Role of immune mediators in predicting hospitalization of SARS-CoV-2 positive patients.

BACKGROUND: Several immune mediators (IM) including cytokines, chemokines, and their receptors have been suggested to play a role in COVID-19 pathophysiology and severity. AIM: To determine if early IM profiles are predictive of clinical outcome and which of the IMs tested possess the most clinical utility. METHODS: A custom bead-based multiplex assay was used to measure IM concentrations in a cohort of SARS-CoV-2 PCR positive patients (n = 326) with varying disease severities as determined by hospitalization status, length of hospital stay, and survival. Patient groups were compared, and clinical utility was assessed. Correlation plots were constructed to determine if significant relationships exist between the IMs in the setting of COVID-19. RESULTS: In PCR positive SARS-CoV-2 patients, IL-6 was the best predictor of the need for hospitalization and length of stay. Additionally, MCP-1 and sIL-2Rα were moderate predictors of the need for hospitalization. Hospitalized PCR positive SARS-CoV-2 patients displayed a notable correlation between sIL-2Rα and IL-18 (Spearman's ρ = 0.48, P=<0.0001). CONCLUSIONS: IM profiles between non-hospitalized and hospitalized patients were distinct. IL-6 was the best predictor of COVID-19 severity among all the IMs tested.

Social determinants of emotional well-being in new refugees in the UK.

OBJECTIVES: Refugees are most vulnerable to mental health problems of all migrant groups, and an understanding of the role of postdisplacement social factors in refugee emotional well-being can help to shape the future interventions for this group. We aimed to investigate the effect of social determinants, such as employment, language ability and accommodation, on mental health in refugees in the UK. STUDY DESIGN: This prospective longitudinal cohort study was set in the UK. The study population of new UK refugees was drawn from an existing data set of the Longitudinal Survey of New Refugees (n = 5678), in which all new UK refugees (2005-2007) were sent a postal questionnaire at four time points across 2 years. METHODS: Ordered logistic regression models were used to evaluate associations between social determinants and the dependent variables, emotional well-being or change in emotional well-being, using a question from the Short Form-36 Health Survey Questionnaire. RESULTS: Refugees who were unemployed in the UK, could not speak English well or were unsatisfied with their accommodation had significantly higher odds of poorer emotional well-being in the cross-sectional analysis (P < 0.05 at all time points measured). CONCLUSIONS: Postdisplacement social factors, including language ability, employment status and accommodation satisfaction, were important determinants of refugee emotional well-being. Changes in these social determinants have the potential to improve refugee mental health, making them legitimate, modifiable targets for important public health interventions. Accounting for this, further research into how to improve refugee well-being is crucial given the increase in refugee numbers around the developed world.

Differentiating salmon populations at broad and fine geographical scales with microsatellites and single nucleotide polymorphisms.

Single nucleotide polymorphisms (SNPs) are appealing genetic markers due to several beneficial attributes, but uncertainty remains about how many of these bi-allelic markers are necessary to have sufficient power to differentiate populations, a task now generally accomplished with highly polymorphic microsatellite markers. In this study, we tested the utility of 37 SNPs and 13 microsatellites for differentiating 29 broadly distributed populations of Chinook salmon (n = 2783). Information content of all loci was determined by In and G'(ST), and the top 12 markers ranked by In were microsatellites, but the 6 highest, and 7 of the top 10 G'(ST) ranked markers, were SNPs. The mean ratio of random SNPs to random microsatellites ranged from 3.9 to 4.1, but this ratio was consistently reduced when only the most informative loci were included. Individual assignment test accuracy was higher for microsatellites (73.1%) than SNPs (66.6%), and pooling all 50 markers provided the highest accuracy (83.2%). When marker types were combined, as few as 15 of the top ranked loci provided higher assignment accuracy than either microsatellites or SNPs alone. Neighbour-joining dendrograms revealed similar clustering patterns and pairwise tests of population differentiation had nearly identical results with each suite of markers. Statistical tests and simulations indicated that closely related populations were better differentiated by microsatellites than SNPs. Our results indicate that both types of markers are likely to be useful in population genetics studies and that, in some cases, a combination of SNPs and microsatellites may be the most effective suite of loci.

Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect.

Msh2 is a key mammalian DNA mismatch repair (MMR) gene and mutations or deficiencies in mammalian Msh2 gene result in microsatellite instability (MSI+) and the development of cancer. Here, we report that primary mouse embryonic fibroblasts (MEFs) deficient in the murine MMR gene Msh2 (Msh2(-/-)) showed a significant increase in chromosome aneuploidy, centrosome amplification, and defective mitotic spindle organization and unequal chromosome segregation. Although Msh2(-/-) mouse tissues or primary MEFs had no apparent change in telomerase activity, telomere length, or recombination at telomeres, Msh2(-/-) MEFs showed an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA. These data suggest that MSH2 helps to maintain genomic stability through the regulation of the centrosome and normal telomere capping in vivo and that defects in MMR can contribute to oncogenesis through multiple pathways.

Blunt trauma and operative care in microgravity: a review of microgravity physiology and surgical investigations with implications for critical care and operative treatment in space.

BACKGROUND: The assembly of the International Space Station in a low earth orbit will soon become a reality. The National Aeronautics and Space Administration envisions inhabited lunar bases and staffed missions to Mars in the future. Increasing numbers of astronauts, construction of high-mass structures, increased extra-vehicular activity, and prolonged if not prohibitive medical evacuation times to earth underscore the need to address requirements for trauma care in nonterrestrial environments. STUDY DESIGN: A search was carried out to review the relevant literature in the MEDLINE and SPACELINE databases. All related Technical, Corporate, and Flight Test Reports in the KRUG Life Sciences corporate library were also reviewed. Bibliographies of all articles were then reviewed from these papers to identify additional pertinent literature. Senior Russian investigators reviewed the Russian literature and translated Russian publications when appropriate. Personal communication and discussion with active microgravity investigators and ongoing microgravity research supplemented published reports. RESULTS: A large volume of data exist to document the multiple detrimental physiologic effects of microgravity exposure on human physiology. Organs systems such as cardiovascular, neurohumoral, immune, hematopoetic, and musculoskeletal systems may be particularly affected. These physiologic changes suggest an impaired ability to withstand major systemic trauma. Observational data also suggest adverse changes in numerous aspects of response to wounding and injury, and in areas such as the behavior of hemorrhage, microbiologic flora, and wound healing. In addition to an increased volume of ongoing and anticipated basic science research in microgravity physiology, preliminary studies of clinical diagnosis and therapy have been carried out in microgravity and microgravity laboratories. The feasibility of a wide range of ancillary critical care techniques has been verified in the parabolic flight model of microgravity. Although Russian investigators first performed laparotomies on rabbits in parabolic flight in 1967, only recently have American investigators demonstrated the reproducible feasibility of open and endoscopic surgical procedures under general anesthetic in animal models in a microgravity environment. CONCLUSIONS: With appropriate instrumentation and personnel, the majority of resuscitative and surgical interventions required to stabilize a severely injured astronaut are feasible in a microgravity environment. Onboard limitations in mass, volume, and power that are ever present in any spacecraft design will limit the realistic capabilities of the medical system. Standard proved and tested trauma and operative management protocols will constitute the basis for extra-terrestrial care. Surgeons should familiarize themselves with the microgravity environment and remain active in planning trauma care for the continued exploration of space.

Endoscopic surgery in weightlessness: the investigation of basic principles for surgery in space.

BACKGROUND: Performing a surgical procedure in weightlessness, also called 0-gravity (0-g), has been shown to be no more difficult than in a 1-g environment if the requirements for the restraint of the patient, operator, surgical hardware, are observed. The performance of laparoscopic and thorascopic procedures in weightlessness, if feasible, would offer several advantages over the performance of an open operation. Concerns about the feasibility of performing minimally invasive procedures in weightlessness have included impaired visualization from the absence of gravitational retraction of the bowel (laparoscopy) or thoracic organs (thoracoscopy) as well as obstruction and interference from floating debris such as blood, pus, and irrigation fluid. The purpose of this study was to determine the feasibility of performing laparoscopic and thorascopic procedures and the degree of impaired surgical endoscopic visualization in weightlessness. METHODS: From 1993 to 2000, laparoscopic and thorascopic procedures were performed on 10 anesthetized adult pigs weighing approximately 50 kg in the National Aeronautics and Space Administration (NASA) Microgravity Program using a modified KC-135 airplane. The parabolic simulation system for advanced life support was used in this project, and 20 to 40 parabolas were used for laparoscopic or thorascopic investigation, each containing approximately 30 s of 0-g alternating with 2-g pullouts. The animal model was restrained in the supine position on a floor-level Crew Medical Restraint System, and the abdominal cavity was insufflated with carbon dioxide. The intraabdominal and intrathoracic anatomy was visualized in the 1-g, 0-g, and 2-g periods of parabolic flight. Bleeding was created in the animals, and the behavior of the blood in the abdominal and thoracic cavities was observed. In the thoracic cavity, gas insufflation and mechanical retraction was used at times unilaterally to decrease pulmonary ventilation enough to increase the thoracic domain. RESULTS: Visualization was improved in laparoscopy, from tethering of the bowel by the elastic mesentery, and from the strong tendency for debris and blood to adhere to the abdominal wall because of surface tension forces. The lack of adequate thoracic domain made thorascopy more difficult. Fluid in the thoracic cavity did not impair visualization because the fluid at 0-g does not loculate posteriorly, but disperses along the thoracic wall and mediastinal reflections. CONCLUSIONS: Performing minimally invasive procedures instead of open surgical procedures in a weightless environment has theoretical advantages, especially in the ability to prevent cabin atmosphere contamination from surgical fluids (blood, pus, irrigation). Visualization will become more important and practical as the endoscopic hardware is miniaturized from its current form, as endoscopic technology becomes more advanced, and as more surgically capable medical crew officers are present in future long-duration space exploration missions.

Ultrasound evaluation of the magnitude of pneumothorax: a new concept.

Pneumothorax is commonly seen in trauma patients; the diagnosis is confirmed by radiography. The use of ultrasound where radiographic capabilities are absent, is being investigated by the National Aeronautics and Space Administration. We investigated the ability of ultrasound to assess the magnitude of pneumothorax in a porcine model. Sonography was performed on anesthetized pigs in both ground-based laboratory (n = 5) and microgravity conditions (0 x g) aboard the KC-135 aircraft during parabolic flight (n = 4). Aliquots of air (50-100 cm3) were introduced into the chest to simulate pneumothorax. Results were videorecorded and digitized for later interpretation. Several distinct sonographic patterns of partial lung sliding were noted including the combination of a sliding zone with a still zone and a "segmented" sliding zone. These "partial lung sliding" patterns exclude massive pneumothorax manifested by a complete separation of the lung from the parietal pleura. In 0 x g, the sonographic picture is more diverse; one x g differences between posterior and anterior aspects are diminished. Modest pneumothorax can be inferred by the ultrasound sign of "partial lung sliding." This finding, which increases the negative predictive value of thoracic ultrasound, may be attributed to intermittent pleural contact, small air spaces, or alterations in pleural lubricant. Further studies of these phenomena are warranted.

A review of microgravity surgical investigations.

The likelihood of performing a surgical procedure in space will increase as the Soviet Mir space station is expanded and the Space Station Freedom becomes operational. A review of previous research and hardware development, performed mostly in parabolic flight both in the Soviet Union and the U.S., reveals an interest in surgical chambers to prevent cabin atmosphere contamination. Surgical techniques appear to be no more difficult than in a 1-G environment if a restraint system is used. Minimizing the chances of wound infection from the high particle count spacecraft atmosphere is an additional concern. Additional research is necessary to delineate the clinical significance of these problems and to further develop surgical techniques in microgravity.

Animal surgery in microgravity.

The first surgical procedure in microgravity using an animal model is described. The investigation resulted in a realistic evaluation of prototype hardware and procedures that could be applied to a surgical support system on Space Station Freedom. This was especially true for the issue of the management of surgical bleeding, which was observed and studied in microgravity for the first time.

Surgical instrument restraint in weightlessness.

BACKGROUND: Performing a surgical procedure during spaceflight will become more likely in the future as the duration of missions becomes longer. Only minimal surgical capability was available on previous missions since the definitive medical care time was short and the likelihood of a surgical event too low to justify carrying surgical hardware onboard. Early demonstrations of surgical procedures in the microgravity environment of parabolic flight indicated the need for careful logistical planning and restraint of surgical hardware. Human ergonomics also has more effect in microgravity than in the conventional 1-G environment. METHODS: Three methods of surgical instrument restraint--a Minor Surgical Kit (MSK), a Surgical Restraint Scrub Suit (SRSS), and a Surgical Tray (ST)--were evaluated in parabolic flight surgical procedures. RESULTS: The MSK was easily stored, easily deployed, and demonstrated the best ability to facilitate a surgical procedure in microgravity. CONCLUSION: Important factors in a surgical restraint system for microgravity include excellent organization of supplies, ability to maintain sterility, accessibility while providing secure restraint, ability to dispose of sharp items and biological trash, and ergonomic efficiency.

Percutaneous aspiration of fluid for management of peritonitis in space.

BACKGROUND: As a medical emergency that can affect even well-screened, healthy individuals, peritonitis developing during a long-duration space exploration mission may dictate deviation from traditional clinical practice due to the absence of otherwise indicated surgical capabilities. Medical management can treat many intra-abdominal processes, but treatment failures are inevitable. In these circumstances, percutaneous aspiration under sonographic guidance could provide a "rescue" strategy. HYPOTHESIS: Sonographically guided percutaneous aspiration of intra-peritoneal fluid can be performed in microgravity. METHODS: Investigations were conducted in the microgravity environment of NASA's KC-135 research aircraft (0 G). The subjects were anesthetized female Yorkshire pigs weighing 50 kg. The procedures were rehearsed in a terrestrial animal lab (1 G). Colored saline (500 mL) was introduced through an intra-peritoneal catheter during flight. A high-definition ultrasound system (HDI-5000, ATL, Bothell, WA) was used to guide a 16-gauge needle into the peritoneal cavity to aspirate fluid. RESULTS: Intra-peritoneal fluid collections were easily identified, distinct from surrounding viscera, and on occasion became more obvious during weightless conditions. Subjectively, with adequate restraint of the subject and operators, the procedure was no more demanding than during the 1-G rehearsals. CONCLUSIONS: Sonographically guided percutaneous aspiration of intra-peritoneal fluid collections is feasible in weightlessness. Treatment of intra-abdominal inflammatory conditions in spaceflight might rely on pharmacological options, backed by sonographically guided percutaneous aspiration for the "rescue" of treatment failures. While this risk mitigation strategy cannot guarantee success, it may be the most practical option given severe resource limitations.

Surgical bleeding in microgravity.

A surgical procedure performed during space flight would occur in a unique microgravity environment. Several experiments performed during weightlessness in parabolic flight were reviewed to ascertain the behavior of surgical bleeding in microgravity. Simulations of bleeding using dyed fluid and citrated bovine blood, as well as actual arterial and venous bleeding in rabbits, were examined. The high surface tension property of blood promotes the formation of large fluid domes, which have a tendency to adhere to the wound. The use of sponges and suction will be adequate to prevent cabin atmosphere contamination with all bleeding, with the exception of temporary arterial droplet streams. The control of the bleeding with standard surgical techniques should not be difficult.

Candidate mutator genes in mismatch repair-deficient thymic lymphomas: no evidence of mutations in the DNA polymerase delta gene.

DNA mismatch repair (MMR) proteins recognize nucleotides that are incorrectly paired. Deficiencies in MMR lead to increased genomic instability reflected in an increased mutation frequency and predisposition to tumorigenesis. Mice lacking the MMR gene, Msh2, develop thymic lymphomas that exhibit much higher mutational frequencies than other Msh2(-/-) tumours and Msh2(-/-) normal thymic tissue, suggesting that an additional mutator may have been acquired in a tissue-specific manner. Clustered mutations observed exclusively in the thymic lymphomas suggests that a gene(s) associated with the replication machinery might have become altered during tumorigenesis. Based on mutation studies in Saccharomyces cerevisiae lacking Msh2 and DNA polymerase delta (DNA pol delta), we hypothesized that the acquisition of mutations in DNA pol delta could contribute to the hypermutator phenotype and tumorigenesis in Msh2(-/-) thymic tissue. Furthermore, previous reports have suggested that genes containing mononucleotide repeats are non-random mutational targets in the absence of MMR. Therefore, we sequenced all 26 exons of the DNA pol delta catalytic subunit, including the six exons containing mononucleotide repeats of >5 bp, from nine Msh2(-/-) thymic lymphomas and two wild-type controls. No DNA pol delta pathogenic mutations were found in the thymic lymphomas, although several DNA base differences compared with published DNA pol delta sequences were observed. We conclude, therefore, that inactivating mutations in DNA pol delta are not a contributing factor in the development of the hypermutator phenotype in MMR-deficient murine thymic lymphomas.

Laparoscopic surgery in weightlessness.

BACKGROUND: Performing a surgical procedure in weightlessness has been shown not to be any more difficult than in a 1g environment if the requirements for the restraint of the patient, operator, and surgical hardware are observed. The feasibility of performing a laparoscopic surgical procedure in weightlessness, however, has been questionable. Concerns have included the impaired visualization from the lack of gravitational retraction of the bowel and from floating debris such as blood. METHODS: In this project, laparoscopic surgery was performed on a porcine animal model in the weightlessness of parabolic flight. RESULTS: Visualization was unaffected due to the tethering of the bowel by the elastic mesentery and the strong tendency for debris and blood to adhere to the abdominal wall due to surface tension forces. CONCLUSIONS: There are advantages to performing a laparoscopic instead of an open surgical procedure in a weightless environment. These will become important as the laparoscopic support hardware is miniaturized from its present form, as laparoscopic technology becomes more advanced, and as more surgically capable crew medical officers are present in future long-duration space-exploration missions.

A dominant interference collagen X mutation disrupts hypertrophic chondrocyte pericellular matrix and glycosaminoglycan and proteoglycan distribution in transgenic mice.

Collagen X transgenic (Tg) mice displayed skeleto-hematopoietic defects in tissues derived by endochondral skeletogenesis.(1) Here we demonstrate that co-expression of the transgene product containing truncated chicken collagen X with full-length mouse collagen X in a cell-free translation system yielded chicken-mouse hybrid trimers and truncated chicken homotrimers; this indicated that the mutant could assemble with endogenous collagen X and thus had potential for dominant interference. Moreover, species-specific collagen X antibodies co-localized the transgene product with endogenous collagen X to hypertrophic cartilage in growth plates and ossification centers; proliferative chondrocytes also stained diffusely. Electron microscopy revealed a disrupted hexagonal lattice network in the hypertrophic chondrocyte pericellular matrix in Tg growth plates, as well as altered mineral deposition. Ruthenium hexamine trichloride-positive aggregates, likely glycosaminoglycans (GAGs)/proteoglycans (PGs), were also dispersed throughout the chondro-osseous junction. These defects likely resulted from transgene co-localization and dominant interference with endogenous collagen X. Moreover, altered GAG/PG distribution in growth plates of both collagen X Tg and null mice was confirmed by a paucity of staining for hyaluronan and heparan sulfate PG. A provocative hypothesis links the disruption of the collagen X pericellular network and GAG/PG decompartmentalization to the potential locus for hematopoietic failure in the collagen X mice.

Prospective evaluation of thoracic ultrasound in the detection of pneumothorax.

BACKGROUND: Thoracic ultrasound may rapidly diagnose pneumothorax when radiographs are unobtainable; the accuracy is not known. METHODS: We prospectively evaluated thoracic ultrasound detection of pneumothorax in patients at high suspicion of pneumothorax. The presence of "lung sliding" or "comet tail" artifacts were determined in patients by ultrasound before radiologic verification of pneumothorax by residents instructed in thoracic ultrasound. Results were compared with standard radiography. RESULTS: There were 382 patients enrolled; the cause of injury was blunt (281 of 382), gunshot wound (22 of 382), stab wound (61 of 382), and spontaneous (18 of 382). Pneumothorax was demonstrated on chest radiograph in 39 patients and confirmed by ultrasound in 37 of 39 patients (95% sensitivity); two pneumothoraces could not be diagnosed because of subcutaneous air; the true-negative rate was 100%. CONCLUSION: Thoracic ultrasound reliably diagnoses pneumothorax. Expansion of the focused abdominal sonography for trauma (FAST) examination to include the thorax should be investigated for terrestrial and space medical applications.