Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.

Improving the stability of temporal statistics in transition path theory with sparse data.

Ulam's method is a popular discretization scheme for stochastic operators that involves the construction of a transition probability matrix controlling a Markov chain on a set of cells covering some domain. We consider an application to satellite-tracked undrogued surface-ocean drifting buoy trajectories obtained from the National Oceanic and Atmospheric Administration Global Drifter Program dataset. Motivated by the motion of Sargassum in the tropical Atlantic, we apply Transition Path Theory (TPT) to drifters originating off the west coast of Africa to the Gulf of Mexico. We find that the most common case of a regular covering by equal longitude-latitude side cells can lead to a large instability in the computed transition times as a function of the number of cells used. We propose a different covering based on a clustering of the trajectory data that is stable against the number of cells in the covering. We also propose a generalization of the standard transition time statistic of TPT that can be used to construct a partition of the domain of interest into weakly dynamically connected regions.

Normal Transaminases in Methamphetamine- and Heroin-Associated Hyperammonemic Encephalopathy.

Detecting undisclosed methamphetamine and heroin abuse is a challenge for life underwriters and medical directors. A common clinical assumption is that if substance abusers experience liver damage, it will be indicated by elevated serum transaminases. The following case suggests that assumption may not be true for heavy substance abusers who consume no or minimal alcohol. This report describes a 44-year-old male with long-term use of inhaled combined methamphetamine and heroin ("speedballs") and minimal alcohol use, whose transaminases remained normal while episodes of acute liver failure and transient hepatic encephalopathy from hyperammonemia were observed. In this case, a fatal motor vehicle accident occurred following the sudden onset of hepatic encephalopathy hours after consuming a "speedball." Normal transaminases may not be proof of a normal healthy liver among methamphetamine and heroin abusers.

Infección por bartonella henselae en pacientes pediátricos. Lesión pseudotumoral de calota. Reporte de caso

Los tumores de calota en pacientes pediátricos poseen múltiples etiologías. Dentro de las causas pseudotumorales, las infecciones juegan un rol importante, siendo la osteomielitis por Bartonella henselae (Enfermedad por Arañazo de Gato) una posibilidad diagnóstica rara, pero que debe ser estudiada y descartada. Se presenta el caso de una lactante de 1 año, con lesión expansiva de calota, a nivel frontal derecho, hipervascularizada e infiltrativa. Se realizó estudio con ultrasonido, tomografía cerebral y cintigrama óseo. Se realizó resección quirúrgica completa de la lesión, con preservación de la duramadre y zona fontanelar, además de un cuidadoso trato con el seno sagital superior. Evolucionó sin complicaciones perioperatorias. El resultado de la biopsia fue compatible con proceso inflamatorio crónico, osteomielitis supurada. Tinción de Warthin Starry positiva sugerente de Bartonella henselae. Se descartó etiología tuberculosa y fúngica. Serología positiva para Bartonella henselae. La paciente completó antibioticoterapia, azitromicina y cotrimoxazol, con evolución clínica favorable.

Calvarial tumors in pediatric patients have multiple etiologies. Among the pseudotumoral causes, infections play an important role, being Bartonella henselae osteomyelitis (Cat Scratch Disease) a rare diagnostic possibility, but it should be studied and ruled out. We present the case of a 1 year old infant, with an expansive lesion of the calvaria, at right frontal level, hypervascularized and infiltrative. Ultrasound, brain tomography and bone scintigram were performed. Complete surgical resection of the lesion was performed, with preservation of the dura mater and fontanel area, in addition to a careful treatment with the superior sagittal sinus. The patient evolved without perioperative complications. The biopsy result was compatible with a chronic inflammatory process, suppurative osteomyelitis. Positive Warthin Starry stain suggestive of Bartonella henselae. Tuberculous and fungal etiology was ruled out. Positive serology for Bartonella henselae. The patient completed antibiotic therapy, azithromycin and cotrimoxazole, with favorable clinical evolution.

ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.

Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.

Relación genética entre las enfermedades pulmonares de origen ambiental u ocupacional y la osteoporosis: un enfoque bioinformático / Genetic relationship between pulmonary diseases of environmental or occupational origin and osteoporosis: a bioinformatic approach

Objetivo: Identificación de biomarcadores que relacionan la osteoporosis con enfermedades pulmonares ocupacionales y ambientales. Material y métodos: Mediante bases de datos de terminología médica unificada se obtuvieron enfermedades relacionadas con enfermedades pulmonares que, junto con la osteoporosis, fueron analizadas en DisGeNET para obtener los genes asociados a cada enfermedad y formar una red de interacción proteína-proteína (PPI) mediante el uso de STRING dentro de Cytoscape. A través de la aplicación de diferentes algoritmos de centralidad utilizando CythoHubba en Cytoscape, se seleccionaron las 5 proteínas de la red con el mayor grado de centralidad. Resultados: 9 enfermedades fueron incluidas en el grupo de enfermedades pulmonares. Se obtuvieron 2.698 genes asociados a enfermedades pulmonares y a osteoporosis. Los genes vinculados con osteoporosis y con al menos dos de las enfermedades pulmonares incluidas dieron lugar a una red PPI con 152 nodos y 1.378 ejes. Las proteínas con mayor grado de centralidad de la red fueron AKT1, ALB, IL6, TP53 y VEGFA. Conclusiones: Existe una elevada relación entre la osteoporosis y las enfermedades pulmonares ambientales estudiadas, a través de genes con una implicación dual. Nosotros proponemos cinco genes importantes que vinculan estas enfermedades y que podrían constituir una base coherente para investigaciones más profundas en este campo. (AU)

Objetives: Identifying biomarkers that relate osteoporosis to occupational and environmental lung diseases. Material and methods: Using integrated medical terminology databases, diseases related to lung diseases were obtained which, together with osteoporosis, were analyzed in DisGeNET to obtain the genes associated with each disease and form a protein-protein interaction network (PPI) through the Cytoscape StringApp. Applying different centrality algorithms using CythoHubba in Cytoscape, the 5 network proteins with the highest degree of centrality were selected. Results: 9 diseases were included in the group of pulmonary diseases. 2,698 genes associated with lung diseases and osteoporosis were obtained. Genes associated with osteoporosis and with at least two of the included lung diseases resulted in a PPI network with 152 nodes and 1,378 axes. The proteins with the highest degree of network centrality were AKT1, ALB, IL6, TP53 and VEGFA. Conclusions: There is a significant relationship between osteoporosis and the environmental lung diseases studied, through genes with dual involvement. We propose five important genes that link these diseases. This could provide a coherent basis for further research in this field. (AU)

The limited state of training on the social dimensions of antimicrobial resistance.

BACKGROUND: Training is needed to increase awareness and understanding of the complex problem of antimicrobial resistance (AMR) among professionals. However, AMR capacity building often does not stretch beyond the biomedical sciences, limiting interdisciplinary collaboration. OBJECTIVES: Considering the relevance of including the social sciences, this scoping review assesses the state of training on the social dimensions of AMR. METHODS: Twenty-eight training courses covering social dimensions of AMR were identified via a survey (n = 133), interviews (n = 6) and an additional internet search. General characteristics, quality and social science relevance indicators were extracted and analysed for each of these training courses. RESULTS: Because only 57% of the analysed training courses were fully focused on AMR, AMR was usually superficially covered, focusing on the biomedical basics and just mentioning some social aspects without using social science theories or experts. Only 3 of the 28 training courses covered AMR primarily from a social science perspective, while only 14% of the educators involved had social science expertise. Biomedical dimensions of AMR were covered twice as much as the social science dimensions. In the social science domain, institution and policy elements are most frequently covered, while transformations are the least covered. CONCLUSIONS: There is a clear gap in educational resources on AMR, but moreover for social scientists wanting to engage in AMR, or for non-social scientists wanting to learn about the social dimensions of AMR from an interdisciplinary perspective. This gap needs to be bridged if we want social sciences to become a relevant partner in the struggle against AMR.

SwissPKcdw - A clinical data warehouse for the optimization of pediatric dosing regimens.

Clinical trials have been performed mainly in adults and accordingly the necessary information is lacking for pediatric patients, especially regarding dosage recommendation for approved drugs. This gap in information could be filled with results from pharmacokinetic (PK) modeling, based on data collected in daily clinical routine. In order to make this data accessible and usable for research, the Swiss Pharmacokinetics Clinical Data Warehouse (SwissPKcdw ) project has been set up, including a clinical data warehouse (CDW) and the regulatory framework for data transfer and use within. Embedded into the secure BioMedIT network, the CDW can connect to various data providers and researchers in order to collaborate on the data securely. Due to its modularity, partially containerized deployment and open-source software, each of the components can be extended, modified, and re-used for similar projects that require integrated data management, data analysis, and web tools in a secure scientific data and information technology (IT) environment. Here, we describe a collaborative and interprofessional effort to implement the aforementioned infrastructure between several partners from medical health care and academia. Furthermore, we describe a real-world use case where blood samples from pediatric patients were analyzed for the presence of genetic polymorphisms and the results were aggregated and further analyzed together with the health-related patient data in the SwissPKcdw .

Factors Associated with Home Remedy Use by Adults Who Do Not Attend Health Care Facilities: Evidence from Peruvian Population-based Survey, 2019.

We estimated home remedy use (HRU) prevalence and associated factors in adults who present symptoms, disease, or accidents using the National Household Survey 2019. The estimation was performed in a population that did not access a health care facility. We conducted an analytical cross-sectional study in adults over 18 years of age. The dependent variable was HRU (Yes/No) as the main reason for not going to health care facilities. We collected these variables: age, sex, education, marital status, ethnicity, region of residence, chronic diseases or disability, and health insurance. The HRU prevalence was associated with older participants, who lived in the highlands or the jungle, belonged to Quechua or Aymara ethnic groups, and had comprehensive health insurance. In contrast, there was a lower HRU prevalence for those enrolled in private insurance. The HRU was associated with various socio-demographic factors in adults with any symptoms, illness, or accidents not attending health centers.

Gentamicin Population Pharmacokinetics in Pediatric Patients-A Prospective Study with Data Analysis Using the saemix Package in R.

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children's Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPKcdw platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0-21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were <1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment.

Transition paths of marine debris and the stability of the garbage patches.

We used transition path theory (TPT) to infer "reactive" pathways of floating marine debris trajectories. The TPT analysis was applied on a pollution-aware time-homogeneous Markov chain model constructed from trajectories produced by satellite-tracked undrogued buoys from the National Oceanic and Atmospheric Administration's Global Drifter Program. The latter involved coping with the openness of the system in physical space, which further required an adaptation of the standard TPT setting. Directly connecting pollution sources along coastlines with garbage patches of varied strengths, the unveiled reactive pollution routes represent alternative targets for ocean cleanup efforts. Among our specific findings we highlight: constraining a highly probable pollution source for the Great Pacific garbage patch; characterizing the weakness of the Indian Ocean gyre as a trap for plastic waste; and unveiling a tendency of the subtropical gyres to export garbage toward the coastlines rather than to other gyres in the event of anomalously intense winds.

Bioconjugate Supramolecular Pd2+ Metallacages Penetrate the Blood Brain Barrier In Vitro and In Vivo.

The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and theranostic agents, we explore here the possibility to target [Pd2L4]4+ cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage (CPepH3) tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures. The cage translocation efficacy was assessed by inductively coupled mass spectrometry (ICP-MS) in a BBB cellular model in vitro. Biodistribution studies of the radiolabeled cage [[99mTcO4]- ⊂ CPepH3] in the CD1 mice model demonstrate its brain penetration properties in vivo. Further DFT studies were conducted to model the structure of the [[99mTcO4]- ⊂ cage] complex. Moreover, the encapsulation capabilities and stability of the cage were investigated using the [ReO4]- anion, the "cold" analogue of [99mTcO4]-, by 1H NMR spectroscopy. Overall, our study constitutes another proof-of-concept of the unique potential of supramolecular coordination complexes for modifying the physiochemical and biodistribution properties of diagnostic species.

In Vivo Pretargeting Based on Cysteine-Selective Antibody Modification with IEDDA Bioorthogonal Handles for Click Chemistry.

Pretargeted imaging has emerged as an effective multistep strategy aiming to improve imaging contrast and reduce patient radiation exposure through decoupling of the radioactivity from the targeting vector. The inverse electron-demand Diels-Alder (IEDDA) reaction between a trans-cyclooctene (TCO)-conjugated antibody and a labeled tetrazine holds great promise for pretargeted imaging applications due to its bioorthogonality, rapid kinetics under mild conditions, and formation of stable products. Herein, we describe the use of functionalized carbonylacrylic reagents for site-specific incorporation of TCO onto a human epidermal growth factor receptor 2 (HER2) antibody (THIOMAB) containing an engineered unpaired cysteine residue, generating homogeneous conjugates. Precise labeling of THIOMAB-TCO with a fluorescent or radiolabeled tetrazine revealed the potential of the TCO-functionalized antibody for imaging the HER2 after pretargeting in a cellular context in a HER2 positive breast cancer cell line. Control studies with MDA-MD-231 cells, which do not express HER2, further confirmed the target specificity of the modified antibody. THIOMAB-TCO was also evaluated in vivo after pretargeting and subsequent administration of an 111In-labeled tetrazine. Biodistribution studies in breast cancer tumor-bearing mice showed a significant activity accumulation on HER2+ tumors, which was 2.6-fold higher than in HER2- tumors. Additionally, biodistribution studies with THIOMAB without the TCO handle also resulted in a decreased uptake of 111In-DOTA-Tz on HER2+ tumors. Altogether, these results clearly indicate the occurrence of the click reaction at the tumor site, i.e., pretargeting of SK-BR-3 HER2-expressing cells with THIOMAB-TCO and reaction through the TCO moiety present in the antibody. The combined advantages of site-selectivity and stability of TCO tagged-antibodies could allow application of biorthogonal chemistry strategies for pretargeting imaging with minimal side-reactions and background.

Bile Acids: A Communication Channel in the Gut-Brain Axis.

Bile acids are signalling hormones involved in the regulation of several metabolic pathways. The ability of bile acids to bind and signal through their receptors is modulated by the gut microbiome, since the microbiome contributes to the regulation and synthesis of bile acids as well to their physiochemical properties. From the gut, bacteria have been shown to send signals to the central nervous system via their metabolites, thus affecting the behaviour and brain function of the host organism. In the last years it has become increasingly evident that bile acids affect brain function, during normal physiological and pathological conditions. Although bile acids may be synthesized locally in the brain, the majority of brain bile acids are taken up from the systemic circulation. Since the composition of the brain bile acid pool may be regulated by the action of intestinal bacteria, it is possible that bile acids function as a communication bridge between the gut microbiome and the brain. However, little is known about the molecular mechanisms and the physiological roles of bile acids in the central nervous system. The possibility that bile acids may be a direct link between the intestinal microbiome and the brain is also an understudied subject. Here we review the influence of gut bacteria on the bile acid pool composition and properties, as well as striking evidence showing the role of bile acids as neuroactive molecules.

Improved Fmoc-solid-phase peptide synthesis of an extracellular loop of CFTR for antibody selection by the phage display technology.

Cystic fibrosis (CF), a life-shortening genetic disease, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that codes for the CFTR protein, the major chloride channel expressed at the apical membrane of epithelial cells. The development of an imaging probe capable of non-invasively detect CFTR at the cell surface could be of great advantage for the management of CF. With that purpose, we synthesized the first extracellular loop of CFTR protein (ECL1) through fluorenylmethyloxycarbonyl (Fmoc)-based microwave-assisted solid-phase peptide synthesis (SPPS), according to a reported methodology. However, aspartimide formation, a well-characterized side reaction in Fmoc-SPPS, prompted us to adopt a different side-chain protection strategy for aspartic acid residues present in ECL1 sequence. The peptide was subsequently modified via PEGylation and biotinylation, and cyclized through disulfide bridge formation, mimicking the native loop conformation in CFTR protein. Herein, we report improvements in the synthesis of the first extracellular loop of CFTR, including peptide modifications that can be used to improve antigen presentation in phage display for selection of novel antibodies against plasma membrane CFTR.

Lipid efflux mechanisms, relation to disease and potential therapeutic aspects.

Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired ß-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.

Stability of the Malvinas Current.

Deterministic and probabilistic tools from nonlinear dynamics are used to assess enduring near-surface Lagrangian aspects of the Malvinas Current. The deterministic tools are applied to a multiyear record of velocities derived from satellite altimetry data, revealing a resilient cross-stream transport barrier. This is composed of shearless-parabolic Lagrangian coherent structures (LCSs), which, extracted over sliding time windows along the multiyear altimetry-derived velocity record, lie in near-coincidental position. The probabilistic tools are applied on a large collection of historical satellite-tracked drifter trajectories, revealing weakly communicating flow regions as basins of attraction for long-time asymptotic almost-invariant sets on either side of the altimetry-derived barrier. Shearless-parabolic LCSs are detected for the first time from altimetry data, and their significance is supported on satellite-derived ocean color data, which reveal shapes that quite closely resemble the peculiar V shapes, dubbed "chevrons," that have recently confirmed the presence of similar LCSs in the atmosphere of Jupiter. Finally, using available in situ velocity and hydrographic data, sufficient and necessary conditions for nonlinear symmetric stability are found to be satisfied, suggesting a duality between Lagrangian and Eulerian stability for the Malvinas Current.

Markov-chain-inspired search for MH370.

Markov-chain models are constructed for the probabilistic description of the drift of marine debris from Malaysian Airlines flight MH370. En route from Kuala Lumpur to Beijing, MH370 mysteriously disappeared in the southeastern Indian Ocean on 8 March 2014, somewhere along the arc of the 7th ping ring around the Inmarsat-3F1 satellite position when the airplane lost contact. The models are obtained by discretizing the motion of undrogued satellite-tracked surface drifting buoys from the global historical data bank. A spectral analysis, Bayesian estimation, and the computation of most probable paths between the Inmarsat arc and confirmed airplane debris beaching sites are shown to constrain the crash site, near 25°S on the Inmarsat arc.

Coherent Lagrangian swirls among submesoscale motions.

The emergence of coherent Lagrangian swirls (CLSs) among submesoscale motions in the ocean is illustrated. This is done by applying recent nonlinear dynamics tools for Lagrangian coherence detection on a surface flow realization produced by a data-assimilative submesoscale-permitting ocean general circulation model simulation of the Gulf of Mexico. Both mesoscale and submesoscale CLSs are extracted. These extractions prove the relevance of coherent Lagrangian eddies detected in satellite-altimetry-based geostrophic flow data for the arguably more realistic ageostrophic multiscale flow.