Decompression illness: a comprehensive overview.

Decompression illness is a collective term for two maladies (decompression sickness [DCS] and arterial gas embolism [AGE]) that may arise during or after surfacing from compressed gas diving. Bubbles are the presumed primary vector of injury in both disorders, but the respective sources of bubbles are distinct. In DCS bubbles form primarily from inert gas that becomes dissolved in tissues over the course of a compressed gas dive. During and after ascent ('decompression'), if the pressure of this dissolved gas exceeds ambient pressure small bubbles may form in the extravascular space or in tissue blood vessels, thereafter passing into the venous circulation. In AGE, if compressed gas is trapped in the lungs during ascent, pulmonary barotrauma may introduce bubbles directly into the pulmonary veins and thence to the systemic arterial circulation. In both settings, bubbles may provoke ischaemic, inflammatory, and mechanical injury to tissues and their associated microcirculation. While AGE typically presents with stroke-like manifestations referrable to cerebral involvement, DCS can affect many organs including the brain, spinal cord, inner ear, musculoskeletal tissue, cardiopulmonary system and skin, and potential symptoms are protean in both nature and severity. This comprehensive overview addresses the pathophysiology, manifestations, prevention and treatment of both disorders.

The first deep rebreather dive using hydrogen: case report.

Bounce diving with rapid descents to very deep depths may provoke the high-pressure neurological syndrome (HPNS). The strategy of including small fractions of nitrogen in the respired gas to produce an anti-HPNS narcotic effect increases the gas density which may exceed recommended guidelines. In 2020 the 'Wetmules' dive team explored the Pearse Resurgence cave (New Zealand) to 245 m breathing trimix (approximately 4% oxygen, 91% helium and 5% nitrogen). Despite the presence of nitrogen, one diver experienced HPNS tremors beyond 200 m. The use of hydrogen (a light yet slightly narcotic gas) has been suggested as a solution to this problem but there are concerns, including the potential for ignition and explosion of hydrogen-containing gases, and accelerated heat loss. In February 2023 a single dive to 230 m was conducted in the Pearse Resurgence to experience hydrogen as a breathing gas in a deep bounce dive. Using an electronic closed-circuit rebreather, helihydrox (approximately 3% oxygen, 59% helium and 38% hydrogen) was breathed between 200 and 230 m. This was associated with amelioration of HPNS symptoms in the vulnerable diver and no obvious adverse effects. The use of hydrogen is a potential means of progressing deeper with effective HPNS amelioration while maintaining respired gas density within advised guidelines.

Propagating variational model uncertainty for bioacoustic call label smoothing.

Along with propagating the input toward making a prediction, Bayesian neural networks also propagate uncertainty. This has the potential to guide the training process by rejecting predictions of low confidence, and recent variational Bayesian methods can do so without Monte Carlo sampling of weights. Here, we apply sample-free methods for wildlife call detection on recordings made via passive acoustic monitoring equipment in the animals' natural habitats. We further propose uncertainty-aware label smoothing, where the smoothing probability is dependent on sample-free predictive uncertainty, in order to downweigh data samples that should contribute less to the loss value. We introduce a bioacoustic dataset recorded in Malaysian Borneo, containing overlapping calls from 30 species. On that dataset, our proposed method achieves an absolute percentage improvement of around 1.5 points on area under the receiver operating characteristic (AU-ROC), 13 points in F1, and 19.5 points in expected calibration error (ECE) compared to the point-estimate network baseline averaged across all target classes.

Support-vector classification of low-dose nitrous oxide administration with multi-channel EEG power spectra.

Support-vector machines (SVMs) can potentially improve patient monitoring during nitrous oxide anaesthesia. By elucidating the effects of low-dose nitrous oxide on the power spectra of multi-channel EEG recordings, we quantified the degree to which these effects generalise across participants. In this single-blind, cross-over study, 32-channel EEG was recorded from 12 healthy participants exposed to 0, 20, 30 and 40% end-tidal nitrous oxide. Features of the delta-, theta-, alpha- and beta-band power were used within a 12-fold, participant-wise cross-validation framework to train and test two SVMs: (1) binary SVM classifying EEG during 0 or 40% exposure (chance = 50%); (2) multi-class SVM classifying EEG during 0, 20, 30 or 40% exposure (chance = 25%). Both the binary (accuracy 92%) and the multi-class (accuracy 52%) SVMs classified EEG recordings at rates significantly better than chance (p < 0.001 and p = 0.01, respectively). To determine the relative importance of frequency band features for classification accuracy, we systematically removed features before re-training and re-testing the SVMs. This showed the relative importance of decreased delta power and the frontal region. SVM classification identified that the most important effects of nitrous oxide were found in the delta band in the frontal electrodes that was consistent between participants. Furthermore, support-vector classification of nitrous oxide dosage is a promising method that might be used to improve patient monitoring during nitrous oxide anaesthesia.

Full-face snorkel masks increase the incidence of hypoxaemia and hypercapnia during simulated snorkelling compared to conventional snorkels.

Introduction: Air flow in full-face snorkel masks (FFSMs) should be unidirectional to prevent rebreathing of exhaled air. This study evaluated rebreathing and its consequences when using FFSMs compared to a conventional snorkel. Methods: In a dry environment 20 participants wore three types of snorkel equipment in random order: Subea Easybreath FFSM; QingSong 180-degree panoramic FFSM; and a Beuchat Spy conventional snorkel (with nose clip), in three conditions: rest in a chair; light; and moderate intensity exercise on a cycle ergometer. Peripheral oxygen saturation, partial pressure of carbon dioxide (PCO2) and oxygen (PO2) in the end tidal gas and FFSM eye-pockets, respiratory rate, minute ventilation, were measured continuously. Experiments were discontinued if oxygen saturation dropped below 85%, or if end-tidal CO2 exceeded 7.0 kPa. Results: Experimental runs with the FFSMs had to be discontinued more often after exceeding 7.0 kPa end-tidal CO2 compared to a conventional snorkel e.g., 18/40 (45%) versus 4/20 (20%) during light intensity exercise, and 9/22 (41%) versus 3/16 (19%) during moderate intensity exercise. Thirteen participants exhibited peripheral oxygen saturations below 95% (nine using FFSMs and four using the conventional snorkel) and five fell below 90% (four using FFSMs and one using the conventional snorkel). The PCO2 and PO2 in the eye-pockets of the FFSMs fluctuated and were significantly higher and lower respectively than in inspired gas, which indicated rebreathing in all FFSM wearers. Conclusions: Use of FFSMs may result in rebreathing due to non-unidirectional flow, leading to hypercapnia and hypoxaemia.

Comparing the EMMA capnograph with sidestream capnography and arterial carbon dioxide pressure at 284 kPa.

Introduction: Capnography aids assessment of the adequacy of mechanical patient ventilation. Physical and physiological changes in hyperbaric environments create ventilation challenges which make end-tidal carbon dioxide (ETCO2) measurement particularly important. However, obtaining accurate capnography in hyperbaric environments is widely considered difficult. This study investigated the EMMA capnograph for hyperbaric use. Methods: We compared the EMMA capnograph to sidestream capnography and the gold standard arterial carbon dioxide blood gas analysis in a hyperbaric chamber. In 12 resting subjects breathing air at 284 kPa, we recorded ETCO2 readings simultaneously derived from the EMMA and sidestream capnographs during two series of five breaths (total 24 measurements). An arterial blood gas sample was also taken simultaneously in five participants. Results: Across all measurements there was a difference of about 0.1 kPa between the EMMA and sidestream capnographs indicating a very slight over-estimation of ETCO2 by the EMMA capnograph, but fundamentally good agreement between the two end-tidal measurement methods. Compared to arterial blood gas pressure the non-significant difference was about 0.3 and 0.4 kPa for the EMMA and sidestream capnographs respectively. Conclusions: In this study, the EMMA capnograph performed equally to the sidestream capnograph when compared directly, and both capnography measures gave clinically acceptable estimates of arterial PCO2.

A systematic review of electroencephalography in acute cerebral hypoxia: clinical and diving implications.

Introduction: Hypoxia can cause central nervous system dysfunction and injury. Hypoxia is a particular risk during rebreather diving. Given its subtle symptom profile and its catastrophic consequences there is a need for reliable hypoxia monitoring. Electroencephalography (EEG) is being investigated as a real time monitor for multiple diving problems related to inspired gas, including hypoxia. Methods: A systematic literature search identified articles investigating the relationship between EEG changes and acute cerebral hypoxia in healthy adults. Quality of clinical evidence was assessed using the Newcastle-Ottawa scale. Results: Eighty-one studies were included for analysis. Only one study investigated divers. Twelve studies described quantitative EEG spectral power differences. Moderate hypoxia tended to result in increased alpha activity. With severe hypoxia, alpha activity decreased whilst delta and theta activities increased. However, since studies that utilised cognitive testing during the hypoxic exposure more frequently reported opposite results it appears cognitive processing might mask hypoxic EEG changes. Other analysis techniques (evoked potentials and electrical equivalents of dipole signals), demonstrated sustained regulation of autonomic responses despite worsening hypoxia. Other studies utilised quantitative EEG analysis techniques, (Bispectral index [BISTM], approximate entropy and Lempel-Ziv complexity). No change was reported in BISTM value, whilst an increase in approximate entropy and Lempel-Ziv complexity occurred with worsening hypoxia. Conclusions: Electroencephalographic frequency patterns change in response to acute cerebral hypoxia. There is paucity of literature on the relationship between quantitative EEG analysis techniques and cerebral hypoxia. Because of the conflicting results in EEG power frequency analysis, future research needs to quantitatively define a hypoxia-EEG response curve, and how it is altered by concurrent cognitive task loading.

NF-κB fingerprinting reveals heterogeneous NF-κB composition in diffuse large B-cell lymphoma.

Introduction: Improving treatments for Diffuse Large B-Cell Lymphoma (DLBCL) is challenged by the vast heterogeneity of the disease. Nuclear factor-κB (NF-κB) is frequently aberrantly activated in DLBCL. Transcriptionally active NF-κB is a dimer containing either RelA, RelB or cRel, but the variability in the composition of NF-κB between and within DLBCL cell populations is not known. Results: Here we describe a new flow cytometry-based analysis technique termed "NF-κB fingerprinting" and demonstrate its applicability to DLBCL cell lines, DLBCL core-needle biopsy samples, and healthy donor blood samples. We find each of these cell populations has a unique NF-κB fingerprint and that widely used cell-of-origin classifications are inadequate to capture NF-κB heterogeneity in DLBCL. Computational modeling predicts that RelA is a key determinant of response to microenvironmental stimuli, and we experimentally identify substantial variability in RelA between and within ABC-DLBCL cell lines. We find that when we incorporate NF-κB fingerprints and mutational information into computational models we can predict how heterogeneous DLBCL cell populations respond to microenvironmental stimuli, and we validate these predictions experimentally. Discussion: Our results show that the composition of NF-κB is highly heterogeneous in DLBCL and predictive of how DLBCL cells will respond to microenvironmental stimuli. We find that commonly occurring mutations in the NF-κB signaling pathway reduce DLBCL's response to microenvironmental stimuli. NF-κB fingerprinting is a widely applicable analysis technique to quantify NF-κB heterogeneity in B cell malignancies that reveals functionally significant differences in NF-κB composition within and between cell populations.

Computational modeling of DLBCL predicts response to BH3-mimetics.

In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphoma (DLBCL) likely contributes to variability in response to BH3-mimetics. Successful deployment of BH3-mimetics in DLBCL requires reliable predictions of which lymphoma cells will respond. Here we show that a computational systems biology approach enables accurate prediction of the sensitivity of DLBCL cells to BH3-mimetics. We found that fractional killing of DLBCL, can be explained by cell-to-cell variability in the molecular abundances of signaling proteins. Importantly, by combining protein interaction data with a knowledge of genetic lesions in DLBCL cells, our in silico models accurately predict in vitro response to BH3-mimetics. Furthermore, through virtual DLBCL cells we predict synergistic combinations of BH3-mimetics, which we then experimentally validated. These results show that computational systems biology models of apoptotic signaling, when constrained by experimental data, can facilitate the rational assignment of efficacious targeted inhibitors in B cell malignancies, paving the way for development of more personalized approaches to treatment.

Rebreather Forum Four consensus statements.

Closed circuit rebreathers have been widely adopted by technical divers as tools for reducing gas consumption and extending depth and duration capabilities. Rebreathers are technologically complex with many failure points, and their use appears associated with a higher accident rate than open circuit scuba. Rebreather Forum Four (RF4) was held in Malta in April 2023 attracting approximately 300 attendees and representatives of multiple manufacturers and training agencies. Over two and a half days a series of lectures was given by influential divers, engineers, researchers and educators on topics of contemporary relevance to rebreather diving safety. Each lecture was followed by a discussion session with audience participation. Potential consensus statements were drafted by the authors (SJM and NWP) during the course of the meeting. These were worded to be confluent with some important messages emerging from the presentations and subsequent discussions. The statements were presented one by one in a half-day plenary session of participants, and discussion was invited on each. After discussion and any necessary revision, the participants voted on whether to adopt the statement as a position of the forum. A clear majority was required for acceptance. Twenty-eight statements embracing thematic areas designated 'safety', 'research', 'operational issues', 'education and training', and 'engineering' were adopted. Those statements are presented along with contextualising narrative where necessary. The statements may help shape research and teaching initiatives, and research and development strategies over subsequent years.

NF-kB and the CLL microenvironment.

Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia in the western world. Despite the positive clinical effects of new targeted therapies, CLL still remains an incurable and refractory disease and resistance to treatments are commonly encountered. The Nuclear Factor-Kappa B (NF-κB) transcription factor has been implicated in the pathology of CLL, with high levels of NF-κB associated with disease progression and drug resistance. This aberrant NF-κB activation can be caused by genetic mutations in the tumor cells and microenvironmental factors, which promote NF-κB signaling. Activation can be induced via two distinct pathways, the canonical and non-canonical pathway, which result in tumor cell proliferation, survival and drug resistance. Therefore, understanding how the CLL microenvironment drives NF-κB activation is important for deciphering how CLL cells evade treatment and may aid the development of novel targeting therapeutics. The CLL microenvironment is comprised of various cells, including nurse like cells, mesenchymal stromal cells, follicular dendritic cells and CD4+ T cells. By activating different receptors, including the B cell receptor and CD40, these cells cause overactivity of the canonical and non-canonical NF-κB pathways. Within this review, we will explore the different components of the CLL microenvironment that drive the NF-κB pathway, investigating how this knowledge is being translated in the development of new therapeutics.

The NF-κB multidimer system model: A knowledge base to explore diverse biological contexts.

The nuclear factor κB (NF-κB) system is critical for various biological functions in numerous cell types, including the inflammatory response, cell proliferation, survival, differentiation, and pathogenic responses. Each cell type is characterized by a subset of 15 NF-κB dimers whose activity is regulated in a stimulus-responsive manner. Numerous studies have produced different mathematical models that account for cell type-specific NF-κB activities. However, whereas the concentrations or abundances of NF-κB subunits may differ between cell types, the biochemical interactions that constitute the NF-κB signaling system do not. Here, we synthesized a consensus mathematical model of the NF-κB multidimer system, which could account for the cell type-specific repertoires of NF-κB dimers and their cell type-specific activation and cross-talk. Our review demonstrates that these distinct cell type-specific properties of NF-κB signaling can be explained largely as emergent effects of the cell type-specific expression of NF-κB monomers. The consensus systems model represents a knowledge base that may be used to gain insights into the control and function of NF-κB in diverse physiological and pathological scenarios and that describes a path for generating similar regulatory knowledge bases for other pleiotropic signaling systems.

A prospective observational study on the effect of emboli exposure on cerebral autoregulation in cardiac surgery requiring cardiopulmonary bypass.

OBJECTIVE: Cerebrovascular autoregulation impairment has been associated with stroke risk in cardiac surgery. We hypothesized that greater arterial emboli exposure in open-chamber surgery might promote dysautoreguation. METHODS: Forty patients underwent closed or open-chamber surgery. Transcranial Doppler detected emboli and measured bilateral middle cerebral artery flow velocities. Cerebral autoregulation was assessed by averaging the mean velocity index ("Mx," a continuous moving correlation between cerebral blood flow velocity and mean arterial pressure) over 30 min before and after aortic cross-clamp removal. RESULTS: Median (interquartile range) emboli counts were 775 (415, 1211) and 2664 (793, 3734) in the closed-chamber and open-chamber groups. Most appeared after the removal of the aortic cross-clamp (open-chamber 1631 (606, 2296)), (closed-chamber 229 (142, 384)), with emphasis on the right hemisphere (open-chamber: 826 (371, 1622)), (closed-chamber 181 (66, 276)). Linear mixed model analyses of mean velocity index change showed no significant overall effect of group (0.08, 95% CI: -0.04, 0.21; p = 0.19) or side (0.01, 95% CI: -0.03, 0.05; p = 0.74). There was an interaction between group and side (p = 0.001), manifesting as a greater increase in mean velocity index in the right hemisphere in the open than the closed group (mean difference: 0.15, 95% CI: 0.02, 0.27; p = 0.03). CONCLUSIONS: Overall, change in mean velocity index before and after cross-clamp removal did not differ between groups. However, most emboli entered the right cerebral hemisphere where this change was significantly greater in the open-chamber group, suggesting a possible association between embolic exposure and dysautoregulation.

Logged tropical forests have amplified and diverse ecosystem energetics.

Old-growth tropical forests are widely recognized as being immensely important for their biodiversity and high biomass1. Conversely, logged tropical forests are usually characterized as degraded ecosystems2. However, whether logging results in a degradation in ecosystem functions is less clear: shifts in the strength and resilience of key ecosystem processes in large suites of species have rarely been assessed in an ecologically integrated and quantitative framework. Here we adopt an ecosystem energetics lens to gain new insight into the impacts of tropical forest disturbance on a key integrative aspect of ecological function: food pathways and community structure of birds and mammals. We focus on a gradient spanning old-growth and logged forests and oil palm plantations in Borneo. In logged forest there is a 2.5-fold increase in total resource consumption by both birds and mammals compared to that in old-growth forests, probably driven by greater resource accessibility and vegetation palatability. Most principal energetic pathways maintain high species diversity and redundancy, implying maintained resilience. Conversion of logged forest into oil palm plantation results in the collapse of most energetic pathways. Far from being degraded ecosystems, even heavily logged forests can be vibrant and diverse ecosystems with enhanced levels of ecological function.

Safeguarding Imperiled Biodiversity and Evolutionary Processes in the Wallacea Center of Endemism.

Wallacea-the meeting point between the Asian and Australian fauna-is one of the world's largest centers of endemism. Twenty-three million years of complex geological history have given rise to a living laboratory for the study of evolution and biodiversity, highly vulnerable to anthropogenic pressures. In the present article, we review the historic and contemporary processes shaping Wallacea's biodiversity and explore ways to conserve its unique ecosystems. Although remoteness has spared many Wallacean islands from the severe overexploitation that characterizes many tropical regions, industrial-scale expansion of agriculture, mining, aquaculture and fisheries is damaging terrestrial and aquatic ecosystems, denuding endemics from communities, and threatening a long-term legacy of impoverished human populations. An impending biodiversity catastrophe demands collaborative actions to improve community-based management, minimize environmental impacts, monitor threatened species, and reduce wildlife trade. Securing a positive future for Wallacea's imperiled ecosystems requires a fundamental shift away from managing marine and terrestrial realms independently.

Does hyperbaric oxygen cause narcosis or hyperexcitability? A quantitative EEG analysis.

Divers breathe higher partial pressures of oxygen at depth than at the surface. The literature and diving community are divided on whether or not oxygen is narcotic. Conversely, hyperbaric oxygen may induce dose-dependent cerebral hyperexcitability. This study evaluated whether hyperbaric oxygen causes similar narcotic effects to nitrogen, and investigated oxygen's hyperexcitability effect. Twelve human participants breathed "normobaric" air and 100% oxygen, and "hyperbaric" 100% oxygen at 142 and 284 kPa, while psychometric performance, electroencephalography (EEG), and task load perception were measured. EEG was analyzed with functional connectivity and temporal complexity algorithms. The spatial functional connectivity, estimated using mutual information, was summarized with the global efficiency network measure. Temporal complexity was calculated with a "default-mode-network (DMN) complexity" algorithm. Hyperbaric oxygen-breathing caused no change in EEG global efficiency or in the psychometric test. However, oxygen caused a significant reduction of DMN complexity and a reduction in task load perception. Hyperbaric oxygen did not cause the same changes in EEG global efficiency seen with hyperbaric air, which likely related to a narcotic effect of nitrogen. Hyperbaric oxygen seemed to disturb the time evolution of EEG patterns that could be taken as evidence of early oxygen-induced cortical hyperexcitability. These findings suggest that hyperbaric oxygen is not narcotic and will help inform divers' decisions on suitable gas mixtures.

Extended lifetimes of bubbles at hyperbaric pressure may contribute to inner ear decompression sickness during saturation diving.

Inner ear decompression sickness (IEDCS) may occur after upward or downward excursions in saturation diving. Previous studies in nonsaturation diving strongly suggest that IEDCS is caused by arterialization of small venous bubbles across intracardiac or intrapulmonary right-to-left shunts and bubble growth through inward diffusion of supersaturated gas when they arrive in the inner ear. The present study used published saturation diving data and models of inner ear inert gas kinetics and bubble dynamics in arterial conditions to assess whether IEDCS after saturation excursions could also be explained by arterialization of venous bubbles and whether such bubbles might survive longer and be more likely to reach the inner ear under deep saturation diving conditions. Previous data show that saturation excursions produce venous bubbles. Modeling shows that gas supersaturation in the inner ear persists longer than in the brain after such excursions, explaining why the inner ear would be more vulnerable to injury by arriving bubbles. Estimated survival of arterialized bubbles is significantly prolonged at high ambient pressure such that bubbles large enough to be filtered by pulmonary capillaries but able to cross right-to-left shunts are more likely to survive transit to the inner ear than at the surface. IEDCS after saturation excursions is plausibly caused by arterialization of venous bubbles whose prolonged arterial survival at deep depths suggests that larger bubbles in greater numbers reach the inner ear.NEW & NOTEWORTHY Inner ear decompression sickness that occurs during deep saturation diving is explained by arterialization of venous bubbles across intracardiac or intrapulmonary right-to-left shunts and growth of these bubbles if they arrive in the inner ear. Bubbles in arterial blood have prolonged lifetimes at hyperbaric pressures compared with at sea level. This can explain why inner ear decompression sickness is more characteristic of rapid decompressions at great depths than of decompression at sea level.

Comment on Mankowska et al. Critical Flicker Fusion Frequency: A Narrative Review. Medicina 2021, 57, 1096.

We have read with great interest the review by Mankowska et al. [...].

Dissecting the impact of bromodomain inhibitors on the Interferon Regulatory Factor 4-MYC oncogenic axis in multiple myeloma.

B-cell progenitor fate determinant interferon regulatory factor 4 (IRF4) exerts key roles in the pathogenesis and progression of multiple myeloma (MM), a currently incurable plasma cell malignancy. Aberrant expression of IRF4 and the establishment of a positive auto-regulatory loop with oncogene MYC, drives a MM specific gene-expression program leading to the abnormal expansion of malignant immature plasma cells. Targeting the IRF4-MYC oncogenic loop has the potential to provide a selective and effective therapy for MM. Here we evaluate the use of bromodomain inhibitors to target the IRF4-MYC axis through combined inhibition of their known epigenetic regulators, BRD4 and CBP/EP300. Although all inhibitors induced cell death, we found no synergistic effect of targeting both of these regulators on the viability of MM cell-lines. Importantly, for all inhibitors over a time period up to 72 h, we detected reduced IRF4 mRNA, but a limited decrease in IRF4 protein expression or mRNA levels of downstream target genes. This indicates that inhibitor-induced loss of cell viability is not mediated through reduced IRF4 protein expression, as previously proposed. Further analysis revealed a long half-life of IRF4 protein in MM cells. In support of our experimental observations, gene network modeling of MM suggests that bromodomain inhibition is exerted primarily through MYC and not IRF4. These findings suggest that despite the autofeedback positive regulatory loop between IRF4 and MYC, bromodomain inhibitors are not effective at targeting IRF4 in MM and that novel therapeutic strategies should focus on the direct inhibition or degradation of IRF4.