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A murine model of central nervous system (CNS) decompression sickness demonstrates that high gas pressure activates astrocytes and microglia triggering inflammatory microparticle (MP) production. Thrombospondin-expressing MPs are released from the CNS via enhanced glymphatic flow to the systemic circulation where they activate neutrophils. Secondary production of neutrophil-derived MPs causes further cell activation and neutrophil adherence to the brain microvasculature establishing a feed-forward neuroinflammatory cycle.

The proinflammatory state associated with diabetes mellitus (DM) remains poorly understood. We found patients with DM have 3- to 14-fold elevations of blood-borne microparticles (MPs) that bind phalloidin (Ph; Ph positive [+] MPs), indicating the presence of F-actin on their surface. We hypothesized that F-actin–coated MPs were an unrecognized cause for DM-associated proinflammatory status. Ph+MPs, but not Ph-negative MPs, activate human and murine (Mus musculus) neutrophils through biophysical attributes of F-actin and membrane expression of phosphatidylserine (PS). Neutrophils respond to Ph+MPs via a linked membrane array, including the receptor for advanced glycation end products and CD36, PS-binding membrane receptors. These proteins in conjunction with TLR4 are coupled to NO synthase 1 adaptor protein (NOS1AP). Neutrophil activation occurs because of Ph+MPs causing elevations of NF-κB and Src kinase (SrcK) via a concurrent increased association of NO synthase 2 and SrcK with NOS1AP, resulting in SrcK S-nitrosylation. We conclude that NOS1AP links PS-binding receptors with intracellular regulatory proteins. Ph+MPs are alarmins present in normal human plasma and are increased in those with DM and especially those with DM and a lower-extremity ulcer.

OBJECTIVE: The goal of this study was to evaluate whether circulating endothelial precursor cells (CEPCs) and neutrophil microparticles (MP) can predict diabetic foot ulcer healing. RESEARCH DESIGN AND METHODS: A multicenter study was designed to evaluate circulating cellular markers, CEPCs and MPs, as prognostic factors associated with the healing of DFU by the 16(th) week of care. Flow cytometry analysis of CEPCS and MPs were obtained at the first visit and compared to wound healed status. RESULTS: 207 subjects were enrolled at four sites. 40.0% (28.4,41.5) of the subjects healed by the 16(th) week of care. Several CEPCs measured were associated with healing after adjustment for wound area and wound duration. Typical of this analysis was CD34(+)CD45(dim), the univariate OR was 1.19(0.88,1.61) and after adjustment for wound area and wound duration the OR was 1.67(1.16,2.42) p=0.006). A prognostic model with CEPCs CD34(+) CD45(dim), wound area, and wound duration had an area under the curve (AUC) of 0.75(0.67, 0.82) and, simpler, CD34(+) CD45(dim) per initial wound area, as a solitary predictor, has an AUC of 0.72 (0.64, 0.79). MPs were not associated with a healed wound. CONCLUSIONS: Previous studies have indicated that CEPCs measured at the first office visit are associated with a healed DFU. In this multi-centered prospective study, we confirm this finding, show the importance of adjusting CEPCs measurements by wound are, and show that a single number based on CEPCs per wound area is highly predictive of a healed DFU by 16(th) week of care.

Oxygen is a powerful trigger for cellular reactions, but there are few comparative investigations assessing the effects over a large range of partial pressures. We investigated a metabolic response to single exposures to either normobaric (10%, 15%, 30%, 100%) or hyperbaric (1.4 ATA, 2.5 ATA) oxygen. Forty-eight healthy subjects (32 males/16 females; age: 43.7 ± 13.4 years, height: 172.7 ± 10.07 cm; weight 68.4 ± 15.7 kg) were randomly assigned, and blood samples were taken before and 2 h after each exposure. Microparticles (MPs) expressing proteins specific to different cells were analyzed, including platelets (CD41), neutrophils (CD66b), endothelial cells (CD146), and microglia (TMEM). Phalloidin binding and thrombospondin-1 (TSP), which are related to neutrophil and platelet activation, respectively, were also analyzed. The responses were found to be different and sometimes opposite. Significant elevations were identified for MPs expressing CD41, CD66b, TMEM, and phalloidin binding in all conditions but for 1.4 ATA, which elicited significant decreases. Few changes were found for CD146 and TSP. Regarding OPB, further investigation is needed to fully understand the future applications of such findings.

The SARS-Cov-2 (COVID-19) pandemic remains a major worldwide public health issue. Initially, improved supportive and anti-inflammatory intervention, often employing known drugs or technologies, provided measurable improvement in management. We have recently seen advances in specific therapeutic interventions and in vaccines. Nevertheless, it will be months before most of the world’s population can be vaccinated to achieve herd immunity. In the interim, hyperbaric oxygen (HBO2) treatment offers several potentially beneficial therapeutic effects. Three small published series, one with a propensity-score-matched control group, have demonstrated safety and initial efficacy. Additional anecdotal reports are consistent with these publications. HBO2 delivers oxygen in extreme conditions of hypoxemiaand tissue hypoxia, even in the presence of lung pathology. It provides anti-inflammatory and anti-proinflammatory effects likely to ameliorate the overexuberant immune response common to COVID-19. Unlike steroids, it exerts these effects without immune suppression. One study suggests HBO2 may reduce the hypercoagulability seen in COVID patients. Also, hyperbaric oxygen offers a likely successful intervention to address the oxygen debt expected to arise from a prolonged period of hypoxemia and tissue hypoxia. To date, 11 studies designed to investigate the impact of HBO2 on patients infected with SARS-Cov-2 have been posted on clinicaltrials.gov. This paper describes the promising physiologic and biochemical effects of hyperbaric oxygen in COVID-19 and potentially in other disorders with similar pathologic mechanisms.

Background Spinal injuries (SIs) can pose a significant burden to patients and family; delayed surgical intervention, associated with interhospital transfer, results in worse outcomes. Objective This study aimed to identify early patient-centered factors associated with risk for near-shore SIs to assist clinicians with expeditious medical decision-making. Methods We performed a multicenter retrospective study of all adults transported from Ocean City, Maryland to two emergency departments (EDs) and one regional trauma center for evaluation of suspected SIs from 2006 to 2017. Outcomes were any SI and any spinal cord injury (SCI). Multivariable logistic regression was performed for association of environmental and clinical factors with outcomes. Results We analyzed 278 records, 102 patients (37%) were diagnosed with any SI and 41 (15%) were diagnosed with SCIs. Compared with patients without SI, patients with SI were more likely to be older (48 vs. 39 years), male (90% vs. 70%), with pre-existing spinal condition (62% vs. 33%), and injury caused by diving (11% vs. 2%). Multivariable logistic regression showed age (odd ratio [OR] 1.07; 95% confidence interval [CI] 1.04–1.11), diving (OR 3.5; 95% CI 3–100+), and wave height (OR 4.5; 95% CI 1.35–15.2) were associated with any SI, and a chief complaint of extremity numbness or tingling (OR 5.73; 95% CI 1.2–27.9) was associated with SCI. Conclusions We identified older age, diving, and higher wave height as risk factors for any SI and symptoms of numbness and tingling were associated with SCIs. Clinicians should consider expediting these patients’ transfers to a trauma center with neurosurgical capability.

Diabetic foot ulcers (DFU) are a critical problem for those with diabetes mellitus. Predicting the healing likelihood of a DFU is important to implementing appropriate care, allocating resources, having access to advanced therapies, having successful clinical trials, calibrating clinical trial results, and providing information to administrative entities on patient and provider outcomes. Prognostic modeling can also be important when attempting to compare results across trials or care centers. In a prospective cohort study, we demonstrate and replicate that simple wound characteristics like wound area and wound duration can be used to predict wound healing by the 16(th) week of care. The models were based on previous literature and replicated using a machine learning algorithm. The use of wound duration and wound area in a prognostic model continues to be important when comparing study results, center-based outcomes, as well as designing clinical trials.

We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance increases blood-borne MPs by 8-fold, and by 10-fold in deep cervical lymph nodes draining brain glymphatics. MPs express proteins specific to cells including neutrophils, microglia, astrocytes, neurons and oligodendrocytes. Interleukin (IL)-1β content of MPs increases 68-fold. IL-1β antagonist administration diminishes blood-borne and cervical lymph node MPs, and abrogates tolerance induction. Intravenous polyethylene glycol Telomer B, a surfactant that lyses MPs, and intraperitoneal methylnaltrexone also inhibit MPs elevations and tolerance. Critically, neutropenic mice do not develop anti-nociceptive tolerance, elevations of blood-borne or cervical node MPs. Immunohistochemical evidence for microglial activation by morphine does not correlated with the MPs response pattern. Neutrophil-derived MPs appear to be required for morphine-induced anti-nociceptive tolerance. Further, patients entering treatment for opioid use disorder exhibit similar MPs elevations as do tolerant mice.

Objective Mechanical thrombectomy is the treatment of choice for acute ischemic strokes from large vessel occlusions. Absolute blood pressure and blood pressure variability (BPV) may affect patients’ outcome. We hypothesized that patients’ outcomes were not associated with BPV during transport between hospitals in the era of effective thrombectomy. Methods We performed a retrospective observational review of adult patients admitted to our comprehensive stroke center who underwent mechanical thrombectomy between January 1, 2015, and December 31, 2018. Data were collected from our stroke registry and transportation records. Outcomes were defined as 90-day modified Rankin Scale (mRS) ≤2 and any acute kidney injury (AKI) during hospitalization. Results We analyzed 134 eligible patients. The mean age was 66 years (standard deviation = 14 years). Forty percent achieved mRS ≤2, and 16% had an AKI. BPV and maximum systolic blood pressures during transport were examined as variables to determine outcome. We found BPV was similar between patients with good and bad functional independence. Furthermore, the maximum systolic blood pressure during transport (odds ratio = 0.98; 95% confidence interval, 0.96-0.99; P = .038), not BPV, was associated with a lower likelihood of mRS ≤2. No similar correlation of analyzed blood pressure variables could be found for AKI as an outcome. Conclusion The maximum systolic blood pressure was associated with worse functional outcomes in stroke patients transported for thrombectomy. Prehospital clinicians should be cognizant of high blood pressure among patients with acute ischemic stroke from large vessel occlusion during transport and treat accordingly.

This short review addresses the mechanisms of injury mediated by carbon monoxide (CO) and current information on efficacy of hyperbaric oxygen therapy (HBOT). Recent clinical series involving large, country-wide databases and prospective randomized trials are summarized. We conclude that there is an abundance of basic science and preclinical and clinical research supporting the use of HBOT for acute CO poisoning. With appropriate consideration for pathology and therapeutic mechanisms, HBOT at a dose of 2.5-3.0 atm absolute is a necessary treatment for this toxidrome.

Blood-borne extracellular vesicles and inflammatory mediators were evaluated in divers using a closed circuit rebreathing apparatus and custom-mixed gases to diminish some diving risks. “Deep” divers (n = 8) dove once to mean (±SD) 102.5 ± 1.2 m of sea water (msw) for 167.3 ± 11.5 min. “Shallow” divers (n = 6) dove 3 times on day 1, and then repetitively over 7 days to 16.4 ± 3.7 msw, for 49.9 ± 11.9 min. There were statistically significant elevations of microparticles (MPs) in deep divers (day 1) and shallow divers at day 7 that expressed proteins specific to microglia, neutrophils, platelets, and endothelial cells, as well as thrombospondin (TSP)-1 and filamentous (F-) actin. Intra-MP IL-1β increased by 7.5-fold (p < 0.001) after day 1 and 41-fold (p = 0.003) at day 7. Intra-MP nitric oxide synthase-2 (NOS2) increased 17-fold (p < 0.001) after day 1 and 19-fold (p = 0.002) at day 7. Plasma gelsolin (pGSN) levels decreased by 73% (p < 0.001) in deep divers (day 1) and 37% in shallow divers by day 7. Plasma samples containing exosomes and other lipophilic particles increased from 186% to 490% among the divers but contained no IL-1β or NOS2. We conclude that diving triggers inflammatory events, even when controlling for hyperoxia, and many are not proportional to the depth of diving.

We hypothesized that carbon monoxide (CO) establishes an inflammatory cycle mediated by microparticles (MPs). Mice exposed to a CO protocol (1000 ​ppm for 40 ​min and then 3000 ​ppm for 20 ​min) that causes neuroinflammation exhibit NF-κB activation in astrocytes leading to generation of MPs expressing thrombospondin-1(TSP-1) that collect in deep cervical lymph nodes draining the brain glymphatic system. TSP-1 bearing MPs gain access to the blood stream where they activate neutrophils to generate a new family of MPs, and also stimulate endothelial cells as documented by leakage of intravenous 2000 ​kDa dextran. At the brain microvasculature, neutrophil and MPs sequestration, and myeloperoxidase activity result in elevations of the p65 subunit of NF-κB, serine 536 phosphorylated p65, CD36, and loss of astrocyte aquaporin-4 that persist for at least 7 days. Knock-out mice lacking the CD36 membrane receptor are resistant to all CO inflammatory changes. Events triggered by CO are recapitulated in naïve wild type mice injected with cervical node MPs from CO-exposed mice, but not control mice. All MPs-mediated events are inhibited with a NF-κB inhibitor, a myeloperoxidase inhibitor, or anti-TSP-1 antibodies. We conclude that astrocyte-derived MPs expressing TSP-1 establish a feed-forward neuroinflammatory cycle involving endothelial CD36-to-astrocyte NF-κB crosstalk. As there is currently no treatment for CO-induced neurological sequelae, these findings pose several possible sites for therapeutic interventions., Highlights • Carbon monoxide (CO) causes neurological injuries poorly correlated to hypoxic stress. • Astrocyte NF-κB triggers thrombospondin-1(TSP-1) microparticle (MP) production. • TSP-1 MPs enter the blood stream, stimulating neutrophils and endothelium. • Circulating MPs linkage to endothelial cell CD36 causes vascular damage. • Endothelial CD36-to-astrocyte NF-κB crosstalk establishes a neuroinflammatory cycle.

Introduction Patients with acute aortic diseases (AAoD) usually require transfer to tertiary centers for possible surgical care, for which intratransport management represents important continuing spectrum of care. There is little information comparing intratransport efficacy of air (ART) vs ground transport (GRT), nor how effectively they manage these patients’ pain. Our study aims to compare how effective ART and GRT manage patients’ intratransport HR, pressure. Methods Charts were reviewed of adult patients interhospital transferred to a quaternary academic center (UMMC) between 01/01/2011 and 09/30/2015. Outcomes were percentages of patients achieving target hemodynamic parameters, mortality. Results We analyzed 226 patients, 58 (26%) transported by Air and 102 (45%) type A dissection. Ground transport was associated with higher percentage of patients with target HR 60-80 bpm comparing to ART (58% vs 43%, 95% CI 0.3-0.99). Both ART and GRT were associated with similar frequencies of patients achieving target SBP and adequate pain control. Time intervals from transfer request to surgery, and mortality were similar for both types of transport. Conclusion Ground transport teams were more successful at achieving predefined target heart rate than Air transport. Intra-transport management of other vital signs and pain were equally effectively between both Air and Ground transport.

Hyperbaric oxygen (HBO2) became a mainstay for treating decompression sickness (DCS) because bubbles are associated with the disorder. Inflammatory processes including production of circulating microparticles (MPs) have now been shown to occur with DCS, leading to questions regarding pathophysiology and the role for HBO2. We investigated effects of HBO2 on mice exposed to 790 kPa air pressure for 2 h, which triggers elevations of MPs ladened with interleukin (IL)-1β that cause diffuse vascular injuries. Exposure to 283 kPa O2 (HBO2) inhibited MP elevations at 2 h postdecompression by 50% when applied either prophylactically or as treatment after decompression, and the MP number remained suppressed for 13 h in the prophylactic group. Particle content of IL-1β at 2 h postdecompression was 139.3 ± 16.2 [means ± SE; n = 11, P < 0.05) pg/million MPs vs. 8.2 ± 1.0 ( n = 15) in control mice, whereas it was 31.5 ± 6.1 ( n = 6, not significant vs. control (NS)] in mice exposed to HBO2 prophylactically, and 16.6 ± 6.3 ( n = 7, NS) when HBO2 was administered postdecompression. IL-1β content in MPs was similar in HBO2-exposed mice at 13 h postdecompression. HBO2 also inhibited decompression-associated neutrophil activation and diffuse vascular leak. Immunoprecipitation studies demonstrated that HBO2 inhibits high-pressure-mediated neutrophil nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome oligomerization. Furthermore, MPs isolated from decompressed mice cause vascular injuries when injected into naïve mice, but if decompressed mice were exposed to HBO2 before MP harvest, vascular injuries were inhibited. We conclude that HBO2 impedes high-pressure/decompression-mediated inflammatory events by inhibiting inflammasome formation and IL-1β production. NEW & NOTEWORTHY High pressure/decompression causes vascular damage because it stimulates production of microparticles that contain high concentrations of interleukin-1β, and hyperbaric oxygen can prevent injuries.

Plasma gelsolin (pGSN) levels fall in association with diverse inflammatory conditions. We hypothesized that pGSN would decrease due to the stresses imposed by high pressure and subsequent decompression, and repletion would ameliorate injuries in a murine decompression sickness (DCS) model. Research subjects were found to exhibit a modest decrease in pGSN level while at high pressure and a profound decrease after decompression. Changes occurred concurrent with elevations of circulating microparticles (MPs) carrying interleukin (IL)-1β. Mice exhibited a comparable decrease in pGSN after decompression along with elevations of MPs carrying IL-1β. Infusion of recombinant human (rhu)-pGSN into mice before or after pressure exposure abrogated these changes and prevented capillary leak in brain and skeletal muscle. Human and murine MPs generated under high pressure exhibited surface filamentous actin (F-actin) to which pGSN binds, leading to particle lysis. In addition, human neutrophils exposed to high air pressure exhibit an increase in surface F-actin that is diminished by rhu-pGSN resulting in inhibition of MP production. Administration of rhu-pGSN may have benefit as prophylaxis or treatment for DCS. NEW & NOTEWORTHY Inflammatory microparticles released in response to high pressure and decompression express surface filamentous actin. Infusion of recombinant human plasma gelsolin lyses these particles in decompressed mice and ameliorates particle-associated vascular damage. Human neutrophils also respond to high pressure with an increase in surface filamentous actin and microparticle production, and these events are inhibited by plasma gelsolin. Gelsolin infusion may have benefit as prophylaxis or treatment for decompression sickness.

The SARS-Cov-2 (COVID-19) pandemic remains a major worldwide public health issue. Initially, improved supportive and anti-inflammatory intervention, often employing known drugs or technologies, provided measurable improvement in management. We have recently seen advances in specific therapeutic interventions and in vaccines. Nevertheless, it will be months before most of the world's population can be vaccinated to achieve herd immunity. In the interim, hyperbaric oxygen (HBO2) treatment offers several potentially beneficial therapeutic effects. Three small published series, one with a propensity-score-matched control group, have demonstrated safety and initial efficacy. Additional anecdotal reports are consistent with these publications. HBO2 delivers oxygen in extreme conditions of hypoxemia and tissue hypoxia, even in the presence of lung pathology. It provides anti-inflammatory and anti-proinflammatory effects likely to ameliorate the overexuberant immune response common to COVID-19. Unlike steroids, it exerts these effects without immune suppression. One study suggests HBO2 may reduce the hypercoagulability seen in COVID patients. Also, hyperbaric oxygen offers a likely successful intervention to address the oxygen debt expected to arise from a prolonged period of hypoxemia and tissue hypoxia. To date, 11 studies designed to investigate the impact of HBO2 on patients infected with SARS-Cov-2 have been posted on clinicaltrials.gov. This paper describes the promising physiologic and biochemical effects of hyperbaric oxygen in COVID-19 and potentially in other disorders with similar pathologic mechanisms.

The idea of a global orthodontic organization, the World Federation of Orthodontists (WFO), made up of national and regional orthodontic organizations, was realized in 1995 in San Francisco at the 4th International Orthodontic Congress that was held in conjunction with the 95th annual American Association of Orthodontists meeting. This umbrella organization strives to promote quality orthodontic care, practiced and delivered by orthodontic specialists in all parts of the world. In addition, it supports its member organizations with governing principles that promote appropriate membership criteria, qualified individual leadership participation, and long-term stability of the organization over time. In response to the Coronavirus Disease 2019 pandemic, the WFO has responded proactively and plans to augment its digital resources even further in the near future. This article describes the formation of the organization, the idea that germinated through the first three international orthodontic congresses, its workflow and membership criteria, the accountability and commitment it has toward its affiliates and individual members, and its plans for future years to come.

Background/objective This case series pilot study assessed the effects of hyperbaric oxygen therapy (HBO2) for treating rheumatoid arthritis (RA). Methods Ten RA subjects received 30 HBO2 treatments over 6 to 10 weeks. Serial rheumatologic evaluations (ie, the Disease Activity Scale [DAS28], the Routine Assessment of Patient Index Data 3, and the Pain and Sleep Quality Questionnaire) were completed at baseline, throughout the course of the study, and at the 6-month follow-up. Results There was a statistically significant effect of HBO2 therapy over time on the DAS28-Global Health (p = 0.01), the DAS28-C-reactive protein (p = 0.002), and the DAS28-erythrocyte sedimentation rate (p = 0.008) measures; these analyses excluded 2 patients who were in clinical remission at baseline. Selected post hoc comparisons showed significantly lower DAS28-Global Health, DAS28-C-reactive protein, and DAS28-erythrocyte sedimentation rate scores at 3 and 6 months relative to baseline. In addition, statistically significant decreases in pain as measured by the Routine Assessment of Patient Index Data 3 and Pain and Sleep Quality Questionnaire were observed at the end of HBO2 relative to baseline. Conclusions Hyperbaric oxygen therapy is effective for joint pain in patients with RA based on data from multiple, validated clinical measures. Further research with more subjects and the use of a control group is necessary.

Objective To determine the effects of adjunctive therapeutic hypothermia, by comparing hyperbaric oxygen therapy versus hyperbaric oxygen therapy combined with therapeutic hypothermia in acute severe carbon monoxide poisoning. Design Retrospective analysis of data from our prospectively collected carbon monoxide poisoning registry. Setting A single academic medical center in Wonju, Republic of Korea. Patients Patients with acute severe carbon monoxide poisoning older than 18 years. Acute severe carbon monoxide poisoning was defined as mental status showing response to painful stimulus or unresponsive at the emergency department, and a continuation of this depressed mental status even after the first hyperbaric oxygen therapy. Patients were classified into the no-therapeutic hypothermia and therapeutic hypothermia groups. Hyperbaric oxygen therapy was performed up to twice within 24 hours after emergency department arrival, whereas therapeutic hypothermia was performed at a body temperature goal of 33°C for 24 hours using an endovascular cooling device after the first hyperbaric oxygen therapy. Interventions Hyperbaric oxygen therapy versus hyperbaric oxygen therapy combined with therapeutic hypothermia. Measurements and main results We investigated the difference in the Global Deterioration Scale score at 1 and 6 months after carbon monoxide exposure, between the no-therapeutic hypothermia and therapeutic hypothermia groups. Global Deterioration Scale scores were classified as follows: 1-3 points (favorable neurocognitive outcome) and 4-7 points (poor neurocognitive outcome). During the study period, 37 patients were treated for acute severe carbon monoxide poisoning, with 16 and 21 patients in the no-therapeutic hypothermia and therapeutic hypothermia groups, respectively. The therapeutic hypothermia group demonstrated significantly higher number of patients with favorable outcomes (p = 0.008) at 6 months after carbon monoxide exposure and better improvement of the 6-month Global Deterioration Scale score than the 1-month score (p = 0.006). Conclusions Our data suggest that in acute severe carbon monoxide poisoning, patients who were treated using therapeutic hypothermia combined with hyperbaric oxygen therapy had significantly more favorable neurocognitive outcomes at 6 months after carbon monoxide exposure than those treated with hyperbaric oxygen therapy alone.

The pathogenesis of predominantly neurological decompression sickness (DCS) is multifactorial. In SCUBA diving, besides gas bubbles, DCS has been linked to microparticle release, impaired endothelial function, and platelet activation. This study focused on vascular damage and its potential role in the genesis of DCS in breath-hold diving. Eleven breath-hold divers participated in a field study comprising eight deep breath-hold dives with short surface periods and repetitive breath-hold dives lasting for 6 h. Endothelium-dependent vasodilation of the brachial artery, via flow-mediated dilation (FMD), and the number of microparticles (MPs) were assessed before and after each protocol. All measures were analyzed by two-way within-subject ANOVA (2 × 2 ANOVA; factors: time and protocol). Absolute FMD was reduced following both diving protocols (p < 0.001), with no interaction (p = 0.288) or main effect of protocol (p = 0.151). There was a significant difference in the total number of circulating MPs between protocols (p = 0.007), where both increased post-dive (p = 0.012). The number of CD31+/CD41– and CD66b+ MP subtypes, although different between protocols (p < 0.001), also increased by 41.0% ± 56.6% (p = 0.050) and 60.0% ± 53.2% (p = 0.045) following deep and repetitive breath-hold dives, respectively. Both deep and repetitive breath-hold diving lead to endothelial dysfunction that may play an important role in the genesis of neurological DCS.

The recent coronavirus disease 2019 (COVID-19) pandemic produced high and excessive demands for hospitalizations and equipment with depletion of critical care resources. The results of these extreme therapeutic efforts have been sobering. Further, we are months away from a robust vaccination effort, and current therapies provide limited clinical relief. Therefore, several empirical oxygenation support initiatives have been initiated with intermittent hyperbaric oxygen (HBO) therapy to overcome the unrelenting and progressive hypoxemia during maximum ventilator support in intubated patients, despite high FiO2. Overall, few patients have been successfully treated in different locations across the globe. More recently, less severe patients at the edge of impending hypoxemia were exposed to HBO preventing intubation and obtaining the rapid resolution of symptoms. The few case descriptions indicate large variability in protocols and exposure frequency. This summary illustrates the biological mechanisms of action of increased O2 pressure, hoping to clarify more appropriate protocols and more useful application of HBO in COVID-19 treatment.

Poor persistence of perennial ryegrass swards is a common problem; however, there is a lack of long-term studies to understand the mechanisms associated with poor persistence. This study describes an experiment to test the hypothesis that high ryegrass seeding rates (>18 kg seed per ha) reduce long-term population persistence because of smaller plant size and poorer survival during the first year after sowing. Four cultivars, representing four functional types of perennial ryegrass, were sown at five seeding rates (equivalent to 6, 12, 18, 24 and 30 kg seed per ha) with white clover in three regions of New Zealand. Swards were monitored for 5 years. No evidence was found to indicate a lack of persistence of ryegrass-based swards sown at higher seeding rates. During the first year, swards sown at higher seeding rates had greater herbage accumulation (except at the Waikato site), greater ryegrass tiller density and greater ryegrass content. This initial impact of high seeding rates had largely dissipated by the fourth year, resulting in swards with similar annual herbage accumulation, tiller density and botanical composition. Similarly, there were relatively few differences among cultivars for these variables. Although high seeding rates did not negatively impact sward persistence, geographical location did, with strong evidence of ryegrass population decline at the Waikato site for all treatment combinations, some decline in Northland, and stable populations in Canterbury. It is possible that productive perennial ryegrass pastures can only be sustained for 4–5 years in some situations, even when the best ryegrass technology and management practices are used.

The purpose of this study was to explore perceptions among people with type 2 diabetes about foot ulcers and lower extremity amputations. This was a qualitative observational study utilizing open-ended, semistructured interviews of 39 people with diabetes who were purposively selected because they had either a foot ulcer (n = 19) or a lower extremity amputation (n = 20). Interviews were audio-recorded, deidentified, and entered into NVivo 10.0 for coding and analysis. Our integrated analytic approach combined inductively and deductively derived codes that were applied to all transcripts. Coded data were summarized and examined for patterns. Participants' description of the relationship between diabetes and their foot ulcer or amputation revealed a limited understanding of the disease process. Disruption and loss of independence was expressed whether the person had a foot ulcer or an amputation. Treatment recommendations for foot ulcers were viewed by most as extremely difficult. Amputation was a feared outcome, but some learned to adapt and, at times felt that the amputation enhanced their quality of life. Clinicians have assumed that a focus on limb salvage is preferred over a major amputation. However, because of the complexity of care requiring frequent healthcare provider visits, the frequency of care failure, the frequency of recurrence, and mortality associated with having had a foot ulcer, it may be more appropriate for clinicians to prioritize quality-of-life salvage. Foot ulcer treatment failure may be due to a lack of providers' understanding of the impact of treatment on a patient's life.

Health risks are described from elevated indoor air carbon dioxide (CO2), which often ranges from 1,000 to 4,000 ppm, but the mechanisms are unknown. Here, we demonstrate that mice exposed for 2 h to 2,000 or 4,000 ppm CO2exhibit, respectively, 3.4 ± 0.9-fold (SE, n = 6) and 4.1 ± 0.7-fold ( n = 10) elevations in circulating microparticles (MPs); neutrophil and platelet activation, and vascular leak in brain, muscle, and distal colon. Interleukin (IL)-1β content of MPs also increases after 2,000 ppm by 3.8 ± 0.6-fold ( n = 6) and after 4,000 ppm CO2by 9.3 ± 1.1-fold ( n = 10) greater than control. CO2–induced vascular damage is abrogated by treating mice with an antibody to IL-1β or an IL-1β receptor inhibitor. Injecting naïve mice with CO2-induced MPs expressing a protein found on mature neutrophils recapitulates vascular damage as seen with elevated CO2, and destruction of MPs in CO2-exposed mice abrogates vascular injuries without altering neutrophil or platelet activation. We conclude that environmentally relevant elevations of CO2trigger neutrophils to generate MPs containing high concentrations of IL-1β that cause diffuse inflammatory vascular injury.NEW & NOTEWORTHY Elevated levels of CO2are often found in indoor air and cause adverse health effects, but the mechanisms have not been identified. In a murine model, environmentally relevant levels of CO2were found to cause diffuse vascular damage because neutrophils are stimulated to produce microparticles that contain high concentrations of interleukin-1β.

It is unclear why many with diabetes develop foot ulcers (DFU) and why some do not heal. It could be associated with genetic variation. We have previously shown that NOS1AP variation is associated with lower extremity amputation in those with diabetes and that circulating stem progenitor cell concentration (SPC) is associated with impaired foot ulcer healing in those with diabetes. The goal of this study was to determine if NOS1AP variation is associated with impaired wound healing and with SPC mobilization in those with DFU. In longitudinal cohort study we demonstrate that NOS1AP variants rs16849113 and rs19649113 are associated with impaired wound healing and with SPC mobilization in those with DFU. We believe that further study of NOS1AP is merited and that it NOS1AP might be associated with a functional impairment.

Purpose/Aim: High pressures of gases such as nitrogen enhance production of singlet oxygen. Therefore, we hypothesized that growth of non-small cell lung cancer (NSCLC) A549 cells and a human-derived NSCLC explant could be inhibited by an oxidative stress mechanism using high-pressure nitrogen.Growth of human NSCLC explants and A549 cells in Matrigel were assessed after implantation into nude mice who were exposed to elevated pressures.Subcutaneous implant growth of NSCLC in nude mice was inhibited by a daily 78-minute protocol using nitrogen/oxygen breathing mixture such that at the maximum pressure of 2.78 atmospheres over ambient, mice breathed oxygen at normal atmospheric pressure. In vivo growth inhibition of A549 cells by high-pressure nitrogen could be abrogated in subcutaneous Matrigel implants when supplemented with 10-mM N-acetylcysteine as an antioxidant. Ex vivo A549 cell exposures exhibited elevated singlet oxygen production, and reactive oxygen species were produced for up to 4 hours after short-term high-pressure nitrogen exposure.This pilot study demonstrates that elevated normoxic nitrogen pressure can exacerbate oxidative stress in NSCLC to inhibit growth.

We hypothesized that elevations of carbon dioxide (CO2) commonly found in modern buildings will stimulate leukocytes to produce microparticles (MPs) and activate the nucleotide-binding domain-like receptor 3 (NLRP3) inflammasome due to mitochondrial oxidative stress. Human and murine neutrophils generate MPs with high interleukin-1β (IL-1β) content when incubated ex vivo in buffer equilibrated with 0.1-0.4% additional CO2. Enhanced MPs production requires mitochondrial reactive oxygen species production, which is mediated by activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Subsequent events leading to MPs generation include perturbation of inositol 1,3,5-triphosphate receptors, a transient elevation of intracellular calcium, activation of protein kinase C and NADPH oxidase (Nox). Concomitant activation of type-2 nitric oxide synthase yields secondary oxidants resulting in actin S-nitrosylation and enhanced filamentous actin turnover. Numerous proteins are linked to short filamentous actin including vasodilator-stimulated phosphoprotein, focal adhesion kinase, the membrane phospholipid translocation enzymes flippase and floppase, and the critical inflammasome protein ASC (Apoptosis-associated Speck protein with CARD domain). Elevations of CO2 cause oligomerization of the inflammasome components ASC, NLRP3, caspase 1, thioredoxin interacting protein, and calreticulin - a protein from endoplasmic reticulum, leading to IL-1β synthesis. An increased production rate of MPs containing elevated amounts of IL-1β persists for hours after short-term exposures to elevated CO2.

Production of blood-borne microparticles (MPs), 0.1–1 µm diameter vesicles, and interleukin (IL)-1β in response to high pressure is reported in lab animals and associated with pathological changes. It is unknown whether the responses occur in humans, and whether they are due to exposure to high pressure or to the process of decompression. Blood from research subjects exposed in hyperbaric chambers to air pressure equal to 18 meters of sea water (msw) for 60 minutes or 30 msw for 35 minutes were obtained prior to and during compression and 2 hours post-decompression. MPs and intra-particle IL-1β elevations occurred while at pressure in both groups. At 18 msw (n = 15) MPs increased by 1.8-fold, and IL-1β by 7.0-fold (p ex vivo did not generate MPs, those exposed to air pressure at 180 kPa for 1 hour generated 1.4 ± 0.1 MPs/cell (n = 8, p

Objective Patients with spontaneous intracranial hemorrhage (sICH) have poor outcomes, in part because of blood pressure variability (BPV). Patients with sICH causing elevated intracranial pressure (ICP) are frequently transferred to tertiary centers for neurosurgical interventions. We hypothesized that BPV and care intensity during transport would correlate with outcomes in patients with sICH and elevated ICP. Methods We analyzed charts from adult sICH patients who were transferred from emergency departments to a quaternary academic center from January 1, 2011, to September 30, 2015, and received external ventricular drainage. Outcomes were in-hospital mortality and the Glasgow Coma Scale on day 5 (HD5GCS). Multivariable and ordinal logistic regressions were used for associations between clinical factors and outcomes. Results We analyzed 154 patients, 103 (67%) had subarachnoid hemorrhage and 51 (33%) intraparenchymal hemorrhage; 38 (25%) died. BPV components were similar between survivors and nonsurvivors and not associated with mortality. Each additional intervention during transport was associated with a 5-fold increase in likelihood to achieve a higher HD5GCS (odds ratio = 5.4; 95% confidence interval, 1.7-16; P = .004). Conclusion BPV during transport was not associated with mortality. However, high standard deviation in systolic blood pressure during transport was associated with lower HD5GCS in patients with intraparenchymal hemorrhage. Further studies are needed to confirm our observations.