Transition to a weaker Sun: Changes in the solar atmosphere during the decay of the Modern Maximum

Context. The Sun experienced a period of unprecedented activity during the 20th century, now called the Modern Maximum (MM). The decay of the MM after its maximum in cycle 19 has changed the Sun, the heliosphere, and the planetary environments in many ways. However, studies disagree on whether this decay has proceeded synchronously in different solar parameters or not.Aims. One of the related key issues is if the relation between two long parameters of solar activity, the sunspot number and the solar 10.7 cm radio flux, has remained the same during this decay. A recent study argues that there is an inhomogeneity in the 10.7 cm radio flux in 1980, which leads to a step-like jump (“1980 jump”) in this relation. If true, this result would reduce the versatility of possible long-term studies of the Sun during the MM. Here we aim to show that the relation between sunspot number and 10.7 cm radio flux does indeed vary in time, not due to an inhomogeneous radio flux but due to physical changes in the solar atmosphere.Methods. We used radio flux measurements made in Japan at four different wavelengths, and studied their long-term relation with the sunspot number and the 10.7 cm radio flux during the decay of MM. We also used two other solar parameters, the MgII index and the number of solar active regions, in order to study the nature of the observed long-term changes in more detail.Results. We find that the 1980 jump is only the first of a series of 1–2-year “humps” that mainly occur during solar maxima. All five radio fluxes depict an increasing trend with respect to the sunspot number from the 1970s to 2010s. These results exclude the interpretation of the 1980 jump as an inhomogeneity in the 10.7 cm flux, and reestablish the 10.7 cm flux as a homogeneous measure of solar activity. The fluxes of the longer radio waves are found to increase with respect to the shorter waves, which suggests a long-term change in the solar radio spectrum. We also find that the MgII index of solar UV irradiance and the number of active regions also increased with respect to the sunspot number, further verifying the difference in the long-term evolution in chromospheric and photospheric parameters.Conclusions. Our results provide evidence for important structural changes in solar magnetic fields and the solar atmosphere during the decay of the MM, which have not been reliably documented so far. We also emphasize that the changing relation between the different (e.g., photospheric and chromospheric) solar parameters should be taken into account when using the sunspot number or any single parameter in long-term studies of solar activity

TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade

Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p <0.0001) and overall survival (p <0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody.Peer reviewe

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance : systematic review and meta-analysis

OBJECTIVE To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols. DESIGN Systematic review and meta-analysis. DATA SOURCES Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016. ELIGIBILITY CRITERIA Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months. DATA SYNTHESIS Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I-2 statistics. MAIN OUTCOME MEASURES Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months). RESULTS 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I-2= 77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I-2= 82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I-2= 90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I-2= 0%), 23% (two studies, 226/938 women, 20% to 26%; I-2= 97%), and 11% (three studies, 163/1033 women, 5% to 19%; I-2= 67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%. CONCLUSIONS Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.Peer reviewe

Evaluation of a Rapid Immunochromatographic ODK-0901 Test for Detection of Pneumococcal Antigen in Middle Ear Fluids and Nasopharyngeal Secretions

Since the incidence of penicillin-resistant Streptococcus pneumoniae has been increasing at an astonishing rate throughout the world, the need for accurate and rapid identification of pneumococci has become increasingly important to determine the appropriate antimicrobial treatment. We have evaluated an immunochromatographic test (ODK-0901) that detects pneumococcal antigens using 264 middle ear fluids (MEFs) and 268 nasopharyngeal secretions (NPSs). A sample was defined to contain S. pneumoniae when optochin and bile sensitive alpha hemolytic streptococcal colonies were isolated by culture. The sensitivity and specificity of the ODK-0901 test were 81.4% and 80.5%, respectively, for MEFs from patients with acute otitis media (AOM). In addition, the sensitivity and specificity were 75.2% and 88.8%, respectively, for NPSs from patients with acute rhinosinusitis. The ODK-0901 test may provide a rapid and highly sensitive evaluation of the presence of S. pneumoniae and thus may be a promising method of identifying pneumococci in MEFs and NPSs

Systematic reviews of observational studies of Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS) : introduction and methodology

Funding Information: The Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS) project was conducted by the Clinical Urology and Epidemiology (CLUE) Working Group and supported by the Academy of Finland (309387, 340957), Sigrid Jusélius Foundation and Competitive Research Funding of the Helsinki University Hospital (TYH2019321; TYH2020248). The sponsors had no role in the analysis and interpretation of the data or the manuscript preparation, review, or approval. Funding Information: KMA received a research grant from Astra Zeneca, and is consultant for Gedeon Richter, and received reimbursement for attending a scientific meeting from GSK (Tesaro Bio). RMT received reimbursement for attending a scientific meeting from Olympus. LIL, GHG, YL, RC, ALL, VJS, IEJK, PJK, RJC, RLA, KA, KMA, IB-L, MHB, JLC, SC, PJG, HAG-P, FZG, HAG, LH, MLI-K, KMJ, PKK, NK, TPK, AJK, TK, HL, AKM, BTN, TPN, CN, SMO, SP, NP, CBBR, ARR, TS, RMT, RWMV, YW, YX, LY, JH, and KAOT have no financial conflicts of interest. GHG and RC were panel members of the European Association of Urology (EAU) ad hoc Guideline on Thromboprophylaxis in Urological Surgery. KAOT was chair of the European Association of Urology (EAU) ad hoc Guideline on Thromboprophylaxis in Urological Surgery and panel member of the American Society of Hematology (ASH) Guideline Panel on Prevention of Venous Thromboembolism (VTE) in Surgical Hospitalized Patients. Publisher Copyright: © 2021, The Author(s).Background Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. Methods We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. Discussion This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. Systematic review registration PROSPERO CRD42021234119Peer reviewe

Comparative analysis of COVID-19 vaccine responses and third booster dose-induced neutralizing antibodies against Delta and Omicron variants

Vaccination shows efficacy in protecting from COVID-19, but regime and dosing optimization is still ongoing. Here the authors show that BNT162b2, mRNA-1273, or their combination with ChAdOx1 induces similar antibody responses, and those receiving three doses of BNT162b2 induce neutralizing antibodies against the Omicron variant.Two COVID-19 mRNA (of BNT162b2, mRNA-1273) and two adenovirus vector vaccines (ChAdOx1 and Janssen) are licensed in Europe, but optimization of regime and dosing is still ongoing. Here we show in health care workers (n = 328) that two doses of BNT162b2, mRNA-1273, or a combination of ChAdOx1 adenovirus vector and mRNA vaccines administrated with a long 12-week dose interval induce equally high levels of anti-SARS-CoV-2 spike antibodies and neutralizing antibodies against D614 and Delta variant. By contrast, two doses of BNT162b2 with a short 3-week interval induce 2-3-fold lower titers of neutralizing antibodies than those from the 12-week interval, yet a third BNT162b2 or mRNA-1273 booster dose increases the antibody levels 4-fold compared to the levels after the second dose, as well as induces neutralizing antibody against Omicron BA.1 variant. Our data thus indicates that a third COVID-19 mRNA vaccine may induce cross-protective neutralizing antibodies against multiple variants.</p

Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors

Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16. OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-alpha 2, IFN-gamma, TNF-alpha, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-alpha 2, IFN-gamma and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-alpha 2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-alpha 2, IFN-gamma and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience.Peer reviewe