Background. Infection following orthopaedic trauma surgery is increasingly recognized as one of the major research priorities with as primary goal, improving patient care. This increased interest has ...been anecdotally recognized through published research, research grants, and, finally, with the development of the fracture-related infection (FRI) consensus group. In 2017, the accepted consensus definition of FRI was published, which has been followed by consensus recommendations from both a surgical and medical perspective. A bibliometric analysis was performed to objectively describe the trends in published clinical research related to FRI. Methods. The terms related to FRI were searched in the Web of Science database between 2000 and 2020. The characteristics of clinical research on FRI regarding the author, country, journal, institution, scientific output, top 100 most cited articles, and trend topics were analyzed using Bibliometrix and WPS Office. Results. A total of 2597 records were eligible for inclusion in this bibliometric approach, with studies originating from 89 countries, including eight languages. The United States of America (USA) published the highest number of articles and citations. International collaborations were present between 72 countries, with the most active country being the USA. The most contributive institution was the University of California. The highest number of papers and citations were from the Injury-International Journal of the Care of the Injured and the Journal of Orthopaedic Trauma. The top 100 most cited articles were published in 27 different journals, with the number of citations ranging between 97 and 1004. The latest trend topics were related to the diagnosis of FRI. Conclusion. The present bibliometric analysis shows the research characteristics and trends of FRI from multiple perspectives. The fact that there is an increasing number of studies being published on FRI shows the agreement among scientists and clinicians that standardization with respect to this topic is very important.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
BackgroundCombination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. A better ...understanding of the cellular and molecular mechanisms of αPD-1 and αCTLA-4 individually, and in combination, will guide the development of safer and more effective combination immunotherapy strategies.MethodsWe performed multimodal (scRNA + TCR + epitope) analysis across time in 32 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or anti-PD-1 + anti-CTLA-4 (combination) therapy. In order to understand the effect of checkpoint blockade on T cells at a single-clone resolution, we developed a novel algorithm Cyclone to track temporal clonal dynamics and their underlying cell states.ResultsAnti-CTLA-4 induced more durable immune responses than anti-PD-1, whereas combination therapy mobilized greater and more sustained immune responses. Using Cyclone, we identified 6 clonotypic trajectories with distinct temporal patterns. These analyses revealed that checkpoint blockade induced waves of immune responses composed of distinct clonotypes that peaked at different timepoints. Combination therapy generated clonal effector and exhausted CD8 T cells (TEX) responses that peaked at 6–9 weeks after treatment. Focused analyses of TEX in additional cohorts identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to generate a large and durable reinvigoration of TEX. Immune profiling of a cohort of patients that first received anti-CTLA-4, followed by anti-PD-1 revealed that these enhanced progenitor responses were largely due to anti-CTLA-4 therapy. The induction of progenitor TEX by anti-CTLA-4 were independently validated using samples collected from the Checkmate 238 clinical trial of adjuvant nivolumab versus ipilimumab in resectable melanoma.ConclusionsFirst, durable immune responses represent waves of immune responses generated by different T cell clones. Second, progenitor TEX induced by CTLA-4 blockade may contribute to durable immune responses through self-renewal and replenishing of the TEX pool.Ethics ApprovalPatients were consented for blood collection under the University of Pennsylvania Abramson Cancer Center’s melanoma research program tissue collection protocol UPCC 08607, in accordance with the Institutional Review Board. For specimens from Checkmate 238, PBMC were obtained following informed consent under an IRB-approved protocol at NYU.
Body-temperature programmable elastic shape memory hybrids (SMHs) have great potential for the comfortable fitting of wearable devices. Traditionally, shore hardness is commonly used in the ...characterization of elastic materials. In this paper, the evolution of shore hardness in body-temperature programmable elastic SMHs upon cyclic loading, and during the shape memory cycle, is systematically investigated. Upon cyclic loading, similar to the Mullins effect, significant softening appears, when the applied strain is over a certain value. On the other hand, after programming, in general, the measured hardness increases with increase in programming strain. However, for certain surfaces, the hardness decreases slightly and then increases rapidly. The underlying mechanism for this phenomenon is explained by the formation of micro-gaps between the inclusion and the matrix after programming. After heating, to melt the inclusions, all samples (both cyclically loaded and programmed) largely recover their original hardness.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to ...other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.
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•Some humans possessed cross-reactive SARS-CoV-2 antibodies prior to the pandemic•Pre-pandemic SARS-CoV-2 reactive antibodies are not associated with protection•Antibodies to a related betacoronavirus are boosted upon SARS-CoV-2 infection
Analysis of human serum samples before and after the onset of the COVID-19 pandemic show that antibodies against common seasonal human coronaviruses are cross-reactive against SARS-CoV-2 but do not confer cross-protection against infection or hospitalization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood ...immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.
Abstract
Some risk factors for severe coronavirus disease 2019 (COVID-19) have been identified, including age, race, and obesity. However, 20%–50% of severe cases occur in the absence of these ...factors. Cytomegalovirus (CMV) is a herpesvirus that infects about 50% of all individuals worldwide and is among the most significant nongenetic determinants of immune system. We hypothesized that latent CMV infection might influence the severity of COVID-19. Our analyses demonstrate that CMV seropositivity is associated with more than twice the risk of hospitalization due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immune profiling of blood and CMV DNA quantitative polymerase chain reaction in a subset of patients for whom respiratory tract samples were available revealed altered T-cell activation profiles in absence of extensive CMV replication in the upper respiratory tract. These data suggest a potential role for CMV-driven immune perturbations in affecting the outcome of SARS-CoV-2 infection and may have implications for the discrepancies in COVID-19 severity between different human populations.
Of severe cases of coronavirus disease 2019 (COVID-19), 20%–50% occur in the absence of identified factors. We demonstrated that cytomegalovirus seropositivity is associated with more than twice the risk of hospitalization due to COVID-19, possibly through systemic immune perturbation.
A systematic review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol to evaluate the diagnostic accuracy of artificial intelligence (AI) in ...ductal carcinoma in situ. Four databases were searched for articles up to December 2022: Embase, PubMed, Scopus, and Web of Science. 23 studies were included, and a search of grey literature was not performed. The following parameters were extracted: the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of each study. Statistical analysis of the included studies revealed that AI-assisted histopathological analysis is of high accuracy (83.78%), sensitivity (83.88%), and specificity (85.49%) and has a high positive predictive value (89.43%). Our results also reported that convolutional neural network (CNN) is the most commonly used mode of machine learning—21 models used only CNN, whereas 2 models used only support vector machines (SVM). On an average, CNN reported slightly higher accuracy and sensitivity (86.71% and 85.22%, respectively) than SVM (accuracy, 85.00%; sensitivity, 70.00%). When the 2 methods were combined, a mean accuracy of 82.52% and a mean sensitivity of 83.00% were achieved. The use of AI as a diagnostic adjunct can markedly improve the accuracy and efficiency of DCIS diagnosis and can, therefore, reduce pathologists’ workload.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ion transport in polymerized ionic liquids (poly-ILs) occurs via a fundamentally different mechanism than in monomeric ionic liquids, and recently progress has been made toward understanding ion ...conduction in poly-ILs. To gain insight into the nature of ionic conductivity in ionic polymers, we investigate the physical properties of the trisaminocyclopropenium (TAC) ion, as it is an aromatic carbocation with unique structural and electronic properties. Herein, we characterize the thermal properties, local morphology, and dielectric response of a series of monomeric and polymeric TAC ionic liquids with different counterions. We have found that the extent of a “superionic” mechanism depends on the nature of the ion pair and can result in anomalously high conductivity at the calorimetric T g. Our results suggest that the molecular volumes of the cationic and anionic species are important parameters that impact ion conductivity in polymerized ionic liquids.
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IJS, KILJ, NUK, PNG, UL, UM
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Background: Many patients treated with anti-PD-1 therapy do not show a clinical response. Preclinical studies suggest that adding hypofractionated radiotherapy (HFRT) to anti-PD1 ...can increase the efficacy of immunotherapy through several mechanisms including increased antigen presentation. We conducted a prospective trial testing the combination of pembrolizumab and HFRT in patients with metastatic solid tumors. Methods: This prospective single-institution phase I trial tested pembrolizumab in combination with HFRT in patients with metastatic cancers (NSCLC, melanoma, pancreas, breast, others) and an ECOG performance status of 0-1. Melanoma and NSCLC patients were required to have progression of disease on anti-PD1, having received ≥ 2 doses of anti-PD1 and progression documented by RECIST v1.1. Patients were required to have an index lesion ≥1 cm that was amenable to HFRT and at least one other lesion that was not irradiated and could be followed for response using RECIST criteria. Pembrolizumab 200 mg IV every 3 weeks was administered beginning 1 week prior to the first fraction of radiation. The HFRT dose was 8 Gy x 3 fractions or 17 Gy x 1 fraction, determined by randomization during the Expansion phase. The primary objective was the safety of HFRT combined with pembrolizumab, with dose-limiting toxicity (DLT) defined as Grade ≥ 3 non-hematological toxicity related to the combination of Pembrolizumab and HFRT. The secondary objective was the radiographic response of metastatic lesions outside the radiation field as measured by RECIST. Results: 59 patients aged 27-90 years (median 60) were enrolled from March 2015 to December 2018 (24 in the Safety Phase and 35 in Expansion Phase). 40 patients (67.7%) had treatment-related AEs, of which 4 were grade 3 and none were grade 4. One patient experienced hepatitis, classified as DLT. While most patients did not have a radiologic response, in patients with metastatic melanoma, 7 of 16 (43.8%, exact 95% CI 19.8-70.1%) had an objective response to HFRT + pembrolizumab, including 3 complete and 4 partial responses. Responses are durable with 3/3 complete responders alive with no progression, and 3/4 partial responders alive with 2 having no evidence of progression. Among melanoma patients, only 2 of 7 (29%) responders received ipilimumab prior to enrollment, compared to 8 of 9 (89%) non-responders (p = 0.035). An increase in Ki67+ PD-1+ non-naïve CD8 T-cells was observed in the blood 2 weeks after HFRT, but the magnitude did not correlate with likelihood of response. Responses were observed after either 17 Gy x 1 fraction or 8 Gy x 3 fractions, with no difference in response rate by fractionation. Conclusions: This study suggests that HFRT administered with concurrent pembrolizumab is associated with acceptable toxicity and that in patients with metastatic melanoma progressing on anti-PD-1 therapy, this approach yields an ORR of 44%. Clinical trial information: NCT02303990.
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