Microwave Imaging System Based on Signal Analysis in a Planar Environment for Detection of Abdominal Aortic Aneurysms.

A proof-of-concept of a microwave imaging system for the fast detection of abdominal aortic aneurysms is shown. This experimental technology seeks to overcome the factors hampering the fast screening for these aneurysms with the usual equipment, such as high cost, long-time operation or hazardous exposure to chemical substances. The hardware system is composed of 16 twin antennas mastered by a microcontroller through a switching network, which connects the antennas to the measurement instrument for sequential measurement. The software system is run by a computer, mastering the whole system, automatizing the measurement process and running the signal processing and medical image generation algorithms. Two image generation algorithms are tested: Delay-and-Sum (DAS) and Improved Delay-and-Sum (IDAS). Own-modified versions of these algorithms adapted to the requirements of our system are proposed. The system is carefully calibrated and fine-tuned with known objects placed at known distances. An experimental proof-of-concept is shown with a human torso phantom, including an aorta phantom and an aneurysm phantom placed in different positions. The results show good imaging capabilities with the potential for detecting and locating possible abdominal aortic aneurysms and reporting acceptable errors.

Diversity and Molecular Evolution of Antimicrobial Peptides in Caecilian Amphibians.

Antimicrobial peptides (AMPs) are key molecules in the innate immune defence of vertebrates with rapid action, broad antimicrobial spectrum, and ability to evade pathogen resistance mechanisms. To date, amphibians are the major group of vertebrates from which most AMPs have been characterised, but most studies have focused on the bioactive skin secretions of anurans (frogs and toads). In this study, we have analysed the complete genomes and/or transcriptomes of eight species of caecilian amphibians (order Gymnophiona) and characterised the diversity, molecular evolution, and antimicrobial potential of the AMP repertoire of this order of amphibians. We have identified 477 candidate AMPs within the studied caecilian genome and transcriptome datasets. These candidates are grouped into 29 AMP families, with four corresponding to peptides primarily exhibiting antimicrobial activity and 25 potentially serving as AMPs in a secondary function, either in their entirety or after cleavage. In silico prediction methods were used to identify 62 of those AMPs as peptides with promising antimicrobial activity potential. Signatures of directional selection were detected for five candidate AMPs, which may indicate adaptation to the different selective pressures imposed by evolutionary arms races with specific pathogens. These findings provide encouraging support for the expectation that caecilians, being one of the least-studied groups of vertebrates, and with ~300 million years of separate evolution, are an underexplored resource of great pharmaceutical potential that could help to contest antibiotic resistance and contribute to biomedical advance.

Soluble and insoluble lysates from the human A53T mutant α-synuclein transgenic mouse model induces α-synucleinopathy independent of injection site.

Pathological aggregation of a-synuclein (aS) is implicated in the pathogenesis of Parkinson's disease (PD) and other a-synucleinopathies. The current view is that neuron-to-neuron spreading of aS pathology contributes to the progression of a-synucleinopathy. We used an A53T mutant human aS transgenic mouse model (TgA53T) to examine whether the site of pathogenic aS inoculation affects the pattern of neuropathology and whether soluble and insoluble fractions derived from crude pathogenic tissue lysates exhibit differential capacities to initiate aS pathology. To test whether the inoculation site impacts the ultimate spatial/temporal patterns of aS pathology, aS preformed fibrils (PFF), or brain homogenates from TgA53T mice with a-synucleinopathy, were injected into the cortex/striatum, brain stem, or skeletal muscle. In all cases, inoculation of pathogenic aS induced end-stage motor dysfunction within ~100 days post-inoculation (dpi). Significantly, irrespective of the inoculation sites, ultimate distribution of the aS pathology was like that seen in normally aged TgA53T mice at end-stage, indicating that the intrinsic neuronal vulnerability is a significant determinant in the induction of aS pathology, even when initiated by inoculation of pathogenic aS. Temporal analysis of brain stem injected TgA53T mice show that initial aS pathology was seen by 30 days post-inoculation and inflammatory changes occur at later stages. To determine if the aS species with differential solubility are differentially pathogenic, brain lysates from end-stage TgA53Tmice were fractionated into highly soluble (S150) and insoluble (P150) fractions, as well as the endoplasmic reticulum (ER)-enriched fraction (P100). Significantly, all fractions were able to seed de novo aS pathology in vivo, when injected unilaterally into TgA53Tmice with the ER fractions being most pathogenic. Our results suggest that multiple aS species from brain can initiate the development of progressive aS pathology.

Eosinophils of patients with localized and diffuse cutaneous leishmaniasis: Differential response to Leishmania mexicana, with insights into mechanisms of damage inflicted upon the parasites by eosinophils.

Eosinophils are mainly associated with parasitic infections and allergic manifestations. They produce many biologically active substances that contribute to the destruction of pathogens through the degranulation of microbicidal components and inflammatory tissue effects. In leishmaniasis, eosinophils have been found within inflammatory infiltrate with protective immunity against the parasite. We analyzed the responses of eosinophils from patients with localized (LCL) and diffuse (DCL) cutaneous leishmaniasis, as well as from healthy subjects, when exposed to Leishmania mexicana. All DCL patients exhibited blood eosinophilia, along with elevated eosinophil counts in non-ulcerated nodules. In contrast, only LCL patients with prolonged disease progression showed eosinophils in their blood and cutaneous ulcers. Eosinophils from DCL patients secreted significantly higher levels of IL-6, IL-8, and IL-13, compared to eosinophils from LCL patients. Additionally, DCL patients displayed higher serum levels of anti-Leishmania IgG antibodies. We also demonstrated that eosinophils from both LCL and DCL patients responded to L. mexicana promastigotes with a robust oxidative burst, which was equally intense in both patient groups and significantly higher than in healthy subjects. Coincubation of eosinophils (from donors with eosinophilia) with L. mexicana promastigotes in vitro revealed various mechanisms of parasite damage associated with different patterns of granule exocytosis: 1) localized degranulation on the parasite surface, 2) the release of cytoplasmic membrane-bound "degranulation sacs" containing granules, 3) release of eosinophil extracellular traps containing DNA and granules with major basic protein. In conclusion, eosinophils damage L. mexicana parasites through the release of granules via diverse mechanisms. However, despite DCL patients having abundant eosinophils in their blood and tissues, their apparent inability to provide protection may be linked to the release of cytokines and chemokines that promote a Th2 immune response and disease progression in these patients.

Gene and stem cell therapy for inherited cardiac arrhythmias.

Inherited cardiac arrhythmias are a group of genetic diseases predisposing to sudden cardiac arrest, mainly resulting from variants in genes encoding cardiac ion channels or proteins involved in their regulation. Currently available therapeutic options (pharmacotherapy, ablative therapy and device-based therapy) can not preclude the occurrence of arrhythmia events and/or provide complete protection. With growing understanding of the genetic background and molecular mechanisms of inherited cardiac arrhythmias, advancing insight of stem cell technology, and development of vectors and delivery strategies, gene therapy and stem cell therapy may be promising approaches for treatment of inherited cardiac arrhythmias. Recent years have witnessed impressive progress in the basic science aspects and there is a clear and urgent need to be translated into the clinical management of arrhythmic events. In this review, we present a succinct overview of gene and cell therapy strategies, and summarize the current status of gene and cell therapy. Finally, we discuss future directions for implementation of gene and cell therapy in the therapy of inherited cardiac arrhythmias.

Partial Cranial Reconstruction Using Titanium Mesh after Craniectomy: An Antiadhesive and Protective Barrier with Improved Aesthetic Outcomes.

OBJECTIVE: Describe a new, safe, technique that uses titanium mesh to partially cover skull defects immediately after decompressive craniectomy (DC). METHODS: This study is a retrospective review of 8 patients who underwent DC and placement of a titanium mesh. The mesh partially covered the defect and was placed between the temporalis muscle and the dura graft. The muscle was sutured to the mesh. All patients underwent cranioplasty at a later time. The study recorded and analyzed demographic information, time between surgeries, extra-axial fluid collections, postoperative infections, need for reoperation, cortical hemorrhages, and functional and aesthetic outcomes. RESULTS: After craniectomy, all patients underwent cranioplasty within an average of 112.5 days (30-240 days). One patient reported temporalis muscle atrophy, which was the only complication observed. During the cranioplasties, no adhesions were found between temporalis muscle, titanium mesh, and underlying dura. None of the patients showed complications in the follow-up computerized tomography scans. All patients had favorable aesthetic and functional results. CONCLUSIONS: Placing a titanium mesh as an extra step during DC could have antiadhesive and protective properties, facilitating subsequent cranioplasty by preventing adhesions and providing a clear surgical plane between the temporalis muscle and intracranial tissues. This technique also helps preserve the temporalis muscle and enhances functional and aesthetic outcomes postcranioplasty. Therefore, it represents a safe alternative to other synthetic anti-adhesive materials. Further studies are necessary to draw definitive conclusions and elucidate long-term outcomes, however, the results obtained hold great promise for the safety and efficacy of this technique.

Underlying mechanism of atrial fibrillation-associated Nppa-I137T mutation and cardiac effect of potential drug therapy.

BACKGROUND: More than a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved. OBJECTIVE: This study aimed to investigate the mechanism and potential treatment of NPPA mutation-associated AF. METHODS: Nppa knock-in (KI, p.I137T) rats were generated, and cardiac function was evaluated. Blood pressure was recorded using a tail-cuff system. The expression levels were measured using real-time polymerase chain reaction, enzyme-linked immunosorbent assay or Western blot analysis, and RNA-sequence analysis. Programmed electrical stimulation, patch clamp, and multielectrode array were used to record the electrophysical characteristics. RESULTS: Mutant rats displayed downregulated expression of atrial natriuretic peptide but elevated blood pressure and enlarged left atrial end-diastolic diameter. Further, gene topology analysis suggested that the majority of differently expressed genes in Nppa KI rats were related to inflammation, electrical remodeling, and structural remodeling. The expression levels of C-C chemokine ligand 5 and galectin-3 involved in remodeling were higher, while there were declined levels of Nav1.5, Cav1.2, and connexin 40. AF was more easily induced in KI rats. Electrical remodeling included abbreviated action potentials, effective refractory period, increased late sodium current, and reduced calcium current, giving rise to conduction abnormalities. These electrophysiological changes could be reversed by the late sodium current blocker ranolazine and the Nav1.8 blocker A-803467. CONCLUSION: Our findings suggest that structural remodeling related to inflammation and fibrosis and electrical remodeling involved in late sodium current underly the major effects of the Nppa (p.I137T) variant to induce AF, which can be attenuated by the late sodium current blocker and Nav1.8 blocker.

Human immunodeficiency virus patients with low CD4 counts are more likely to have precancerous polyps identified during index colonoscopy.

BACKGROUND: Antiretroviral treatment (ART) has improved the life expectancy of patients living with human immunodeficiency virus (HIV). As these patients age, they are at increased risk for developing non-acquired immunodeficiency syndrome defining malignancies (NADMs) such as colon cancers. AIM: To determine which factors are associated with the development of precancerous polyps on screening colonoscopy in patients with HIV and to investigate whether HIV disease status, measured by viral load and CD4 count, might influence precancerous polyp development. METHODS: A retrospective review of records at two urban academic medical centers was performed for HIV patients who had a screening colonoscopy between 2005-2015. Patients with a history of colorectal cancer or polyps, poor bowel preparation, or inflammatory bowel disease were excluded. Demographic data such as sex, age, race, and body mass index (BMI) as well as information regarding the HIV disease status such as CD4 count, viral load, and medication regimen were collected. Well-controlled patients were defined as those that had viral load < 50 copies, and poorly-controlled patients were those with viral load ≥ 50. Patients were also stratified based on their CD4 count, comparing those with a low CD4 count to those with a high CD4 count. Using colonoscopy reports in the medical record, the size, histology, and number of polyps were recorded for each patient. Precancerous polyps included adenomas and proximal serrated polyps. Data was analyzed using Fisher's exact tests and logistic regression through SAS 3.8 software. RESULTS: Two hundred and seven patients met our inclusion criteria. The mean age was 56.13 years, and 58% were males. There were no significant differences in terms of age, race or ethnicity, insurance, and smoking status between patients with CD4 counts above or below 500. BMI was lower in patients with CD4 count < 500 as compared to those with count > 500 (P = 0.0276). In patients with CD4 > 500, 53.85% of patients were female, and 70.87% of patients with CD4 < 500 were male (P = 0.0004). Only 1.92% of patients with CD4 ≥ 500 had precancerous polyps vs 10.68% of patients with CD4 < 500 (P = 0.0102). When controlled for sex, BMI, and ART use, patients with CD4 < 500 were 9.01 times more likely to have precancerous polyps [95% confidence interval (CI): 1.69-47.97; P = 0.0100]. Patients taking non-nucleoside reverse transcriptase inhibitors were also found to be 10.23 times more likely to have precancerous polyps (95%CI: 1.08-97.15; P = 0.0428). There was not a significant difference noted in precancerous polyps between those that had viral loads greater or less than 50 copies. CONCLUSION: Patients with low CD4 counts were more likely to have precancerous polyps on their screening colonoscopy although the etiology for this association is unclear. We also found an increased risk of precancerous polyps in patients taking non-nucleoside reverse transcriptase inhibitors, which is contradictory to prior literature showing ART has decreased the risk of development of NADMs. However, there have not been studies looking at colorectal cancer and ART by drug class, to our knowledge. Further prospective studies are needed to determine the effect of HIV control and therapies on polyp development.

Emergence of a three-sample conditional discrimination as foundation for reasoning capabilities.

We hypothesized that a three-sample conditional discrimination can emerge as a result of learning conditional discriminations with relational stimuli. After learning three first-order conditional discriminations AB, PQ, and CD, we taught a second-order conditional discrimination XAB in which X1 indicated selection of related stimuli (e.g., A1 and B1) and X2 of unrelated stimuli (e.g., A1 and B2). Then, we probed the emergence of conditional discriminations PQX and XCD in which the X stimuli were comparisons and contextual stimuli, respectively. Finally, a conditional discrimination was probed with stimuli P, Q, and C as samples and D1 and D2 as comparisons. When the P and Q stimuli were related (and related to X1 in PQX), all participants selected the D stimulus that was related to the C stimulus (D1 when C1 was present and D2 when C2 was present); when the P and Q stimuli were unrelated (and related to X2 in PQX), they selected the D stimulus unrelated to the C stimulus (D2 when C1 and D1 when C2), which demonstrated emergence based on the relations established among all stimuli. In Experiment 2, the teaching of XAB was omitted and only one in six participants demonstrated emergence, which indicated that relational stimuli X1 and X2 played an important role in emergence. Thus, a new type of emergence that mimics analogical reasoning was demonstrated. The obtained outcome suggests that this procedure provides a learning foundation for acquiring reasoning capabilities.

A simple but effective solution for proximal mark absence on some microcatheters in intracranial aneurysm embolization: Technical note.

Background: Endovascular coil embolization is increasingly being used for the treatment of intracranial aneurysms and other pathologies such as arteriovenous (AV) malformations and AV fistulas. Appropriate embolization technique requires a microcatheter with two radiopaque marks, one proximal and one distal. We present an alternative coils deployment technique for intracranial aneurysms, using a microcatheter without a proximal radiopaque mark. Methods: We describe the technique for embolization that was used in a 36-year-old female patient, in which we used a microcatheter without a proximal radiopaque mark for coil embolization of an intracranial aneurysm. Results: We used a Headway Duo flow directed microcatheter for a coiling embolization of an intracranial aneurysm, solving the absence of the proximal radiopaque mark by cannulating the microcatheter with a Traxcess 0.014 microguidewire, and placing an external mark on the screen in the proximal portion of the microguidewire 30 mm radiopaque tip to indirectly mark the proximal mark of the microcatheter. Conclusion: There is scarce evidence supporting the use of microcatheters with no proximal radiopaque mark for coil embolization. This report attempts to disclose how an easy and simple technique can be used as a rescue method to solve the proximal radiopaque mark absence during endovascular coil release procedures. To the best of our knowledge, this technique has not been previously described; therefore, its use is not widespread among neurointerventionists.

Capsular warning syndrome and its clinical awareness and therapeutic approach: two case reports and a systematic review of the literature.

Introduction: Capsular warning syndrome (CWS) is characterized by recurrent stereotyped episodes of unilateral transient motor and/or sensory symptoms affecting the face and upper and lower limbs, without cortical signs in 24 h and with a high risk of developing stroke. Among the possible underlying mechanisms, small perforating artery disease is the most common. The aim was to assess the most common risk factors, the therapeutic alternatives, and the different outcomes in patients with CWS, along with the presentation of two cases treated in our Emergency Department. Methods: Stroke Code, launched at our institution in January 2017, was triggered 400 times, and by December 2022, 312 patients were admitted as having an acute ischemic stroke. Among them, two of them fulfilled the criteria of CWS. A systematic search was carried out in PubMed, Scopus, and Web of Science databases to seek demography and therapeutic approaches in CWS. Results: Of 312 cases, two with acute ischemic stroke exhibited CWS. The first patient had six events of right hemiparesis with recovery in 10-30 min; after MRI and digital subtraction angiography (DSA), he received apixaban and clopidogrel; however, a day after admission, he developed ischemic infarction with partial recovery. The second patient presented five transient events of right hemiparesis. After MRI and DSA with an intra-arterial infusion of nimodipine, oral aspirin, and ticagrelor, he presented another event-developing stroke and was discharged with partial recovery. A systematic review found 190 cases of CWS in 39 articles from 1993 to 2022. Most were male subjects (66.4%), and hypertension (60%), smoking (36%), diabetes (18%), and dyslipidemia (55%) were the most common risk factors. Over 50% of the cases were secondary to small perforating artery disease. The most commonly used treatments were dual antiplatelet therapy (DAT), recombinant tissue plasminogen activator, and anticoagulant therapy (ACT), where the combination of DAT plus ACT was linked to the most positive functional outcomes (82.6%). Conclusion: Our cases fit with the description of patients with partial recovery and risk factors (hypertension, diabetes, and smoking) in male patients. There is a lack of evidence regarding the best treatment option; dual antiplatelet therapy and anticoagulation therapy are strong contenders for a favorable result.

TP53/p53 Facilitates Stress-Induced Exosome and Protein Secretion by Adipocytes.

Besides the secretion of fatty acids, lipolytic stimulation of adipocytes results in the secretion of triglyceride-rich extracellular vesicles and some free proteins (e.g., fatty acid binding protein 4) that, in sum, affect adipose homeostasis as well as the development of metabolic disease. At the mechanistic level, lipolytic signals activate p53 in an adipose triglyceride lipase-dependent manner, and pharmacologic inhibition of p53 attenuates adipocyte-derived extracellular vesicle (AdEV) protein and FABP4 secretion. Mass spectrometry analyses of the lipolytic secretome identified proteins involved in glucose and fatty acid metabolism, translation, chaperone activities, and redox control. Consistent with a role for p53 in adipocyte protein secretion, activation of p53 by the MDM2 antagonist nutlin potentiated AdEV particles and non-AdEV protein secretion from cultured 3T3-L1 or OP9 adipocytes while the levels of FABP4 and AdEV proteins were significantly reduced in serum from p53-/- mice compared with wild-type controls. The genotoxin doxorubicin increased AdEV protein and FABP4 secretion in a p53-dependent manner and DNA repair-depleted ERCC1-/Δ-haploinsufficient mice expressed elevated p53 in adipose depots, along with significantly increased serum FABP4. In sum, these data suggest that lipolytic signals, and cellular stressors such as DNA damage, facilitate AdEV protein and FABP4 secretion by adipocytes in a p53-dependent manner.

Multiple Instances of Adaptive Evolution in Aquaporins of Amphibious Fishes.

Aquaporins (AQPs) are a highly diverse family of transmembrane proteins involved in osmotic regulation that played an important role in the conquest of land by tetrapods. However, little is known about their possible implication in the acquisition of an amphibious lifestyle in actinopterygian fishes. Herein, we investigated the molecular evolution of AQPs in 22 amphibious actinopterygian fishes by assembling a comprehensive dataset that was used to (1) catalogue AQP paralog members and classes; (2) determine the gene family birth and death process; (3) test for positive selection in a phylogenetic framework; and (4) reconstruct structural protein models. We found evidence of adaptive evolution in 21 AQPs belonging to 5 different classes. Almost half of the tree branches and protein sites that were under positive selection were found in the AQP11 class. The detected sequence changes indicate modifications in molecular function and/or structure, which could be related to adaptation to an amphibious lifestyle. AQP11 orthologues appear to be the most promising candidates to have facilitated the processes of the water-to-land transition in amphibious fishes. Additionally, the signature of positive selection found in the AQP11b stem branch of the Gobiidae clade suggests a possible case of exaptation in this clade.

Functional identification of hot-spot mutations in cardiac calcium channel genes associated with the J wave syndromes.

J wave syndrome (JWS) is an inherited cardiac channelopathy associated with malignant ventricular arrhythmias and sudden cardiac death (SCD), which comprises early repolarization syndrome and Brugada syndrome. Here, we explore the association between variants in the L-type calcium channel gene subunits, α1C (CACNA1C) and ß2b (CACNB2b), and the JWS phenotype. Using next-generation genetic sequencing of 402 JWS probands and their family members, we identified a CACNA1C-G37R (p.Gly37Arg) mutation in five individuals in four families, two of which had a family history of SCD as well as a CACNB2b-S143F (p.Ser143Phe) mutation in seven individuals in three families, two of which had a family history of SCD. The variants were located in exon 2 in CACNA1C and exon 5 in CACNB2b; both were in highly conserved amino acid residues. Whole-cell patch-clamp results showed that compared with the wild-type group, calcium current density of CACNB2b-S143F and CACNA1C-G37R were significantly lower displaying a dominant-negative effect. Our findings provide further support for the hypothesis that variants in CACNA1C and CACNB2b are associated with JWS. The results suggest that mutations in these two genes lead to loss-of-function of the cardiac calcium channel current warranting their inclusion in genetic screening protocols. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Advances in basic and translational research in atrial fibrillation.

Atrial fibrillation (AF) is a very common cardiac arrhythmia with an estimated prevalence of 33.5 million patients globally. It is associated with an increased risk of death, stroke and peripheral embolism. Although genetic studies have identified a growing number of genes associated with AF, the definitive impact of these genetic findings is yet to be established. Several mechanisms, including electrical, structural and neural remodelling of atrial tissue, have been proposed to contribute to the development of AF. Despite over a century of exploration, the molecular and cellular mechanisms underlying AF have not been fully established. Current antiarrhythmic drugs are associated with a significant rate of adverse events and management of AF using ablation is not optimal, especially in cases of persistent AF. This review discusses recent advances in our understanding and management of AF, including new concepts of epidemiology, genetics and pathophysiological mechanisms. We review the current status of antiarrhythmic drug therapy for AF, new potential agents, as well as mechanism-based AF ablation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Mechanisms underlying the antiarrhythmic effect of ARumenamide-787 in experimental models of the J wave syndromes and hypothermia.

BACKGROUND: Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia. METHODS: We studied the effects of AR-787 on INa and IKr in HEK-293 cells stably expressing the α- and ß1-subunits of the cardiac (NaV1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on Ito, INa and ICa in dissociated canine ventricular myocytes along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The Ito agonist, NS5806 (5-10 µM), ICa blocker, verapamil (2.5 µM), and INa blocker, ajmaline (2.5 µM), were used to mimic the genetic defects associated with JWS and to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves/ST segment elevation, phase 2 reentry and polymorphic VT/VF) in canine ventricular wedge preparations. RESULTS: AR-787 (1, 10 and 50 µM) exerted pleiotropic effects on cardiac ion channels. The predominant effect was inhibition of the transient outward current (Ito) and enhancement of the sodium channel current (INa), with lesser effects to inhibit IKr and augment calcium channel current (ICa). AR-787 diminished the electrocardiographic J wave and prevented and/or suppressed all arrhythmic activity in canine RV and LV experimental models of BrS, ERS and hypothermia. CONCLUSIONS: Our findings point to AR-787 as promising candidate for the pharmacologic treatment of JWS and hypothermia.

Use of sotrovimab in vaccinated versus unvaccinated COVID-19 patients in a resource-limited emergency department during the omicron surge.

Objective: The treatment of outpatient COVID-19 patients at high risk of disease progression has been challenging, as both the virus and available therapeutics change. Here, we sought to evaluate the effect of vaccination status on the use of sotrovimab during the early phase of the Omicron surge. Methods: This was a retrospective observational study performed at El Centro Regional Medical Center, a rural hospital on the southern Californian border. The electronic medical record was queried for all emergency department (ED) patients who received an infusion of sotrovimab between January 6 and February 6, 2022. We obtained patient demographics, COVID-19 vaccination status, medical comorbidities, and whether patients returned to the ED within 30 days. We stratified our cohort according to vaccination status and performed a multivariable logistic regression model to evaluate the relationship between these factors. Results: One hundred seventy patients received an infusion of sotrovimab in the ED. The patient cohort had a median age of 65 years, 78.2% were Hispanic, and obesity (63.5%) was the most common comorbidity. A total of 73.5% of patients were vaccinated against COVID-19. A total of 12/125 (9.6%) of vaccinated patients returned to the ED within 30 days, versus 10/45 (22.2%) in the unvaccinated cohort, which was statically significant (P = 0.03). The presence of medical comorbidities was not associated with the primary outcome. Conclusion: Of patients who received sotrovimab, those who were vaccinated were less likely to return to the ED within 30 days compared to those who were unvaccinated. Given the effectiveness of the COVID-19 vaccination campaign, and with the emergence of new variants, it is unclear what role monoclonal antibody therapy should play in the treatment of outpatient COVID-19 patients.

The primary root procambium contributes to lateral root formation through its impact on xylem connection.

The postembryonic formation of lateral roots (LRs) starts in internal root tissue, the pericycle. An important question of LR development is how the connection of the primary root vasculature with that of the emerging LR is established and whether the pericycle and/or other cell types direct this process. Here, using clonal analysis and time-lapse experiments, we show that both the procambium and pericycle of the primary root (PR) affect the LR vascular connectivity in a coordinated manner. We show that during LR formation, procambial derivates switch their identity and become precursors of xylem cells. These cells, together with the pericycle-origin xylem, participate in the formation of what we call a "xylem bridge" (XB), which establishes the xylem connection between the PR and the nascent LR. If the parental protoxylem cell fails to differentiate, XB is still sometimes formed but via a connection with metaxylem cells, highlighting that this process has some plasticity. Using mutant analyses, we show that the early specification of XB cells is determined by CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIP III) transcription factors (TFs). Subsequent XB cell differentiation is marked by the deposition of secondary cell walls (SCWs) in spiral and reticulate/scalariform patterns, which is dependent on the VASCULAR-RELATED NAC-DOMAIN (VND) TFs. XB elements were also observed in Solanum lycopersicum, suggesting that this mechanism may be more widely conserved in plants. Together, our results suggest that plants maintain vascular procambium activity, which safeguards the functionality of newly established lateral organs by assuring the continuity of the xylem strands throughout the root system.