Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Early development in the velvet worm Euperipatoides kanangrensis Reid 1996 (Onychophora: Peripatopsidae)

We present here a description of early development in the onychophoran Euperipatoides kanangrensis with emphasis on processes that are ambiguously described in older literature. Special focus has been on the pattern of early cleavage, blastoderm and germinal disc development and gastrulation. The formation of the blastopore, stomodeum and proctodeum is described from sectioned material using light and transmission electron microscopy as well as whole-mount material stained for nuclei and gene expression. The early cleavages were found to be superficial, contrary to earlier descriptions of cleavage in yolky, ovoviviparous onychophorans. Also, contrary to earlier descriptions, the embryonic anterior-posterior axis is not predetermined in the egg. Our data support the view of a blastopore that becomes elongated and slit-like, resembling some of the earliest descriptions. From gene expression data, we concluded that the position of the proctodeum is the most posterior pit in the developing embryo. This description of early development adds to our knowledge of the staging of embryonic development in onychophorans necessary for studies on the role of developmental changes in evolution.11 page(s

Ultrastructure of the eggshell and its formation in Planipapillus mundus (Onychophora : Peripatopsidae)

Although the majority of onychophorans are viviparous or ovoviviparous, oviparity has been described in a number of species found exclusively in Australia and New Zealand. Light microscopy and scanning and transmission electron microscopy were used to examine developing eggs and the reproductive tract of the oviparous Planipapillus mundus. Deposited eggs and fully developed eggs dissected from the terminal end of the uteri have an outer thick, slightly opaque chorion, and an inner thin, transparent vitelline membrane. The chorion comprises an outermost extrachorion, sculptured with domes equally spaced over the surface; a middle exochorion, with pores occurring in a pattern of distribution equivalent to that of the domes of the extrachorion above; and an innermost, thick endochorion consisting of a spongelike reticulum of cavities comparable to the respiratory network found in insect eggs. The vitelline membrane lies beneath the chorion, from which it is separated by a fluid-filled space. The vitelline membrane tightly invests the developing egg. Examination of oocytes in the ovary and developing eggs at various stages of passage through the uterus indicate that the majority of chorion deposition occurs in the midregion of the uterus, where vast networks of endoplasmic reticulum are present in the columnar epithelium. The vitelline membrane, however, is believed to begin its development as a primary egg membrane, surrounding the developing oocytes in the ovary. The vitelline membrane is transformed after fertilization, presumably by secretions from the anterior region of the uterus; hence, it should be more accurately referred to as a fertilization membrane. Aspects of the reproductive biology of P. mundus are also included.13 page(s

Onychophoran Hox genes and the evolution of arthropod Hox gene expression

Introduction: Onychophora is a relatively small phylum within Ecdysozoa, and is considered to be the sister group to Arthropoda. Compared to the arthropods, that have radiated into countless divergent forms, the onychophoran body plan is overall comparably simple and does not display much in-phylum variation. An important component of arthropod morphological diversity consists of variation of tagmosis, i.e. the grouping of segments into functional units (tagmata), and this in turn is correlated with differences in expression patterns of the Hox genes. How these genes are expressed in the simpler onychophorans, the subject of this paper, would therefore be of interest in understanding their subsequent evolution in the arthropods, especially if an argument can be made for the onychophoran system broadly reflecting the ancestral state in the arthropods. Results: The sequences and embryonic expression patterns of the complete set of ten Hox genes of an onychophoran (Euperipatoides kanangrensis) are described for the first time. We find that they are all expressed in characteristic patterns that suggest a function as classical Hox genes. The onychophoran Hox genes obey spatial colinearity, and with the exception of Ultrabithorax (Ubx), they all have different and distinct anterior expression borders. Notably, Ubx transcripts form a posterior to anterior gradient in the onychophoran trunk. Expression of all onychophoran Hox genes extends continuously from their anterior border to the rear end of the embryo. Conclusions: The spatial expression pattern of the onychophoran Hox genes may contribute to a combinatorial Hox code that is involved in giving each segment its identity. This patterning of segments in the uniform trunk, however, apparently predates the evolution of distinct segmental differences in external morphology seen in arthropods. The gradient-like expression of Ubx may give posterior segments their specific identity, even though they otherwise express the same set of Hox genes. We suggest that the confined domains of Hox gene expression seen in arthropods evolved from an ancestral onychophoran-like Hox gene pattern. Reconstruction of the ancestral arthropod Hox pattern and comparison with the patterns in the different arthropod classes reveals phylogenetic support for Mandibulata and Tetraconata, but not Myriochelata and Atelocerata

The role of ventral and preventral organs as attachment sites for segmental limb muscles in Onychophora

Background: The so-called ventral organs are amongst the most enigmatic structures in Onychophora (velvet worms). They were described as segmental, ectodermal thickenings in the onychophoran embryo, but the same term has also been applied to mid-ventral, cuticular structures in adults, although the relationship between the embryonic and adult ventral organs is controversial. In the embryo, these structures have been regarded as anlagen of segmental ganglia, but recent studies suggest that they are not associated with neural development. Hence, their function remains obscure. Moreover, their relationship to the anteriorly located preventral organs, described from several onychophoran species, is also unclear. To clarify these issues, we studied the anatomy and development of the ventral and preventral organs in several species of Onychophora. Results: Our anatomical data, based on histology, and light, confocal and scanning electron microscopy in five species of Peripatidae and three species of Peripatopsidae, revealed that the ventral and preventral organs are present in all species studied. These structures are covered externally with cuticle that forms an internal, longitudinal, apodeme-like ridge. Moreover, phalloidin-rhodamine labelling for f-actin revealed that the anterior and posterior limb depressor muscles in each trunk and the slime papilla segment attach to the preventral and ventral organs, respectively. During embryonic development, the ventral and preventral organs arise as large segmental, paired ectodermal thickenings that decrease in size and are subdivided into the smaller, anterior anlagen of the preventral organs and the larger, posterior anlagen of the ventral organs, both of which persist as paired, medially-fused structures in adults. Our expression data of the genes Delta and Notch from embryos of Euperipatoides rowelli revealed that these genes are expressed in two, paired domains in each body segment, corresponding in number, position and size with the anlagen of the ventral and preventral organs. Conclusions: Our findings suggest that the ventral and preventral organs are a common feature of onychophorans that serve as attachment sites for segmental limb depressor muscles. The origin of these structures can be traced back in the embryo as latero-ventral segmental, ectodermal thickenings, previously suggested to be associated with the development of the nervous system.17 page(s

Onychophoran Hox genes and the evolution of arthropod Hox gene expression

Introduction: Onychophora is a relatively small phylum within Ecdysozoa, and is considered to be the sister group to Arthropoda. Compared to the arthropods, that have radiated into countless divergent forms, the onychophoran body plan is overall comparably simple and does not display much in-phylum variation. An important component of arthropod morphological diversity consists of variation of tagmosis, i.e. the grouping of segments into functional units (tagmata), and this in turn is correlated with differences in expression patterns of the Hox genes. How these genes are expressed in the simpler onychophorans, the subject of this paper, would therefore be of interest in understanding their subsequent evolution in the arthropods, especially if an argument can be made for the onychophoran system broadly reflecting the ancestral state in the arthropods. Results: The sequences and embryonic expression patterns of the complete set of ten Hox genes of an onychophoran (Euperipatoides kanangrensis) are described for the first time. We find that they are all expressed in characteristic patterns that suggest a function as classical Hox genes. The onychophoran Hox genes obey spatial colinearity, and with the exception of Ultrabithorax (Ubx), they all have different and distinct anterior expression borders. Notably, Ubx transcripts form a posterior to anterior gradient in the onychophoran trunk. Expression of all onychophoran Hox genes extends continuously from their anterior border to the rear end of the embryo. Conclusions: The spatial expression pattern of the onychophoran Hox genes may contribute to a combinatorial Hox code that is involved in giving each segment its identity. This patterning of segments in the uniform trunk, however, apparently predates the evolution of distinct segmental differences in external morphology seen in arthropods. The gradient-like expression of Ubx may give posterior segments their specific identity, even though they otherwise express the same set of Hox genes. We suggest that the confined domains of Hox gene expression seen in arthropods evolved from an ancestral onychophoran-like Hox gene pattern. Reconstruction of the ancestral arthropod Hox pattern and comparison with the patterns in the different arthropod classes reveals phylogenetic support for Mandibulata and Tetraconata, but not Myriochelata and Atelocerata

Head patterning and Hox gene expression in an onychophoran and its implications for the arthropod head problem

The arthropod head problem has puzzled zoologists for more than a century. The head of adult arthropods is a complex structure resulting from the modification, fusion and migration of an uncertain number of segments. In contrast, onychophorans, which are the probable sister group to the arthropods, have a rather simple head comprising three segments that are well defined during development, and give rise to the adult head with three pairs of appendages specialised for sensory and food capture/manipulative purposes. Based on the expression pattern of the anterior Hox genes labial, proboscipedia, Hox3 and Deformed, we show that the third of these onychophoran segments, bearing the slime papillae, can be correlated to the tritocerebrum, the most anterior Hox-expressing arthropod segment. This implies that both the onychophoran antennae and jaws are derived from a more anterior, Hox-free region corresponding to the proto and deutocerebrum of arthropods. Our data provide molecular support for the proposal that the onychophoran head possesses a well-developed appendage that corresponds to the anterior, apparently appendage-less region of the arthropod head