findings were subsequently corroborated by a variety of cellular assays, including reactive oxygen species (ROS) generation and glutathione (GSH) depletion, DNA damage (pH2AX detection and 8-hydroxy-2'-deoxyguanosine [8-OH-dg] assay), cell cycle analysis, and caspase 3/7 activity. Collectively, the results of the current study accord with previous in vivo and in vitro findings, provide further evidence that oxidative stress-caused DNA damage contributes to usnic acid-induced hepatotoxicity, shed new light on molecular mechanisms of usnic acid-induced hepatotoxicity, and demonstrate the usefulness of iPSC-derived hepatocytes as an in vitro model for hepatotoxicity testing and prediction.

Machine perfusion in liver transplantation: recent advances and coming challenges.

PURPOSE OF REVIEW: Machine perfusion has been adopted into clinical practice in Europe since the mid-2010s and, more recently, in the United States (US) following approval of normothermic machine perfusion (NMP). We aim to review recent advances, provide discussion of potential future directions, and summarize challenges currently facing the field. RECENT FINDINGS: Both NMP and hypothermic-oxygenated perfusion (HOPE) improve overall outcomes after liver transplantation versus traditional static cold storage (SCS) and offer improved logistical flexibility. HOPE offers additional protection to the biliary system stemming from its' protection of mitochondria and lessening of ischemia-reperfusion injury. Normothermic regional perfusion (NRP) is touted to offer similar protective effects on the biliary system, though this has not been studied prospectively.The most critical question remaining is the optimal use cases for each of the three techniques (NMP, HOPE, and NRP), particularly as HOPE and NRP become more available in the US. There are additional questions regarding the most effective criteria for viability assessment and the true economic impact of these techniques. Finally, with each technique purported to allow well tolerated use of riskier grafts, there is an urgent need to define terminology for graft risk, as baseline population differences make comparison of current data challenging. SUMMARY: Machine perfusion is now widely available in all western countries and has become an essential tool in liver transplantation. Identification of the ideal technique for each graft, optimization of viability assessment, cost-effectiveness analyses, and proper definition of graft risk are the next steps to maximizing the utility of these powerful tools.

Natural Language Processing to Identify Home Health Care Patients at Risk for Becoming Incapacitated With No Evident Advance Directives or Surrogates.

OBJECTIVES: Home health care patients who are at risk for becoming Incapacitated with No Evident Advance Directives or Surrogates (INEADS) may benefit from timely intervention to assist them with advance care planning. This study aimed to develop natural language processing algorithms for identifying home care patients who do not have advance directives, family members, or close social contacts who can serve as surrogate decision-makers in the event that they lose decisional capacity. DESIGN: Cross-sectional study of electronic health records. SETTING AND PARTICIPANTS: Patients receiving post-acute care discharge services from a large home health agency in New York City in 2019 (n = 45,390 enrollment episodes). METHODS: We developed a natural language processing algorithm for identifying information documented in free-text clinical notes (n = 1,429,030 notes) related to 4 categories: evidence of close relationships, evidence of advance directives, evidence suggesting lack of close relationships, and evidence suggesting lack of advance directives. We validated the algorithm against Gold Standard clinician review for 50 patients (n = 314 notes) to calculate precision, recall, and F-score. RESULTS: Algorithm performance for identifying text related to the 4 categories was excellent (average F-score = 0.91), with the best results for "evidence of close relationships" (F-score = 0.99) and the worst results for "evidence of advance directives" (F-score = 0.86). The algorithm identified 22% of all clinical notes (313,290 of 1,429,030) as having text related to 1 or more categories. More than 98% of enrollment episodes (48,164 of 49,141) included at least 1 clinical note containing text related to 1 or more categories. CONCLUSIONS AND IMPLICATIONS: This study establishes the feasibility of creating an automated screening algorithm to aid home health care agencies with identifying patients at risk of becoming INEADS. This screening algorithm can be applied as part of a multipronged approach to facilitate clinician support for advance care planning with patients at risk of becoming INEADS.

The Variability of MCID, SCB, PASS, and MOI Thresholds for PROMs in the Reverse Total Shoulder Arthroplasty Literature: A Systematic Review.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) is a common procedure utilized to address degenerative pathologies of the glenohumeral joint and rotator cuff. Increased reliance on patient-reported outcome measures (PROMs) has placed emphasis on the utilization of the minimum clinically important difference (MCID), substantial clinical benefit (SCB), patient acceptable symptom state (PASS), and maximal outcome improvement (MOI) thresholds to assess the clinical efficacy of RTSA. In this study, we systematically reviewed the MCID, SCB, PASS, and MOI thresholds reported for PROMs following RTSA. METHODS: PubMed, Embase, MEDLINE, Cochrane Library, and Google Scholar were queried for articles from Jan. 1, 2000-Aug. 31, 2023 reporting MCID, SCB, PASS, or MOI values for PROMs following RTSA. Patient demographic data, study characteristics, MCID/SCB/PASS/MOI thresholds, and threshold calculation methods were extracted. RESULTS: 141 articles were screened with 39 ultimately included, comprising 11,984 total patients that underwent RTSA. 34 (87%) studies reported MCID thresholds, 20 (51%) reported SCB, 5 (13%) reported PASS, and 2 (5%) reported MOI. 25/39 (64%) studies referenced a previous study when reporting MCID, SCB, PASS, or MOI values, 11 (28%) used an anchor-based method to calculate threshold values, 1 (3%) used a distribution-based method, and 2 (5%) used both anchor and distribution methods. There were 19 newly calculated MCID (11), SCB (5), PASS (1), and MOI (2) thresholds. For five of the six most utilized PROMs (ASES, SST, Constant, UCLA, SPADI), the range of reported MCID values exceeded 50% of the most common threshold. For three of the six, the range of SCB values exceeded 25% of the most common threshold. CONCLUSION: There is substantial variability in the MCID and SCB threshold values reported in the RTSA literature. Standardizing the methodologic calculation and utilization of MCID, SCB, PASS, and MOI thresholds for RTSA may allow for improved assessment of PROMs.

Development of endothelial-targeted CD39 as a therapy for ischaemic stroke.

BACKGROUND: Ischaemic stroke is characterized by a necrotic lesion in the brain surrounded by an area of dying cells termed the penumbra. Salvaging the penumbra either with thrombolysis or mechanical retrieval is the cornerstone of stroke management. At-risk neuronal cells release extracellular adenosine triphosphate (eATP) triggering microglial activation and causing a thromboinflammatory response culminating in endothelial activation and vascular disruption. This is further aggravated by ischaemia-reperfusion (I/R) injury that follows all reperfusion therapies. The ecto-enzyme CD39 regulates eATP by hydrolysing to adenosine which has anti-thrombotic and anti-inflammatory properties and reverses I/R injury. METHODS: We developed anti-VCAM-CD39 that targets the antithrombotic and anti-inflammatory properties of recombinant CD39 to the activated endothelium of the penumbra by binding to vascular cell adhesion molecule (VCAM)-1. Mice were subjected to 30 minutes of middle cerebral artery occlusion (MCAo) and analysed at 24h. Anti-VCAM-CD39 or control agents (saline, non-targeted CD39, or anti-VCAM-inactive CD39) were given at 3h post-MCAo. RESULTS: Anti-VCAM-CD39 treatment reduced neurological deficit; MRI confirmed significantly smaller infarcts together with an increase in cerebrovascular perfusion. Anti-VCAM-CD39 also restored blood brain barrier (BBB) integrity and reduced microglial activation. Coadministration of anti-VCAM-CD39 with thrombolytics (tPA) further reduced infarct volumes and attenuated BBB permeability with no associated increase in intracranial haemorrhage. CONCLUSION: Anti-VCAM-CD39, uniquely targeted to endothelial cells, could be a new stroke therapy even when administered 3 h post ischaemia and may further synergise with thrombolytic therapy to improve stroke outcomes.

Role of systematic lymphadenectomy at the time of interval debulking surgery for patients with advanced-stage epithelial ovarian carcinoma who achieved complete gross resection.

OBJECTIVE: To evaluate the role of systematic lymphadenectomy at the time of interval cytoreductive surgery for patients with advanced-stage epithelial ovarian carcinoma who achieved complete gross resection. METHODS: The National Cancer DataBase was accessed, and patients diagnosed between 2010 and 2015 with advanced-stage ovarian carcinoma who underwent interval cytoreductive surgery and achieved complete gross resection were identified. Patients who did not undergo lymphadenectomy and those who underwent systematic lymphadenectomy (defined as at least 20 lymph nodes removed) were selected for further analysis. Median overall survival was compared with the log-rank test and controlled for a priori selected confounders. RESULTS: A total of 1060 patients were identified. Systematic lymphadenectomy was performed for 125 (11.8%) patients with a median of 29 lymph nodes (range 20-72) removed. Rate of lymph node metastasis was 62.4%. Patients who underwent systematic lymphadenectomy had higher rate of unplanned readmission (8.9% vs 1.6%, p<0.001), and median hospital stay (6 vs 4 days, p<0.001). Median overall survival for patients who did and did not undergo systematic lymphadenectomy was 44.2 and 40.4 months, respectively, p=0.40. After controlling for confounders, performance of systematic lymphadenectomy was not associated with better survival (HR=0.98, 95% CI 0.80 to 1.19). CONCLUSION: Systematic lymphadenectomy is rarely performed at the time of interval cytoreductive surgery and not associated with a survival benefit for patients who achieved complete gross resection.

Impact of Advanced Image-Guided Systems on Correction of Corneal Astigmatism During Femtosecond Laser-Assisted Cataract Surgery.

PURPOSE: To determine the effectiveness of the correction of corneal astigmatism utilizing the Alcon Image Guidance system (Ft. Worth, Texas) versus manual marking in the orientation of femtosecond laser-assisted astigmatic keratotomy incisions. SETTING: This study was based in a private practice in Albany, New York, USA. DESIGN: Retrospective review of patients undergoing FLACS from January 2018 to June 2022. METHODS: Patients who underwent FLACS with Image Guidance (IG) and without IG were investigated. Variables including pre-operative K values, cylinder, spherical equivalent (SE), and visual acuity (VA) were collected, as well as the cyclorotation angle delta registered by IG, post- operative refractive cylinder, SE, and VA. The primary outcome was post-operative refractive cylinder in patients with IG compared to those without IG. RESULTS: A total of 160 eyes were included, with 103 eyes who had IG and 57 eyes who did not have IG. Post-operative cylinder was similar in those with IG (0.31 +/- 0.36 D) compared to those without IG (0.31 +/- 0.37 D) (p=0.97). Average cyclorotation in the IG group was 2.82 ± 3.03 degrees. When cyclorotation was stratified into three groups (<2.8 degrees, 2.8-8.5 degrees, >8.5 degrees), no differences were found in post-operative refractive cylinder (p=0.35). CONCLUSIONS: Patients who underwent FLACS with Image Guidance had similar post-operative cylinder outcomes compared to those without Image Guidance. This study suggests that the accommodation of cyclotorsion using an advanced image guidance system is similar to that obtained with manual marking techniques in patients having 2 diopters or less of astigmatism corrected.

Percutaneous Cementation for Improvement of Pain and Function for Osteolytic Pelvic Metastasis: A Systematic Review.

INTRODUCTION: Pelvic metastasis is a common presentation among patients presenting with skeletal metastasis. Image-guided percutaneous cementation of these lesions is becoming increasingly popular for the treatment of these lesions. The objective of this study was to conduct a systematic review that investigates clinical outcomes after percutaneous cementation for pelvic metastasis. METHODS: A systematic review was registered with International Prospective Register of Systematic Reviews and performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, SCOPUS, and Ovid MEDLINE databases. All level I to IV clinical studies published in the English language investigating the clinical outcomes after percutaneous cementation for pelvic metastasis were included. RESULTS: Fourteen studies with 579 patients (278 men, 301 women) and 631 metastatic pelvic lesions were included in the study. The mean follow-up range was 0.7 to 26.4 months. Percutaneous cementation alone was performed in 441 patients (76.2%). Supplemental ablative procedures were performed in 77 patients (13.3%), and supplemental internal fixation using cannulated screws was performed in 107 patients (18.5%). Twelve studies with 430 patients (74.2%) reported pain-related and/or functional outcome scores, of which all studies reported overall clinically notable improvement at short-term follow-up. All studies reported periprocedural complications. Local cement leakage was the most common complication (162/631 lesions, 25.7%) followed by transient local pain (25/579 patients, 4.3%). There were no reported cases of major complications. Seven patients (1.2%) underwent re-intervention for persistent symptoms. CONCLUSIONS: Percutaneous cementation may be an effective method for treating pain and function related to pelvic metastasis. The most common complication was cement leakage surrounding the lesion. The rates of major complications were low, and most complications appeared minor and transient. Additional prospective studies are needed to further assess the efficacy of this procedure. LEVEL OF EVIDENCE: IV, systematic review of level I to IV therapeutic studies.

Characterization of an Algorithm for Autonomous, Closed-Loop Neuromodulation During Motor Rehabilitation.

BACKGROUND: Recent evidence demonstrates that manually triggered vagus nerve stimulation (VNS) combined with rehabilitation leads to increased recovery of upper limb motor function after stroke. This approach is premised on studies demonstrating that the timing of stimulation relative to movements is a key determinant in the effectiveness of this approach. OBJECTIVE: The overall goal of the study was to identify an algorithm that could be used to automatically trigger VNS on the best movements during rehabilitative exercises while maintaining a desired interval between stimulations to reduce the burden of manual stimulation triggering. METHODS: To develop the algorithm, we analyzed movement data collected from patients with a history of neurological injury. We applied 3 different algorithms to the signal, analyzed their triggering choices, and then validated the best algorithm by comparing triggering choices to those selected by a therapist delivering VNS therapy. RESULTS: The dynamic algorithm triggered above the 95th percentile of maximum movement at a rate of 5.09 (interquartile range [IQR] = 0.74) triggers per minute. The periodic algorithm produces stimulation at set intervals but low movement selectivity (34.05%, IQR = 7.47), while the static threshold algorithm produces long interstimulus intervals (27.16 ± 2.01 seconds) with selectivity of 64.49% (IQR = 25.38). On average, the dynamic algorithm selects movements that are 54 ± 3% larger than therapist-selected movements. CONCLUSIONS: This study shows that a dynamic algorithm is an effective strategy to trigger VNS during the best movements at a reliable triggering rate.

Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis.

Human aging is marked by the emergence of a tapestry of clonal expansions in dividing tissues, particularly evident in blood as clonal hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations in a set of established genes. However, the majority of clones lack known drivers. Here we infer gene-level positive selection in whole blood exomes from 200,618 individuals in UK Biobank. We identify 17 additional genes, ZBTB33, ZNF318, ZNF234, SPRED2, SH2B3, SRCAP, SIK3, SRSF1, CHEK2, CCDC115, CCL22, BAX, YLPM1, MYD88, MTA2, MAGEC3 and IGLL5, under positive selection at a population level, and validate this selection pattern in 10,837 whole genomes from single-cell-derived hematopoietic colonies. Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.

Which Pre-Operative, Modifiable Risk Factors are Most Predictive of Complications in orthopedic Upper Extremity Surgery?

Objectives: Identification of modifiable comorbid conditions in the preoperative period is important in optimizing outcomes. We evaluate the association between such risk factors and postoperative outcomes after upper extremity surgery using a national database. Methods: The National Surgical Quality Improvement Program (NSQIP) 2006-2016 database was used to identify patients undergoing an upper extremity principle surgical procedure using CPT codes. Modifiable risk factors were defined as smoking status, use of alcohol, obesity, recent loss of >10% body weight, malnutrition, and anemia. Outcomes included discharge destination, major complications, bleeding complications, unplanned re-operation, sepsis, and prolonged length of stay. Chi square and multivariable logistic regressions were used to identify significant predictors of outcomes. Significance was defined as P<0.01. Results: After applying exclusion criteria, 53,780 patients were included in the final analysis. Preoperative malnutrition was significantly associated with non-routine discharge (OR=4.75), major complications (OR=7.27), bleeding complications (OR=7.43), unplanned re-operation (OR=2.44), sepsis (OR=10.22), and prolonged length of stay (OR=5.27). Anemia was associated with non-routine discharge (OR=2.67), bleeding complications (OR=13.27), and prolonged length of stay (OR=3.26). In patients who had a weight loss of greater than 10%, there was an increase of non-routine discharge (OR=2.77), major complications (OR=2.93), and sepsis (OR=3.7). Smoking, alcohol use, and obesity were not associated with these complications. Conclusion: Behavioral risk factors (smoking, alcohol use, and obesity) were not associated with increased complication rates. Malnutrition, weight loss, and anemia were associated with an increase in postoperative complication rates in patients undergoing upper limb orthopaedic procedures and should be addressed prior to surgery, suggesting nutrition labs should be part of the initial blood work.

RFWD3 modulates response to platinum chemotherapy and promotes cancer associated phenotypes in high grade serous ovarian cancer.

Background: DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences in tumours. RFWD3, a key component of multiple DNA repair and maintenance pathways, was investigated to characterise its impact in HGSOC. Methods: RFWD3 expression and association with clinical features was assessed using in silico analysis in the TCGA HGSOC dataset, and in a further cohort of HGSOC tumours stained for RFWD3 using immunohistochemistry. RFWD3 expression was modulated in cell lines using siRNA and CRISPR/cas9 gene editing, and cells were characterised using cytotoxicity and proliferation assays, flow cytometry, and live cell microscopy. Results: Expression of RFWD3 RNA and protein varied in HGSOCs. In cell lines, reduction of RFWD3 expression led to increased sensitivity to interstrand crosslinking (ICL) inducing agents mitomycin C and carboplatin. RFWD3 also demonstrated further functionality outside its role in DNA damage repair, with RFWD3 deficient cells displaying cell cycle dysregulation, reduced cellular proliferation and reduced migration. In tumours, low RFWD3 expression was associated with increased tumour mutational burden, and complete response to platinum chemotherapy. Conclusion: RFWD3 expression varies in HGSOCs, which can lead to functional effects at both the cellular and tumour levels.

Tuning the optoelectronic properties of emerging solar absorbers through cation disorder engineering.

Chalcogenide solar absorbers, such as AgBiS2 and kesterites, have gained a resurgence of interest recently, owing to their high stability compared to metal-halide compounds, as well as their rising efficiencies in photovoltaic devices. Although their optical and electronic properties are conventionally tuned through the composition and structure, cation disorder has increased in prominence as another important parameter that influences these properties. In this minireview, we define cation disorder as the occupation of a cation crystallographic site with different species, and the homogeneity of this cation disorder as how regular the alternation of species in this site is. We show that cation disorder is not necessarily detrimental, and can lead to increases in absorption coefficient and reductions in bandgap, enabling the development of ultrathin solar absorbers for lightweight photovoltaics. Focusing on kesterites and ABZ2 materials (where A = monovalent cation, B = divalent cation, and Z is a chalcogenide anion), we discuss how the degree and homogeneity of cation disorder influences the optical properties, charge-carrier transport and photovoltaic performance of these materials, as well as how cation disorder could be tuned and quantified. We finish with our perspectives on the important questions moving forward in making use of cation disorder engineering as a route to achieve more efficient solar absorbers.

The complementary dominance hypothesis: a model for remediating the 'good' hand in stroke survivors.

The complementary dominance hypothesis is a novel model of motor lateralization substantiated by decades of research examining interlimb differences in the control of upper extremity movements in neurotypical adults and hemisphere-specific motor deficits in stroke survivors. In contrast to earlier ideas that attribute handedness to the specialization of one hemisphere, our model proposes complementary motor control specializations in each hemisphere. The dominant hemisphere mediates optimal control of limb dynamics as required for smooth and efficient movements, whereas the non-dominant hemisphere mediates impedance control, important for countering unexpected mechanical conditions and achieving steady-state limb positions. Importantly, this model proposes that each hemisphere contributes its specialization to both arms (though with greater influence from either arm's contralateral hemisphere) and thus predicts that lesions to one hemisphere should produce hemisphere-specific motor deficits in not only the contralesional arm, but also the ipsilesional arm of stroke survivors - a powerful prediction now supported by a growing body of evidence. Such ipsilesional arm motor deficits vary with contralesional arm impairment, and thus individuals with little to no functional use of the contralesional arm experience both the greatest impairments in the ipsilesional arm, as well as the greatest reliance on it to serve as the main or sole manipulator for activities of daily living. Accordingly, we have proposed and tested a novel intervention that reduces hemisphere-specific ipsilesional arm deficits and thereby improves functional independence in stroke survivors with severe contralesional impairment.

Physicochemical control of solvation and molecular assembly of charged amphiphilic oligomers at air-aqueous interfaces.

HYPOTHESIS: Understanding the rules that control the assembly of nanostructured soft materials at interfaces is central to many applications. We hypothesize that electrolytes can be used to alter the hydration shell of amphiphilic oligomers at the air-aqueous interface of Langmuir films, thereby providing a means to control the formation of emergent nanostructures. EXPERIMENTS: Three representative salts - (NaF, NaCl, NaSCN) were studied for mediating the self-assembly of oligodimethylsiloxane methylimidazolium (ODMS-MIM+) amphiphiles in Langmuir films. The effects of the different salts on the nanostructure assembly of these films were probed using vibrational sum frequency generation (SFG) spectroscopy and Langmuir trough techniques. Experimental data were supported by atomistic molecular dynamic simulations. FINDINGS: Langmuir trough surface pressure - area isotherms suggested a surprising effect on oligomer assembly, whereby the presence of anions affects the stability of the interfacial layer irrespective of their surface propensities. In contrast, SFG results implied a strong anion effect that parallels the surface activity of anions. These seemingly contradictory trends are explained by anion driven tail dehydration resulting in increasingly heterogeneous systems with entangled ODMS tails and appreciable anion penetration into the complex interfacial layer comprised of headgroups, tails, and interfacial water molecules. These findings provide physical and chemical insight for tuning a wide range of interfacial assemblies.

Systematic analysis of ocular features and responses of cultured spotted wolffish (Anarhichas minor).

A better understanding of unique anatomical and functional features of the visual systems of teleost fish could provide key knowledge on how these systems influence the health and survival of these animals in both wild and culture environments. We took a systematic approach to assess some of the visual systems of spotted wolffish (Anarhichas minor), a species of increasing importance in North Atlantic aquaculture initiatives. The lumpfish (Cyclopterus lumpus) was included in these studies in a comparative manner to provide reference. Histology, light and electron microscopy were used to study the spatial distribution and occurrence of cone photoreceptor cells and the nature of the retinal tissues, while immunohistochemistry was used to explore the expression patterns of two photoreceptor markers, XAP-1 and XAP-2, in both species. A marine bacterial infection paradigm in lumpfish was used to assess how host-pathogen responses might impact the expression of these photoreceptor markers in these animals. We define a basic photoreceptor mosaic and present an ultrastructural to macroscopic geographical configuration of the retinal pigment tissues in both animals. Photoreceptor markers XAP-1 and XAP-2 have novel distribution patterns in spotted wolffish and lumpfish retinas, and exogenous pathogenic influences can affect the normal expression pattern of XAP-1 in lumpfish. Live tank-side ophthalmoscopy and spectral domain optical coherence tomography (SD-OCT) revealed that normal cultured spotted wolffish display novel variations in the shape of the retinal tissue. These two complementary imaging findings suggest that spotted wolffish harbour unique ocular features not yet described in marine teleosts and that visual function might involve specific retinal tissue shape dynamics in these animals. Finally, extensive endogenous biofluorescence is present in the retinal tissues of both animals, which raises questions about how these animals might use retinal tissue in novel ways for visual perception and/or communication. This work advances fundamental knowledge on the visual systems of two economically important but now threatened North Atlantic teleosts and provides a basic foundation for further research on the visual systems of these animals in health versus disease settings. This work could also be useful for understanding and optimizing the health and welfare of lumpfish and spotted wolffish in aquaculture towards a one health or integrative perspective.

Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.