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Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

Objective Due to high cost of amyloid imaging, its use of amyloid imaging to confirm amyloid pathology is limited in clinical practice. It is of importance to develop a model to predict cerebral amyloid positivity using clinical data obtained from a memory clinic.Methods A total of 410 participants who had symptom of subjective cognitive decline and underwent amyloid PET and apolipoprotein ε (APOE) genotyping were retrospectively enrolled from January 2016 to January 2019. Models for cerebral amyloid positivity prediction were developed in all subjects, mild cognitive impairment (MCI) subjects, and Alzheimer’s disease (AD) dementia subjects through multivariate logistic regression analysis. The performance of the models was assessed using receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) values.Results Age, sex, years of education, body mass index (BMI), APOE4, and mini mental state examination score (MMSE) were selected for the final model for all subjects. The AUC value of the ROC curve was 0.775. Age, sex, years of education, BMI, and APOE4 were selected for the final model for MCI subjects. The AUC value was 0.735. Age, sex, years of education, BMI, APOE4, MMSE, and history of hypertension were selected for the final model for AD dementia subjects. The AUC value was 0.845.Conclusion This study found that models using clinical data can predict cerebral amyloid positivity according to cognitive status. These models can be useful as a screening tool predict cerebral amyloid deposition in cognitively impaired patients in a memory clinic.

Background/Aims: Infliximab (IFX) has proven effective as rescue therapy in steroid-refractory acute severe ulcerative colitis (ASUC), however, the long-term real-world data are scarce. Our study aimed to assess the long-term treatment outcomes of IFX in a real-life cohort.Methods: We established a multicenter retrospective cohort of hospitalized patients with ASUC, who met Truelove and Witt’s criteria and received intravenous corticosteroid (IVCS) or IFX during index hospitalization between 2006 and 2016 in 5 university hospitals in Korea. The cohort was systematically followed up until colectomy, death or last follow-up visit.Results: A total of 296 patients were followed up for a mean of 68.9 ± 44.0 months. During index hospitalization, 49 patients were treated with IFX; as rescue therapy for IVCS failure in 37 and as first-line medical therapy for ASUC in 12. All patients treated with IFX avoided colectomy during index hospitalization. The cumulative rates of rehospitalization and colectomy were 20.4% and 6.1% at 3 months and 39.6% and 18.8% at the end of follow-up, respectively. Patients treated with IFX presented with significantly shorter colectomy-free survival than IVCS responders (P= 0.04, log-rank test). Both cytomegalovirus colitis and Clostridioides difficile infection (CDI) were the significant predictors of colectomy in the overall study cohort (hazard ratios of 6.57 and 4.61, respectively). There were no fatalities.Conclusions: Our real-world cohort study demonstrated that IFX is an effective therapeutic option in Korean patients with ASUC, irrespective of IFX indication. Aggressive vigilance for cytomegalovirus colitis and CDI is warranted for hospitalized patients with ASUC.

Objective Alzheimer’s disease (AD) is the most common type of dementia and the prevalence rapidly increased as the elderly population increased worldwide. In the contemporary model of AD, it is regarded as a disease continuum involving preclinical stage to severe dementia. For accurate diagnosis and disease monitoring, objective index reflecting structural change of brain is needed to correctly assess a patient’s severity of neurodegeneration independent from the patient’s clinical symptoms. The main aim of this paper is to develop a random forest (RF) algorithm-based prediction model of AD using structural magnetic resonance imaging (MRI).Methods We evaluated diagnostic accuracy and performance of our RF based prediction model using newly developed brain segmentation method compared with the Freesurfer’s which is a commonly used segmentation software.Results Our RF model showed high diagnostic accuracy for differentiating healthy controls from AD and mild cognitive impairment (MCI) using structural MRI, patient characteristics, and cognitive function (HC vs. AD 93.5%, AUC 0.99; HC vs. MCI 80.8%, AUC 0.88). Moreover, segmentation processing time of our algorithm (

Objective To evaluate the severity of depression, anxiety, associated risk factors, and cognitive distortion in Korean patients with ulcerative colitis (UC) and Crohn’s disease (CD).Methods This study included 369 patients with inflammatory bowel disease. The severity of depression and anxiety was examined using Patient Health Questionnaire-9 and Hospital Anxiety and Depression Scale. The Anxious Thoughts and Tendencies scale was used to measure catastrophizing tendency. Multivariate regression analyses were performed.Results The predictors of depression were marital status, anti-tumor necrosis factor-α (TNF-α) agent use, age, and body mass index in UC patients and marital status, disease activity, alcohol use, and employment status in CD patients. For anxiety, sex and marital status were the associated factors in UC patients, whereas steroid use was the only significant predictor in CD patients. Comparing the cognitive distortion level, there were no significant differences between UC and CD patients although there was an increasing tendency according to the severity of depression or anxiety.Conclusion If patients are accompanied by high levels of depression or anxiety and their associated risk factors including TNF-α agent or steroid use, it is recommended that not only symptoms are treated but also cognitive approach and evaluation be performed.

Objective Previous studies investigating association of alcohol intake and fracture risk in elderly yielded conflicting results. We first examined the association between alcohol intake and total fracture risk in elderly subjects and further analyzed whether the association varied by fracture locations.Methods This is a nationwide population-based cohort study which included all people aged 66 (n=1,431,539) receiving the National Screening Program during 2009–2014. Time-to-event were defined as duration from study recruitment, the day they received health screening, to the occurrence of fracture.Results Total fracture was significantly lower in mild drinkers [adjusted hazard ratio (aHR)=0.952; 95% confidence interval (95% CI) =0.931–0.973] and higher in heavy drinkers (aHR=1.246; 95% CI=1.201–1.294) than non-drinkers. Risk pattern of alcohol consumption and fracture differed according to affected bones. Similar J-shaped trends were observed for vertebra fractures, but risk of limb fracture showed a linear relationship with alcohol intake. For hip fracture, risk decrement was more pronounced in mild and moderate drinkers, and significant increment was noted only in very severe drinkers [≥60 g/day; (aHR)=1.446; 1.162–1.801].Conclusion Light to moderate drinking generally lowered risk of fractures, but association between alcohol and fracture risk varied depending on the affected bone lesions.

Objectives The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. Design Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. Setting Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1). Patients Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. Interventions None. Measurements and main results Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4-18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. Conclusions Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

Objective We aimed to explore the impact of moderate intensity exercise on the cortical thickness and subcortical volumes of preclinical Alzheimer’s disease (AD) patients.Methods Sixty-three preclinical AD patients with magnetic resonance imaging (MRI) and 18-florbetaben positron emission tomography (PET) data were enrolled in the study. Information on demographic characteristics, cognitive battery scores, self-reported exercise habits were attained. Structural magnetic resonance images were analyzed and processed using Freesurfer v6.0.Results Compared to Exercise group, Non-Exercise group demonstrated reduced cortical thickness in left parstriangularis, rostral middle frontal, entorhinal, superior frontal, lingual, superior parietal, lateral occipital, inferior parietal gyrus, temporal pole, precuneus, insula, fusiform gyrus, right precuneus, superiorparietal, lateral orbitofrontal, rostral middle frontal, medial orbitofrontal, superior frontal, lingual, middle temporal gyrus, insula, supramarginal, parahippocampal, paracentral gyrus. Volumes of right thalamus, caudate, putamen, pallidum, hippocampus, amygdala were also reduced in Non-Exercise group.Conclusion Moderate intensity exercise affects cortical and subcortical structures in preclinical AD patients. Thus, physical exercise has a potential to be an effective intervention to prevent future cognitive decline in those at high risk of AD.

Age-related macular degeneration (AMD) is a major blinding disease, affecting over 14% of the elderly. Risk for AMD is related to age, diet, environment, and genetics. Dietary modulation of AMD risk is a promising treatment modality, but requires appropriate animal models to demonstrate advantages of diet. Mice lacking the antioxidant transcription factor Nrf2 (Nfe2l2) develop age-related retinopathy relevant to human AMD. Here we evaluated the effect of consuming high glycemic (HG) or low glycemic (LG) diets until 18-months of age on development of features relevant to AMD in Nrf2-null mice. Nrf2-null mice that consumed HG diets developed atrophic AMD, characterized by photoreceptor degeneration, retinal pigment epithelium (RPE) atrophy and pigmentary abnormalities, basal laminar deposits, and loss of the choriocapillaris. In contrast, Nrf2-null-mice that consumed LG diets did not develop retinal disease phenotypes. Consumption of HG diets was associated with accumulation of advanced glycation end-products in the RPE and systemically, whereas consumption of the LG diet was associated with increased levels of anti-glycative and anti-oxidative detoxification machinery. Together our data indicate that the Nrf2-null HG mouse is a good model for atrophic AMD studies and that the LG diet can activate protective pathways to prevent AMD, even in a genetically predisposed animal.

Tumor-associated myeloid cells (TAMCs) are key drivers of immunosuppression in the tumor microenvironment, which profoundly impedes the clinical response to immune-dependent and conventional therapeutic modalities. As a hallmark of glioblastoma (GBM), TAMCs are massively recruited to reach up to 50% of the brain tumor mass. Therefore, they have recently been recognized as an appealing therapeutic target to blunt immunosuppression in GBM with the hope of maximizing the clinical outcome of antitumor therapies. Here we report a nano-immunotherapy approach capable of actively targeting TAMCs in vivo. As we found that programmed death-ligand 1 (PD-L1) is highly expressed on glioma-associated TAMCs, we rationally designed a lipid nanoparticle (LNP) formulation surface-functionalized with an anti–PD-L1 therapeutic antibody (αPD-L1). We demonstrated that this system (αPD-L1-LNP) enabled effective and specific delivery of therapeutic payload to TAMCs. Specifically, encapsulation of dinaciclib, a cyclin-dependent kinase inhibitor, into PD-L1–targeted LNPs led to a robust depletion of TAMCs and an attenuation of their immunosuppressive functions. Importantly, the delivery efficiency of PD-L1–targeted LNPs was robustly enhanced in the context of radiation therapy (RT) owing to the RT-induced up-regulation of PD-L1 on glioma-infiltrating TAMCs. Accordingly, RT combined with our nano-immunotherapy led to dramatically extended survival of mice in 2 syngeneic glioma models, GL261 and CT2A. The high targeting efficiency of αPD-L1-LNP to human TAMCs from GBM patients further validated the clinical relevance. Thus, this study establishes a therapeutic approach with immense potential to improve the clinical response in the treatment of GBM and warrants a rapid translation into clinical practice.

Faced with unique immunobiology and marked heterogeneity, treatment strategies for glioblastoma require therapeutic approaches that diverge from conventional oncological strategies. The selection and prioritization of targeted and immunotherapeutic strategies will need to carefully consider these features and companion biomarkers developed alongside treatment strategies to identify the appropriate patient populations. Novel clinical trial strategies that interrogate the tumor microenvironment for drug penetration and target engagement will inform go/no-go later-stage clinical studies. Innovative trial designs and analyses are needed to move effective agents toward regulatory approvals more rapidly. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Chest X-rays (CXRs) are the first-line investigation in patients presenting to emergency departments (EDs) with dyspnoea and are a valuable adjunct to clinical management of COVID-19 associated lung disease. Artificial intelligence (AI) has the potential to facilitate rapid triage of CXRs for further patient testing and/or isolation. In this work we develop an AI algorithm, CovIx, to differentiate normal, abnormal, non-COVID-19 pneumonia, and COVID-19 CXRs using a multicentre cohort of 293,143 CXRs. The algorithm is prospectively validated in 3289 CXRs acquired from patients presenting to ED with symptoms of COVID-19 across four sites in NHS Greater Glasgow and Clyde. CovIx achieves area under receiver operating characteristic curve for COVID-19 of 0.86, with sensitivity and F1-score up to 0.83 and 0.71 respectively, and performs on-par with four board-certified radiologists. AI-based algorithms can identify CXRs with COVID-19 associated pneumonia, as well as distinguish non-COVID pneumonias in symptomatic patients presenting to ED. Pre-trained models and inference scripts are freely available at https://github.com/beringresearch/bravecx-covid.

We characterized serology following a nursing home outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) where residents were serially tested by reverse-transcription polymerase chain reaction (RT-PCR) and positive residents were cohorted. When tested 46–76 days later, 24 of 26 RT-PCR–positive residents were seropositive; none of the 124 RT-PCR–negative residents had confirmed seropositivity, supporting serial SARS-CoV-2 RT-PCR testing and cohorting in nursing homes.

Food processing can generate large amounts of carbohydrate-rich waste that inevitably has environmental and social impacts. Meanwhile, certain heterotrophic marine microorganisms, including algae and thraustochytrids, have the potential to convert carbohydrate-rich substrates into oil-rich biomass over relatively short time frames. To assess the merits of this apparent synergy, an initial conceptual process was developed based on the use of raw potato processing waste as feed in an algal bioreactor to produce bio-oil for further use within the food industry. A practical flowsheet was established with a conventional 200 kL bioreactor whereby the unit processes were identified, the mass balance developed, and estimates made of the various material and energy demands. These inputs were used to develop a baseline life cycle assessment (LCA) model and to identify opportunities for reducing environmental impacts. With the functional unit (FU) being 1 tonne cooking oil, the baseline configuration had a greenhouse gas (GHG) footprint of 2.4 t CO2-e/FU, which is comparable to conventional process routes. More detailed LCA revealed that electricity for stirring the bioreactor contributed approximately 78% of the total GHG footprint. By adjusting the operating conditions, the most promising scenario produced 0.85 t CO2-e/FU—approximately four times less than the conventional process—and shows the potential advantages of applying LCA as a tool to develop and design a new production process.

International audience; In two cohorts of patients with glioblastoma who received anti-PD-1, Sonabend and colleagues show that ERK1/2 phosphorylation, detected by immunohistochemistry, provides a biomarker for MAPK/ERK pathway activity and better survival on this therapy. Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.

Objective To investigate the risk factors for fall in the elderly population residing in rural areas of Korea and provide useful data for their prevention. Methods As part of farmers' health promotion project, a retrospective study was conducted with a total of 350 elderly people recruited from March 2016 to December 2016. These subjects were divided into two groups: 254 non-fallers and 96 fallers. A person who fell to the floor at least once in the past year was defined as a faller. Participants were asked to visit the hospital once. The demographic characteristics, social environment, and educational levels were surveyed using a questionnaire. Physical examination was performed in the following order: cognitive function, lower leg strength and torque, body composition, and knee image test. Results Statistically significant factors for falls in univariate analysis were female gender, age, living alone, educational level less than middle school, skeletal muscle mass, Mini-Mental State Exam, knee osteoarthritis, hip torque, hip power mean, knee torque, and knee power mean. Multivariate analysis was performed to identify variables most relevant to falls among statistically significant factors in univariate logistic analysis. It was confirmed that female gender and age of 70-79 years were statistically significant factors related to falls. Conclusion Female gender and elderly status (70-79 years) are important risk factors for falls in rural areas underscoring the need for special attention when considering risk factors for falls among the elderly living in rural areas.

High availability and reliability have been considered promising requirements for the support of seamless network services such as real‐time video streaming, gaming, and virtual and augmented reality. Increased availability can be achieved within a local area network with the use of the virtual router redundancy protocol that utilizes backup routers to provide a backup path in the case of a master router failure. However, the network may still lose a large number of packets during a failover owing to a late failure detections and lazy responses. To achieve an efficient failover, we propose the implementation of fast detection with virtual router redundancy protocol (FDVRRP) in which the backup router quickly detects a link failure and immediately serves as the master router. We implemented the FDVRRP using open neutralized network operating system (OpenN2OS), which is an open‐source‐based network operating system. Based on the failover performance test of OpenN2OS, we verified that the FDVRRP exhibits a very fast failure detection and a failover with low‐overhead packets.

Toxocariasis, a parasitic infection, causes hyper eosinophilia resulting in radiological presentation of eosinophilic infiltrations in the involved organs. In the abdomen, toxocariasis has been reported to manifest as infiltrations in the liver or in the gastrointestinal tract, but it is known to be uncommon to manifest as multiple lymphadenopathy. There have been two case reports of toxocariasis presenting as generalized lymphadenopathy in the chest, neck and inguinal regions. To the best of our knowledge, generalized conglomerated lymphadenopathy occurring mostly in the abdomen from toxocariasis has not been published in the English literature. Herein, we report a rare case of toxocariasis presenting as multiple conglomerated lymphadenopathy mimicking lymphoma on CT.

Objectives To report changes in practice brought about by COVID‐19 and the implementation of new guidelines for the management of tonsillitis and peritonsillar abscess (PTA), and to explore factors relating to unscheduled re‐presentations for patients discharged from the emergency department (ED). Design Prospective multicentre national audit over 12 weeks from 6 April 2020. Setting UK secondary care ENT departments. Participants Adult patients with acute tonsillitis or PTA. Main outcome measures Re‐presentation within 10 days for patients discharged from the ED. Results 83 centres submitted 765 tonsillitis and 416 PTA cases. 54.4% (n = 410) of tonsillitis and 45.3% (187/413) of PTAs were discharged from ED. 9.6% (39/408) of tonsillitis and 10.3% (19/184) of PTA discharges re‐presented within 10 days, compared to 9.7% (33/341) and 10.6% (24/224) for those admitted from ED. The subsequent admission rate of those initially discharged from ED was 4.7% for tonsillitis and 3.3% for PTAs. IV steroids and antibiotics increased the percentage of patients able to swallow from 35.8% to 72.5% for tonsillitis (n = 270/754 and 441/608) and from 22.3% to 71.0% for PTA (n = 92/413 and 265/373). 77.2% of PTAs underwent drainage (n = 319/413), with no significant difference in re‐presentations in those drained vs not‐drained (10.6% vs 9.5%, n = 15/142 vs 4/42, P = .846). Univariable logistic regression showed no significant predictors of re‐presentation within 10 days. Conclusions Management of tonsillitis and PTA changed during the initial peak of the pandemic, shifting towards outpatient care. Some patients who may previously have been admitted to hospital may be safely discharged from the ED.

Summary Background Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma. Methods This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 1010 viral particles administered by 5·00 × 107 NSCs, the second cohort a dose of 1·25 × 1011 viral particles administered by 1·00 × 108 NSCs, and the third cohort a dose of 1·875 × 1011 viral particles administered by 1·50 × 108 NSCs. No further dose escalation was planned. Within 10–14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov , NCT03072134 . Findings Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14–22). One patient receiving 1·50 × 108 NSCs loading 1·875 × 1011 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5–not reached) and median overall survival was 18·4 months (15·7–not reached). Interpretation NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial. Funding US National Institutes of Health.

Purpose We hypothesized that exposure to Porphyromonas gingivalis (Pg) increases the risk for early diabetic retinopathy (DR) and that the risk can be modulated. Methods We identified 116 early DR cases, and 116 non-DR controls were selected randomly by frequency matching for age, sex, race, and education from the US Third National Health and Nutrition Examination Survey. DR was assessed using non-mydriatic fundus photographs and graded by trained graders using the Modified Airlie House Classification scheme and the Early Treatment for Diabetic Retinopathy Study severity scale. Serum Pg immunoglobulin G (IgG) antibody (Ab) was measured in enzyme-linked immunosorbent assay units. Logistic regression was used to relate serum Pg IgG Ab levels to the risk for early DR. Results Per tenfold increase in Pg IgG Ab levels, there was an over 60% increased risk for early DR (odds ratio = 1.64; 95% confidence interval, 1.36-1.97), and a linear trend was noted for the estimated probabilities of early DR at various Pg IgG Ab levels (P for trend = 0.0053). The analysis also suggested that moderate alcohol consumption (less than 12 drinks in the past 12 months; P for interaction = 0.0003) and maintaining a normal serum glycated hemoglobulin level (HbA1c ≤ 5.7%; P for interaction < 0.0001) helped reduce the Pg-related DR risk. Conclusions The increased Pg-related DR risk could be alleviated by managing alcohol consumption and maintaining a normal blood glucose level. Translational Relevance Findings from this study provide new directions for developing novel therapeutics and prevention strategies for DR.

Unexpected viral infections outbreaks, significantly affect human health, leading to increased mortality and life disruption. Among them is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged as a deadly pandemic, calling for intense research efforts on its pathogenicity mechanism and development of therapeutic strategies. In the SARS-CoV-2 cytokine storm, systemic inflammation has been associated with severe illness and mortality. Recent studies have demonstrated special pro-resolving lipids mediators (SPMs) lipoxins, resolvins, maresins, and protectins as potential therapeutic options for abnormal viral-triggered inflammation. Pro-resolving lipids mediators have shown great promise for the treatment of Herpes simplex virus, respiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus. Based on this, studies are being conducted on their therapeutic effects in SARS-CoV-2 infection. In this review, we discussed SPMs and reviewed evidence from recent studies on SPMs as therapeutic options for viral infections, including SARS-CoV2. Based on our analysis of the previous study, we argue that SPMs are a potential treatment for SARS-CoV-2 infection and other viral infections. We expect further research on how SPMs modulate viral-triggered inflammation through G-protein-coupled receptors (GPCRs), and chemical stability and druggability of SPMs.

Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNg stimulation. BVaxmigrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice. GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce tumor-specific antibodies able to control tumor growth via antibody-mediated cell cytotoxicity. In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

Background Despite the tremendous effort in basic, translational and clinical research, the standard-of-care of patients with glioblastoma (GBM) has been virtually unchanged for the past two decades, aside from tumor-treating fields. GBM is one of the immunologically ‘coldest tumors’ where T-cell exclusion is at its maximum, and myeloid infiltration predominates. This is due to profound immunosuppression, the metabolically hostile microenvironment, and the low mutational burden of these tumors. Together, these barriers have hindered the development of effective immunotherapies. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNgamma stimulation. Methods Studies on B-cell-driven inflammation have identified a subset of B cells expressing the co-stimulatory marker 4-1BBL (or CD137L) capable of enhancing CD8+ T-cell anti-tumor cytotoxicity. Such activation was achieved through multiple mechanisms, including antigen presentation, T-cell co-stimulation (4-1BBL and CD86), and cytokine production (TNFalpha). Thus, 4-1BBL+ B cells could be utilized to boost anti-tumor CD8+ T-cell response. In order to stabilize their antigen presentation function in-vivo and avoid potential immunosuppressive functions, we activated 4-1BBL+ B cells using CD40 and IFNgamma receptor (IFNgR) ligation (designated as BVax, figure 1A), both of which were effective to enhance B-cell-mediated antigen presentation (figure 1B-E). In the present study, we explored the ability of BVax to inhibit GBM growth by promoting tumor-specific CD8+ T-cell immunity and production of tumor-reactive antibodies. BVax’s therapeutic effectiveness was examined both alone and in combination with radiation and checkpoint blockade. Results BVax migrate to key secondary lymphoid organs and are proficient at antigen cross-presentation (figure 2A), which promotes both the survival and functionality of CD8+ T cells (figure 2B and C). A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals (figure 2D and E). This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice (figure 2D and E). GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce mainly IgGs able to react to tumor cells (figure 4A) and tumor-associated antigens (figure 4B). Treatment of glioma bearing-mice with BVax-derived IgG elicited extended animal survival (figure 4C). Statistical analysis: Data are shown as mean±SD for a continuous variable and number (percentages or optical density measures) for a categorical variable. Differences between two groups were analyzed by Student’s t-test. Differences among multiple groups were evaluated using one-way ANOVA with post hoc Tukey’s test followed by post hoc Dunn’s multiple tests as appropriate. Survival curves were generated via the Kaplan-Meier method and compared by log-rank test and multiple comparisons were adjusted using the Bonferroni method. All the tests are two-sided and p-values or Benjamini-Hochberg adjusted false discovery rates less than 0.05 were considered as significant. Statistical analyses were performed using SAS9.4 and GraphPad Prism7.03. Conclusions In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic. Ethics Approval All human samples (tumor, peripheral blood, and frozen tissue) were collected by the Nervous System Tumor Bank at Northwestern University (NSTB) under the institutional review board (IRB) protocol N° STU00202003. All animal experimentation protocols are approved by the Institutional Animal Care and Use Committee (IACUC) under protocol # IS00002459 at Northwestern University. Acknowledgements In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

This paper presents a triboelectric generator using mesoporous (PDMS) polydimethylsiloxane and gold layer which was demonstrated in energy harvesting applications. The performance of power generation by the means of triboelectric principle at a small dimension, namely triboelectric generator is characterized. In this paper, triboelectric generator device adapted vertical contact-separation operation mode, whereby the device derives power generation based on contact electrification caused by cyclic tapping motion. Being primarily a two-layer structure, this device comprises a top layer of aluminum (Al) electrode coated with mesoporous polydimethylsiloxane (PDMS) film and another bottom layer of Al electrode coated with gold (Au) deposit. The characterization of this device is done by varying frequencies and cyclic compression force applied to triboelectric generator. The optimal performance of the 2 cm x 2 cm triboelectric generator contact surface area generated an open-circuit voltage of 4.4 V and a current of 0.1 μA at 5 Hz frequency. This research and device can be improved by magnifying the effective surface area of triboelectric generator to generate significant power for small base area.

Lee-Chang et al. explore the B cell–based vaccine as immunotherapy to treat deadly tumors, including glioblastoma. Their approach utilizes 4-1BBL+ B cells as a cellular platform to promote antitumor immunity., Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell–based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation. BVax migrates to key secondary lymphoid organs and is proficient at antigen cross-presentation, which promotes both the survival and the functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunological memory that prevented the growth of new tumors upon subsequent reinjection in cured mice. GBM patient–derived BVax was successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic., Graphical Abstract

A review of the recent research on the use by heterosexuals in industrialized countries of condoms to prevent HIV infection revealed widespread variation in definitions of at-risk populations growing interest in the potential of qualitative methods to explore individual-level motivations and practices and a search for an independent variable that will provide the key to AIDS prevention. Reviewed were all the articles published in biomedical and social science journals in 1985-94. Perception of susceptibility to HIV appears to be a major determinant of condom use and can override objections based on aesthetic or pleasure-related responses. Risk perceptions are highest in new casual and short-term relationships and lowest in regular partnerships. Positive attitudes toward condom use are not necessarily associated with use patterns. The social psychological literature has focused extensively on the role of self-efficacy in enabling individuals to translate an intention to use condoms into practice. Consistent condom use is further associated with high levels of informal social support positive interpersonal ties and sexual negotiation skills. Skills training as opposed to health information alone appears to be one of the most promising interventions for encouraging condom use.

Objectives To characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality. Design Multicenter prospective cohort study between September 2017 and February 2018. Settings Thirty-four hospitals in the United States and Jordan. Patients Consecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor. Interventions None. Measurement and main results Of 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18). Conclusions The use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

Replacement of fish oil by 5% thraustochytrid whole cell biomass in diets for Atlantic salmon had no ill effect on fish growth performance, carcass total lipid and total fatty acid content. Carcass fatty acid composition indicated incorporation of the dietary thraustochytrid-derived fatty acids. This was confirmed by compound specific stable isotope analysis (CSIA) which revealed significantly 13C-depleted (&delta, 13C value of &minus, 24&permil, ) &omega, 3 long-chain (&ge, C20) polyunsaturated fatty acids (&omega, 3 LC-PUFAs) in the fingerlings fed the thraustochytrid biomass containing diet, reflecting the highly 13C-depleted glycerol used to grow the thraustochytrid cultures. This finding demonstrates the bioavailability of the &omega, 3 LC-PUFA of the Australian strain thraustochytrid culture (TC) 20 from the whole cell biomass that was partly cultivated on crude glycerol produced during biodiesel manufacturing. This paper demonstrates the value of Australian thraustochytrid strains grown heterotrophically for their wider biotechnological potential including as a source of higher value lipids, in particular the health-benefitting &omega, 3 LC-PUFA, for use in aquaculture and other applications.

Objectives We investigated the disease flare rate in patients with rheumatoid arthritis (RA) who achieved low disease activity following long-term methotrexate (MTX) treatment and the factors related to flare. Methods This retrospective longitudinal cohort study included patients with RA and low disease activity who were exposed to MTX for >10 years. Disease flare was defined as an increase in Disease Activity Score of 28 joints (DAS28) of >1.2 within 6 months of discontinuation of MTX. Logistic regression analysis was performed to identify the factors associated with flare. Results In total, 97 patients with RA were included in the study. The mean baseline DAS28 was 1.96 ± 0.56. The median cumulative MTX dose was 11.7 g; the median duration of exposure to MTX was 19 years. Following MTX discontinuation, flare occurred in 43 (44.3%) patients; the median time to flare was 99 (28-168) days. According to univariate logistic regression analysis, C-reactive protein, erythrocyte sedimentation rate (ESR) at discontinuation, the average ESR in the 6 months before discontinuation of MTX, a weekly dose of MTX before discontinuation, and use of other conventional synthetic disease-modifying antirheumatic drugs were associated with a higher risk of disease flare. In multivariable analysis, a weekly dose of MTX before discontinuation (odds ratio 1.014; 95% CI 1.014-1.342; P = .031) was significantly associated with flare risk. Conclusion Among patients with RA who achieved low disease activity with long-term treatment with MTX, more than half remained flare free after MTX discontinuation. A higher MTX dose before discontinuation was associated with a high flare risk.

Purpose To investigate the feasibility of adjunct critical care ultrasound (CCUS) curriculum via Facebook, and evaluate its impact on fellow’s interest and knowledge acquisition. Materials and methods All University of Southern California (USC), Pulmonary, Critical Care and Sleep Medicine (PCCM) fellows were provided the usual CCUS curriculum. The intervention group provided access to an adjunct CCUS curriculum delivered via Facebook. Results Out of a total of 21 fellows, 10 (47.6%) participated in the Facebook group. The mean number of posts viewed was 24 with a range of 8 to 36 (total 41). Of those who responded, 56% responded Facebook was effective, 89% felt the content was moderate to very useful, 56% responded it enhanced their CCUS education, and 44% stated it motivated them to learn. Pre- and post-testing was done using paired t-tests; the average pre and post-intervention raw score means (of a total of 41 questions) for controls were 35.4±2.9 and 38.2±1.75 (p=0.005). Intervention scores were 37.56±1.94 and 38.0±1.50 (=0.602). Conclusions Evaluating the feasibility of the adjunct CCUS curriculum using social media, we found that Facebook may be acceptable to fellows, however, there was no significant improvement in knowledge. For learners, social media is easily accessible, widely available, and may motivate increased interest in learning and its potential uses warrants further study.

Objectives: The associations of physical activity and depressive symptoms with cognitive decline are likely age dependent. The study was therefore aimed to investigate the age differences in the associations of leisure-time physical activity (LTPA) and depressive symptoms with cognitive decline in older Taiwanese.Method: A total of 3545 participants, age ≥50, from 2003 (baseline) and 2007 (end-point) survey datasets were analyzed. Cognitive decline was defined as a decrease of two or more points on the Short Portable Mental Status Questionnaire. The long-term LTPA and depressive symptoms were the change of status between the two time-points. Multivariable logistic regression was conducted to evaluate the longitudinal associations, stratified by age.Results: Significant associations between all levels of long-term LTPA status and cognitive decline were observed for the older group (age ≥70), but not any for the younger group (age 50-69). Significant associations between long-term depressive symptoms status and cognitive decline were also found in all levels for the older group, but only in one level for the younger group. The two odds ratios of cognitive decline between the age groups were further found to be significantly different for those with active LTPA in both time-points (p=.005) and for those with depressive symptoms decreased (p=.014).Conclusion: The findings suggest that there are age differences in the longitudinal associations of LTPA and depressive symptoms with cognitive decline in older Taiwanese. Understanding the pattern of age differences could be helpful in preventing cognitive decline of the elderly.

Simple Summary Glioblastoma is the most common primary brain tumor in adults, and its aggressive nature yields a poor prognosis despite current treatment strategies. The aim of our literature review is to discuss various immunotherapeutic strategies currently being investigated in the treatment of glioblastoma. Checkpoint inhibitors, various vaccination strategies, and CAR T-cell therapies serve as some of the most investigated immunotherapeutic strategies. However, all strategies face various limitations, such as the low relative mutational burden, the immunosuppressive tumor microenvironment, and genetic heterogeneity, which serve as the current challenges. Abstract Glioblastoma (GBM) is a lethal primary brain tumor. Despite extensive effort in basic, translational, and clinical research, the treatment outcomes for patients with GBM are virtually unchanged over the past 15 years. GBM is one of the most immunologically “cold” tumors, in which cytotoxic T-cell infiltration is minimal, and myeloid infiltration predominates. This is due to the profound immunosuppressive nature of GBM, a tumor microenvironment that is metabolically challenging for immune cells, and the low mutational burden of GBMs. Together, these GBM characteristics contribute to the poor results obtained from immunotherapy. However, as indicated by an ongoing and expanding number of clinical trials, and despite the mostly disappointing results to date, immunotherapy remains a conceptually attractive approach for treating GBM. Checkpoint inhibitors, various vaccination strategies, and CAR T-cell therapy serve as some of the most investigated immunotherapeutic strategies. This review article aims to provide a general overview of the current state of glioblastoma immunotherapy. Information was compiled through a literature search conducted on PubMed and clinical trials between 1961 to 2021.

GBM is the most common primary brain tumor in adults, and the aggressive nature of this tumor contributes to its extremely poor prognosis. Over the years, the heterogeneous and adaptive nature of GBM has been highlighted as a major contributor to the poor efficacy of many treatments including various immunotherapies. The major challenge lies in understanding and manipulating the complex interplay among the different components within the tumor microenvironment (TME). This interplay varies not only by the type of cells interacting but also by their spatial distribution with the TME. This review highlights the various immune and non-immune components of the tumor microenvironment and their consequences f the efficacy of immunotherapies. Understanding the independent and interdependent aspects of the various sub-populations encapsulated by the immune and non-immune components will allow for more targeted therapies. Meanwhile, understanding how the TME creates and responds to different environmental pressures such as hypoxia may allow for other multimodal approaches in the treatment of GBM. Ultimately, a better understanding of the GBM TME will aid in the development and advancement of more effective treatments and in improving patient outcomes.