Epidemiology of renal replacement therapy for critically ill patients across seven health jurisdictions.

INTRODUCTION: Acute kidney injury (AKI) requiring treatment with renal replacement therapy (RRT) is a common complication after admission to an intensive care unit (ICU) and is associated with significant morbidity and mortality. However, the prevalence of RRT use and the associated outcomes in critically patients across the globe are not well described. Therefore, we describe the epidemiology and outcomes of patients receiving RRT for AKI in ICUs across several large health system jurisdictions. METHODS: Retrospective cohort analysis using nationally representative and comparable databases from seven health jurisdictions in Australia, Brazil, Canada, Denmark, New Zealand, Scotland, and the United States (USA) between 2006-2023, depending on data availability of each dataset. Patients with history of end-stage kidney disease receiving chronic RRT and patients with a history of renal transplant were excluded. RESULTS: A total of 4,104,480 patients in the ICU cohort and 3,520,516 patients in the mechanical ventilation cohort were included. Overall, 156,403 (3.8%) patients in the ICU cohort and 240,824 (6.8%) patients in the mechanical ventilation cohort were treated with RRT for AKI. In the ICU cohort, the proportion of patients treated with RRT was lowest in Australia and Brazil (3.3%) and highest in Scotland (9.2%). The in-hospital mortality for critically ill patients treated with RRT was almost four-fold higher (57.1%) than those not receiving RRT (16.8%). The mortality of patients treated with RRT varied across the health jurisdictions from 37-65%. CONCLUSION: The outcomes of patients who receive RRT in ICUs throughout the world vary widely. Our research suggests differences in access to and provision of this therapy are contributing factors.

Human iPSC-derived liver co-culture spheroids to model liver fibrosis.

The lack of adequate human in vitro models that recapitulate the cellular composition and response of the human liver to injury hampers the development of anti-fibrotic drugs. The goal of this study was to develop a human spheroid culture model to study liver fibrosis by using induced pluripotent stem cell (iPSC)-derived liver cells. iPSCs were independently differentiated towards hepatoblasts (iHepatoblasts), hepatic stellate cells (iHSCs), endothelial cells (iECs) and macrophages (iMΦ), before assembly into free floating spheroids by culturing cells in 96-well U-bottom plates and orbital shaking for up to 21 days to allow further maturation. Through transcriptome analysis, we show further maturation of iECs and iMΦ, the differentiation of the iHepatoblasts towards hepatocyte-like cells (iHeps) and the inactivation of the iHSCs by the end of the 3D culture. Moreover, these cultures display a similar expression of cell-specific marker genes (CYP3A4, PDGFRß, CD31 and CD68) and sensitivity to hepatoxicity as spheroids made using freshly isolated primary human liver cells. Furthermore, we show the functionality of the iHeps and the iHSCs by mimicking liver fibrosis through iHep-induced iHSC activation, using acetaminophen. In conclusion, we have established a reproducible human iPSC-derived liver culture model that can be used to mimic fibrosis in vitro as a replacement of primary human liver derived 3D models. The model can be used to investigate pathways involved in fibrosis development and to identify new targets for chronic liver disease therapy.

Liver Steatosis is Prevalent in Lean People With HIV and Associated With Exposure to Antiretroviral Treatment-A Cross-sectional Study.

Background: Steatotic liver disease is suggested to have a higher prevalence and severity in people with HIV (PHIV), including in those with a normal body mass index (BMI). In this study, we used data from the 2000HIV cohort to (1) assess the prevalence of liver steatosis and fibrosis in lean versus overweight/obese PHIV and (2) assess associations in these subgroups between steatosis and fibrosis with traditional risk factors and HIV-specific characteristics. Methods: The 2000HIV study cohort comprises 1895 virally suppressed PHIV that were included between 2019 and 2021 in 4 HIV treatment centers in the Netherlands. The majority (58.5%) underwent vibration-controlled transient elastography for the assessment of liver steatosis and fibrosis. The prevalence of steatosis (controlled attenuation parameter ≥263 dB/m) and fibrosis (liver stiffness measurement ≥7.0 kPa) was estimated. Multiple factors including HIV characteristics and antiretroviral drugs were tested in a logistic regression model for association with steatosis and fibrosis. Analyses were performed separately for lean (Asian descent: BMI < 23 kg/m2, other descent: BMI < 25 kg/m2) and overweight/obese (other BMI) participants. Results: Of 1050 PHIV including 505 lean and 545 overweight/obese PHIV, liver steatosis was observed in 37.7% of the overall study population, 19.7% of lean, and 54% of overweight/obese PHIV, whereas fibrosis was observed in 9.0% of the overall study population, 5.9% of lean, and 12.0% of overweight/obese PHIV.All associations with fibrosis and most associations with steatosis concerned metabolic factors such as type 2 diabetes mellitus (overall population: adjusted odds ratio [aOR] for steatosis: 2.3 [1.21-4.4], P = .011; aOR for fibrosis: 3.7 [1.82-7.53], P < .001). Furthermore, in lean PLHIV, liver steatosis was associated with CD4 and CD8 counts at enrollment, dual therapy, and history of treatment with raltegravir (aOR: 3.6 [1.53-8.47], P = .003), stavudine (aOR: 3.73 [1.69-8.2], P = .001), and indinavir (aOR: 3.86 [1.59-9.37], P = .003). These associations were not observed in overweight/obese PHIV. Conclusions: Liver steatosis was highly prevalent, affecting approximately one-fifth of lean PHIV and half of overweight/obese PHIV. Fibrosis was observed in a minority. Both steatosis and fibrosis were associated with traditional metabolic risk factors. In addition, (prior) exposure to specific antiretroviral drugs was associated liver steatosis in lean, but not in overweight/obese PHIV. Implementing increased screening protocols could enhance the identification of steatotic liver disease in lean PHIV.

Decreased Macular Choriocapillaris Perfusion Correlates with Contrast Sensitivity Function in Dry Age-related Macular Degeneration.

PURPOSE: To investigate the relationships between contrast sensitivity (CS), choriocapillaris perfusion and other structural optical coherence tomography (OCT) biomarkers in dry age-related macular degeneration (AMD). DESIGN: Cross-sectional, observational study. PARTICIPANTS: One hundred AMD eyes (22 early, 52 intermediate and 26 late) from 74 patients and 45 control eyes from 37 age-similar subjects. METHODS: All participants had visual acuity (VA) assessment, quantitative contrast sensitivity function (qCSF) testing, macular OCT, and 6x6-mm swept-source OCT angiography (OCTA) scans on the same day. OCT volumes were analyzed for subretinal drusenoid deposits and hyporeflective drusen cores, and to measure thickness of the outer nuclear layer (ONL). OCTA scans were utilized to calculate drusen volume, inner choroid flow deficit percentage (IC-FD%), and to measure the area of choroidal hypertransmission defects (HTD). IC-FD% was measured from a 16 µm-thick choriocapillaris slab after compensation and binarization with Phansalkar's method. Generalized linear mixed-effects models were used to evaluate the associations between functional and structural variables. MAIN OUTCOME MEASURES: To explore the associations between qCSF-measured CS, ICFD% and various AMD imaging biomarkers. RESULTS: AMD exhibited significantly reduced qCSF metrics eyes across all stages compared to controls. Univariate analysis revealed significant associations between various imaging biomarkers, reduced qCSF metrics and VA in both groups. Multivariate analysis confirmed that higher IC-FD% in the central 5 mm was significantly associated with decreases in all qCSF metrics in AMD eyes (ß= -0.74 to -0.25, all p<0.05), but not with VA (p>0.05). ONL thickness in the central 3 mm correlated with both VA (ß= 2.85, p<0.001) and several qCSF metrics (ß= 0.01-0.90, all p<0.05), especially in AMD eyes. Further, larger HTD areas were associated with decreased VA (ß=-0.89, p<0.001) and reduced CS at low-intermediate frequencies across AMD stages (ß= -0.30 to -0.29, p<0.001). CONCLUSIONS: The significant association between IC-FD% in the central 5 mm and qCSF-measured CS reinforces the hypothesis that decreased macular choriocapillaris perfusion contributes to visual function changes in AMD, which are more pronounced in CS than in VA.

Transcriptomic gene signatures measure satellite cell activity in muscular dystrophies.

The routine need for myonuclear turnover in skeletal muscle, together with more sporadic demands for hypertrophy and repair, are performed by resident muscle stem cells called satellite cells. Muscular dystrophies are characterized by muscle wasting, stimulating chronic repair/regeneration by satellite cells. Here, we derived and validated transcriptomic signatures for satellite cells, myoblasts/myocytes, and myonuclei using publicly available murine single cell RNA-Sequencing data. Our signatures distinguished disease from control in transcriptomic data from several muscular dystrophies including facioscapulohumeral muscular dystrophy (FSHD), Duchenne muscular dystrophy, and myotonic dystrophy type I. For FSHD, the expression of our gene signatures correlated with direct counts of satellite cells on muscle sections, as well as with increasing clinical and pathological severity. Thus, our gene signatures enable the investigation of myogenesis in bulk transcriptomic data from muscle biopsies. They also facilitate study of muscle regeneration in transcriptomic data from human muscle across health and disease.

Use of an Artificial Intelligence Device for Evaluating Blood Loss in Complex Major Orthopaedic Surgery Procedures.

BACKGROUND: An artificial intelligence algorithm that analyzes the pulse oximeter waveform in the fingertip can be used to determine the compensatory reserve index (CRI) in trauma patients. This measurement shows the remaining cardiovascular capacity and is known to be more specific and sensitive in detecting blood loss than are routine vital signs. We hypothesized that the CRI measurement could predict loss of reserve cardiovascular capacity in patients undergoing major orthopaedic surgery, and therefore could help in their management. METHODS: A total of 304 patients undergoing lower extremity arthroplasty consented to participate in waveform monitoring. Pulse oximeter waveforms were sensed with a fingertip probe and processed with a tablet computer that remained with the patient during surgery and recovery in the hospital. The CRI, systolic blood pressure, and heart rate were evaluated throughout the postoperative period. RESULTS: The CRI measurement identified a group of patients who were significantly more likely to require transfusions and emergency medical care (P = .000021). Patients who had morbid obesity were especially likely to have low CRI results and a high percentage of clinical events. A CRI of 0.40 or more was evaluated retrospectively as the criterion for withholding transfusion in 54 patients, but that group had a significantly higher incidence of transfusion later in treatment than did the cohort as a whole. The systolic blood pressure and heart rate were not useful in predicting the need for transfusion until late in treatment. CONCLUSIONS: This study suggests that the CRI measurement can identify patients at risk for transfusion and the need for urgent medical care and may aid in the management of blood loss and transfusion in major orthopedic surgery.

Safety and efficacy of active blood-pressure reduction to the recommended thresholds for intravenous thrombolysis in patients with acute ischaemic stroke in the Netherlands (TRUTH): a prospective, observational, cluster-based, parallel-group study.

BACKGROUND: Intravenous thrombolysis is contraindicated in patients with ischaemic stroke with blood pressure higher than 185/110 mm Hg. Prevailing guidelines recommend to actively lower blood pressure with intravenous antihypertensive agents to allow for thrombolysis; however, there is no robust evidence for this strategy. Because rapid declines in blood pressure can also adversely affect clinical outcomes, several Dutch stroke centres use a conservative strategy that does not involve the reduction of blood pressure. We aimed to compare the clinical outcomes of both strategies. METHODS: Thrombolysis and Uncontrolled Hypertension (TRUTH) was a prospective, observational, cluster-based, parallel-group study conducted across 37 stroke centres in the Netherlands. Participating centres had to strictly adhere to an active blood-pressure-lowering strategy or to a non-lowering strategy. Eligible participants were adults (≥18 years) with ischaemic stroke who had blood pressure higher than 185/110 mm Hg but were otherwise eligible for intravenous thrombolysis. The primary outcome was functional status at 90 days, measured using the modified Rankin Scale and assessed through telephone interviews by trained research nurses. Secondary outcomes were symptomatic intracranial haemorrhage, the proportion of patients treated with intravenous thrombolysis, and door-to-needle time. All ordinal logistic regression analyses were adjusted for age, sex, stroke severity, endovascular thrombectomy, and baseline imbalances as fixed-effect variables and centre as a random-effect variable to account for the clustered design. Analyses were done according to the intention-to-treat principle, whereby all patients were analysed according to the treatment strategy of the participating centre at which they were treated. FINDINGS: Recruitment began on Jan 1, 2015, and was prematurely halted because of a declining inclusion rate and insufficient funding on Jan 5, 2022. Between these dates, we recruited 853 patients from 27 centres that followed an active blood-pressure-lowering strategy and 199 patients from ten centres that followed a non-lowering strategy. Baseline characteristics of participants from the two groups were similar. The 90-day mRS score was missing for 15 patients. The adjusted odds ratio (aOR) for a shift towards a worse 90-day functional outcome was 1·27 (95% CI 0·96-1·68) for active blood-pressure reduction compared with no active blood-pressure reduction. 798 (94%) of 853 patients in the active blood-pressure-lowering group were treated with intravenous thrombolysis, with a median door-to-needle time of 35 min (IQR 25-52), compared with 104 (52%) of 199 patients treated in the non-lowering group with a median time of 47 min (29-78). 42 (5%) of 852 patients in the active blood-pressure-lowering group had a symptomatic intracranial haemorrhage compared with six (3%) of 199 of those in the non-lowering group (aOR 1·28 [95% CI 0·62-2·62]). INTERPRETATION: Insufficient evidence was available to establish a difference between an active blood-pressure-lowering strategy-in which antihypertensive agents were administered to reduce blood pressure below 185/110 mm Hg-and a non-lowering strategy for the functional outcomes of patients with ischaemic stroke, despite higher intravenous thrombolysis rates and shorter door-to-needle times among those in the active blood-pressure-lowering group. Randomised controlled trials are needed to inform the use of an active blood-pressure-lowering strategy. FUNDING: Fonds NutsOhra.

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations.

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) reprogrammed from a family with HNF1B-associated DKMs. Mutant organoids contained enlarged malformed tubules displaying deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cyclic AMP (cAMP)-mediated dilatation seen in controls. Bulk and single-cell RNA sequencing (scRNA-seq) analyses indicated abnormal Wingless/Integrated (WNT), calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) was upregulated in malformed mutant nephron tubules and prominent in HNF1B mutant fetal human dysplastic kidney epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule differentiation and morphogenesis illuminating the developmental origin of mutant-HNF1B-causing kidney disease.

Discovery of calcite as a new pro-inflammatory calcium-containing crystal in human osteoarthritic synovial fluid.

OBJECTIVE: We aimed to characterize calcium-containing crystals present in synovial fluid from patients with knee osteoarthritis (OA) using Raman spectroscopy, and specifically investigate the biological effects of calcite crystals. DESIGN: Thirty-two synovial fluid samples were collected pre-operatively from knee OA patients undergoing total joint arthroplasty. An integrated Raman polarized light microscope was used for identification of crystals in synovial fluid. Human peripheral blood mononuclear cells (PBMC's), human OA articular chondrocytes (HACs) and fibroblast-like synoviocytes (FLSs) were exposed to calcite crystals. Expression of relevant cytokines and inflammatory genes were measured using ELISA and real-time PCR. RESULTS: Various calcium-containing crystals were identified, including calcium pyrophosphate (37.5 %) and basic calcium phosphate (21.8 %), but they were never found simultaneously in the same OA synovial fluid sample. For the first time, we discovered the presence of calcite crystals in 93.8 % of the samples, while dolomite was detected in 25 % of the cases. Characterization of the cellular response to calcite crystal exposure revealed increased production of innate immune-derived cytokines by PBMC's, when co-stimulated with lipopolysaccharide (LPS). Additionally, calcite crystal stimulation of HACs and FLSs resulted in enhanced secretion of pro-inflammatory molecules and alterations in the expression of extracellular matrix remodeling enzymes. CONCLUSIONS: This study highlights the unique role of Raman spectroscopy in OA crystal research and identified calcite as a novel pro-inflammatory crystal type in OA synovial fluid. Understanding the role of specific crystal species in the OA joint may open new avenues for pharmacological interventions and personalized approaches to treating OA.

Orphan receptor GPR176 in hepatic stellate cells exerts a profibrotic role in chronic liver disease.

Background & Aims: Chronic liver disease (CLD) remains a global health issue associated with a significant disease burden. Liver fibrosis, a hallmark of CLD, is characterised by the activation of hepatic stellate cells (HSCs) that gain profibrotic characteristics including increased production of extracellular matrix protein. Currently, no antifibrotic therapies are available clinically, in part because of the lack of HSC-specific drug targets. Here, we aimed to identify HSC-specific membrane proteins that can serve as targets for antifibrotic drug development. Methods: Small interfering RNA-mediated knockdown of GPR176 was used to assess the in vitro function of GPR176 in HSCs and in precision cut liver slices (PCLS). The in vivo role of GPR176 was assessed using the carbon tetrachloride (CCl4) and common bile duct ligation (BDL) models in wild-type and GPR176 knockout mice. GPR176 in human CLD was assessed by immunohistochemistry of diseased human livers and RNA expression analysis in human primary HSCs and transcriptomic data sets. Results: We identified Gpr176, an orphan G-protein coupled receptor, as an HSC-enriched activation associated gene. In vitro, Gpr176 is strongly induced upon culture-induced and hepatocyte-damage-induced activation of primary HSCs. Knockdown of GPR176 in primary mouse HSCs or PCLS cultures resulted in reduced fibrogenic characteristics. Absence of GPR176 did not influence liver homeostasis, but Gpr176-/- mice developed less severe fibrosis in CCl4 and BDL fibrosis models. In humans, GPR176 expression was correlated with in vitro HSC activation and with fibrosis stage in patients with CLD. Conclusions: GPR176 is a functional protein during liver fibrosis and reducing its activity attenuates fibrogenesis. These results highlight the potential of GPR176 as an HSC-specific antifibrotic candidate to treat CLD. Impact and implications: The lack of effective antifibrotic drugs is partly attributed to the insufficient knowledge about the mechanisms involved in the development of liver fibrosis. We demonstrate that the G-protein coupled receptor GPR176 contributes to fibrosis development. Since GPR176 is specifically expressed on the membrane of activated hepatic stellate cells and is linked with fibrosis progression in humans, it opens new avenues for the development of targeted interventions.

Associations of quantitative contrast sensitivity with vascular metrics on widefield swept-source OCT angiography across stages of diabetic retinopathy.

PURPOSE: To investigate structure-function associations between contrast sensitivity (CS) and widefield swept-source optical coherence tomography angiography (WF SS-OCTA) vascular metrics across stages of non-proliferative (NPDR) and proliferative diabetic retinopathy (PDR), without diabetic macular oedema. METHODS: Prospective cross-sectional study in 140 eyes of 99 patients: 33 mild NPDR, 24 moderate/severe NPDR, 15 PDR, 33 diabetic without DR (DMnoDR) and 46 control eyes. Mixed-effects multivariable regression models to evaluate associations between quantitative contrast sensitivity function (Adaptive Sensory Technology) and vessel density (VD) and vessel skeletonised density (VSD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) on same-day imaging with WF SS-OCTA (Plex Elite 9000, Carl Zeiss Meditec). RESULTS: Standardised ß coefficients for area under the logarithm of contrast sensitivity function curve (AULCSF) versus visual acuity (VA) at 3×3 mm scans: SCP VSD (ß=0.32, p<0.001 vs -0.18, p=0.044), DCP VSD (ß=0.30, p<0.001 vs -0.21, p=0.02), SCP VD (ß=0.25, p=0.004 vs -0.13, p=0.129), DCP VD (ß=0.26, p=0.003 vs -0.19, p=0.034). AULCSF was significantly reduced in mild NPDR (ß=-0.28, p<0.001) and DMnoDR (ß=-0.19, p=0.005) versus controls, while VA was not significantly different. AULCSF performed better than VA in differentiating between controls and DMnoDR (0.69 vs 0.50), controls and mild NPDR (0.76 vs 0.61) and controls and moderate/severe NPDR (0.89 vs 0.73). CONCLUSIONS: DR-induced microvascular changes on OCTA are associated with larger changes on CS than in VA. CS is affected earlier than VA in the course of DR and performed better in discriminating between controls, DMnoDR and across DR stages.

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity.

Introduction: Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects. Methods: The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli. Results: The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production. Conclusions: INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

A comprehensive genetic map of cytokine responses in Lyme borreliosis.

The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource.

Effectiveness of Conventional Digital Fundus Photography-Based Teleretinal Screening for Diabetic Retinopathy and Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

PURPOSE: This American Academy of Ophthalmology Ophthalmic Technology Assessment aims to assess the effectiveness of conventional teleretinal screening (TS) in detecting diabetic retinopathy (DR) and diabetic macular edema (DME). METHODS: A literature search of the PubMed database was conducted most recently in July 2023 to identify data published between 2006 and 2023 on any of the following elements related to TS effectiveness: (1) the accuracy of TS in detecting DR or DME compared with traditional ophthalmic screening with dilated fundus examination or 7-standard field Early Treatment Diabetic Retinopathy Study photography, (2) the impact of TS on DR screening compliance rates or other patient behaviors, and (3) cost-effectiveness and patient satisfaction of TS compared with traditional DR screening. Identified studies then were rated based on the Oxford Centre for Evidence-Based Medicine grading system. RESULTS: Eight level I studies, 14 level II studies, and 2 level III studies were identified in total. Although cross-study comparison is challenging because of differences in reference standards and grading methods, TS demonstrated acceptable sensitivity and good specificity in detecting DR; moderate to good agreement between TS and reference-standard DR grading was observed. Performance of TS was not as robust in detecting DME, although the number of studies evaluating DME specifically was limited. Two level I studies, 5 level II studies, and 1 level III study supported that TS had a positive impact on overall DR screening compliance, even increasing it by more than 2-fold in one study. Studies assessing cost-effectiveness and patient satisfaction were not graded formally, but they generally showed that TS was cost-effective and preferred by patients over traditional surveillance. CONCLUSIONS: Conventional TS is an effective approach to DR screening not only for its accuracy in detecting referable-level disease, but also for improving screening compliance in a cost-effective manner that may be preferred by patients. Further research is needed to elucidate the ideal approach of TS that may involve integration of artificial intelligence or other imaging technologies in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Treatment of Noninfectious Uveitic Macular Edema with Periocular and Intraocular Corticosteroid Therapies: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the effectiveness and complications of periocular and intraocular corticosteroid therapies for noninfectious uveitic macular edema. METHODS: A literature search of the PubMed database was conducted last in December 2021 and a post-assessment search was conducted in March 2023. The searches were limited to articles published in English and no date restrictions were imposed. The combined searches yielded 739 citations; 53 articles were selected for inclusion because the studies (1) evaluated periocular corticosteroid injection, intraocular corticosteroid injection or implant, suprachoroidal corticosteroid injection, or a combination thereof for uveitic macular edema; (2) had outcomes that included visual acuity (VA) or macular edema assessed clinically or imaged by OCT or fluorescein angiography; and (3) included more than 20 patients. RESULTS: This assessment reviewed 23 articles that provided level I or level II evidence from 18 studies on the use of periocular, suprachoroidal, and intravitreal triamcinolone acetonide injections and intravitreal dexamethasone and fluocinolone acetonide implants or inserts in noninfectious uveitic macular edema. These reports consistently demonstrated that all investigated periocular and intraocular corticosteroid therapies improved VA, macular structure, or both. One comparative study showed that intravitreal triamcinolone acetonide injection and the dexamethasone intravitreal implant had effectiveness superior to that of periocular triamcinolone acetonide injection for these outcomes. As a group, the studies highlighted the potential for these therapies to elevate intraocular pressure and to accelerate cataract formation. CONCLUSIONS: The published literature provides high-quality evidence that periocular and intraocular corticosteroid therapies are effective and safe for the treatment of noninfectious uveitic macular edema. However, information on the relative effectiveness and complication rates across the different therapies is limited. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Conditional deletion of CEACAM1 causes hepatic stellate cell activation.

Objectives: Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with MASH. Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcriptoin and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. Methods: We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre+Cc1 fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. Results: LratCre+Cc1 fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HDCs. This was inhibited by nicotinic acid treatment which stemmed the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. Conclusions: Loss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.

Evolution of the redox-altered, two-tiered Muralha Flow in the Fronteira Oeste Rift, southern Paraná Volcanic Province.

The thorough redox alteration of a lava flow is an undescribed feature in intraplate basaltic provinces. The Early Cretaceous (134.5 Ma) Paraná Province displays that alteration in the major Muralha Flow. This oxidized and reduced flow from the southern part of the province was studied with satellite images, field surveying, petrography, and published whole rock geochemistry. The 100 x 100 km flow from the Cuesta de Haedo presents two hydrothermal tiers - lower Tier 1 is gray to white, upper Tier 2 is red. Iron oxyhydroxides characterize Tier 2. Tier 1 contains clay minerals, zeolites, pyrite and calcite, and agate (possibly amethyst) geodes. In a first event, the upper Tier 2 was oxidized by hot water from the underlying Guarani Paleoaquifer. The high water/rock ratio decreased due to porosity clogging by precipitation of secondary minerals, and the fluid became reducing. Lowering of Eh and pH was caused by reaction of water with reducing particles (calcite, organic molecules) present in the paleoerg sandstones and with fresh rock surfaces. A lower Tier 1 was then formed during slow, hot water percolation. Reduction was interrupted below 30 °C (calcite formation). Large scale, similar alteration occurred in all studied oceanic ridges and only rarely in continental environments.

Assessment of Microvascular Changes After Rhegmatogenous Retinal Detachment Repair Using Wide-Field Swept-Source Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVE: Our objective was to evaluate retinal microvascular changes and visual outcomes following rhegmatogenous retinal detachment (RRD) repair using wide-field swept-source optical coherence tomography angiography (WF SS-OCTA). PATIENTS AND METHODS: The study included 116 eyes of 111 patients with macula-off (n = 68) or macula-on (n = 48) RRD treated with a single successful procedure, 79 fellow eyes, and 183 eyes of control patients imaged with WF SS-OCTA (3 ×3, 6 ×6, and 12 ×12 mm images). Mixed-effects multiple linear regression models were used for statistical analysis. RESULTS: Vessel density (VD) and vessel skeletonized density (VSD) of the superficial capillary plexus (3 ×3 mm scans) and full-thickness retina (12 ×12 mm) were significantly reduced in RRD eyes compared to fellow and control eyes. Decreased VSD and VD in all layers (3 ×3 mm and 6 ×6 mm) were significantly associated with greater preoperative extent of retinal detachment (P < 0.05) and poorer postoperative best-corrected visual acuity (BCVA) in RRD eyes (P < 0.05). Macula-off status was associated with increased foveal avascular zone irregularity (12 ×12 mm, P = 0.02). CONCLUSIONS: Decreased VD on WF SS-OCTA is associated with poorer postoperative BCVA following RRD repair. [Ophthalmic Surg Lasers Imaging Retina 2024;55:310-317.].

Postnatal survival of phrenic motor neurons is promoted by BDNF/TrkB.FL signaling.

The number of motor neurons (MNs) declines precipitously during the final trimester before birth. Thereafter, the number of MNs remains relatively stable, with their connections to skeletal muscle dependent on neurotrophins, including brain-derived neurotrophic factor (BDNF) signaling through its high-affinity full-length tropomyosin-related kinase receptor subtype B (TrkB.FL) receptor. As a genetic knockout of BDNF leads to extensive MN loss and postnatal death within 1-2 days after birth, we tested the hypothesis that postnatal inhibition of BDNF/TrkB.FL signaling is important for postnatal phrenic MN (PhMN) survival. In the present study, we used a 1NMPP1-sensitive TrkBF616A mutant mouse to evaluate the effects of inhibition of TrkB kinase activity on phrenic MN (PhMN) numbers and diaphragm muscle (DIAm) fiber cross-sectional area (CSA). Pups were exposed to 1NMPP1 or vehicle (DMSO) from birth to 21 days old (weaning) via the mother's ingestion in the drinking water. Following weaning, the right phrenic nerve was exposed in the neck and the proximal end dipped in a rhodamine solution to retrogradely label PhMNs. After 24 h, the cervical spinal cord and DIAm were excised. Labeled PhMNs were imaged using confocal microscopy, whereas DIAm strips were frozen at ∼1.5× resting length, cryosectioned, and stained with hematoxylin and eosin to assess CSA. We observed an ∼34% reduction in PhMN numbers and increased primary dendrite numbers in 1NMPP1-treated TrkBF616A mice. The distribution of PhMN size (somal surface area) DIAm fiber cross-sectional areas did not differ. We conclude that survival of PhMNs during early postnatal development is sensitive to BDNF/TrkB.FL signaling.NEW & NOTEWORTHY During early postnatal development, BDNF/TrkB signaling promotes PhMN survival. Inhibition of BDNF/TrkB signaling in early postnatal development does not impact PhMN size. Inhibition of BDNF/TrkB signaling in early postnatal development does not impact the number or CSA of DIAm fibers.