This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Severe cases of SARS-CoV-2 infection are characterized by hypercoagulopathies and systemic endotheliitis of the lung microvasculature. The dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of an immune cell-mediated cytokine storm remain unknown. Using a vascularized lung-on-chip model, we find that infection of alveolar epithelial cells leads to limited apical release of virions, consistent with reports of monoculture infection. However, viral RNA and proteins are rapidly detected in underlying endothelial cells, which are themselves refractory to apical infection in monocultures. Although endothelial infection is unproductive, it leads to the formation of cell clusters with low CD31 expression, a progressive loss of barrier integrity and a pro-coagulatory microenvironment. Viral RNA persists in individual cells generating an inflammatory response, which is transient in epithelial cells but persistent in endothelial cells and typified by IL-6 secretion even in the absence of immune cells. Inhibition of IL-6 signalling with tocilizumab reduces but does not prevent loss of barrier integrity. SARS-CoV-2-mediated endothelial cell damage thus occurs independently of cytokine storm.

Objective Peripartum is a period of profound hormonal changes in the body and COVID‐19 seems to have an additional impact on these women's psychosocial functioning. This calls for a need to address the psychosocial and behavioural impact of COVID‐19 on peripartum women's lives. Methods Three focus group discussions and ten in‐depth interviews were conducted. A format to guide discussions and interviews was made to bring uniformity across groups and participants. Participants were recruited through purposive sampling. In verbatim transcription was done, followed by thematic analysis to extract key conceptual themes. Results Fourteen pregnant and eleven postpartum women were included. The mean age was 28.5 years. Two major domains were identified: 1) the psychological domain including the categories of thoughts, emotions, and behaviour, and 2) the social domain comprising categories of relationships with family members and friends, perceived loss of social support, doctor‐patient relationship, and social determinants of health. Conclusion The pandemic has indeed affected the psychosocial functioning of peripartum women. The study results might prove to be helpful for clinicians and mental health specialists who can suggest and develop different coping strategies for peripartum women during this pandemic.

We establish a murine lung-on-chip infection model and use time-lapse imaging to reveal the dynamics of host-Mycobacterium tuberculosis interactions at an air-liquid interface with a spatiotemporal resolution unattainable in animal models and to probe the direct role of pulmonary surfactant in early infection. Surfactant deficiency results in rapid and uncontrolled bacterial growth in both macrophages and alveolar epithelial cells. In contrast, under normal surfactant levels, a significant fraction of intracellular bacteria are non-growing. The surfactant-deficient phenotype is rescued by exogenous addition of surfactant replacement formulations, which have no effect on bacterial viability in the absence of host cells. Surfactant partially removes virulence-associated lipids and proteins from the bacterial cell surface. Consistent with this mechanism, the attenuation of bacteria lacking the ESX-1 secretion system is independent of surfactant levels. These findings may partly explain why smokers and elderly persons with compromised surfactant function are at increased risk of developing active tuberculosis.

Uropathogenic Escherichia coli (UPEC) proliferate within superficial bladder umbrella cells to form intracellular bacterial communities (IBCs) during early stages of urinary tract infections. However, the dynamic responses of IBCs to host stresses and antibiotic therapy are difficult to assess in situ. We develop a human bladder-chip model wherein umbrella cells and bladder microvascular endothelial cells are co-cultured under flow in urine and nutritive media respectively, and bladder filling and voiding mimicked mechanically by application and release of linear strain. Using time-lapse microscopy, we show that rapid recruitment of neutrophils from the vascular channel to sites of infection leads to swarm and neutrophil extracellular trap formation but does not prevent IBC formation. Subsequently, we tracked bacterial growth dynamics in individual IBCs through two cycles of antibiotic administration interspersed with recovery periods which revealed that the elimination of bacteria within IBCs by the antibiotic was delayed, and in some instances, did not occur at all. During the recovery period, rapid proliferation in a significant fraction of IBCs reseeded new foci of infection through bacterial shedding and host cell exfoliation. These insights reinforce a dynamic role for IBCs as harbours of bacterial persistence, with significant consequences for non-compliance with antibiotic regimens.

No abstract

Background: Severe manifestations of COVID-19 include hypercoagulopathies and systemic endothelialitis. The underlying dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of immune cell-mediated cytokine storms is unknown. This is in part because in vitro infection models are typically monocultures of epithelial cells or fail to recapitulate vascular physiology. Methods: We establish a vascularised lung-on-chip infection model consisting of a co-culture of primary human alveolar epithelial (epithelial) cells and human lung microvascular endothelial (endothelial) cells, with the optional addition of CD14+ macrophages to the epithelial side. This model was used to study the dynamics of viral replication and host responses to a low dose infection of SARS-CoV-2 of the epithelial layer. Findings: SARS-CoV-2 inoculation does not lead to a productive amplification of infectious virions. However, both genomic and antisense viral RNA can be found in endothelial cells within 1-day post infection (dpi) and persist upnto 3 dpi. This generates an NF-KB-mediated inflammatory response typified by IL-6 secretion and signalling coupled with a weak antiviral interferon response, even in the absence of immune cells. Endothelial inflammation leads to a progressive loss of barrier integrity, a subset of cells also shows a transient hyperplasic phenotype. Administration of Tocilizumab slows the loss of barrier integrity but does not reduce the occurrence of the latter. Interpretation: Endothelial infection can occur through basolateral transmission from infected epithelial cells at the air-liquid interface. SARS-CoV-2 mediated inflammation occurs despite the lack of rapid viral replication and is transient in epithelial cells but persistent in endothelial cells. Infected endothelial cells might be a key source of circulating IL-6 in COVID-19 patients. Vascular damage occurs independently of immune-cell mediated cytokine storms, whose effect would only exacerbate the damage. Funding: Core support from EPFL.

Introduction: Hurricanes have increased in severity over the past 35 years, and climate change has led to an increased frequency of catastrophic flooding. The impact of floods on emergency department (ED) operations and patient health has not been well studied. We sought to detail challenges and lessons learned from the severe weather event caused by Hurricane Harvey in Houston, Texas, in August 2017.Methods: This report combines narrative data from interviews with retrospective data on patient volumes, mode of arrival, and ED lengths of stay (LOS). We compared the five-week peri-storm period for the 2017 hurricane to similar periods in 2015 and 2016.Results: For five days, flooding limited access to the hospital, with a consequent negative impact on provider staffing availability, disposition and transfer processes, and resource consumption. Interruption of patient transfer capabilities threatened patient safety, but flexibility of operations prevented poor outcomes. The total ED patient census for the study period decreased in 2017 (7062 patients) compared to 2015 (7665 patients) and 2016 (7770) patients). Over the five-week study period, the arrival-by-ambulance rate was 12.45% in 2017 compared to 10.1% in 2016 (p < 0.0001) and 13.7% in 2015 (p < 0.0001). The median ED length of stay (LOS) in minutes for admitted patients was 976 minutes in 2015 (p < 0.0001) compared to 723 minutes in 2016 and 591 in 2017 (p < 0.0001). For discharged patients, median ED LOS was 336 minutes in 2016 compared to 356 in 2015 (p < 0.0001) and 261 in 2017 (p < 0.0001). Median boarding time for admitted ED patients was 284 minutes in 2016 compared to 470 in 2015 (p < 0.0001) and 234.5 in 2017 (p < 0.001). Water damage resulted in a loss of 133 of 179 inpatient beds (74%). Rapid and dynamic ED process changes were made to share ED beds with admitted patients and to maximize transfers postflooding to decrease ED boarding times. Conclusion:A number of pre-storm preparations could have allowed for smoother and safer ride-out functioning for both hospital personnel and patients. These measures include surplus provisioning of staff and supplies to account for limited facility access. During a disaster, innovative flexibility of both ED and hospital operations may be critical when disposition and transfer capibilities or bedding capacity are compromised. [