Carbon dioxide (CO2) elicits an attractive host-seeking response from mosquitos 1–3 yet is innately aversive to Drosophila melanogaster 4, 5 despite being a plentiful byproduct of attractive ...fermenting food sources. Prior studies used walking flies exclusively, yet adults track distant food sources on the wing 6. Here we show that a fly tethered within a magnetic field allowing free rotation about the yaw axis 7 actively seeks a narrow CO2 plume during flight. Genetic disruption of the canonical CO2-sensing olfactory neurons does not alter in-flight attraction to CO2; however, antennal ablation and genetic disruption of the Ir64a acid sensor do. Surprisingly, mutation of the obligate olfactory coreceptor (Orco 8) does not abolish CO2 aversion during walking 4 yet eliminates CO2 tracking in flight. The biogenic amine octopamine regulates critical physiological processes during flight 9–11, and blocking synaptic output from octopamine neurons inverts the valence assigned to CO2 and elicits an aversive response in flight. Combined, our results suggest that a novel Orco-mediated olfactory pathway that gains sensitivity to CO2 in flight via changes in octopamine levels, along with Ir64a, quickly switches the valence of a key environmental stimulus in a behavioral-state-dependent manner.
► During flight, flies actively orient toward a narrow CO2 plume ► CO2 tracking requires both Ir64a and the olfactory coreceptor Orco ► Synaptic output from octopamine neurons mediates CO2 tracking in flight
Cyclosporine is used in the prevention of allograft rejection. Owing to its narrow therapeutic index, regular monitoring of the whole blood levels of cyclosporine is required. We observed that ...immunoassays measured significantly higher cyclosporine levels than did high-performance liquid chromatography (HPLC) over time after transplantation. As cyclosporine metabolites cross-react even with immunoassays, this observation might be due to alterations of the cyclosporine metabolism. We analyzed cyclosporine metabolite concentrations in the early and in the late posttransplantation periods in 127 patients after kidney, bone marrow, heart-lung, and liver transplantation by HPLC and determined whole blood levels of cyclosporine by 4 immunoassays (enzyme-multiplied immunoassay EMIT, cloned enzyme donor immunoassay CEDIA, AxSYM Abbott Laboratories, Chicago, IL, and TDx Abbott Laboratories). Despite reduced dose, we found significantly higher cyclosporine concentrations measured by the EMIT, AxSYM, and TDx assays in various patient groups. These results are due to the increased metabolite/cyclosporine ratio in the late posttransplantation period. In particular, the metabolites AM1 and AM19 increased significantly over time in bone marrow transplant recipients. Therefore, cyclosporine levels measured by immunoassays should be interpreted with caution.
The effect of cytokine transduction on the tumorigenicity and immunogenicity of murine non-immunogeneic mammary carcinoma (4T1), acute myeloid leukemia (mAML) and partially immunogenic B-cell ...leukemia (BCL1) has been evaluated in syngeneic strains of mice. Transduction by retroviral vectors containing the genes for GM-CSF, IL-2 or IFN-gamma did not lead to a marked antitumor effect in 4T1 mammary tumor or BCL1. A reduced local tumor size was observed in mice inoculated with 4T1 cells transduced with both GM-CSF and IL-2 genes followed by an in vitro exposure to recombinant IFN-gamma, but survival was not prolonged. Tumorigenicity of mAML cells transduced with the gene coding for IFN-gamma was significantly reduced as manifested by prolonged survival of mice in comparison with animals inoculated with non-transduced mAML cells. Transduction by each of the aforementioned cytokines did not affect the immunogenicity of these tumor model cells. The results suggest that genetic modification of spontaneous and non-immunogenic experimental tumor models does not necessarily support direct utilization of cytokine gene therapy for clinical application. More effective methods have yet to be established in order to achieve an antitumor effect in spontaneous non-immunogenic malignancies.
Patients with cancer undergoing treatment are at high risk of COVID-19 following SARS-CoV-2 infection; however, their ability to produce an adequate antibody response to messenger RNA SARS-CoV-2 ...vaccines is unclear.
To evaluate rates of antispike (anti-S) antibody response to a BNT162b2 vaccine in patients with cancer who are undergoing systemic treatment vs healthy controls.
This prospective cohort study included 102 adult patients with solid tumors undergoing active intravenous anticancer treatment and 78 controls who received the second dose of the BNT162b2 vaccine at least 12 days before enrollment. The controls were taken from a convenience sample of the patients' family/caregivers who accompanied them to treatment. The study was conducted between February 22, 2021, and March 15, 2021 at Davidoff Cancer Center at Beilinson Hospital (Petah Tikva, Israel).
Blood samples were drawn from the study participants. Serum samples were analyzed and the titers of the IgG antibodies against SARS-CoV-2 spike receptor-binding domain were determined using a commercially available immunoassay. Seropositivity was defined as 50 or greater AU/mL.
The primary outcome was the rate of seropositivity. Secondary outcomes included comparisons of IgG titers and identifying factors that were associated with seropositivity using univariate/multivariable analyses.
The analysis included 180 participants, which comprised 102 patients with cancer (median interquartile range (IQR) age, 66 56-72 years; 58 men 57%) and 78 healthy controls (median IQR age, 62 49-70 years; 25 men 32%). The most common tumor type was gastrointestinal (29 28%). In the patient group, 92 (90%) were seropositive for SARS-CoV 2 antispike IgG antibodies after the second vaccine dose, whereas in the control group, all were seropositive. The median IgG titer in the patients with cancer was significantly lower than that in the controls (1931 IQR, 509-4386 AU/mL vs 7160 IQR, 3129-11 241 AU/mL; P < .001). In a multivariable analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy (β, -3.5; 95% CI, -5.6 to -1.5).
In this cohort study of patients with cancer who were receiving active systemic therapy, 90% of patients exhibited adequate antibody response to the BNT162b2 vaccine, although their antibody titers were significantly lower than those of healthy controls. Further research into the clinical relevance of lower titers and their durability is required. Nonetheless, the data support vaccinating patients with cancer as a high priority, even during therapy.
To describe the qualitative and quantitative changes in choroidal neovascularization (CNV) flow pattern after anti-vascular endothelial growth factor therapy, by optical coherence tomography ...angiography (OCTA).
Consecutive patients with neovascular age-related macular degeneration underwent multimodal imaging, including OCTA at initial examination and at last visit. High-flow networks in the choriocapillaris segmentation of OCTA were qualitatively and quantitatively analyzed at baseline and at follow-up, to characterize vascular flow changes after anti-vascular endothelial growth factor treatment and to correlate these changes with final exudation signs on spectral domain optical coherence tomography.
Seventeen eyes were included. Mean follow-up was of 11.7 ± 3.3 months. Baseline images showed six medusa pattern (35.3%), four seafan pattern (23.5%), and seven indistinct network patterns (41.2%). Mean CNV area at baseline was 1.58 ± 1.72 mm. Final OCTA images revealed a decrease in CNV total area of 21.6%. In 6/17 eyes, the baseline neovascular pattern was unchanged; these cases were associated with exudation at the final spectral domain optical coherence tomography examination (P = 0.034) and a decrease in CNV area of 34.1%. Conversely, in 11/17 eyes (64.7%), the initial pattern had changed to a pruned vascular tree pattern, with variable exudative status on spectral domain optical coherence tomography at the final visit and a decrease in total CNV area of 0.07%.
The vascular flow remodeling induced by recurrent anti-vascular endothelial growth factor treatment can be assessed by OCTA. Optical coherence tomography angiography may help to accurately evaluate treatment response and to recognize patterns usually associated with recurrent exudative activity.
Understanding antibody-based SARS-CoV-2 immunity is critical for overcoming the COVID-19 pandemic and informing vaccination strategies. We evaluated SARS-CoV-2 antibody dynamics over 10 months in 963 ...individuals who predominantly experienced mild COVID-19. Investigating 2,146 samples, we initially detected SARS-CoV-2 antibodies in 94.4% of individuals, with 82% and 79% exhibiting serum and IgG neutralization, respectively. Approximately 3% of individuals demonstrated exceptional SARS-CoV-2 neutralization, with these “elite neutralizers” also possessing SARS-CoV-1 cross-neutralizing IgG. Multivariate statistical modeling revealed age, symptomatic infection, disease severity, and gender as key factors predicting SARS-CoV-2-neutralizing activity. A loss of reactivity to the virus spike protein was observed in 13% of individuals 10 months after infection. Neutralizing activity had half-lives of 14.7 weeks in serum versus 31.4 weeks in purified IgG, indicating a rather long-term IgG antibody response. Our results demonstrate a broad spectrum in the initial SARS-CoV-2-neutralizing antibody response, with sustained antibodies in most individuals for 10 months after mild COVID-19.
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•Broad variation in neutralizing antibodies in SARS-CoV-2-convalescent individuals•∼3% of individuals showed a potent antibody response with SARS-CoV-1 cross-reactivity•Older age, symptoms, and severe disease predict higher SARS-CoV-2 neutralization•Serum and IgG neutralization half-lives were 14.7 and 31.4 weeks, respectively
Vanshylla et al. report longitudinal antibody kinetics in a mainly mild COVID-19 convalescent cohort of 963 individuals. There is broad variation in the initial response with older age and disease severity predicting higher SARS-CoV-2 neutralizing activity. Neutralizing IgG antibodies are detectable for up to 10 months in the majority of individuals.
The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 play a ...role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetic variability in man. We generated human induced pluripotent stem cells (iPSCs) with controllable expression of SIRT1. By differentiating edited iPSCs into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown iPSC-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically edited human liver tissue may become an important tool for investigating human liver biology and disease.
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•Edited human iPSCs can control SIRT1 expression•Low SIRT1 expression in human iPSC hepatocytes increases fatty acid biosynthesis•Human iPSC-derived livers developed macrosteatosis and inflammatory phenotype•Metabolic profile in human iPSC-derived fatty livers is similar to human NASH livers
Collin de l’Hortet et al. biofabricated human fatty livers using genetically modified human hepatocytes differentiated from induced pluripotent stem cells, mesenchymal cells, fibroblasts, and macrophages. This methodology uncovered the molecular mechanisms of downregulated SIRT1 in human liver tissue. The biofabricated tissue reflected many aspects of human livers with non-alcoholic fatty liver disease.
Purpose To characterize the optical coherence tomography angiography (OCTA) appearance of the perifoveal macular microvasculature in visually asymptomatic patients with sickle cell disease, and to ...compare these findings with those of fluorescein angiography (FA). Design Retrospective observational case series. Methods Eighteen eyes of 9 consecutive patients with a median age of 41 years (range: 19–54 years) with electrophoretic confirmation of sickle cell disease were included and analyzed. A complete ophthalmologic examination was performed, including fundus examination, FA, and OCTA. Nine eyes of 5 healthy subjects were also analyzed with OCTA to serve as a control group. Results OCTA demonstrated microvascular abnormalities in the perifoveal region of the macula in all eyes, whereas FA appeared normal in 9 of 18 eyes (50%). Most capillary abnormalities were located in the temporal juxtafoveal region and involved both the superficial and the deep capillary plexuses. The nonflow area (foveal avascular zone) was significantly larger in sickle cell disease patients than in the control group, both in the superficial and the deep capillary plexuses ( P < .0001). The perifoveal vessel density was significantly lower in the sickle cell disease patients than in the control group in both the superficial ( P = .0011) and the deep capillary plexuses ( P = .0018). Conclusion OCTA provided detailed imaging of the perifoveal microvasculature in sickle cell disease. It appeared more sensitive than FA in detecting macular microangiopathy in asymptomatic patients. Microvascular abnormalities in sickle cell disease involved both the superficial and the deep capillary plexuses.
ObjectivesWhile almost 60% of the world has received at least one dose of COVID-19 vaccine, the global distribution of vaccination has not been equitable. Only 4% of the population of low-income ...countries (LICs) has received a full primary vaccine series, compared with over 70% of the population of high-income nations.DesignWe used economic and epidemiological models, parameterised with public data on global vaccination and COVID-19 deaths, to estimate the potential benefits of scaling up vaccination programmes in LICs and lower-middle-income countries (LMICs) in 2022 in the context of global spread of the Omicron variant of SARS-CoV2.SettingLow-income and lower-middle-income nations.Main outcome measuresOutcomes were expressed as number of avertable deaths through vaccination, costs of scale-up and cost per death averted. We conducted sensitivity analyses over a wide range of parameter estimates to account for uncertainty around key inputs.FindingsGlobally, universal vaccination in LIC/LMIC with three doses of an mRNA vaccine would result in an estimated 1.5 million COVID-19 deaths averted with a total estimated cost of US$61 billion and an estimated cost-per-COVID-19 death averted of US$40 800 (sensitivity analysis range: US$7400–US$81 500). Lower estimated infection fatality ratios, higher cost-per-dose and lower vaccine effectiveness or uptake lead to higher cost-per-death averted estimates in the analysis.ConclusionsScaling up COVID-19 global vaccination would avert millions of COVID-19 deaths and represents a reasonable investment in the context of the value of a statistical life. Given the magnitude of expected mortality facing LIC/LMIC without vaccination, this effort should be an urgent priority.
Biplane mode for more precise intrauterine procedures Chalouhi, Gihad E.; Guenuec, Alexandra; Rameh, Georges ...
American journal of obstetrics and gynecology,
February 2022, 2022-02-00, 20220201, Letnik:
226, Številka:
2
Journal Article
Recenzirano
The evolution of ultrasound and the introduction of 3- and 4-dimensional ultrasound techniques led to a shift in the perception and usage of ultrasound in fetal medicine. The biplane mode might help ...in multiple fetal procedures, including but not limited to basic intrauterine thoracocentesis, thoracoamniotic shunting, amnioreduction, amnioinfusion, cordocentesis, intraumbilical infusion, and umbilical cord coagulation, with a possible reduction in the complication rate. Despite its theoretical usefulness, more studies are required to assess the clinical importance of this technique.
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