Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults ...with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 10
, 10
or up to 10
cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.
Autologous macrophage therapy represents a potentially significant therapeutic advance for the treatment of severe progressive liver cirrhosis. Administration of macrophages has been shown to reduce ...inflammation and drive fibrotic scar breakdown and tissue repair in relevant models. This therapeutic approach is being assessed for safety and feasibility in a first-in-human trial (MAcrophages Therapy for liver CirrHosis MATCH trial).
We outline the development and validation phases of GMP production. This includes use of the CliniMACS Prodigy cell sorting system to isolate CD14+ cells; optimizing macrophage culture conditions, assessing cellular identity, product purity, functional capability and determining the stability of the final cell product.
The GMP-compliant macrophage products have a high level of purity and viability, and have a consistent phenotypic profile, expressing high levels of mature macrophage markers 25F9 and CD206 and low levels of CCR2. The macrophages demonstrate effective phagocytic capacity, are constitutively oriented to an anti-inflammatory profile and remain responsive to cytokine and TLR stimulation. The process validation shows that the cell product in excipient is remarkably robust, consistently passing the viability and phenotypic release criteria up to 48 hours after harvest.
This is the first report of validation of a large-scale, fully Good Manufacturing Practice–compliant, autologous macrophage cell therapy product for the potential treatment of cirrhosis. Phenotypic and functional assays confirm that these cells remain functionally viable for up to 48 h, allowing significant flexibility in administration to patients.
Bystander cardiopulmonary resuscitation (BCPR) improves survival from out-of-hospital cardiac arrest (OHCA), yet BCPR rates remain low. It is unknown whether BCPR delivery disparities exist based on ...victim gender. We measured BCPR rates by gender in private and public environments, hypothesizing that females would be less likely than males to receive BCPR in public settings, with an associated difference in survival to hospital discharge.
We analyzed data from adult, nontraumatic OHCA events within the Resuscitation Outcomes Consortium registry (2011-2015). Using logistic regression, we modeled the likelihood of receiving BCPR by gender, including patient-level variables, stratified by location. A cohort of 19 331 OHCAs was assessed. Mean age was 64±17 years, and 63% (12 225/19 331) were male. Overall, 37% of OHCA victims received bystander CPR. In public locations, 39% (272/694) of females and 45% (1170/2600) of males received BCPR ( P<0.01), whereas in private settings, 35% (2198/6328) of females and 36% (3364/9449) of males received BCPR ( P=NS). Among public OHCAs, males had significantly increased odds of receiving BCPR compared with females (odds ratio, 1.27; 95% CI, 1.05-1.53; P=0.01); this was not the case in the private setting (odds ratio, 0.93; 95% CI, 0.87-1.01; P=NS). Controlling for site, age, and race, BCPR was significantly associated with survival to hospital discharge (odds ratio, 1.69; 95% CI, 1.54-1.85; P<0.01); in this model, males had 29% increased odds of survival compared with females (odds ratio, 1.29; 95% CI, 1.17-1.42; P<0.01).
Males had an increased likelihood of receiving BCPR compared with females in public. BCPR improved survival to discharge, with greater survival among males compared with females.
Background
The coronavirus disease 2019 (COVID-19) pandemic has significantly influenced epidemiology, yet its impact on out-of-hospital cardiac arrest (OHCA) remains unclear. We aimed to evaluate ...the impact of the pandemic on the incidence and case fatality rate (CFR) of OHCA. We also evaluated the impact on intermediate outcomes and clinical characteristics.
Methods
PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases were searched from inception to May 3, 2021. Studies were included if they compared OHCA processes and outcomes between the pandemic and historical control time periods. Meta-analyses were performed for primary outcomes annual incidence, mortality, and case fatality rate (CFR), secondary outcomes field termination of resuscitation (TOR), return of spontaneous circulation (ROSC), survival to hospital admission, and survival to hospital discharge, and clinical characteristics (shockable rhythm and etiologies). This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021253879).
Results
The COVID-19 pandemic was associated with a 39.5% increase in pooled annual OHCA incidence (
p
< 0.001). Pooled CFR was increased by 2.65% (
p
< 0.001), with a pooled odds ratio (OR) of 1.95 for mortality 95% confidence interval (95%CI) 1.51–2.51. There was increased field TOR (OR = 2.46, 95%CI 1.62–3.74). There were decreased ROSC (OR = 0.65, 95%CI 0.55–0.77), survival to hospital admission (OR = 0.65, 95%CI 0.48–0.89), and survival to discharge (OR = 0.52, 95%CI 0.40–0.69). There was decreased shockable rhythm (OR = 0.73, 95%CI 0.60–0.88) and increased asphyxial etiology of OHCA (OR = 1.17, 95%CI 1.02–1.33).
Conclusion
Compared to the pre-pandemic period, the COVID-19 pandemic period was significantly associated with increased OHCA incidence and worse outcomes.
Water retention is an important quality attribute for yogurt. Classically, stirred yogurt water retention is investigated using induced syneresis measurement (centrifugation), which does not ...characterize spontaneous syneresis. Low-frequency nuclear magnetic resonance (1H-LF-NMR) is a non-destructive technique to detect spontaneous syneresis. Experimental yogurt from pasteurized skim milk, and commercial stirred yogurts were analyzed with 1H-LF-NMR. After Laplace's transformation of the signal, hydrogen atoms pools were differentiated according to their mobility. Each hydrogen pool stood for a type of water mobility in the matrices characterized by a relaxation time (T2(i)), and a signal intensity (I2(i)). Yogurt water retention was assessed by induced syneresis and their structure was characterized using microscopy. Low frequency 1H-NMR detected four different water mobility groups in the matrices. Among these, there was a signal from bulk water, and another attributed to the separated serum (spontaneous syneresis). In experimental yogurts, spontaneous syneresis was visible, resulting in induced syneresis higher than 50%. Moreover, induced syneresis and spontaneous syneresis detected by 1H-LF-NMR were similar. In commercial yogurts, bulk water mobility reduced with increasing protein content and protein network density. Induced syneresis and bulk-water mobility correlated only in yogurts without gelatin. In the presence of gelatin, the network was more open, probably favoring bulk water mobility. This study shows that 1H-LF-NMR associated with microscopy image analysis efficiently assesses and describes yogurts water retention and spontaneous syneresis.
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•1H-LF-NMR was used to characterize syneresis in yogurts.•1H-LF-NMR allowed differentiating spontaneous syneresis and water-holding capacity.•Microgel sizes and gel heterogeneity were measured using image analysis.•Microstructure correlated to both induced syneresis and 1H-LF-NMR results.
Characterizing the potential health effects of exposure to risk factors such as red meat consumption is essential to inform health policy and practice. Previous meta-analyses evaluating the effects ...of red meat intake have generated mixed findings and do not formally assess evidence strength. Here, we conducted a systematic review and implemented a meta-regression-relaxing conventional log-linearity assumptions and incorporating between-study heterogeneity-to evaluate the relationships between unprocessed red meat consumption and six potential health outcomes. We found weak evidence of association between unprocessed red meat consumption and colorectal cancer, breast cancer, type 2 diabetes and ischemic heart disease. Moreover, we found no evidence of an association between unprocessed red meat and ischemic stroke or hemorrhagic stroke. We also found that while risk for the six outcomes in our analysis combined was minimized at 0 g unprocessed red meat intake per day, the 95% uncertainty interval that incorporated between-study heterogeneity was very wide: from 0-200 g d
. While there is some evidence that eating unprocessed red meat is associated with increased risk of disease incidence and mortality, it is weak and insufficient to make stronger or more conclusive recommendations. More rigorous, well-powered research is needed to better understand and quantify the relationship between consumption of unprocessed red meat and chronic disease.
Ice-binding proteins (IBPs) inhibit the growth of ice through surface adsorption. In some freeze-resistant fishes and insects, circulating IBPs serve as antifreeze proteins to stop ice growth by ...lowering the freezing point. Plants are less able to avoid freezing and some use IBPs to minimize the damage caused in the frozen state by ice recrystallization, which is the growth of large ice grains at the expense of small ones. Here we have accurately and reproducibly measured the ice recrystallization inhibition (IRI) activity of over a dozen naturally occurring IBPs from fishes, insects, plants, and microorganisms using a modified ‘splat’ method on serial dilutions of IBPs whose concentrations were determined by amino acid analysis. The endpoint of IRI, which was scored as the lowest protein concentration at which no recrystallization was observed, varied for the different IBPs over two orders of magnitude from 1000 nM to 5 nM. Moreover, there was no apparent correlation between their IRI levels and reported antifreeze activities. IBPs from insects and fishes had similar IRI activity, even though the insect IBPs are typically 10x more active in freezing point depression. Plant IBPs had weak antifreeze activity but were more effective at IRI. Bacterial IBPs involved in ice adhesion showed both strong freezing point depression and IRI. Two trends did emerge, including that basal plane binding IBPs correlated with stronger IRI activity and larger IBPs had higher IRI activity.
College students are at heightened risk for negative psychological outcomes due to COVID-19. We examined the prevalence of psychological distress and its association with social isolation among ...public university students in the southern United States.
A cross-sectional survey was emailed to all University of North Carolina-Chapel Hill students in June 2020 and was open for two weeks. Students self-reported if they were self-isolating none, some, most, or all of the time. Validated screening instruments were used to assess clinically significant symptoms of depression, loneliness, and increased perceived stress. The data was weighted to the complete student population.
7,012 completed surveys were included. Almost two-thirds (64%) of the students reported clinically significant depressive symptoms and 65% were categorized as lonely. An estimated 64% of students reported self-isolating most or all of the time. Compared to those self-isolating none of the time, students self-isolating some of the time were 1.78 (95% CI 1.37, 2.30) times as likely to report clinically significant depressive symptoms, and students self-isolating most or all of the time were 2.12 (95% CI 1.64, 2.74) and 2.27 (95% CI 1.75, 2.94) times as likely to report clinically significant depressive symptoms, respectively. Similar associations between self-isolation and loneliness and perceived stress were observed.
The prevalence of adverse mental health indicators among this sample of university students in June 2020 was exceptionally high. University responses to the COVID-19 pandemic should prioritize student mental health and prepare a range of support services to mitigate mental health consequences as the pandemic continues to evolve.
Bystander cardiopulmonary resuscitation (CPR) is associated with increased survival from cardiac arrest, yet bystander CPR rates are low in many communities. The overall prevalence of CPR training in ...the United States and associated individual-level disparities are unknown. We sought to measure the national prevalence of CPR training and hypothesized that older age and lower socioeconomic status would be independently associated with a lower likelihood of CPR training.
We administered a cross-sectional telephone survey to a nationally representative adult sample. We assessed the demographics of individuals trained in CPR within 2 years (currently trained) and those who had been trained in CPR at some point in time (ever trained). The association of CPR training and demographic variables were tested using survey weighted logistic regression. Between September 2015 and November 2015, 9022 individuals completed the survey; 18% reported being currently trained in CPR, and 65% reported training at some point previously. For each year of increased age, the likelihood of being currently CPR trained or ever trained decreased (currently trained: odds ratio, 0.98; 95% CI, 0.97-0.99;
<0.01; ever trained: OR, 0.99; 95% CI, 0.98-0.99;
=0.04). Furthermore, there was a greater then 4-fold difference in odds of being currently CPR trained from the 30-39 to 70-79 year old age groups (95% CI, 0.10-0.23). Factors associated with a lower likelihood of CPR training were lesser educational attainment and lower household income (
<0.01 for each of these variables).
A minority of respondents reported current training in CPR. Older age, lesser education, and lower income were associated with reduced likelihood of CPR training. These findings illustrate important gaps in US CPR education and suggest the need to develop tailored CPR training efforts to address this variability.
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