Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.

Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. Understanding the molecular alterations in cerebral microvessels in stroke will provide original opportunities for scientific investigation of novel therapeutic strategies. Toward this goal, using a recently optimized method which minimizes cell activation and preserves endothelial cell interactions and RNA integrity, we conducted a genome-wide transcriptomic analysis of cerebral microvessels in a mouse model of stroke and compared these transcriptomic alterations with the ones observed in human, nonfatal, brain stroke lesions. Results from these unbiased comparative analyses have revealed the common alterations in mouse stroke microvessels and human stroke lesions and identified shared molecular features associated with vascular disease (e.g., Serpine1/Plasminogen Activator Inhibitor-1, Hemoxygenase-1), endothelial activation (e.g., Angiopoietin-2), and alterations in sphingolipid metabolism and signaling (e.g., Sphigosine-1-Phosphate Receptor 2). Sphingolipid profiling of mouse cerebral microvessels validated the transcript data and revealed the enrichment of sphingomyelin and sphingoid species in the cerebral microvasculature compared to brain and the stroke-induced increase in ceramide species. In summary, our study has identified novel molecular alterations in several microvessel-enriched, translationally relevant, and druggable targets, which are potent modulators of endothelial function. Our comparative analyses have revealed the presence of molecular features associated with cerebral microvascular dysfunction in human chronic stroke lesions. The results shared here provide a detailed resource for therapeutic discovery of candidates for neurovascular protection in stroke and potentially, other pathologies exhibiting cerebral microvascular dysfunction.

Gait Characterization in Duchenne Muscular Dystrophy (DMD) Using a Single-Sensor Accelerometer: Classical Machine Learning and Deep Learning Approaches.

Differences in gait patterns of children with Duchenne muscular dystrophy (DMD) and typically developing (TD) peers are visible to the eye, but quantifications of those differences outside of the gait laboratory have been elusive. In this work, we measured vertical, mediolateral, and anteroposterior acceleration using a waist-worn iPhone accelerometer during ambulation across a typical range of velocities. Fifteen TD and fifteen DMD children from 3 to 16 years of age underwent eight walking/running activities, including five 25 m walk/run speed-calibration tests at a slow walk to running speeds (SC-L1 to SC-L5), a 6-min walk test (6MWT), a 100 m fast walk/jog/run (100MRW), and a free walk (FW). For clinical anchoring purposes, participants completed a Northstar Ambulatory Assessment (NSAA). We extracted temporospatial gait clinical features (CFs) and applied multiple machine learning (ML) approaches to differentiate between DMD and TD children using extracted temporospatial gait CFs and raw data. Extracted temporospatial gait CFs showed reduced step length and a greater mediolateral component of total power (TP) consistent with shorter strides and Trendelenberg-like gait commonly observed in DMD. ML approaches using temporospatial gait CFs and raw data varied in effectiveness at differentiating between DMD and TD controls at different speeds, with an accuracy of up to 100%. We demonstrate that by using ML with accelerometer data from a consumer-grade smartphone, we can capture DMD-associated gait characteristics in toddlers to teens.

Gait Event Detection and Travel Distance Using Waist-Worn Accelerometers across a Range of Speeds: Automated Approach.

Estimation of temporospatial clinical features of gait (CFs), such as step count and length, step duration, step frequency, gait speed, and distance traveled, is an important component of community-based mobility evaluation using wearable accelerometers. However, accurate unsupervised computerized measurement of CFs of individuals with Duchenne muscular dystrophy (DMD) who have progressive loss of ambulatory mobility is difficult due to differences in patterns and magnitudes of acceleration across their range of attainable gait velocities. This paper proposes a novel calibration method. It aims to detect steps, estimate stride lengths, and determine travel distance. The approach involves a combination of clinical observation, machine-learning-based step detection, and regression-based stride length prediction. The method demonstrates high accuracy in children with DMD and typically developing controls (TDs) regardless of the participant's level of ability. Fifteen children with DMD and fifteen TDs underwent supervised clinical testing across a range of gait speeds using 10 m or 25 m run/walk (10 MRW, 25 MRW), 100 m run/walk (100 MRW), 6-min walk (6 MWT), and free-walk (FW) evaluations while wearing a mobile-phone-based accelerometer at the waist near the body's center of mass. Following calibration by a trained clinical evaluator, CFs were extracted from the accelerometer data using a multi-step machine-learning-based process and the results were compared to ground-truth observation data. Model predictions vs. observed values for step counts, distance traveled, and step length showed a strong correlation (Pearson's r = -0.9929 to 0.9986, p < 0.0001). The estimates demonstrated a mean (SD) percentage error of 1.49% (7.04%) for step counts, 1.18% (9.91%) for distance traveled, and 0.37% (7.52%) for step length compared to ground-truth observations for the combined 6 MWT, 100 MRW, and FW tasks. Our study findings indicate that a single waist-worn accelerometer calibrated to an individual's stride characteristics using our methods accurately measures CFs and estimates travel distances across a common range of gait speeds in both DMD and TD peers.

Cardiovascular Progerin Suppression and Lamin A Restoration Rescue Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Patients look healthy at birth, and symptoms typically emerge in the first or second year of life. Assessing the reversibility of progerin-induced damage and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. METHODS: We used CRISPR-Cas9 technology to generate LmnaHGPSrev/HGPSrev (HGPSrev) mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time- and cell type-specific manner on Cre recombinase activation. We characterized the phenotype of HGPSrev mice and crossed them with Cre transgenic lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different disease stages as well as specifically in vascular smooth muscle cells and cardiomyocytes. RESULTS: Like patients with HGPS, HGPSrev mice appear healthy at birth and progressively develop HGPS symptoms, including failure to thrive, lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electrocardiographic anomalies, and precocious death (median lifespan of 15 months versus 26 months in wild-type controls, P<0.0001). Ubiquitous progerin suppression and lamin A restoration significantly extended lifespan when induced in 6-month-old mildly symptomatic mice and even in severely ill animals aged 13 months, although the benefit was much more pronounced on early intervention (84.5% lifespan extension in mildly symptomatic mice, P<0.0001, and 6.7% in severely ill mice, P<0.01). It is remarkable that major vascular alterations were prevented and lifespan normalized in HGPSrev mice when progerin suppression and lamin A restoration were restricted to vascular smooth muscle cells and cardiomyocytes. CONCLUSIONS: HGPSrev mice constitute a new experimental model for advancing knowledge of HGPS. Our findings suggest that it is never too late to treat HGPS, although benefit is much more pronounced when progerin is targeted in mice with mild symptoms. Despite the broad expression pattern of progerin and its deleterious effects in many organs, restricting its suppression to vascular smooth muscle cells and cardiomyocytes is sufficient to prevent vascular disease and normalize lifespan.

Flow Cytometry and Molecular Techniques Could Complement Morphological Detection of Leukemic Infiltration in Ascitic Fluids: A Case Report.

Extramedullary involvement of acute myeloid leukemia (AML) is infrequent, and ascitic infiltration is even more unusual. We present a case of a 48-year-old woman diagnosed with NPM1-mutated AML that debuted with ascites, for which morphological studies of the ascitic fluid did not detect leukemic infiltration, maybe due to technical problems in the sample preparation. Multiparameter flow cytometry (MFC) detected a blast population compatible with AML, and allele-specific PCR detected NPM1-mutated transcripts. Body fluid infiltrations are an infrequent initial manifestation or sign of progression in AML. As far as we know, this is the first reported case of an NPM1-mutated AML that debuted with ascites, and also the first description of the utilization of molecular techniques to detect the leukemic origin of the ascites. This case highlights that, given that allele-specific PCR and MFC increase the sensitivity of morphological studies, these techniques should be routinely applied in the study of any kind of effusion detected in an AML patient.

Microcephaly and Zika virus: neonatal neuroradiological aspects.

PURPOSE: The aim of this study is to describe some radiological features in the newborns with microcephaly caused by Zika virus infection during pregnancy. METHODS: We radiologically analyzed 13 cases of newborns with microcephaly born to mothers who were infected by the Zika virus in the early stage of pregnancy. RESULTS: The most frequently observed radiological findings were microcephaly and decreased brain parenchymal volume associated with lissencephaly, ventriculomegaly secondary to the lack of brain tissue (not hypertensive), and coarse and anarchic calcifications mainly involving the subcortical cortical transition, and the basal ganglia. CONCLUSIONS: Although it cannot be concluded that there is a definitive pathognomonic radiographic pattern of microcephaly caused by Zika virus, gross calcifications and anarchic distribution involving the subcortical cortical transition and the basal ganglia, in association with lissencephaly and in the absence of hypertensive ventriculomegaly, are characteristic of this type of infection.

Stromal cell-derived factor-1 alpha improves cardiac function in a novel diet-induced coronary atherosclerosis model, the SR-B1ΔCT/LDLR KO mouse.

BACKGROUND AND AIMS: There are a limited number of pharmacologic therapies for coronary artery disease, and few rodent models of occlusive coronary atherosclerosis and consequent myocardial infarction with which one can rapidly test new therapeutic approaches. Here, we characterize a novel, fertile, and easy-to-use HDL receptor (SR-B1)-based model of atherogenic diet-inducible, fatal coronary atherosclerosis, the SR-B1ΔCT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1α), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse. METHODS: SR-B1ΔCT/LDLR KO mice were fed the Paigen diet or standard chow diet, and we determined the effects of the diets on cardiac function, histology, and survival. After two weeks of feeding either the Paigen diet (n = 24) or standard chow diet (n = 20), the mice received an intramyocardial injection of either SDF-1α or phosphate buffered saline (PBS). Cardiac function and angiogenesis were assessed two weeks later. RESULTS: When six-week-old mice were fed the Paigen diet, they began to die as early as 19 days later and 50% had died by 38 days. None of the mice maintained on the standard chow diet died by day 72. Hearts from mice on the Paigen diet showed evidence of cardiomegaly, myocardial infarction, and occlusive coronary artery disease. For the five mice that survived until day 28 that underwent an intramyocardial injection of PBS on day 15, the average ejection fraction (EF) decreased significantly from day 14 (the day before injection, 52.1 ± 4.3%) to day 28 (13 days after the injection, 30.6 ± 6.8%) (paired t-test, n = 5, p = 0.0008). Of the 11 mice fed the Paigen diet and injected with SDF-1α on day 15, 8 (72.7%) survived to day 28. The average EF for these 8 mice increased significantly from 48.2 ± 7.2% on day 14 to63.6 ± 6.9% on day 28 (Paired t-test, n = 8, p = 0.003). CONCLUSIONS: This new mouse model and treatment with the promising angiogenic cytokine SDF-1α may lead to new therapeutic approaches for ischemic heart disease.

Four decades of progress in heart-lung transplantation: Two hundred seventy-one cases at a single institution.

OBJECTIVE: The objective of this study is to evaluate survival for combined heart-lung transplant (HLTx) recipients across 4 decades at a single institution. We aim to summarize our contemporary practice based on more than 271 HLTx procedures over 40 years. METHODS: Data were collected from a departmental database and the United Network for Organ Sharing. Recipients younger than age 18 years, those undergoing redo HLTx, or triple-organ system transplantation were excluded, leaving 271 patients for analysis. The pioneering era was defined by date of transplant between 1981 and 2000 (n = 155), and the modern era between 2001 and 2022 (n = 116). Survival analysis was performed using cardinality matching of populations based on donor and recipient age, donor and recipient sex, ischemic time, and sex matching. RESULTS: Between 1981 and 2022, 271 HLTx were performed at a single institution. Recipients in the modern era were older (age 42 vs 34 y; P < .001) and had shorter waitlist times (78 vs 234 days; P < .001). Allografts from female donors were more common in the modern era (59% vs 39%; P = .002). In the matched survival analysis, 30-day survival (97% vs 84%; P = .005), 1-year survival (89% vs 77%; P = .041), and 10-year survival (53% vs 26%; P = .012) significantly improved in the modern era relative to the pioneering era, respectively. CONCLUSIONS: Long-term survival in HLTx is achievable with institutional experience and may continue to improve in the coming decades. Advances in mechanical circulatory support, improved maintenance immunosuppression, and early recognition and management of acute complications such as primary graft dysfunction and acute rejection have dramatically improved the prognosis for recipients of HLTx in our contemporary institutional experience.

Parent-child agreement on health-related quality of life (HRQOL): a longitudinal study.

BACKGROUND: Few studies have evaluated changes on parent-child agreement in HRQOL over time. The objectives of the study were to assess parent-child agreement on child's HRQOL in a 3-year longitudinal study, and to identify factors associated with possible disagreement. METHODS: A sample of Spanish children/adolescents aged 8-18 years and their parents both completed the KIDSCREEN-27 questionnaire. Data on age, gender, family socioeconomic status (SES), and mental health (Strengths and Difficulties Questionnaire, SDQ) was also collected at baseline (2003), and again after 3 years (2006). Changes in family composition were collected at follow-up. Agreement was assessed through intraclass correlation coefficient (ICC), and Bland and Altman plots. Generalizing Estimating Equation (GEE) models were built to analyze factors associated with parent-child disagreement. RESULTS: A total of 418 parent-child pairs were analyzed. At baseline the level of agreement on HRQOL was low to moderate and it was related to the level of HRQOL reported. Physical well-being at baseline showed the highest level of parent-child agreement (ICC=0.59; 0.53-0.65) while less "observable" dimensions presented lower levels of agreement, (i.e. Psychological well-being: ICC= 0.46; 0.38-0.53). Agreement parent-child was lower at follow-up. Some interactions were found between rater and child's age; with increasing age, child scored lower than parents on Parents relationships and Autonomy (Beta [B] -0.47; -0.71 / -0.23) and the KIDSCREEN-10 (-0.49; -0.73 /-0.25). CONCLUSIONS: Parent-child agreement on child's HRQOL is moderate to low and tends to diminish with children age. Measuring HRQOL of children/adolescents mainly in healthy population samples might require direct self-assessments.

Genome sequences of Arthrobacter globiformis B-2979 phages MidnightRain and Gusanita.

Phages MidnightRain and Gusanita, with siphovirus morphology, were isolated on Arthrobacter globiformis B-2979. MidnightRain's genome consists of 53,674 bp, encoding 101 putative genes and 1 tRNA, whereas Gusanita's genome is 42,742 bp, encoding 68 putative genes and 2 tRNAs.

Repetition, but not acoustic differentiation, facilitates pseudohomophone learning by children.

Children's ability to learn words with multiple meanings may be hindered by their adherence to a one-to-one form-to-meaning mapping bias. Previous research on children's learning of a novel meaning for a familiar word (sometimes called a pseudohomophone) has yielded mixed results, suggesting a range of factors that may impact when children entertain a new meaning for a familiar word. One such factor is repetition of the new meaning (Storkel & Maekawa, 2005) and another is the acoustic differentiation of the two meanings (Conwell, 2017). This study asked 72 4-year-old English-learning children to assign novel meanings to familiar words and manipulated how many times they heard the words with their new referents as well as whether the productions were acoustically longer than typical productions of the words. Repetition supported the learning of a pseudohomophone, but acoustic differentiation did not.

Anaplasmosis-induced hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory syndrome of severe immune system activation. It is a diagnostic challenge with high morbidity and mortality. We present a case of HLH due to anaplasmosis infection. A 54-year-old man with chronic obstructive pulmonary disease presented with fever, nausea, vomiting, dyspnea, and arthralgias for 6 days. He had a rapidly progressive clinical decline requiring intubation for acute respiratory failure and dialysis for acute renal failure. He tested positive for anaplasmosis. His workup met criteria for HLH. He was treated with doxycycline and a steroid taper with clinical improvement allowing for extubation and renal recovery. Patients with persistent fevers, hepatosplenomegaly, cytopenias, and hyperferritinemia should be worked up for HLH.

A time-series of heavy metal geochemistry in sediments of Galveston Bay estuary, Texas, 2017-2019.

Galveston Bay is an anthropogenic-influenced estuary where industrial runoff, wastewater, and shipping vessel discharges enter the bay alongside natural freshwaters. Here, heavy metal concentrations in Galveston Bay surface sediment (2-year quarterly time-series) and a single sediment core are presented to explore the anthropogenic and geochemical controls on the spatiotemporal distributions, fluxes, sources, and potential toxicity of metals within this estuary. Samples were leached to distinguish authigenic sediment coatings from geogenic crystalline material. Spatial differences dominate the observed concentration variability, with higher metal concentrations in eastern vs. western bay sediments, as the eastern bay is where metals are flocculated from the dissolved phase and/or sediments are hydrodynamically trapped. Temporal variations are a secondary controlling factor, with sediment metal concentrations positively correlated with Trinity River discharge. Core data indicate stable Fe, Pb Ni, Cd and Hg levels during the 20th century but increasing Cu and Zn levels in recent years. Galveston Bay sediments are potentially toxic for As, Cd, Cr, Cu, Ni, Sb, Zn and Hg, based on federal toxicity standards. Enrichment factors and statistical analyses suggest that Ni and Cr originate from natural sources, while anthropogenic sources dominate supply of As, Cd, Hg, Ni, Pb, Sb, and Zn. This unique time-series shows that major flooding events, such as Hurricane Harvey in 2017, affect surface sediment metal distributions in Galveston Bay, but not any more than the natural geochemical controls on spatiotemporal distributions of metals in anthropogenic-influenced estuaries.

Directional DBS of the Fornix in Alzheimer's Disease Achieves Long-Term Benefits: A Case Report.

Background: Current treatments for Alzheimer's disease (AD) modulate global neurotransmission but are neither specific nor anatomically directed. Tailored stimulation of target nuclei will increase treatment efficacy while reducing side effects. We report the results of the first directional deep brain stimulation (dDBS) surgery and treatment of a patient with AD in an attempt to slow the progression of the disease in a woman with multi-domain, amnestic cognitive status. Methods: We aimed to assess the safety of dDBS in patients with AD using the fornix as stimulation target (primary objective) and the clinical impact of the stimulation (secondary objective). In a registered clinical trial, a female patient aged 81 years with a 2-year history of cognitive decline and diagnoses of AD underwent a bilateral dDBS surgery targeting the fornix. Stimulation parameters were set between 3.9 and 7.5 mA, 90 µs, 130 Hz for 24 months, controlling stimulation effects by 18F-fluoro-2-deoxy-D-glucose (18F-FDG) scans (baseline, 12 and 24 months), magnetoencephalography (MEG) and clinical/neuropsychological assessment (baseline, 6, 12, 18, and 24 months). Results: There were no important complications related to the procedure. In general terms, the patient showed cognitive fluctuations over the period, related to attention and executive function patterns, with no meaningful changes in any other cognitive functions, as is shown in the clinical dementia rating scale (CDR = 1) scores over the 24 months. Such stability in neuropsychological scores corresponds to the stability of the brain metabolic function, seen in PET scans. The MEG studies described low functional connectivity at baseline and a subsequent increase in the number of significant connections, mainly in the theta band, at 12 months. Conclusion: The dDBS stimulation in the fornix seems to be a safe treatment for patients in the first stage of AD. Effects on cognition seem to be mild to moderate during the first months of stimulation and return to baseline levels after 24 months, except for verbal fluency. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT03290274], identifier [NCT03290274].

Low-dose Radiation Therapy in the Management of COVID-19 Pneumonia (LOWRAD-Cov19). Final results of a prospective phase I-II trial.

BACKGROUND AND PURPOSE: To evaluate the results of low-dose radiation therapy (LD-RT) to lungs in the management of patients with COVID-19 pneumonia. MATERIAL AND METHODS: We conducted a prospective phase I-II trial enrolling COVID-19 patients ≥50 years-old, with bilateral lung involvement at imaging study and oxygen requirement (oxygen saturation ≤93% on room air). Patients received 1 Gy to whole lungs in a single fraction. Primary outcome was a radiological response assessed as severity and extension scores at days +3 and +7. Secondary outcomes were toxicity (CTCAE v5.0), days of hospitalization, changes in inflammatory blood parameters (ferritin, lymphocytes, C-reactive protein, d-dimer and LDH) and SatO2/FiO2 index (SAFI), at day +3 and +7. Descriptive analyses were summarized as means with standard deviation (SD) and/or medians with interquartile ranges (IQR). A Wilcoxon sign rank test for paired data was used to assess the CT scores and Chi Square was used to assess for comparison of categorical variables. RESULTS: Forty-one patients were included. Median age was 71 (IQR 60-84). Eighteen patients (44%) previously received an anti-COVID treatment (tocilizumab, lopinavir/ritonavir, remdesivir) and thirty-two patients (84%) received steroids during LD-RT. The extension score improved significantly (p = 0.02) on day +7. Mean baseline extension score was 13.7 (SD ± 4.9) with a score of 12.2 (±5.2) at day 3, and 12.4 ± 4.7 at day 7. No differences were found in the severity score. SAFI improved significantly on day +3 and +7 (p < 0.01). Median SAFI on day 0 was 147 (IQR 118-264), 230 (IQR 120-343) on day +3 and 293 (IQR 121-353) on day +7. Significant decrease was found in C-reactive protein on day +7 (p = 0.02) and in lymphocytes counts on day +3 and +7 (p = 0.02). The median number of days in hospital after RT was 11 (range 4-78). With a median follow-up of 60 days after LD-RT, 26 (63%) patients were discharged, 11 (27%) died because of COVID respiratory failure and 4 (10%) died of other causes. CONCLUSIONS: LD-RT is a feasible and well-tolerated treatment that could lead to rapid clinical improvement. Large randomized trials would be required to establish the efficacy of LD-RT to treat COVID-19 pneumonia.

Comparison of Multiple Clinical Testing Modalities for Assessment of NPM1-Mutant AML.

BACKGROUND: NPM1 mutation status can influence prognosis and management in AML. Accordingly, clinical testing (i.e., RT-PCR, NGS and IHC) for mutant NPM1 is increasing in order to detect residual disease in AML, alongside flow cytometry (FC). However, the relationship of the results from RT-PCR to traditional NGS, IHC and FC is not widely known among many practitioners. Herein, we aim to: i) describe the performance of RT-PCR compared to traditional NGS and IHC for the detection of mutant NPM1 in clinical practice, and also compare it to FC, and ii) provide our observations regarding the advantages and disadvantages of each approach in order to inform future clinical testing algorithms. METHODS: Peripheral blood and bone marrow samples collected for clinical testing at variable time points during patient management were tested by quantitative, real-time, RT-PCR and results were compared to findings from a Myeloid NGS panel, mutant NPM1 IHC and FC. RESULTS: RT-PCR showed superior sensitivity compared to NGS, IHC and FC with the main challenge of NGS, IHC and FC being the ability to identify a low disease burden (<0.5% NCN by RT-PCR). Nevertheless, the positive predictive value of NGS, IHC and FC were each ≥ 80% indicating that positive results by those assays are typically associated with RT-PCR positivity. IHC, unlike bulk methods (RT-PCR, NGS and FC), is able provide information regarding cellular/architectural context of disease in biopsies. FC did not identify any NPM1-mutated residual disease not already detected by RT-PCR, NGS or IHC. CONCLUSION: Overall, our findings demonstrate that RT-PCR shows superior sensitivity compared to a traditional Myeloid NGS, suggesting the need for "deep-sequencing" NGS panels for NGS-based monitoring of residual disease in NPM1-mutant AML. IHC provides complementary cytomorphologic information to RT-PCR. Lastly, FC may not be necessary in the setting of post-therapy follow up for NPM1-mutated AML. Together, these findings can help inform future clinical testing algorithms.

Low-Dose Radiation Therapy in the Management of Coronavirus Disease 2019 (COVID-19) Pneumonia (LOWRAD-Cov19): Preliminary Report.

PURPOSE: Low-dose radiation therapy (LD-RT) has been shown to have an anti-inflammatory effect, and preliminary results suggest it is feasible to treat patients with coronavirus disease 2019 (COVID-19) pneumonia. MATERIALS AND METHODS: We conducted a prospective, single-arm, phase 1/2 clinical trial enrolling patients aged ≥50 years, who were coronavirus disease 2019 (COVID-19) positive, at phase 2 or 3 with lung involvement at imaging study and oxygen requirement. Patients received 100 cGy to total lungs in a single fraction. Primary outcome was radiologic response using severity and extension score on baseline computed tomography (CT), at days 3 and 7 after LD-RT. Secondary outcomes were toxicity using Common Terminology Criteria for Adverse Events v.5.0, duration of hospitalization, blood work evolution, and oxygen requirements using SatO2/FiO2 index (SAFI), at days 3 and 7 after LD-RT. RESULTS: Nine patients were included. Median age was 66 (interquartile range, 57-77). Severity score was stable or decreased in the third CT but was not statistically significant (P = .28); however, there were statistically significant changes in the extension score (P = .03). SAFI index significantly improved 72 hours and 1 week after LD-RT (P = .01). Inflammatory blood parameters decreased 1 week after RT compared with baseline; only lactate dehydrogenase decreased significantly (P = .04). Two patients presented grade 2 lymphopenia after RT and another (with baseline grade 3) worsened to grade 4. Overall, the median number of days of hospitalization was 59 (range, 26-151). After RT the median number of days in the hospital was 13 (range, 4-77). With a median follow-up after RT of 112 days (range, 105-150), 7 patients were discharged and 2 patients died, 1 due to sepsis and the other with severe baseline chronic obstructive pulmonary disease from COVID-19 pneumonia. CONCLUSIONS: Our preliminary results show that LD-RT was a feasible and well-tolerated treatment, with potential clinical improvement. Randomized trials are needed to establish whether LD-RT improves severe pneumonia.

Vascular Smooth Muscle Cell-Specific Progerin Expression Provokes Contractile Impairment in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that Is Ameliorated by Nitrite Treatment.

Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid LmnaG609G/G609G mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined LmnaLCS/LCSTie2Cretg/+ and LmnaLCS/LCSSm22αCretg/+ mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.

Thrombin generation in subjects with lupus anticoagulant without prior thrombosis or gestational morbidities.

BACKGROUND: Lupus anticoagulant (LA) can be a cause of thrombosis and/or pregnancy morbidities, producing antiphospholipid syndrome (APS). An increase in thrombin generation (TG) is correlated with prothrombotic status. Several changes in TG-derived parameters have been reported in APS patients. OBJECTIVES: Evaluate whether the TG phenotype of APS can also be described in LA subjects without clinical manifestations of APS, and to investigate the possible influence of both LA potency and antiphospholipid (aPL) profile on it. RESULTS: TG was analyzed in 153 cases of LA and 41 healthy controls. We have observed prolongation of both lag time (3.7 min vs 2.32 min, p < 0.001) and time to peak (6.48 min vs 5.27 min, p < 0.001), increased peak height (221.7 nM vs 182.7 nM, p < 0.001), slightly higher ETP (221.7 nM·min vs 182.7 nM·min, p = 0.041), and higher velocity index (100.7 nM/min vs 74.53 nM/min, p = 0.001) in LA subjects compared to controls. After adding thrombomodulin (TM), ETP%inh was significantly lower in LA group (37.90% vs 59.90%, p < 0.001) showing resistance to TM/activated protein C (APC). Significant differences were found in lag time, time to peak and ETP%inh according to the potency and aPL profile. CONCLUSIONS: Previously described differences in TG-derived parameters in APS patients have been confirmed in incidental LA subjects: prolonged lag time and time to peak, slightly higher ETP, higher peak height, and less sensitivity to TM/APC. High LA potency and triple-positive aPL profile enhance differences in lag time, time to peak and, especially, increase APC resistance, but no effect in ETP was observed.