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Chlamydia trachomatis (Ct) is the most common cause of bacterial sexually transmitted infections (STIs) worldwide. Ct infections are often asymptomatic in women, leading to severe reproductive tract sequelae. Development of a vaccine against Chlamydia is crucial. The Chlamydia major outer membrane protein (MOMP) is a prime vaccine antigen candidate, and it can elicit both neutralizing antibodies and protective CD4+ T cell responses. We have previously designed chimeric antigens composed of immunogenic variable regions (VDs) and conserved regions (CDs) of MOMP from Chlamydia muridarum (Cm) expressed into a carrier protein (PorB), and we have shown that these were protective in a mouse model of Cm respiratory infection. Here, we generated corresponding constructs based on MOMP from Ct serovar F. Preliminary structure analysis of the three antigens, PorB/VD1-3, PorB/VD1-4 and PorB/VD1-2-4, showed that they retained structure features consistent with those of PorB. The antigens induced robust humoral and cellular responses in mice with different genetic backgrounds. The antibodies were cross-reactive against Ct, but only anti-PorB/VD1-4 and anti-PorB/VD1-2-4 IgG antibodies were neutralizing, likely due to the antigen specificity. The cellular responses included proliferation in vitro and production of IFN-γ by splenocytes following Ct re-stimulation. Our results support further investigation of the PorB/VD antigens as potential protective candidates for a Chlamydia subunit vaccine.

We develop a conceptual framework for studying collective adaptation in complex socio-cognitive systems, driven by dynamic interactions of social integration strategies, social environments and problem structures. Going beyond searching for 'intelligent' collectives, we integrate research from different disciplines and outline modelling approaches that can be used to begin answering questions such as why collectives sometimes fail to reach seemingly obvious solutions, how they change their strategies and network structures in response to different problems and how we can anticipate and perhaps change future harmful societal trajectories. We discuss the importance of considering path dependence, lack of optimization and collective myopia to understand the sometimes counterintuitive outcomes of collective adaptation. We call for a transdisciplinary, quantitative and societally useful social science that can help us to understand our rapidly changing and ever more complex societies, avoid collective disasters and reach the full potential of our ability to organize in adaptive collectives.

BackgroundPrevious studies evaluating the accuracy of computed tomography (CT) in detecting caudal vena cava (CVC) invasion by adrenal tumors (AT) used a binary system and did not evaluate for other vessels.ObjectiveTest a 7-point scale CT grading system for accuracy in predicting vascular invasion and for repeatability among radiologists. Build a decision tree based on CT criteria to predict tumor type.MethodsRetrospective observational cross-sectional case study. Abdominal CT studies were analyzed by 3 radiologists using a 7-point CT grading scale for vascular invasion and by 1 radiologist for CT features of AT.AnimalsDogs with AT that underwent adrenalectomy and had pre- and postcontrast CT.ResultsNinety-one dogs; 45 adrenocortical carcinomas (50%), 36 pheochromocytomas (40%), 9 adrenocortical adenomas (10%) and 1 unknown tumor. Carcinoma and pheochromocytoma differed in pre- and postcontrast attenuation, contralateral adrenal size, tumor thrombus short- and long-axis, and tumor and thrombus mineralization. A decision tree was built based on these differences. Adenoma and malignant tumors differed in contour irregularity. Probability of vascular invasion was dependent on CT grading scale, and a large equivocal zone existed between 3 and 6 scores, lowering CT accuracy to detect vascular invasion. Radiologists' agreement for detecting abnormalities (evaluated by chance-corrected weighted kappa statistics) was excellent for CVC and good to moderate for other vessels. The quality of postcontrast CT study had a negative impact on radiologists' performance and agreement.Conclusions and clinical importanceFeatures of CT may help radiologists predict AT type and provide probabilistic information on vascular invasion.

BackgroundPredictive modeling promises to improve our understanding of what variables influence patient satisfaction after total knee arthroplasty (TKA). The purpose of this article was to systematically review the relevant literature using predictive models of clinical outcomes after TKA. The aim was to identify the predictor strategies used for systematic data collection with the highest likelihood of success in predicting clinical outcomes.MethodsA Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic review was conducted using 3 databases (MEDLINE, EMBASE, and PubMed) to identify all clinical studies that had used predictive models or that assessed predictive features for outcomes after TKA between 1996 and 2020. The ROBINS-I tool was used to evaluate the quality of the studies and the risk of bias.ResultsA total of 75 studies were identified of which 48 met our inclusion criteria. Preoperative predictive factors strongly associated with postoperative clinical outcomes were knee pain, knee-specific Patient-Reported Outcome Measure (PROM) scores, and mental health scores. Demographic characteristics, pre-existing comorbidities, and knee alignment had an inconsistent association with outcomes. The outcome measures that correlated best with the predictive models were improvement of PROM scores, pain scores, and patient satisfaction.ConclusionsSeveral algorithms, based on PROM improvement, patient satisfaction, or pain after TKA, have been developed to improve decision-making regarding both indications for surgery and surgical strategy. Functional features such as preoperative pain and PROM scores were highly predictive for clinical outcomes after TKA. Some variables such as demographics data or knee alignment were less strongly correlated with TKA outcomes.Level of evidenceSystematic review - Level III.

Chlamydia trachomatis is the most frequently detected sexually transmitted bacterial pathogen in the world. Attempts to control these infections with screening programs and antibiotics have failed and, therefore, a vaccine is the best approach to control this epidemic. The Chlamydia major outer membrane protein (MOMP) is the most protective subunit vaccine so far tested. Protection induced by MOMP is, in part, dependent on its tertiary structure. We have previously described new recombinant antigens composed of the Neisseria lactamica PorB engineered to express the variable domains (VD) from Chlamydia muridarum MOMP. Here we tested antigens containing each individual MOMP VD and different VD combinations. Following immunization, mice were challenged intranasally with C. muridarum. Our results show that three constructs, PorB/VD1-3, PorB/VD1-4, and PorB/VD1-2-4, elicited high serum IgG titers in vivo, significant IFN-γ levels upon T cells re-stimulation in vitro, and evidence of protective immunity in vivo. PorB/VD1-3, PorB/VD1-4, and PorB/VD1-2-4 immunized mice lost less body weight, had lighter lungs, and decreased numbers of inclusion forming units (IFUs) in lungs than other PorB/VD construct tested and mock PBS-immunized mice. These results suggest that this approach may be a promising alternative to the use of MOMP in a Chlamydia vaccine.

Background and purposeStent-assisted coil embolization using the new generation Neuroform Atlas Stent System has shown promising safety and efficacy. The primary study results of the anterior circulation aneurysm cohort of the treatment of wide-neck, saccular, intracranial, aneurysms with the Neuroform Atlas Stent System (ATLAS trial [Safety and Effectiveness of the Treatment of Wide Neck, Saccular Intracranial Aneurysms With the Neuroform Atlas Stent System]) are presented.MethodsATLAS IDE trial (Investigational Device Exemption) is a prospective, multicenter, single-arm, open-label study of wide-neck (neck ≥4 mm or dome-to-neck ratio 50%) at the target location. The primary safety end point was any major stroke or ipsilateral stroke or neurological death within 12 months. Adjudication of the primary end points was performed by an independent Imaging Core Laboratory and the Clinical Events Committee.ResultsA total of 182 patients with wide-neck anterior circulation aneurysms at 25 US centers were enrolled. The mean age was 60.3±11.4 years, 73.1% (133/182) women, and 80.8% (147/182) white. Mean aneurysm size was 6.1±2.2 mm, mean neck width was 4.1±1.2 mm, and mean dome-to-neck ratio was 1.2±0.3. The most frequent aneurysm locations were the anterior communicating artery (64/182, 35.2%), internal carotid artery ophthalmic artery segment (29/182, 15.9%), and middle cerebral artery bifurcation (27/182, 14.8%). Stents were placed in the anticipated anatomic location in all patients. The study met both primary safety and efficacy end points. The composite primary efficacy end point of complete aneurysm occlusion (Raymond-Roy 1) without parent artery stenosis or aneurysm retreatment was achieved in 84.7% (95% CI, 78.6%-90.9%) of patients. Overall, 4.4% (8/182, 95% CI, 1.9%-8.5%) of patients experienced a primary safety end point of major ipsilateral stroke or neurological death.ConclusionsIn the ATLAS IDE anterior circulation aneurysm cohort premarket approval study, the Neuroform Atlas stent with adjunctive coiling met the primary end points and demonstrated high rates of long-term complete aneurysm occlusion at 12 months, with 100% technical success and

BackgroundRemdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2.MethodsWe provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.ResultsOf the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.ConclusionsIn this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Chlamydia trachomatis is the most frequently detected sexually transmitted bacterial pathogen in the world. Attempts to control these infections with screening programs and antibiotics have failed and, therefore, a vaccine is the best approach to control this epidemic. The Chlamydia major outer membrane protein (MOMP) is the most protective subunit vaccine so far tested. Protection induced by MOMP is, in part, dependent on its tertiary structure. We have previously described new recombinant antigens composed of the Neisseria lactamica PorB engineered to express the variable domains (VD) from Chlamydia muridarum MOMP. Here we tested antigens containing each individual MOMP VD and different VD combinations. Following immunization, mice were challenged intranasally with C. muridarum. Our results show that three constructs, PorB/VD1-3, PorB/VD1-4, and PorB/VD1-2-4, elicited high serum IgG titers in vivo, significant IFN-γ levels upon T cells re-stimulation in vitro, and evidence of protective immunity in vivo. PorB/VD1-3, PorB/VD1-4, and PorB/VD1-2-4 immunized mice lost less body weight, had lighter lungs, and decreased numbers of inclusion forming units (IFUs) in lungs than other PorB/VD construct tested and mock PBS-immunized mice. These results suggest that this approach may be a promising alternative to the use of MOMP in a Chlamydia vaccine.

Chlamydia trachomatis is the most frequently detected sexually transmitted bacterial pathogen in the world. Attempts to control these infections with screening programs and antibiotics have failed and, therefore, a vaccine is the best approach to control this epidemic. The Chlamydia major outer membrane protein (MOMP) is the most protective subunit vaccine so far tested. Protection induced by MOMP is, in part, dependent on its tertiary structure. We have previously described new recombinant antigens composed of the Neisseria lactamica PorB engineered to express the variable domains (VD) from Chlamydia muridarum MOMP. Here we tested antigens containing each individual MOMP VD and different VD combinations. Following immunization, mice were challenged intranasally with C. muridarum. Our results show that three constructs, PorB/VD1-3, PorB/VD1-4, and PorB/VD1-2-4, elicited high serum IgG titers in vivo, significant IFN-γ levels upon T cells re-stimulation in vitro, and evidence of protective immunity in vivo. PorB/VD1-3, PorB/VD1-4, and PorB/VD1-2-4 immunized mice lost less body weight, had lighter lungs, and decreased numbers of inclusion forming units (IFUs) in lungs than other PorB/VD construct tested and mock PBS-immunized mice. These results suggest that this approach may be a promising alternative to the use of MOMP in a Chlamydia vaccine.

Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host sialic acids that cap and mask lipooligosaccharide termini, while restricting complement activation. We hypothesized that gonococci selectively target human anti-inflammatory sialic acid-recognizing Siglec receptors on innate immune cells to blunt host responses and that pro-inflammatory Siglecs and SIGLEC pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. N. gonorrhoeae can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract--including Siglec-11 (inhibitory) and Siglec-16 (activating), which we detected for the first time on human cervical epithelium. Surprisingly, in addition to LOS sialic acid, we found that gonococcal porin (PorB) mediated binding to multiple Siglecs. PorB also bound preferentially to human Siglecs and not chimpanzee orthologs, modulating host immune reactions in a human-specific manner. Lastly, we studied the distribution of null SIGLEC polymorphisms in a Namibian cohort with a high prevalence of gonorrhea and found that uninfected women preferentially harbor functional SIGLEC16 alleles encoding an activating immune receptor. These results contribute to the understanding of the human specificity of N. gonorrhoeae and how it evolved to evade the human immune defense.

Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host sialic acids that cap and mask lipooligosaccharide termini, while restricting complement activation. We hypothesized that gonococci selectively target human anti-inflammatory sialic acid-recognizing Siglec receptors on innate immune cells to blunt host responses and that pro-inflammatory Siglecs and SIGLEC pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. N. gonorrhoeae can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract--including Siglec-11 (inhibitory) and Siglec-16 (activating), which we detected for the first time on human cervical epithelium. Surprisingly, in addition to LOS sialic acid, we found that gonococcal porin (PorB) mediated binding to multiple Siglecs. PorB also bound preferentially to human Siglecs and not chimpanzee orthologs, modulating host immune reactions in a human-specific manner. Lastly, we studied the distribution of null SIGLEC polymorphisms in a Namibian cohort with a high prevalence of gonorrhea and found that uninfected women preferentially harbor functional SIGLEC16 alleles encoding an activating immune receptor. These results contribute to the understanding of the human specificity of N. gonorrhoeae and how it evolved to evade the human immune defense.

We suggest a novel experimental concept for detecting MeV-to-GeV-mass dark matter, in which the dark matter scatters off electrons in a scintillating target and produces a signal of one or a few photons. New large-area photodetectors are needed to measure the photon signal with negligible dark counts, which could be constructed from transition edge sensor (TES) or microwave kinetic inductance detector (MKID) technology. Alternatively, detecting two photons in coincidence may allow the use of conventional photodetectors like photomultiplier tubes. We describe why scintillators may have distinct advantages over other experiments searching for a low ionization signal from sub-GeV dark matter, as there are fewer potential sources of spurious backgrounds. We discuss various target choices, but focus on calculating the expected dark matter-electron scattering rates in three scintillating crystals: sodium iodide (NaI), cesium iodide (CsI), and gallium arsenide (GaAs). Among these, GaAs has the lowest band gap (1.52 eV) compared to NaI (5.9 eV) or CsI (6.4 eV), which in principle allows it to probe dark matter masses as low as ∼0.5 MeV, compared to ∼1.5 MeV with NaI or CsI. We compare these scattering rates with those expected in silicon (Si) and germanium (Ge). The proposed experimental concept presents an important complementary path to existing efforts, and its potential advantages may make it the most sensitive direct-detection probe of dark matter down to MeV masses.

We suggest a novel experimental concept for detecting MeV-to-GeV-mass dark matter, in which the dark matter scatters off electrons in a scintillating target and produces a signal of one or a few photons. New large-area photodetectors are needed to measure the photon signal with negligible dark counts, which could be constructed from transition edge sensor (TES) or microwave kinetic inductance detector (MKID) technology. Alternatively, detecting two photons in coincidence may allow the use of conventional photodetectors like photomultiplier tubes. We describe why scintillators may have distinct advantages over other experiments searching for a low ionization signal from sub-GeV dark matter, as there are fewer potential sources of spurious backgrounds. We discuss various target choices, but focus on calculating the expected dark matter-electron scattering rates in three scintillating crystals: sodium iodide (NaI), cesium iodide (CsI), and gallium arsenide (GaAs). Among these, GaAs has the lowest band gap (1.52 eV) compared to NaI (5.9 eV) or CsI (6.4 eV), which in principle allows it to probe dark matter masses as low as ∼0.5 MeV, compared to ∼1.5 MeV with NaI or CsI. We compare these scattering rates with those expected in silicon (Si) and germanium (Ge). The proposed experimental concept presents an important complementary path to existing efforts, and its potential advantages may make it the most sensitive direct-detection probe of dark matter down to MeV masses.

ABSTRACT: We derived chemical abundances for C, N, O, Na, Mg, and Al in 20 asymptotic giant branch (AGB) stars in the globular cluster (GC) NGC 6752. All these elements (but Mg) show intrinsic star-to-star variations and statistically significant correlations or anticorrelations analogous to those commonly observed in red giant stars of GCs hosting multiple populations. This demonstrates that, at odds with previous findings, both first- and second-generation (SG) stars populate the AGB of NGC 6752. The comparison with the Na abundances of red giant branch stars in the same cluster reveals that SG stars (with mild Na and He enrichment) do reach the AGB phase. The only objects that are not observed along the AGB of NGC 6752 are stars with extreme Na enhancement. This is also consistent with standard stellar evolution models, showing that highly Na and He enriched stars populate the bluest portion of the horizontal branch and, because of their low stellar masses, evolve directly to the white dwarf cooling sequence, skipping the AGB phase.

Postmenopausal osteoporosis (PO) is a major public health issue which affects a large fraction of elderly women. Emerging in vitro evidence suggests a central role of oxidative stress (OxS) in postmenopausal osteoporosis (PO) development. Contrariwise, the human studies on this topic are still scarce and inconclusive. In the attempt to address this issue, we sought to determine if OxS, as assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG), may influence the level of receptor activator of nuclear factor-κb ligand (RANKL)/osteoprotegerin (OPG) ratio (a central regulator of bone metabolism) in a sample (n = 124), including postmenopausal women with osteoporosis, osteopenia and normal bone mass density (BMD). The most striking result that emerged in our study was the independent and positive (beta = 0.449, p = 0.004, and R(2) = 0.185) association between the OxS marker and RANKL/OPG ratio which was found in osteopenic but not in the other 2 sample groups. If confirmed by longitudinal studies, our findings would suggest that OxS is implicated in the derangement of bone homeostasis which precedes PO development. In line with these considerations, antioxidant treatment of postmenopausal women with moderately low BMD might contribute to preventing PO and related complications.

Vaccines formulated with the Chlamydia muridarum native major outer membrane protein (nMOMP) have so far been shown to elicit the most robust protection against this pathogen. nMOMP is a membrane protein and therefore, detergents are used to keep it in solution. Detergents however, have toxic effects. To address this limitation, we tested a nMOMP proteosome vaccine and compared its ability to elicit protection against nMOMP solubilized in the detergent Z3-14. The two preparations were formulated with or without CpG + Montanide (C/M). As a control antigen we used ovalbumin. Mice vaccinated with nMOMP developed strong humoral and cell mediated Chlamydia-specific immune responses. Based on the IgG2a/IgG1 levels in serum and amounts of IFN-γ in splenocytes supernatants the immune responses were predominantly Th1-biased. The animals were subsequently challenged intranasally with 2 × 10(3)Chlamydia inclusion forming units (IFU) and the course of the infection was followed for 10 days when the mice were euthanized. Based on changes in body weight, weight of the lungs and number of IFU recovered from the lungs, mice immunized with nMOMP-Ps and nMOMP + Z3-14 adjuvanted with C/M showed the most robust protection. In summary, nMOMP-Ps should be considered as Chlamydia vaccine candidates.

Abstract The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

BackgroundWhile the relationship between average adherence to HIV potent antiretroviral therapy is well defined, the relationship between patterns of adherence within adherence strata has not been investigated. We examined medication event monitoring system (MEMS) defined adherence patterns and their relation to subsequent virologic rebound.Methods and resultsWe selected subjects with at least 3-months of previous virologic suppression on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen from two prospective cohorts in France and North America. We assessed the risk of virologic rebound, defined as HIV RNA of >400 copies/mL according to several MEMS adherence measurements. Seventy two subjects were studied, five of them experienced virologic rebound. Subjects with and without virologic rebound had similar baseline characteristics including treatment durations, regimen (efavirenz vs nevirapine), and dosing schedule. Each 10% increase in average adherence decreased the risk of virologic rebound (OR = 0.56; 95% confidence interval (CI) [0.37, 0.81], P

BackgroundWhile the relationship between average adherence to HIV potent antiretroviral therapy is well defined, the relationship between patterns of adherence within adherence strata has not been investigated. We examined medication event monitoring system (MEMS) defined adherence patterns and their relation to subsequent virologic rebound.Methods and resultsWe selected subjects with at least 3-months of previous virologic suppression on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen from two prospective cohorts in France and North America. We assessed the risk of virologic rebound, defined as HIV RNA of >400 copies/mL according to several MEMS adherence measurements. Seventy two subjects were studied, five of them experienced virologic rebound. Subjects with and without virologic rebound had similar baseline characteristics including treatment durations, regimen (efavirenz vs nevirapine), and dosing schedule. Each 10% increase in average adherence decreased the risk of virologic rebound (OR = 0.56; 95% confidence interval (CI) [0.37, 0.81], P