Detailed phenotype and long-term follow-up of RAB28-associated cone-rod dystrophy.

PURPOSE: To gain an insight into the pathophysiology of RAB28-associated inherited retinal degeneration through detailed phenotyping and long-term longitudinal follow-up. METHODS: The patient underwent complete ophthalmic examinations. Visual function was assessed with microperimetry, full-field electroretinography (ffERG), imaging with optical coherence tomography (OCT), short-wave (SW), and near-infrared (NIR) fundus autofluorescence (FAF). RESULTS: A healthy Haitian woman with homozygous pathogenic variants (c.68C > T; p.Ser23Phe) in RAB28 presented at 16 years of age with a four-year history of blurred vision. Visual acuities were 20/125 in each eye, which remained relatively stable since. At age 27, cone ffERGs were non-detectable and borderline for rod-mediated responses. Kinetic fields were full to a V-4e target, undetectable to a small I-4e stimulus. Microperimetry showed an absolute central scotoma surrounded by a pericentral relative scotoma. SD-OCT showed an undetectable or barely detectable foveal and parafoveal photoreceptor outer nuclear layer (ONL), photoreceptor outer segment (POS), and retinal pigment epithelium (RPE) signals and loss of the SW- and NIR-FAF signals. This atrophic region was separated from a normally laminated retina by a narrow transition zone (TZ) of hyper SW- and NIR-FAF that co-localized with preserved ONL but abnormally thinned POS and RPE. There was minimal centrifugal (<100 µm) expansion over a six-year period. CONCLUSION: The cone-rod dystrophy phenotype documented herein supports a critical role of RAB28 for cone function and POS maintenance. Severe central photoreceptor and RPE loss with a predilection for POS loss in TZs suggests possible disruptions of complex mechanisms that maintain central cone photoreceptor and RPE homeostasis.

Intraretinal hemorrhages and detailed retinal phenotype of three patients with Alagille syndrome.

PURPOSE: To explore patterns of disease expression in Alagille syndrome (ALGS). METHODS: Patients underwent ophthalmic examination, optical coherence tomography (OCT) imaging, fundus intravenous fluorescein angiography (IVFA), perimetry and full-field electroretinograms (ffERGs). An adult ALGS patient had multimodal imaging and specialized perimetry. RESULTS: The proband (P1) had a heterozygous pathogenic variant in JAG1; (p.Gln410Ter) and was incidentally diagnosed at age 7 with a superficial retinal hemorrhage, vascular tortuosity, and midperipheral pigmentary changes. The hemorrhage recurred 15 months later. Her monozygotic twin sister (P2) had a retinal hemorrhage at the same location at age 11. Visual acuities for both patients were 20/30 in each eye. IVFA was normal. OCT showed thinning of the outer nuclear in the peripapillary retina. A ffERG showed normal cone-mediated responses in P1 (rod-mediated ERGs not documented), normal ffERGs in P2. Coagulation and liver function were normal. An unrelated 42-year-old woman with a de-novo pathogenic variant (p. Gly386Arg) in JAG1 showed a similar pigmentary retinopathy and hepatic vascular anomalies; rod and cone function was normal across large expanses of structurally normal retina that sharply transitioned to a blind atrophic peripheral retina. CONCLUSION: Nearly identical recurrent intraretinal hemorrhages in monozygotic twins with ALGS suggest a shared subclinical microvascular abnormality. We hypothesize that the presence of large areas of functionally and structurally intact retina surrounded by severe chorioretinal degeneration, is against a predominant involvement of JAG1 in the function of the neurosensory retina, and that instead, primary abnormalities of chorioretinal vascular development and/or homeostasis may drive the peculiar phenotypes.

Real-time structural characterization of protein response to a caged compound by fast detector readout and high-brilliance synchrotron radiation.

Protein dynamics are essential to biological function, and methods to determine such structural rearrangements constitute a frontier in structural biology. Synchrotron radiation can track real-time protein dynamics, but accessibility to dedicated high-flux single X-ray pulse time-resolved beamlines is scarce and protein targets amendable to such characterization are limited. These limitations can be alleviated by triggering the reaction by laser-induced activation of a caged compound and probing the structural dynamics by fast-readout detectors. In this work, we established time-resolved X-ray solution scattering (TR-XSS) at the CoSAXS beamline at the MAX IV Laboratory synchrotron. Laser-induced activation of caged ATP initiated phosphoryl transfer in the adenylate kinase (AdK) enzyme, and the reaction was monitored up to 50 ms with a 2-ms temporal resolution achieved by the detector readout. The time-resolved structural signal of the protein showed minimal radiation damage effects and excellent agreement to data collected by a single X-ray pulse approach.

Gene Editing for CEP290-Associated Retinal Degeneration.

BACKGROUND: CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant). METHODS: We performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children). RESULTS: EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score. CONCLUSIONS: The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.).

Retinal response to light exposure in BEST1-mutant dogs evaluated with ultra-high resolution OCT.

Mutations in BEST1 cause an autosomal recessive disease in dogs where the earliest changes localize to the photoreceptor-RPE interface and show a retina-wide micro-detachment that is modulated by light exposure. The purpose of this study was to define the spatial and temporal details of the outer retina and its response to light with ultra-high resolution OCT across a range of ages and with different BEST1 mutations. Three retinal regions were selected in each eye: near the fovea-like area, near the optic nerve, both in the tapetal area, and inferior to the optic nerve in the non-tapetal area. The OS+ slab thickness was defined between the peak near the junction of inner and outer segments (IS/OS) and the transition between basal RPE, Bruch membrane, choriocapillaris and proximal tapetum (RPE/T). In wildtype (WT) dogs, two tapetal regions showed additional hyperscattering OCT peaks within the OS+ slab likely representing cone and rod outer segment tips (COST and ROST). The inferior non-tapetal region of WT dogs had only one of these peaks, likely ROST. In dogs with BEST1 mutations, all three locations showed a single peak, likely suggesting optical silence of COST. Light-dependent expansion of the micro-detachment by about 10 um was detectable in both tapetal and non-tapetal retina across all ages and BEST1 mutations.

Stimulus type and duration affect magnitude and evolution of flicker-induced hyperemia measured by laser speckle flowgraphy at the optic disc and peripapillary vessels.

Neurovascular coupling is a vital mechanism employed by the cerebrovascular system, including the eye, to regulate blood flow in periods of neuronal activation. This study aims to investigate if laser speckle flowgraphy (LSFG) can detect coupling response elicited by flickering light stimuli and how variations in stimulus type and duration can affect the magnitude and evolution of blood flow in the optic nerve head (ONH) and peripapillary vessels. Healthy adults were exposed to two types of 10-Hz flicker stimuli: a photopic negative response-like stimulus (PhNR-S) or a visual evoked potential-like stimulus (VEP-S)-each presented in separate 10- and 60-s epochs. Both PhNR-S and VEP-S significantly increased ONH blood flow (p < 0.001) immediately after flicker cessation, with a trend of 60-s stimuli (PhNR-S = 11.6%; VEP-S = 10.4%) producing a larger response than 10-s stimuli (PhNR-S = 7.5%; VEP-S = 6.2%). Moreover, exposure to 60-s stimuli elicited a significantly prolonged ONH hyperemic response, especially with PhNR-S. Lastly, stimulation with either 60-s stimuli elicited a robust increase in blood flow within the peripapillary arterioles (p < 0.01) and venules (p < 0.01) as well. Flicker stimulation with common visual electrophysiology stimuli (PhNR-S and VEP-S) induced a demonstrable increase in ONH and peripapillary vessel blood flow, which varied with flicker duration. Our results validate that LSFG is a robust method to quantify flicker-induced hyperemic responses and to study neurovascular coupling in humans.

FOVEAL PHENOTYPES IN CHOROIDEREMIA ON ADAPTIVE OPTICS SCANNING LIGHT OPHTHALMOSCOPY.

PURPOSE: Choroideremia is an X-linked inherited retinal degeneration involving the choriocapillaris, retinal pigment epithelium, and photoreceptors. Adaptive optics scanning light ophthalmoscopy allows visualization of retinal structure at the level of individual cells and is well poised to provide insight into the pathophysiologic mechanisms underpinning the retinal degeneration in choroideremia. METHODS: Foveal adaptive optics scanning light ophthalmoscopy images of 102 eyes of 54 individuals with choroideremia were analyzed. Measures were compared with those from standard clinical imaging. Visual acuity was also measured and compared with quantitative foveal metrics. RESULTS: The 3 distinct phenotypes observed were: relatively normal (5 eyes, 4 individuals), spiderweb (9 eyes, 7 individuals), and salt and pepper (87 eyes, 47 individuals). Peak cone density (86 eyes of 51 individuals) was significantly lower in choroideremia than in healthy retinas (P < 0.0001, range: 29,382-157,717 cones/mm2). Peak cone density was significantly related to extent of retained ellipsoid zone on en face optical coherence tomography (r2 = 0.47, P = 0.0009) and inversely related to visual acuity (r2 = 0.20, P = 0.001). CONCLUSION: Distinct phenotypes can be observed on adaptive optics scanning light ophthalmoscopy imaging in choroideremia that cannot always be discerned on standard clinical imaging. Quantitative measures on adaptive optics imaging are related to the structural and functional severity of disease.

Treatment Strategy With Gene Editing for Late-Onset Retinal Degeneration Caused by a Founder Variant in C1QTNF5.

Purpose: Genome editing is an emerging group of technologies with the potential to ameliorate dominant, monogenic human diseases such as late-onset retinal degeneration (L-ORD). The goal of this study was to identify disease stages and retinal locations optimal for evaluating the efficacy of a future genome editing trial. Methods: Twenty five L-ORD patients (age range, 33-77 years; median age, 59 years) harboring the founder variant S163R in C1QTNF5 were enrolled from three centers in the United Kingdom and United States. Patients were examined with widefield optical coherence tomography (OCT) and chromatic perimetry under dark-adapted and light-adapted conditions to derive phenomaps of retinal disease. Results were analyzed with a model of a shared natural history of a single delayed exponential across all subjects and all retinal locations. Results: Critical age for the initiation of photoreceptor loss ranged from 48 years at the temporal paramacular retina to 74 years at the inferior midperipheral retina. Subretinal deposits (sRET-Ds) became more prevalent as critical age was approached. Subretinal pigment epithelial deposits (sRPE-Ds) were detectable in the youngest patients showing no other structural or functional abnormalities at the retina. The sRPE-D thickness continuously increased, reaching 25 µm in the extrafoveal retina and 19 µm in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. Conclusions: Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.

The Fifth Bioelectronic Medicine Summit: today's tools, tomorrow's therapies.

The emerging field of bioelectronic medicine (BEM) is poised to make a significant impact on the treatment of several neurological and inflammatory disorders. With several BEM therapies being recently approved for clinical use and others in late-phase clinical trials, the 2022 BEM summit was a timely scientific meeting convening a wide range of experts to discuss the latest developments in the field. The BEM Summit was held over two days in New York with more than thirty-five invited speakers and panelists comprised of researchers and experts from both academia and industry. The goal of the meeting was to bring international leaders together to discuss advances and cultivate collaborations in this emerging field that incorporates aspects of neuroscience, physiology, molecular medicine, engineering, and technology. This Meeting Report recaps the latest findings discussed at the Meeting and summarizes the main developments in this rapidly advancing interdisciplinary field. Our hope is that this Meeting Report will encourage researchers from academia and industry to push the field forward and generate new multidisciplinary collaborations that will form the basis of new discoveries that we can discuss at the next BEM Summit.

OUTER RETINOPATHY AND MICROANGIOPATHY IN ACUTE MYELOGENOUS LEUKEMIA.

PURPOSE: To describe a patient with acute myelogenous leukemia who presented with a recurrent, bilateral, outer retinopathy, before and after consolidative peripheral blood stem cell transplantation complicated by chronic graft-versus-host disease. METHODS: This is a retrospective review of records from a 23-year-old woman with acute myelogenous leukemia who underwent comprehensive ophthalmic evaluations for over a year including chromatic perimetry and multifocal electroretinograms, imaging with spectral domain optical coherence tomography, near-infrared and short-wavelength fundus reflectance and autofluorescence, fluorescein and optical coherence tomography angiography. RESULTS: The patient presented with recurrent, unilateral paracentral scotomas. There was localized loss of inner segment ellipsoid (EZ) and photoreceptor outer segment signals (IZ) in the pericentral retina of both eyes co-localizing with hyperreflective lesions on near-infrared reflectance. She subsequently lost vision (visual acuity = 20/200) in the right eye a year after consolidative peripheral blood stem cell transplantation complicated by steroid-resistant-chronic graft-versus-host disease. There was loss of the EZ and IZ signals corresponding to a dense central cone scotoma and multifocal electroretinograms depression. Near-infrared autofluorescence, fluorescein and optical coherence tomography angiography were within normal limits. Visual acuity (20/20) and retinal sensitivities improved with restoration of the EZ/IZ signals after oral prednisone and intravenous rituximab, but left a residual photoreceptor loss and paracentral scotoma. CONCLUSION: We propose that an immune-mediated microangiopathy may explain the protracted, recurrent course of primary photoreceptor abnormalities in our patient, which was further complicated by manifestations of chronic graft-versus-host disease following consolidative peripheral blood stem cell transplantation. Outer retinal findings previously documented in leukemia may be explained by a similar mechanism.

Management of multiple frostbite casualties at a burn center: San Antonio, Texas, 12-20 February 2021.

BACKGROUND: Frostbite is an insidious disease that normally affects people of cold climates. Winter Storm Uri, which occurred from February 12-20, 2021, created unique metrological conditions for Texas. It caused prolonged sub-freezing temperatures and led to rolling blackouts, affecting 2.8 million Texans including 300,000 people in San Antonio. We report 13 frostbite patients admitted to one burn center during this event. OBJECTIVE: We aimed to determine the at-risk population for frostbite, to categorize their injury severity, and to describe their treatment. A secondary aim was to describe the rehabilitation management of these patients. METHODS: This is a single-center retrospective study. Each patient's injuries were assessed by a topographical grading system. Comparisons were made among those who were admitted to the intensive care unit (ICU), admitted to the progressive care unit (PCU), and treated as outpatients. RESULTS: Thirteen patients were identified. Ten (76.9 %) considered themselves homeless, and 9 (69.2 %) were directly exposed to the elements. The median delay between time of injury and presentation to a medical facility was 3 days (IQR 1-6). Only 3 patients presented to a medical facility within 24 h. Six (46 %) sustained grade 2 injuries, 2 (15 %) sustained grade 3 injuries, and 5 (38%) sustained grade 4 injuries. Only one patient met criteria to receive tissue plasminogen activator (tPA), which was discontinued due to hematochezia. Patients admitted to the ICU, when compared to patients admitted to the ward, had a longer length of stay (median 73 days v. 12 days, p = 0.0215), and required more amputations at below-the-knee or higher levels (3 v. 0, p-value 0.0442). CONCLUSION: In a region unaccustomed and perhaps unprepared to deal with winter storms, the population is particularly vulnerable to frostbite. Lack of awareness of frostbite injuries likely led to the delay in the presentation of patients, which prevented the timely use of tPA. Increasing public awareness may increase readiness.

Scale-free correlations in the dynamics of a small (N∼10000) cortical network.

The advent of novel optogenetics technology allows the recording of brain activity with a resolution never seen before. The characterization of these very large data sets offers new challenges as well as unique theory-testing opportunities. Here we discuss whether the spatial and temporal correlations of the collective activity of thousands of neurons are tangled as predicted by the theory of critical phenomena. The analysis shows that both the correlation length ξ and the correlation time τ scale as predicted as a function of the system size. With some peculiarities that we discuss, the analysis uncovers evidence consistent with the view that the large-scale brain cortical dynamics corresponds to critical phenomena.

Fluctuations in tissue growth portray homeostasis as a critical state and long-time non-Markovian cell proliferation as Markovian.

Tissue growth is an emerging phenomenon that results from the cell-level interplay between proliferation and apoptosis, which is crucial during embryonic development, tissue regeneration, as well as in pathological conditions such as cancer. In this theoretical article, we address the problem of stochasticity in tissue growth by first considering a minimal Markovian model of tissue size, quantified as the number of cells in a simulated tissue, subjected to both proliferation and apoptosis. We find two dynamic phases, growth and decay, separated by a critical state representing a homeostatic tissue. Since the main limitation of the Markovian model is its neglect of the cell cycle, we incorporated a refractory period that temporarily prevents proliferation immediately following cell division, as a minimal proxy for the cell cycle, and studied the model in the growth phase. Importantly, we obtained from this last model an effective Markovian rate, which accurately describes general trends of tissue size. This study shows that the dynamics of tissue growth can be theoretically conceptualized as a Markovian process where homeostasis is a critical state flanked by decay and growth phases. Notably, in the growing non-Markovian model, a Markovian-like growth process emerges at large time scales.

In situ biaxial loading and multi-scale deformation measurements of nanostructured materials at the CoSAXS beamline at MAX IV Laboratory.

Characterization of the mechanical response of polymers and composite materials relies heavily on the macroscopic stress-strain response in uniaxial tensile configurations. To provide representative information, the deformation process must be homogeneous within the gauge length, which is a condition that is rarely achieved due to stress concentration or inhomogeneities within the specimen. In this work, the development of a biaxial mechanical testing device at the CoSAXS beamline at MAX IV Laboratory is presented. The design facilitates simultaneous measurement of small- and wide-angle X-ray scattering (SAXS/WAXS), allowing assessment of the microstructural configuration before, after and during the continuous deformation process at multiple length scales. The construction also supports multiple deformation conditions, while guaranteeing stability even at high loads. Furthermore, the mechanical experiments can be complemented with spatially resolved mesoscopic surface deformation measurements using 3D-surface digital image correlation (DIC). Polycarbonate (PC) was used to demonstrate the varied material response to multi-axial deformation, as PC is isotropic with a high glass transition temperature (∼150°) and high strength. As a result, a clear correlation between full-field methods and the microstructural information determined from WAXS measurements is demonstrated. When a uniaxial load is applied, homogeneous strain regions could be observed extending perpendicular to the applied load. When a secondary axial load was added (biaxial mode), it was observed that high strain domains were created near the centre of the sample and at the boundaries after yield. With increased strain, the deformation in the main deformation direction also increases. Mechanical reliability was demonstrated by carrying out static loading of polyacrylonitrile-based carbon fibre (CF) bundles. As a result, the nonlinear stiffening behaviour typically observed in CFs was seen, while no evidence of the creation of new voids during loading was observed. The results support the reliability and broad applicability of the developed technique.

Circulatory HMGB1 is an early predictive and prognostic biomarker of ARDS and mortality in a swine model of polytrauma.

Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in polytrauma patients. Pharmacological treatments of ARDS are lacking, and ARDS patients rely on supportive care. Accurate diagnosis of ARDS is vital for early intervention and improved outcomes but is presently delayed up to days. The use of biomarkers for early identification of ARDS development is a potential solution. Inflammatory mediators high-mobility group box 1 (HMGB1), syndecan-1 (SDC-1), and C3a have been previously proposed as potential biomarkers. For this study, we analyzed these biomarkers in animals undergoing smoke inhalation and 40% total body surface area burns, followed by intensive care for 72 h post-injury (PI) to determine their association with ARDS and mortality. We found that the levels of inflammatory mediators in serum were affected, as well as the degree of HMGB1 and Toll-like receptor 4 (TLR4) signal activation in the lung. The results showed significantly increased HMGB1 expression levels in animals that developed ARDS compared with those that did not. Receiver operating characteristic (ROC) analysis showed that HMGB1 levels at 6 h PI were significantly associated with ARDS development (AUROC=0.77) and mortality (AUROC=0.82). Logistic regression analysis revealed that levels of HMGB1 ≥24.10 ng/ml are associated with a 13-fold higher incidence of ARDS [OR:13.57 (2.76-104.3)], whereas the levels of HMGB1 ≥31.39 ng/ml are associated with a 12-fold increase in mortality [OR: 12.00 (2.36-93.47)]. In addition, we found that mesenchymal stem cell (MSC) therapeutic treatment led to a significant decrease in systemic HMGB1 elevation but failed to block SDC-1 and C3a increases. Immunohistochemistry analyses showed that smoke inhalation and burn injury induced the expression of HMGB1 and TLR4 and stimulated co-localization of HMGB1 and TLR4 in the lung. Interestingly, MSC treatment reduced the presence of HMGB1, TLR4, and the HMGB1-TLR4 co-localization. These results show that serum HMGB1 is a prognostic biomarker for predicting the incidence of ARDS and mortality in swine with smoke inhalation and burn injury. Therapeutically blocking HMGB1 signal activation might be an effective approach for attenuating ARDS development in combat casualties or civilian patients.

Scale-free correlations and potential criticality in weakly ordered populations of brain cancer cells.

Collective behavior spans several orders of magnitude of biological organization, from cell colonies to flocks of birds. We used time-resolved tracking of individual glioblastoma cells to investigate collective motion in an ex vivo model of glioblastoma. At the population level, glioblastoma cells display weakly polarized motion in the (directional) velocities of single cells. Unexpectedly, fluctuations in velocities are correlated over distances many times the size of a cell. Correlation lengths scale linearly with the maximum end-to-end length of the population, indicating that they are scale-free and lack a characteristic decay scale other than the size of the system. Last, a data-driven maximum entropy model captures statistical features of the experimental data with only two free parameters: the effective length scale (nc) and strength (J) of local pairwise interactions between tumor cells. These results show that glioblastoma assemblies exhibit scale-free correlations in the absence of polarization, suggesting that they may be poised near a critical point.

Pregnancy and neonatal outcomes among women with early-onset colorectal cancer: a nationwide case-control study.

Background: Early-onset colorectal cancer has risen worldwide, leaving more women with colorectal cancer at reproductive ages. We aimed to investigate the risk of adverse pregnancy and neonatal outcomes among women with early-onset colorectal cancer. Methods: We conducted a nationwide, matched case-control study of maternal/pregnancy outcomes including pre-eclampsia and Cesarean delivery (C-section) as well as neonatal outcomes including preterm birth among 207 births in women with early-onset colorectal cancer (ages 18-49) and 1019 births in women without colorectal cancer in Sweden (1992-2019). Early-onset colorectal cancer cases were identified through the Cancer Register, and outcome data were retrieved through linkage to Medical Birth Register and National Patient Register. Using conditional logistic regression, we estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Findings: Between Jan 1, 1992, and Dec 31, 2019, women with early-onset colorectal cancer who gave birth had increased odds of pre-eclampsia (7.2% vs 3.2%; OR = 2.52, 95%CI = 1.25-5.08), any C-section (24.6% vs 19.4%; OR = 1.43, 95%CI = 1.00-2.06), particularly emergency C-section (17.4% vs 10.5%; OR = 1.79, 95%CI = 1.17-2.75), after adjustment for maternal education level, country of birth, body mass index and smoking in early pregnancy, and comorbidities. Maternal history of early-onset colorectal cancer was also associated with offspring preterm birth (12.1% vs 5.2%; OR = 2.31, 95%CI = 1.34-3.99), delineated as spontaneous (OR = 1.06, 95%CI = 0.47-2.39) or medically-indicated preterm birth (OR = 4.48, 95%CI = 2.05-9.79). There was no increased risk of congenital malformation or small for gestational age birth. Interpretation: In this population-based study, maternal history of early-onset colorectal cancer was associated with risk of both adverse pregnancy (pre-eclampsia, C-section) and neonatal outcomes (preterm birth). Funding: US National Institutes of Health, Swedish Society of Medicine, Swedish Cancer Foundation.

Immunopathological Alterations after Blast Injury and Hemorrhage in a Swine Model of Prolonged Damage Control Resuscitation.

Trauma-related hemorrhagic shock (HS) remains a leading cause of death among military and civilian trauma patients. We have previously shown that administration of complement and HMGB1 inhibitors attenuate morbidity and mortality 24 h after injury in a rat model of blast injury (BI) and HS. To further validate these results, this study aimed to develop a swine model and evaluate BI+HS-induced pathophysiology. Anesthetized Yucatan minipigs underwent combined BI and volume-controlled hemorrhage. After 30 min of shock, animals received an intravenous bolus of PlasmaLyte A and a continuous PlasmaLyte A infusion. The survival rate was 80% (4/5), and the non-survivor expired 72 min post-BI. Circulating organ-functional biomarkers, inflammatory biomarkers, histopathological evaluation, and CT scans indicated evidence of multiple-organ damage, systemic innate immunological activation, and local tissue inflammation in the injured animals. Interestingly, a rapid and dramatic increase in plasma levels of HMGB1 and C3a and markedly early myocarditis and encephalitis were associated with early death post-BI+HS. This study suggests that this model reflects the immunopathological alterations of polytrauma in humans during shock and prolonged damage control resuscitation. This experimental protocol could be helpful in the assessment of immunological damage control resuscitation approaches during the prolonged care of warfighters.

Complement as a vital nexus of the pathobiological connectome for acute respiratory distress syndrome: An emerging therapeutic target.

The hallmark of acute respiratory distress syndrome (ARDS) pathobiology is unchecked inflammation-driven diffuse alveolar damage and alveolar-capillary barrier dysfunction. Currently, therapeutic interventions for ARDS remain largely limited to pulmonary-supportive strategies, and there is an unmet demand for pharmacologic therapies targeting the underlying pathology of ARDS in patients suffering from the illness. The complement cascade (ComC) plays an integral role in the regulation of both innate and adaptive immune responses. ComC activation can prime an overzealous cytokine storm and tissue/organ damage. The ARDS and acute lung injury (ALI) have an established relationship with early maladaptive ComC activation. In this review, we have collected evidence from the current studies linking ALI/ARDS with ComC dysregulation, focusing on elucidating the new emerging roles of the extracellular (canonical) and intracellular (non-canonical or complosome), ComC (complementome) in ALI/ARDS pathobiology, and highlighting complementome as a vital nexus of the pathobiological connectome for ALI/ARDS via its crosstalking with other systems of the immunome, DAMPome, PAMPome, coagulome, metabolome, and microbiome. We have also discussed the diagnostic/therapeutic potential and future direction of ALI/ARDS care with the ultimate goal of better defining mechanistic subtypes (endotypes and theratypes) through new methodologies in order to facilitate a more precise and effective complement-targeted therapy for treating these comorbidities. This information leads to support for a therapeutic anti-inflammatory strategy by targeting the ComC, where the arsenal of clinical-stage complement-specific drugs is available, especially for patients with ALI/ARDS due to COVID-19.