COVID-19-related changes in outpatient CPAP setup pathways for OSA are linked with decreased 30-day CPAP usage.

The COVID-19 pandemic changed continuous positive airway pressure (CPAP) setup pathways. We evaluated patients commenced on CPAP in 2019 (prepandemic) and 2020 (post-first UK wave). Face-to-face (F2F) setup numbers, with CPAP turned on, decreased from 613 patients (98.9%) in 2019, to 6 (1.1%) in 2020. In 2020, setups were F2F without CPAP turned on (403 (71.1%)), or remote (158 (27.9%)). Prepandemic median CPAP usage at first follow-up was 5.4 (2.7-6.9) hours/night and fell by 0.9 hours/night (95% CI 0.5 to 1.2, p<0.0001) in 2020. We found clinically relevant reductions in CPAP usage with pathway changes post-COVID-19.

Fluid and deformation regime of an advancing subduction system at Marlborough, New Zealand.

Newly forming subduction zones on Earth can provide insights into the evolution of major fault zone geometries from shallow levels to deep in the lithosphere and into the role of fluids in element transport and in promoting rock failure by several modes. The transpressional subduction regime of New Zealand, which is advancing laterally to the southwest below the Marlborough strike-slip fault system of the northern South Island, is an ideal setting in which to investigate these processes. Here we acquired a dense, high-quality transect of magnetotelluric soundings across the system, yielding an electrical resistivity cross-section to depths beyond 100 km. Our data imply three distinct processes connecting fluid generation along the upper mantle plate interface to rock deformation in the crust as the subduction zone develops. Massive fluid release just inland of the trench induces fault-fracture meshes through the crust above that undoubtedly weaken it as regional shear initiates. Narrow strike-slip faults in the shallow brittle regime of interior Marlborough diffuse in width upon entering the deeper ductile domain aided by fluids and do not project as narrow deformation zones. Deep subduction-generated fluids rise from 100 km or more and invade upper crustal seismogenic zones that have exhibited historic great earthquakes on high-angle thrusts that are poorly oriented for failure under dry conditions. The fluid-deformation connections described in our work emphasize the need to include metamorphic and fluid transport processes in geodynamic models.

Continuous Positive Airway Pressure plus Mandibular Advancement Therapy (PAPMAT): study protocol for an adaptive randomised crossover trial comparing the benefits and costs of combining two established treatments for obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) involves repeated breathing pauses during sleep due to upper airway obstruction. It causes excessive daytime sleepiness and has other health impacts. Continuous positive airway pressure (CPAP) therapy is effective first line treatment for moderate to severe OSA. Unfortunately, many patients have difficulty tolerating CPAP and pressure intolerance is probably an important contributing factor. Mandibular advancement devices (MAD) are an alternative to CPAP. They are worn in the mouth during sleep to reduce airway obstruction. There is some evidence that, when used in combination with CPAP, MADs improve airway anatomy enough to reduce the CPAP pressure required to treat OSA and that this combination therapy could improve CPAP adherence. METHODS: Consecutive patients starting on CPAP for moderate to severe OSA will be recruited at a regional NHS sleep service. Patients with high CPAP pressure requirements after initial titration, who satisfy all entry criteria and consent to participate, will undertake a 2-arm randomised crossover trial. The arms will be (i) standalone CPAP and (ii) CPAP + MAD therapy. Each arm will last 12 weeks, including 2 weeks acclimatisation. CPAP machines will be auto-titrating and with facility for data download, so the impact of MAD on CPAP pressure requirements and CPAP adherence can be easily measured. The primary outcome will be CPAP adherence. Secondary outcomes will include measures of OSA severity, patient-reported outcome measures including subjective daytime sleepiness, quality of life, and treatment preference at the trial exit and health service use. Cost-effectiveness analyses will be undertaken. DISCUSSION: If the intervention is shown to be effective and cost-effective in improving adherence in this standard CPAP-eligible OSA patient population it would be relatively straightforward to introduce into existing OSA treatment pathways, within the wider NHS and more widely. Both MAD and CPAP are already used by sleep services so their combination would require only minor adjustments to existing clinical pathways. It would be straightforward to disseminate the results of the study through regional, national, and international respiratory meetings. The health economics analysis would provide cost-effectiveness data to inform service planning and clinical guidelines through policy briefing papers, including those by NICE and SIGN. TRIAL REGISTRATION: PAPMAT was registered with ISRCTN prior to recruitment beginning (ISRCTN Registry 2021): https://www.isrctn.com/ISRCTN33966032 . Registered on 17th November 2021.

The implications of crustal architecture and transcrustal upflow zones on the metal endowment of a world-class mineral district.

Earth's mineral deposits show a non-uniform spatial distribution from the craton-scale, to the scale of individual mineral districts. Although this pattern of differential metal endowment is underpinned by lithospheric-scale processes the geological features that cause clustering of deposits remains enigmatic. The integration of geological and geophysical (seismic, gravity, and magnetotelluric) features has produced the first whole-of-crust image through an iconic Neoarchean volcanic complex and mineral district in the Abitibi Greenstone Belt, Superior Province, Canada. Observations indicate an asymmetry in surface geology, structure, and crustal architecture that defines deep transcrustal magmatic-hydrothermal upflow zones and the limits of the Noranda District ore system. Here, extreme volcanogenic massive sulfide (VMS) endowment is confined to a smaller area adjacent to an ancestral transcrustal structure interpreted to have localized and optimized magmatic and ore forming processes. Although lithospheric-scale evolutionary processes might act as the fundamental control on metal endowment, the new crustal reconstruction explains the clustering of deposits on both belt and district scales. The results highlight a strong magmatic control on metal and in particular Au endowment in VMS systems. Overprinting by clusters of ca. 30 Ma younger orogenic Au deposits suggest the ore systems accessed an upper lithospheric mantle enriched in Au and metals.

Home sweet home: spatiotemporal distribution and site fidelity of the reef manta ray (Mobula alfredi) in Dungonab Bay, Sudan.

BACKGROUND: Reef manta ray (Mobula alfredi) populations along the Northeastern African coastline are poorly studied. Identifying critical habitats for this species is essential for future research and conservation efforts. Dungonab Bay and Mukkawar Island National Park (DMNP), a component of a UNESCO World Heritage Site in Sudan, hosts the largest known M. alfredi aggregation in the Red Sea. METHODS: A total of 19 individuals were tagged using surgically implanted acoustic tags and tracked within DMNP on an array of 15 strategically placed acoustic receivers in addition to two offshore receivers. Two of these acoustically monitored M. alfredi were also equipped with satellite linked archival tags and one individual was fitted with a satellite transmitting tag. Together, these data are used to describe approximately two years of residency and seasonal shifts in habitat use. RESULTS: Tagged individuals were detected within the array on 96% of monitored days and recorded an average residence index of 0.39 across all receivers. Detections were recorded throughout the year, though some individuals were absent from the receiver array for weeks or months at a time, and generalized additive mixed models showed a clear seasonal pattern in presence with the highest probabilities of detection occurring in boreal fall. The models indicated that M. alfredi presence was highly correlated with increasing chlorophyll-a levels and weakly correlated with the full moon. Modeled biological factors, including sex and wingspan, had no influence on animal presence. Despite the high residency suggested by acoustic telemetry, satellite tag data and offshore acoustic detections in Sanganeb Atoll and Suedi Pass recorded individuals moving up to 125 km from the Bay. However, all these individuals were subsequently detected in the Bay, suggesting a strong degree of site fidelity at this location. CONCLUSIONS: The current study adds to growing evidence that M. alfredi are highly resident and site-attached to coastal bays and lagoons but display seasonal shifts in habitat use that are likely driven by resource availability. This information can be used to assist in managing and supporting sustainable ecotourism within the DMNP, part of a recently designated UNESCO World Heritage Site.

Culture-independent analysis of bacterial fuel contamination provides insight into the level of concordance with the standard industry practice of aerobic cultivation.

Bacterial diversity in contaminated fuels has not been systematically investigated using cultivation-independent methods. The fuel industry relies on phenotypic cultivation-based contaminant identification, which may lack accuracy and neglect difficult-to-culture taxa. By the use of industry practice aerobic cultivation, 16S rRNA gene sequencing, and strain genotyping, a collection of 152 unique contaminant isolates from 54 fuel samples was assembled, and a dominance of Pseudomonas (21%), Burkholderia (7%), and Bacillus (7%) was demonstrated. Denaturing gradient gel electrophoresis (DGGE) of 15 samples revealed Proteobacteria and Firmicutes to be the most abundant phyla. When 16S rRNA V6 gene pyrosequencing of four selected fuel samples (indicated by "JW") was performed, Betaproteobacteria (42.8%) and Gammaproteobacteria (30.6%) formed the largest proportion of reads; the most abundant genera were Marinobacter (15.4%; JW57), Achromobacter (41.6%; JW63), Burkholderia (80.7%; JW76), and Halomonas (66.2%; JW78), all of which were also observed by DGGE. However, the Clostridia (38.5%) and Deltaproteobacteria (11.1%) identified by pyrosequencing in sample JW57 were not observed by DGGE or aerobic culture. Genotyping revealed three instances where identical strains were found: (i) a Pseudomonas sp. strain recovered from 2 different diesel fuel tanks at a single industrial site; (ii) a Mangroveibacter sp. strain isolated from 3 biodiesel tanks at a single refinery site; and (iii) a Burkholderia vietnamiensis strain present in two unrelated automotive diesel samples. Overall, aerobic cultivation of fuel contaminants recovered isolates broadly representative of the phyla and classes present but lacked accuracy by overrepresenting members of certain groups such as Pseudomonas.

Concerted roles of PTEN and ATM in controlling hematopoietic stem cell fitness and dormancy.

In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms to preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting their survival, self-renewal, and differentiation. Ablation of the kinase ataxia telangiectasia mutated (ATM), a master regulator of the DNA damage response, impairs HSC fitness. Paradoxically, we show here that loss of a single allele of Atm enhances HSC functionality in mice. To explain this observation, we explored a possible link between ATM and the tumor suppressor phosphatase and tensin homolog (PTEN), which also regulates HSC function. We generated and analyzed a knockin mouse line (PtenS398A/S398A), in which PTEN cannot be phosphorylated by ATM. Similar to Atm+/-, PtenS398A/S398A HSCs have enhanced hematopoietic reconstitution ability, accompanied by resistance to apoptosis induced by genotoxic stress. Single-cell transcriptomic analyses and functional assays revealed that dormant PtenS398A/S398A HSCs aberrantly tolerate elevated mitochondrial activity and the accumulation of reactive oxygen species, which are normally associated with HSC priming for self-renewal or differentiation. Our results unveil a molecular connection between ATM and PTEN, which couples the response to genotoxic stress and dormancy in HSCs.

Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas.

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

Changes in body composition, muscle function and energy expenditure after radical cystectomy.

OBJECTIVE: To determine the changes in body composition, muscle function and energy expenditure after radical cystectomy (RC). PATIENTS AND METHODS: Eleven consecutive men (median age 66 years, range 44-79) who had a RC over a 1-year period had measurements made of their total body protein, by neutron-activation analysis, total body water by tritium dilution, total body potassium by whole-body counting, resting energy expenditure by indirect calorimetry, and grip strength and respiratory muscle strength. These variables were measured on the day before surgery and at 2 weeks and 6 months after RC. Total body fat was derived using a multicompartment model. Artificial nutritional support was not provided after RC and no oral caloric intake was provided until bowel function returned. RESULTS: Five patients were malnourished before RC and four had significant complications afterward. Over the first 2 weeks there were significant losses in mean (sem) protein levels, at 0.68 (0.17) kg (P < 0.001) and water, at 3.00 (0.73) L (P < 0.001), while body fat was unchanged. Resting energy expenditure was 11% higher than predicted at 14 days after RC (P < 0.001). Body potassium changes mirrored the protein changes but were not statistically significant. Over the subsequent 6 months, 63%, i.e. 0.43 (0.24) kg, of the body protein lost after surgery was regained. Muscle function had returned to baseline levels at 6 months. CONCLUSIONS: This study shows that the catabolic loss of body protein after RC is not regained by 6 months. Regimens directed at early nutritional support after RC for these patients might improve the recovery of body composition, with consequent clinical benefits.

Noninvasive Determination of Vortex Formation Time Using Transesophageal Echocardiography During Cardiac Surgery.

Trans-mitral blood flow produces a three-dimensional rotational body of fluid, known as a vortex ring, that enhances the efficiency of left ventricular (LV) filling compared with a continuous linear jet. Vortex ring development is most often quantified with vortex formation time (VFT), a dimensionless parameter based on fluid ejection from a rigid tube. Our group is interested in factors that affect LV filling efficiency during cardiac surgery. In this report, we describe how to use standard two-dimensional (2D) and Doppler transesophageal echocardiography (TEE) to noninvasively derive the variables needed to calculate VFT. We calculate atrial filling fraction (ß) from velocity-time integrals of trans-mitral early LV filling and atrial systole blood flow velocity waveforms measured in the mid-esophageal four-chamber TEE view. Stroke volume (SV) is calculated as the product of the diameter of the LV outflow track measured in the mid-esophageal long axis TEE view and the velocity-time integral of blood flow through the outflow track determined in the deep transgastric view using pulse-wave Doppler. Finally, mitral valve diameter (D) is determined as the average of major and minor axis lengths measured in orthogonal mid-esophageal bicommissural and long axis imaging planes, respectively. VFT is then calculated as 4 × (1-ß) × SV/(πD3). We have used this technique to analyze VFT in several groups of patients with differing cardiac abnormalities. We discuss our application of this technique and its potential limitations and also review our results to date. Noninvasive measurement of VFT using TEE is straightforward in anesthetized patients undergoing cardiac surgery. The technique may allow cardiac anesthesiologists and surgeons to assess the impact of pathological conditions and surgical interventions on LV filling efficiency in real time.

Author Correction: Uplift of the central transantarctic mountains.

The original version of this Article incorrectly referenced the Figures in the Supplementary Information. References in the main Article to Supplementary Figure 7 through to Supplementary Figure 20 were previously incorrectly cited as Supplementary Figure 5 through to Supplementary Figure 18, respectively. This has now been corrected in both the PDF and HTML versions of the Article.

Conservation of reef manta rays (Manta alfredi) in a UNESCO World Heritage Site: Large-scale island development or sustainable tourism?

A large reef manta ray (Manta alfredi) aggregation has been observed off the north Sudanese Red Sea coast since the 1950s. Sightings have been predominantly within the boundaries of a marine protected area (MPA), which was designated a UNESCO World Heritage Site in July 2016. Contrasting economic development trajectories have been proposed for the area (small-scale ecotourism and large-scale island development). To examine space-use, Wildlife Computers® SPOT 5 tags were secured to three manta rays. A two-state switching Bayesian state space model (BSSM), that allowed movement parameters to switch between resident and travelling, was fit to the recorded locations, and 50% and 95% kernel utilization distributions (KUD) home ranges calculated. A total of 682 BSSM locations were recorded between 30 October 2012 and 6 November 2013. Of these, 98.5% fell within the MPA boundaries; 99.5% for manta 1, 91.5% for manta 2, and 100% for manta 3. The BSSM identified that all three mantas were resident during 99% of transmissions, with 50% and 95% KUD home ranges falling mainly within the MPA boundaries. For all three mantas combined (88.4%), and all individuals (manta 1-92.4%, manta 2-64.9%, manta 3-91.9%), the majority of locations occurred within 15 km of the proposed large-scale island development. Results indicated that the MPA boundaries are spatially appropriate for manta rays in the region, however, a close association to the proposed large-scale development highlights the potential threat of disruption. Conversely, the focused nature of spatial use highlights the potential for reliable ecotourism opportunities.

Uplift of the central transantarctic mountains.

The Transantarctic Mountains (TAM) are the world's longest rift shoulder but the source of their high elevation is enigmatic. To discriminate the importance of mechanical vs. thermal sources of support, a 550 km-long transect of magnetotelluric geophysical soundings spanning the central TAM was acquired. These data reveal a lithosphere of high electrical resistivity to at least 150 km depth, implying a cold stable state well into the upper mantle. Here we find that the central TAM most likely are elevated by a non-thermal, flexural cantilever mechanism which is perhaps the most clearly expressed example anywhere. West Antarctica in this region exhibits a low resistivity, moderately hydrated asthenosphere, and concentrated extension (rift necking) near the central TAM range front but with negligible thermal encroachment into the TAM. Broader scale heat flow of east-central West Antarctica appears moderate, on the order of 60-70 mW m-2, lower than that of the U.S. Great Basin.