Masks and respirators for prevention of respiratory infections: a state of the science review.

SUMMARYThis narrative review and meta-analysis summarizes a broad evidence base on the benefits-and also the practicalities, disbenefits, harms and personal, sociocultural and environmental impacts-of masks and masking. Our synthesis of evidence from over 100 published reviews and selected primary studies, including re-analyzing contested meta-analyses of key clinical trials, produced seven key findings. First, there is strong and consistent evidence for airborne transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory pathogens. Second, masks are, if correctly and consistently worn, effective in reducing transmission of respiratory diseases and show a dose-response effect. Third, respirators are significantly more effective than medical or cloth masks. Fourth, mask mandates are, overall, effective in reducing community transmission of respiratory pathogens. Fifth, masks are important sociocultural symbols; non-adherence to masking is sometimes linked to political and ideological beliefs and to widely circulated mis- or disinformation. Sixth, while there is much evidence that masks are not generally harmful to the general population, masking may be relatively contraindicated in individuals with certain medical conditions, who may require exemption. Furthermore, certain groups (notably D/deaf people) are disadvantaged when others are masked. Finally, there are risks to the environment from single-use masks and respirators. We propose an agenda for future research, including improved characterization of the situations in which masking should be recommended or mandated; attention to comfort and acceptability; generalized and disability-focused communication support in settings where masks are worn; and development and testing of novel materials and designs for improved filtration, breathability, and environmental impact.

Multimodality Cardiac Imaging in COVID.

Infection with SARS-CoV-2, the virus that causes COVID, is associated with numerous potential secondary complications. Global efforts have been dedicated to understanding the myriad potential cardiovascular sequelae which may occur during acute infection, convalescence, or recovery. Because patients often present with nonspecific symptoms and laboratory findings, cardiac imaging has emerged as an important tool for the discrimination of pulmonary and cardiovascular complications of this disease. The clinician investigating a potential COVID-related complication must account not only for the relative utility of various cardiac imaging modalities but also for the risk of infectious exposure to staff and other patients. Extraordinary clinical and scholarly efforts have brought the international medical community closer to a consensus on the appropriate indications for diagnostic cardiac imaging during this protracted pandemic. In this review, we summarize the existing literature and reference major societal guidelines to provide an overview of the indications and utility of echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging for the diagnosis of cardiovascular complications of COVID.

Human Tim8a, Tim8b and Tim13 are auxiliary assembly factors of mature Complex IV.

Human Tim8a and Tim8b are paralogous intermembrane space proteins of the small TIM chaperone family. Yeast small TIMs function in the trafficking of proteins to the outer and inner mitochondrial membranes. This putative import function for hTim8a and hTim8b has been challenged in human models, but their precise molecular function(s) remains undefined. Likewise, the necessity for human cells to encode two Tim8 proteins and whether any potential redundancy exists is unclear. We demonstrate that hTim8a and hTim8b function in the assembly of cytochrome c oxidase (Complex IV). Using affinity enrichment mass spectrometry, we define the interaction network of hTim8a, hTim8b and hTim13, identifying subunits and assembly factors of the Complex IV COX2 module. hTim8-deficient cells have a COX2 and COX3 module defect and exhibit an accumulation of the Complex IV S2 subcomplex. These data suggest that hTim8a and hTim8b function in assembly of Complex IV via interactions with intermediate-assembly subcomplexes. We propose that hTim8-hTim13 complexes are auxiliary assembly factors involved in the formation of the Complex IV S3 subcomplex during assembly of mature Complex IV.

Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex.

Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins. Mitochondria isolated from Sengers syndrome patient cells and tissues show a destabilized TIM22 complex and defects in the biogenesis of carrier substrates. Consistent with this phenotype, we observe perturbations in the tricarboxylic acid (TCA) cycle in cells lacking AGK. Our identification of AGK as a bona fide subunit of TIM22 provides an exciting and unexpected link between mitochondrial protein import and Sengers syndrome.

Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.

BACKGROUND: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. METHODS: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. RESULTS: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. CONCLUSIONS: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

Determination of Uranium Central-Field Covalency with 3d4f Resonant Inelastic X-ray Scattering.

Understanding the nature of metal-ligand bonding is a major challenge in actinide chemistry. We present a new experimental strategy for addressing this challenge using actinide 3d4f resonant inelastic X-ray scattering (RIXS). Through a systematic study of uranium(IV) halide complexes, [UX6]2-, where X = F, Cl, or Br, we identify RIXS spectral satellites with relative energies and intensities that relate to the extent of uranium-ligand bond covalency. By analyzing the spectra in combination with ligand field density functional theory we find that the sensitivity of the satellites to the nature of metal-ligand bonding is due to the reduction of 5f interelectron repulsion and 4f-5f spin-exchange, caused by metal-ligand orbital mixing and the degree of 5f radial expansion, known as central-field covalency. Thus, this study furthers electronic structure quantification that can be obtained from 3d4f RIXS, demonstrating it as a technique for estimating actinide-ligand covalency.

Severe weather events and cryptosporidiosis in Aotearoa New Zealand: A case series of space-time clusters.

Occurrence of cryptosporidiosis has been associated with weather conditions in many settings internationally. We explored statistical clusters of human cryptosporidiosis and their relationship with severe weather events in New Zealand (NZ). Notified cases of cryptosporidiosis from 1997 to 2015 were obtained from the national surveillance system. Retrospective space-time permutation was used to identify statistical clusters. Cluster data were compared to severe weather events in a national database. SaTScan analysis detected 38 statistically significant cryptosporidiosis clusters. Around a third (34.2%, 13/38) of these clusters showed temporal and spatial alignment with severe weather events. Of these, nearly half (46.2%, 6/13) occurred in the spring. Only five (38%, 5/13) of these clusters corresponded to a previously reported cryptosporidiosis outbreak. This study provides additional evidence that severe weather events may contribute to the development of some cryptosporidiosis clusters. Further research on this association is needed as rainfall intensity is projected to rise in NZ due to climate change. The findings also provide further arguments for upgrading the quality of drinking water sources to minimize contamination with pathogens from runoff from livestock agriculture.

Population and contact tracer uptake of New Zealand's QR-code-based digital contact tracing app for COVID-19.

This study aimed to understand the population and contact tracer uptake of the quick response (QR)-code-based function of the New Zealand COVID Tracer App (NZCTA) used for digital contact tracing (DCT). We used a retrospective cohort of all COVID-19 cases between August 2020 and February 2022. Cases of Asian and other ethnicities were 2.6 times (adjusted relative risk (aRR) 2.58, 99 per cent confidence interval (95% CI) 2.18, 3.05) and 1.8 times (aRR 1.81, 95% CI 1.58, 2.06) more likely than Maori cases to generate a token during the Delta period, and this persisted during the Omicron period. Contact tracing organization also influenced location token generation with cases handled by National Case Investigation Service (NCIS) staff being 2.03 (95% CI 1.79, 2.30) times more likely to generate a token than cases managed by clinical staff at local Public Health Units (PHUs). Public uptake and participation in the location-based system independent of contact tracer uptake were estimated at 45%. The positive predictive value (PPV) of the QR code system was estimated to be close to nil for detecting close contacts but close to 100% for detecting casual contacts. Our paper shows that the QR-code-based function of the NZCTA likely made a negligible impact on the COVID-19 response in New Zealand (NZ) in relation to isolating potential close contacts of cases but likely was effective at identifying and notifying casual contacts.

Supporting whanau during COVID-19 pandemic in Aotearoa New Zealand: a systems thinking case study.

BACKGROUND: The Aotearoa New Zealand COVID-19 pandemic response has been hailed as a success story, however, there are concerns about how equitable it has been. This study explored the experience of a collective of Maori health and social service providers in the greater Wellington region of Aotearoa New Zeland delivering COVID-19 responses. METHODS: The study was a collaboration between a large urban Maori health and social service provider, Takiri Mai Te Ata whanau ora collective, and public health researchers in Aotearoa New Zealand. Two online workshops were held with staff of the Maori service provider, collectively developing a qualitative causal loop diagram and generating systemic insights. The causal loop diagram showed interactions of various factors affecting COVID-19 response for supporting whanau (Maori family/households) at a community level. The iceberg model of systems thinking offered insights for action in understanding causal loop diagrams, emphasizing impactful changes at less visible levels. RESULTS: Six interacting subsystems were identified within the causal loop diagram that highlighted the systemic barriers and opportunities for effective COVID-19 response to Maori whanau. The medical model of health service produces difficulties for delivering kaupapa Maori services. Along with pre-existing vulnerability and health system gaps, these difficulties increased the risk of negative impacts on Maori whanau as COVID-19 cases increased. The study highlighted a critical need to create equal power in health perspectives, reducing dominance of the individual-focused medical model for better support of whanau during future pandemics. CONCLUSIONS: The study provided insights on systemic traps, their interactions and delays contributing to a relatively less effective COVID-19 response for Maori whanau and offered insights for improvement. In the light of recent changes in the Aotearoa New Zealand health system, the findings emphasize the urgent need for structural reform to address power imbalances and establish kaupapa Maori approach and equity as a norm in service planning and delivery.

The rise and fall of excess winter mortality in New Zealand from 1876 to 2020.

Excess winter mortality (EWM) has been used as a measure of how well populations and policy moderate the health effects of cold weather. We aimed to investigate long-term changes in the EWM of Aotearoa New Zealand (NZ), and potential drivers of change, and to test for structural breaks in trends. We calculated NZ EWM indices from 1876 (4,698 deaths) to 2020 (33,310 deaths), total and by age-group and sex, comparing deaths from June to September (the coldest months) to deaths from February to May and October to January. The mean age and sex-standardised EWM Index (EWMI) for the full study period, excluding 1918, was 1.22. However, mean EWMI increased from 1.20 for 1886 to 1917, to 1.34 for the 1920s, then reduced over time to 1.14 in the 2010s, with excess winter deaths averaging 4.5% of annual deaths (1,450 deaths per year) in the 2010s, compared to 7.9% in the 1920s. Children under 5 years transitioned from a summer to winter excess between 1886 and 1911. Otherwise, the EWMI age-distribution was J-shaped in all time periods. Structural break testing showed the 1918 influenza pandemic strain had a significant impact on trends in winter and non-winter mortality and winter excess for subsequent decades. It was not possible to attribute the post-1918 reduction in EWM to any single factor among improved living standards, reduced severe respiratory infections, or climate change.

TAF15::NR4A3 gene fusion identifies a morphologically distinct subset of extraskeletal myxoid chondrosarcoma mimicking myoepithelial tumors.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation predominantly arising in deep soft tissue. Its conventional morphologic appearance manifests as a relatively well-circumscribed, multilobular tumor composed of uniform short spindle-to-ovoid primitive mesenchymal cells with deeply eosinophilic cytoplasm arranged in anastomosing cords within abundant myxoid matrix. The genetic hallmark of EMC has long been considered to be pathognomonic gene rearrangements involving NR4A3, which when fused to TAF15, often have high-grade morphology with increased cellularity, moderate to severe cytologic atypia, and rhabdoid cytomorphology. Herein, we describe two cases of EMC with TAF15::NR4A3 fusion that appear morphologically distinct from both conventional and high-grade EMC. Both cases had an unusual biphasic appearance and showed diffuse positivity for p63, mimicking myoepithelial tumors. DNA methylation profiling demonstrated that both cases clearly cluster with EMC, indicating that they most likely represent morphologically distinct variants of EMC. The clinical significance and prognostic impact of this morphologic variance remains to be determined. Molecular testing, including DNA methylation profiling, can help to confirm the diagnosis and avoid confusion with mimics; it adds another layer of data to support expanding the morphologic spectrum of EMC.

X-ray Spectroscopic Study of the Electronic Structure of a Trigonal High-Spin Fe(IV)═O Complex Modeling Non-Heme Enzyme Intermediates and Their Reactivity.

Fe K-edge X-ray absorption spectroscopy (XAS) has long been used for the study of high-valent iron intermediates in biological and artificial catalysts. 4p-mixing into the 3d orbitals complicates the pre-edge analysis but when correctly understood via 1s2p resonant inelastic X-ray scattering and Fe L-edge XAS, it enables deeper insight into the geometric structure and correlates with the electronic structure and reactivity. This study shows that in addition to the 4p-mixing into the 3dz2 orbital due to the short iron-oxo bond, the loss of inversion in the equatorial plane leads to 4p mixing into the 3dx2-y2,xy, providing structural insight and allowing the distinction of 6- vs 5-coordinate active sites as shown through application to the Fe(IV)═O intermediate of taurine dioxygenase. Combined with O K-edge XAS, this study gives an unprecedented experimental insight into the electronic structure of Fe(IV)═O active sites and their selectivity for reactivity enabled by the π-pathway involving the 3dxz/yz orbitals. Finally, the large effect of spin polarization is experimentally assigned in the pre-edge (i.e., the α/ß splitting) and found to be better modeled by multiplet simulations rather than by commonly used time-dependent density functional theory.

Increased Incidence of Legionellosis after Improved Diagnostic Methods, New Zealand, 2000-2020.

Legionellosis, notably Legionnaires' disease, is recognized globally and in New Zealand (Aotearoa) as a major cause of community-acquired pneumonia. We analyzed the temporal, geographic, and demographic epidemiology and microbiology of Legionnaires' disease in New Zealand by using notification and laboratory-based surveillance data for 2000‒2020. We used Poisson regression models to estimate incidence rate ratios and 95% CIs to compare demographic and organism trends over 2 time periods (2000-2009 and 2010-2020). The mean annual incidence rate increased from 1.6 cases/100,000 population for 2000-2009 to 3.9 cases/100,000 population for 2010-2020. This increase corresponded with a change in diagnostic testing from predominantly serology with some culture to almost entirely molecular methods using PCR. There was also a marked shift in the identified dominant causative organism, from Legionella pneumophila to L. longbeachae. Surveillance for legionellosis could be further enhanced by greater use of molecular typing of isolates.

The potential human health hazard of nitrates in drinking water: a media discourse analysis in a high-income country.

BACKGROUND: Recent studies linking low levels of nitrate in drinking water to colorectal cancer have raised public concerns over nitrate contamination. The aim of this study was to analyze the media discourse on the potential human health hazard of nitrates in drinking water in a high-income country with a large livestock industry: New Zealand (NZ). METHODS: Searches of media sources ("major newspapers") held by the Factiva database for the NZ setting in the five-year period 17 December 2016 to 20 December 2021. RESULTS: The largest number of media items was observed for 2017 (n = 108), the year of a NZ general election, with a notable decrease in 2020 (n = 20) that was likely due to the Covid-19 pandemic, which dominated health media. However, the percentage of these media items with a health focus steadily increased over time, from 11.1% of all articles in 2017 to 51.2% in 2021. The most commonly mentioned health hazard was colorectal cancer, followed by methemoglobinemia. The temporal pattern of media items suggests that the release of scientific studies and scholarly blogs was associated with the publication of subsequent media items. Major stakeholders involved in the discourse included representatives of local and central government, environmental and recreational interest groups, researchers, local residents, agricultural interest groups, and health organizations. Maori (Indigenous New Zealanders) values or perspectives were rarely mentioned. CONCLUSIONS: Analysis of major newspapers for a five-year period indicated that a wide range of expert comment and opinions were made available to the public and policy makers on the issue of nitrates in water. While many different stakeholder views were captured in the media discourse, there is scope for the media to better report the views of Maori on this topic. There is also a need for articles detailing the health issues to also refer to the environmental, recreational, and cultural aspects of protecting water quality to ensure that the public, policy makers, and regulators are aware of co-benefits.

Environmental Investigation and Surveillance for Legionella in Aotearoa New Zealand, 2000-2020.

The reported rate of legionellosis is increasing in Aotearoa New Zealand (NZ) with most cases community-acquired, sporadic (non-outbreak) and without an identifiable source. This analysis used two datasets to describe the environmental sources that contribute to Legionella in NZ, based on linkages with outbreaks and sporadic clinical cases, and analysis of environmental testing data. These findings highlight the need for enhanced environmental investigation of clinical cases and outbreaks. There is also a need for systematic surveillance testing of high-risk source environments to support more rigorous controls to prevent legionellosis.

Comparing COVID-19 pandemic health responses in two high-income island nations: Iceland and New Zealand.

AIMS: We aimed to compare COVID-19 control measures, epidemiological characteristics and economic performance measures in two high-income island nations with small populations, favorable border control options, and relatively good outcomes: Iceland and New Zealand (NZ). METHODS: We examined peer-reviewed journal articles, official websites, reports, media releases and press articles for data on pandemic preparedness and COVID-19 public health responses from 1 January 2020 to 1 June 2022 in Iceland and NZ. We calculated epidemiological characteristics of the COVID-19 pandemic, as well as measures of economic performance. RESULTS: Both nations had the lowest excess mortality in the OECD from the start of the pandemic up to June 2022. Iceland pursued a mitigation strategy, never used lockdowns or officially closed its border to foreign nationals, and instead relied on extensive testing and contact tracing early in the pandemic. Meanwhile, NZ pursued an elimination strategy, used a strict national lockdown to stop transmission, and closed its international border to everyone except citizens and permanent residents going through quarantine and testing. Iceland experienced a larger decrease in gross domestic product in 2020 (relative to 2019) than NZ (-8·27% vs. -1·22%, respectively). In late 2021, NZ announced a shift to a suppression strategy and in 2022 began to reopen its border in stages, while Iceland ended all public restrictions on 25 February 2022. CONCLUSIONS: Many of Iceland's and NZ's pandemic control measures appeared successful and features of the responses in both countries could potentially be adopted by other jurisdictions to address future disease outbreaks and pandemic threats.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Fatal Retroperitoneal Bleeding in Neurofibromatosis Type 1: A Clinically Occult Complication.

ABSTRACT: Neurofibromatosis type 1 (NF1) is a common, autosomal dominant neurocutaneous syndrome. The most frequent clinical manifestations include multiple neurofibromas, café-au-lait spots, dystrophic scoliosis, benign and malignant peripheral nerve sheath tumors, and paragangliomas. Neurofibromatosis type 1 vasculopathy is a less well-recognized constellation of vascular pathologies that can cause significant medical complications in patients with NF1. A rare manifestation of this process is neurofibroma infiltration of vasculature with resultant bleeding. The case presented herein illustrates a rare example of a massive fatal hemorrhage due to disruption of a large paraspinal artery in the setting of a diffuse, infiltrative neurofibroma. This case highlights the potential of benign neurofibromas to infiltrate major blood vessels, leading to extensive bleeding and death.

Increased Breadth of Group A Streptococcus Antibody Responses in Children With Acute Rheumatic Fever Compared to Precursor Pharyngitis and Skin Infections.

BACKGROUND: Group A Streptococcus (GAS) causes superficial pharyngitis and skin infections as well as serious autoimmune sequelae such as acute rheumatic fever (ARF) and subsequent rheumatic heart disease. ARF pathogenesis remains poorly understood. Immune priming by repeated GAS infections is thought to trigger ARF, and there is growing evidence for the role of skin infections in this process. METHODS: We utilized our recently developed 8-plex immunoassay, comprising antigens used in clinical serology for diagnosis of ARF (SLO, DNase B, SpnA), and 5 conserved putative GAS vaccine antigens (Spy0843, SCPA, SpyCEP, SpyAD, Group A carbohydrate), to characterize antibody responses in sera from New Zealand children with a range of clinically diagnosed GAS disease: ARF (n = 79), GAS-positive pharyngitis (n = 94), GAS-positive skin infection (n = 51), and matched healthy controls (n = 90). RESULTS: The magnitude and breadth of antibodies in ARF was very high, giving rise to a distinct serological profile. An average of 6.5 antigen-specific reactivities per individual was observed in ARF, compared to 4.2 in skin infections and 3.3 in pharyngitis. CONCLUSIONS: ARF patients have a unique serological profile, which may be the result of repeated precursor pharyngitis and skin infections that progressively boost antibody breadth and magnitude.

Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited.

Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases. In animals, the control of an extracellular compartment was achieved by the emergence of multicellular organisms able to produce tight epithelial barriers creating a stable extracellular milieu. Finally, the adaptation to a terrestrian environment was achieved by the evolution of distinct regulatory pathways allowing salt and water conservation. In this review we emphasize the critical and dual role of Na(+)-K(+)-ATPase in the control of the ionic composition of the extracellular fluid and the renin-angiotensin-aldosterone system (RAAS) in salt and water conservation in vertebrates. The action of aldosterone on transepithelial sodium transport by activation of the epithelial sodium channel (ENaC) at the apical membrane and that of Na(+)-K(+)-ATPase at the basolateral membrane may have evolved in lungfish before the emergence of tetrapods. Finally, we discuss the implication of RAAS in the origin of the present pandemia of hypertension and its associated cardiovascular diseases.