bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resilience and Frailty in People Living With HIV During the COVID Era: Two Complementary Constructs Associated With Health-Related Quality of Life
Authors: Guaraldi Giovanni , Milic Jovana , Barbieri Sara , Marchiò Tommaso , Caselgrandi Agnese , Volpi Sara , Aprile Emanuele , Belli Michela , Venuta Maria , Mussini Cristina 
Published: January 2022

Background:
Resilience is defined as an individual's positive adaptation to stressors. The COVID-19 pandemic represents a generalized stressor which may affect differently people living with HIV (PLWH). The objective of this study was to characterize resilience in PLWH with particular regarding the identification of frailty-resilience phenotypes, which may differently affect health-related quality of life (HR-QoL).

Methods:
This was an observational study of PLWH attending Modena HIV Metabolic Clinic. Frailty was assessed in 2019, before the onset of the COVID-19 pandemic by using 37-Item frailty index ranging from 0 to 1. The frailty index score was categorized as fit (<0.25) or frail (>0.25). In January 2021, PLWH were offered to complete a set of electronic questionnaires including the CD-RISC-25 for resilience and EQ-5D5L and SF-36 for HR-QoL. Resilience was defined as CD-RISC-25 score >75.7 (ranging from 0 to 100).

Results:
Of 800 PLWH reached by mail, 575 (72%) completed the questionnaires. The median age and HIV duration were 54.5 and 24.3 years, respectively. Impaired resilience was associated with loneliness [odds ratio (OR = 2.39; 1.20 to 4.76, P < 0.001)]. Predictors for EQ-5D5L <89.7% were the phenotypes “frail/nonresilient” [OR = 5.21, 95% confidence interval (CI): 2.62 to 10.33] and “fit/nonresilient” (OR = 5.48, 95% CI: 2.8 to 10.74). Predictors for SF-36 <64.40 were the phenotypes “frail/nonresilient” (OR = 7.43, 95% CI: 2.57 to 21.22) and “fit/nonresilient” (OR = 6.27, 95% CI: 2.17 to 18.16). Both models were corrected for age, sex, HIV duration, and nadir CD4.

Conclusions:
Resilience characterizes the well-being of PLWH during the COVID-19 crisis. This construct is complementary to frailty in the identification of clinical phenotypes with different impacts on HR-QoL.
Quantification of CD4 Recovery in Early-Treated Infants Living With HIV
Authors: Schröter Juliane , Anelone Anet J. N. , de Boer Rob J. 
Published: January 2022

Background:
Perinatally HIV-acquired infants benefit from an early antiretroviral treatment initiation. Thanks to a short viral exposure time, their immune system can be maintained or reconstituted, allowing a “normal” immune development.

Methods:
In this study, we mathematically modeled and quantified individual CD4+ T-cell reconstitution of a subset of 276 children who started treatment within 6 months of age and achieved sustained viral suppression. Considering natural age differences in CD4+ T-cell dynamics, we fitted distances to age-matched healthy reference values with a linear model approaching an asymptote.

Results:
Depleted CD4+ percentages (CD4%) and CD4+ counts (CD4ct) restored healthy levels during treatment. CD4ct recovered with a median rate of 4 cells/µL/d, and individual recovery rates were correlated negatively with their initial CD4ct. CD4 values at onset of treatment decrease with age, whereas recovery times and levels seem to be age-independent. CD4 recovery correlates positively with viral suppression, and the stabilization of CD4 levels usually occurs after viral suppression. CD4 levels stabilize within 3–13 months after treatment initiation. The recovery dynamics of the CD4% is comparable with those of the CD4ct.

Conclusions:
In early-treated children with successful viral suppression, the CD4 depletion is typically mild and CD4+ T cells tend to “fully” recover in numbers.
Evaluation of a Public Health Referral System to Re-Engage Individuals Living With HIV Who Have Interrupted Antiretroviral Therapy in British Columbia, Canada
Authors: Moore David M. , Kremer Hayden , Wang Lu , Lepik Katherine J. , Li Jenny , Salters Kate , Montaner Julio S. G. , Tam Clara , Kling Rakel , Bharmal Aamir , Goodison Karin , Pakhomova Tatiana , Barrios Rolando 
Published: January 2022

Background:
In 2016, the British Columbia HIV/AIDS Drug Treatment Program modified its prescriber alert system for antiretroviral therapy (ART) interruptions to include referrals to regional public health nursing teams for direct outreach support for those who remain off treatment for 4 months or longer. We evaluated clinically relevant outcomes of this Re-Engagement and Engagement in Treatment for Antiretroviral Interrupted and Naïve populations (RETAIN) initiative, in comparison to previous time-periods.

Methods:
We analyzed ART interruptions triggering alerts in pre-RETAIN (July 2013-April 2016) and post-RETAIN periods (May 2016–October 2017) with follow-up continuing until October 2018. We compared the proportions of those who restarted ART and achieved viral suppression in pre-RETAIN and post-RETAIN periods and the time to ART restart using generalized estimating equations. Cox proportional hazards modelling was used to examine associations with time-to-ART-restart.

Results:
A total of 1805 individuals experienced ART interruptions triggering 3219 alerts; 2050 in pre-RETAIN and 1169 in post-RETAIN periods. Participants were predominantly men (74%) and had a median duration of ART of 5 years. Among persons who remained interrupted >4 months after an ART interruption alert was sent, the median time from interruption to ART re-initiation declined from 8.7 months to 7.4 months (P < 0.001) from pre-to post-RETAIN periods. Interruptions in the post-RETAIN era were associated with an increased hazard of restarting ART (adjusted hazard ratio 1.51; 95% CI: 1.34 to 1.69).

Conclusions:
Public health referrals shortened the length of ART interruptions after alerts sent to prescribers had not resulted in re-engagement. Similar programs should be considered in other jurisdictions.
“General anxiety and depression are associated with the physical activity and social interaction levels: Study in Argentinean university students during the COVID-19 outbreak”
Authors: Barbuzza Alejo , Benedetti Pedro , Goyeneche Celina , Reppucci Victoria , Moscato Franco , Butavand Daniela Ramirez , Katche Cynthia , Medina Jorge Horacio , Moncada Diego , Viola Haydée , Ballarini Fabricio 
Published: January 2022

AbstractBackgroundDue to the coronavirus disease 2019 (COVID-19), the planet is going through a historical time of exceptional concern and uncertainty, which impacts people’s mental health. Here, we explored the levels of depression and Generalized Anxiety Disorder (GAD) and their relation with the degree of physical activity and social interaction during the pandemic.MethodsWe performed a structured survey containing the PHQ-9 and GAD-7 tests to evaluate depressive symptoms and GAD levels. We also asked about weekly physical activity and the level of social interaction. We surveyed two groups of University students in the Buenos Aires Metropolitan Area: an internal group from the Instituto Tecnológico de Buenos Aires (ITBA), and an external group of students from multiple universities. The survey was conducted in late October/early-November 2020, after a peak of contagions. Some of the participants were surveyed again in January 2021, during academic holidays and after a valley of contagion, for longitudinal analysisResultsOur data show that men and women of both groups exhibited a significant positive linear correlation between depression and GAD levels. Moreover, low levels of depression and anxiety were associated with performing physical activity for more than two days a week and to longer periods of social interaction. Finally, the second survey revealed a decrease of the symptoms.ConclusionsOur results suggest that performing regular physical activity and avoiding long periods of social isolation gave benefits to mental health. We suggest that public policies could consider protecting these behaviors under health and safety standards.
RelCoVax®, a two antigen subunit protein vaccine candidate against SARS-CoV-2 induces strong immune responses in mice
Authors: Phatarphekar Abhishek , Vidyadhar Reddy G. E. C. , Gokhale Abhiram , Karanam Gopala , Kuchroo Pushpa , Shinde Ketaki , Masand Girish , Pagare Shyam , Khadpe Nilesh , Pai Sangita S. , Vijayan Vijita , Ramnath R. L. , Reddy K. Pratap , Rao Praveen , Rao S. Harinarayana , Ramana Venkata 
Published: January 2022

AbstractThe COVID-19 pandemic has spurred an unprecedented movement to develop safe and effective vaccines against the SARS-CoV-2 virus to immunize the global population. The first set of vaccine candidates that received emergency use authorization targeted the spike (S) glycoprotein of the SARS-CoV-2 virus that enables virus entry into cells via the receptor binding domain (RBD). Recently, multiple variants of SARS-CoV-2 have emerged with mutations in S protein and the ability to evade neutralizing antibodies in vaccinated individuals. We have developed a dual RBD and nucleocapsid (N) subunit protein vaccine candidate named RelCoVax® through heterologous expression in mammalian cells (RBD) and E. coli (N). The RelCoVax® formulation containing a combination of aluminum hydroxide (alum) and a synthetic CpG oligonucleotide as adjuvants elicited high antibody titers against RBD and N proteins in mice after a prime and boost dose regimen administered 2 weeks apart. The vaccine also stimulated cellular immune responses with a potential Th1 bias as evidenced by increased IFN-γ release by splenocytes from immunized mice upon antigen exposure particularly N protein. Finally, the serum of mice immunized with RelCoVax® demonstrated the ability to neutralize two different SARS-CoV-2 viral strains in vitro including the Delta strain that has become dominant in many regions of the world and can evade vaccine induced neutralizing antibodies. These results warrant further evaluation of RelCoVax® through advanced studies and contribute towards enhancing our understanding of multicomponent subunit vaccine candidates against SARS-CoV-2.
RAB18 is a key regulator of GalNAc conjugated siRNA induced silencing in Hep3B cells
Authors: Lu Jiamiao , Swearingen Elissa , Hardy Miki , Collins Patrick , Wu Bin , Yuan Eric , Lu Daniel , Li Chi-Ming , Wang Songli , Ollmann Michael 
Published: January 2022

ABSTRACTSmall interfering RNAs (siRNA) therapeutics have developed rapidly in recent years, despite the challenges associated with delivery of large, highly charged nucleic acids. Delivery of siRNA therapeutics to the liver has been established, with conjugation of siRNA to N-acetylgalactosamine (GalNAc) providing durable gene knockdown in hepatocytes following subcutaneous injection. GalNAc binds the asialoglycoprotein receptor (ASGPR) that is highly expressed on hepatocytes and exploits this scavenger receptor to deliver siRNA across the plasma membrane by endocytosis. However, siRNA needs to access the RNA-induced silencing complex (RISC) in the cytoplasm to provide effective gene knockdown and the entire siRNA delivery process is very inefficient, likely due to steps required for endosomal escape, intracellular trafficking, and stability of siRNA. To reveal the cellular factors limiting delivery of siRNA therapeutics, we performed a pooled, genome wide knockout screen based on delivery of GalNAc conjugated siRNA targeting the HPRT1 gene in the human hepatocellular carcinoma line Hep3B. Our primary pooled genome wide knockout screen identified candidate genes that when knocked out significantly enhanced siRNA efficacy in Hep3B cells. Follow-up studies indicate that knockout of one gene in particular, RAB18, improved siRNA efficacy.
Trade-Offs Between Hepatic Host Defense and Metabolic Programs Underlie Sex-Biased Diseases
Authors: Nikkanen Joni , Leong Yew Ann , Krause William C. , Dermadi Denis , Maschek J. Alan , Van Ry Tyler , Cox James E. , Weiss Ethan J. , Gokcumen Omer , Chawla Ajay , Ingraham Holly A. 
Published: January 2022

ABSTRACTCurrent concepts in evolutionary medicine propose that trade-offs and mismatches with a shifting environment increase disease risk. While biological sex also impacts disease prevalence, contributions of environmental pressures to sex-biased diseases remain unexplored. Here, we show that sex-dependent hepatic programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor BCL6, which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 comes at a cost following dietary excess, resulting in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male fitness during infection, thus establishing a sex-dependent tradeoff between host defense and metabolic systems. We suggest that these tradeoffs, coupled with current environmental pressures, drive metabolic disease in males.
EstimatingPanevolutionary history from nucleotide site patterns
Authors: Brand Colin M. , White Frances J. , Rogers Alan R. , Webster Timothy H. 
Published: January 2022

AbstractIntrogression appears increasingly ubiquitous in the evolutionary history of various taxa, including humans. However, accurately estimating introgression is difficult, particularly when 1) there are many parameters, 2) multiple models fit the data well, and 3) parameters are not simultaneously estimated. Here, we use the software Legofit to investigate the evolutionary history of bonobos (Pan paniscus) and chimpanzees (P. troglodytes) using whole genome sequences. This approach 1) ignores within-population variation, reducing the number of parameters requiring estimation, 2) allows for model selection, and 3) simultaneously estimates all parameters. We tabulated site patterns from the autosomes of 71 bonobos and chimpanzees representing all five extantPanlineages. We then compared previously proposed demographic models and estimated parameters using a deterministic approach. We further considered sex bias inPanevolutionary history by analyzing the site patterns from the X chromosome. Introgression from bonobos into the ancestor of eastern and central chimpanzees and from western into eastern chimpanzees best explained the autosomal site patterns. This second event was substantial with an estimated 0.21 admixture proportion. Estimates of effective population size and most divergence dates are consistent with previous findings; however, we observe a deeper divergence within chimpanzees at 987 ka. Finally, we identify male-biased reproduction inPanevolutionary history and suggest that western to eastern chimpanzee introgression was driven by western males mating with eastern females.
Single-Cell Proteomics Study of Immune Cell Diversity by Quantitating 465 Proteins
Authors: Yang Liwei , Liu Jesse , Reddy Revanth , Wang Jun 
Published: January 2022

AbstractThe identification and characterization of T cell subpopulations is critical to reveal cell development throughout life and immune responses to environmental factors. Next-generation sequencing technologies have dramatically advanced the single-cell genomics and transcriptomics for T cell classification. However, gene expression is often not correlated with protein expression, and immunotyping is mostly accepted in the protein format. Current single-cell proteomics technologies are either limited in multiplex capacity or not sensitive enough to detect the critical functional proteins. Herein we present a cyclic multiplex in situ tagging (Cyclic MIST) technology to simultaneously measure 465 proteins, a scale of >10 times than similar technologies, in single cells. Such a high multiplexity is achieved by reiterative staining of the single cells coupled with a MIST array for detection. This technology has been thoroughly validated through comparison with flow cytometry and fluorescence immunostaining techniques. Both THP1 and CD4+ T cells are analyzed by the Cyclic MIST technology, and over 300 surface markers have been profiled to classify the subpopulations. This represents the most comprehensive mapping of the diversity of immune cells at the protein level. With additional information from intracellular proteins of the same single cells, our technology can potentially facilitate mechanistic studies of immune responses, particularly cytokine storm that results in sepsis.
RNA-sequencing of human post-mortem hypothalamus and nucleus accumbens identifies expression profiles associated with obesity
Authors: Wake Christian , Schneider Julie A. , Stein Thor D. , Bregu Joli , Labadorf Adam , McKee Ann , De Jager Philip L. , Bennett David A. , Seshadri Sudha , Myers Richard H. , DeStefano Anita L. 
Published: January 2022

AbstractObesity, the accumulation of body fat to excess, may cause serious negative health effects, including increased risk of heart disease, type 2 diabetes, stroke and certain cancers. The biology of obesity is complex and not well understood, involving both environmental and genetic factors and affecting metabolic and endocrine mechanisms in tissues of the gut, adipose, and brain. Previous RNA sequencing studies have identified transcripts associated with obesity and body mass index in blood and fat, often using animal models, but RNA sequencing studies in human brain tissue related to obesity have not been previously undertaken. We conducted both large and small RNA sequencing of hypothalamus (207 samples) and nucleus accumbens (276 samples) from individuals defined as consistently obese (124 samples), consistently normal weight as controls (148 samples) or selected without respect to BMI and falling within neither case nor control definition (211 samples), based on longitudinal BMI measures. The samples were provided by three cohort studies with brain donation programs; the Framingham Heart Study (FHS), the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). For each brain region and large/small RNA sequencing set, differential expression of obesity, BMI, brain region and sex was performed. Analyses were done transcriptome-wide as well as with a priori defined sets of obesity or BMI-associated mRNAs and microRNAs (miRNAs). There are sixteen mRNAs and five microRNAs that are differentially expressed (adjusted p < 0.05) by obesity or BMI in these tissues, several of which were validated with qPCR data. The results include many that are BMI-associated, such as APOBR and CES1, as well as many associated with the immune system and some with addiction, such as the gene sets “cytokine signaling in immune system” and “opioid signaling”. In spite of the relatively large number of samples, our study was likely under-powered to detect other transcripts or miRNA with relevant but smaller effects.
Withdrawal from repeated nicotine vapor exposure increases somatic signs of physical dependence, anxiety-like behavior, and brain reward thresholds in adult male rats
Authors: Martinez Michelle , Uribe Kevin , Garcia Valeria , Lira Omar , Matos-Ocasio Felix , Negishi Kenichiro , Khan Arshad M. , O’Dell Laura E. , Mendez Ian A. 
Published: January 2022

AbstractIn recent years, there has been a dramatic increase in nicotine vapor consumption via electronic nicotine delivery systems (i.e., e-cigarettes), particularly in adolescents. While recent work has focused on the health effects of nicotine vapor exposure, its effects on the brain and behavior remain unclear. In this study, we assessed the effects that cessation from repeated nicotine vapor exposure had on behavioral and neuronal measures of withdrawal. For Experiment 1, fifty-six adult male rats were tested for plasma cotinine levels, somatic withdrawal signs, and anxiety-like behavior in the elevated plus maze, immediately following precipitated withdrawal from repeated exposure to 12 or 24 mg/mL nicotine vapor. In Experiment 2, twelve adult male rats were tested for intracranial self-stimulation (ICSS) across 14 days of exposure to 24 mg/mL nicotine vapor and across the 14 days immediately following nicotine exposure. Results revealed that plasma cotinine, somatic signs, anxiety-like behavior, and ICSS stimulation thresholds were all observed to be elevated during withdrawal in the 24 mg/mL nicotine group, when compared to vehicle controls (50/50 vegetable glycerin/propylene glycol). The data suggest that cessation from repeated nicotine vapor exposure using our preclinical model leads to nicotine dependence and withdrawal, and demonstrates that the vapor system described in these experiments is a viable pre-clinical model of e-cigarette use in humans. Further characterization of the mechanisms driving nicotine vapor abuse and dependence is needed to improve policies and educational campaigns related to e-cigarette use.HighlightsA rodent model of nicotine e-cigarette vapor use was utilized to assess effects of cessation from repeated nicotine vapor exposure on behavioral and neuronal measures of drug withdrawal.Cessation of repeated nicotine vapor exposure resulted in increased plasma cotinine levels, somatic withdrawal signs, and anxiety-like behavior.Cessation of repeated nicotine vapor exposure resulted in elevations of ICSS reward threshold.Electrode implantations for ICSS were mapped by location and threshold to a standardized reference atlas of the rat brain to facilitate comparisons with the published literature.
COVID-19 Time of Intubation Mortality Evaluation (C-TIME): A System for Predicting Mortality of Patients with COVID-19 Pneumonia at the Time They Require Mechanical Ventilation
Authors: Raschke Robert A , Rangan Pooja , Agarwal Sumit , Uppalapu Suresh , Sher Nehan , Curry Steven C , Heise C. William 
Published: January 2022

AbstractBackgroundAn accurate system to predict mortality in patients requiring intubation for COVID-19 could help to inform consent, frame family expectations and assist end-of-life decisions.Research objectiveTo develop and validate a mortality prediction system called C-TIME (COVID-19 Time of Intubation Mortality Evaluation) using variables available before intubation, determine its discriminant accuracy, and compare it to APACHE IVa and SOFA.MethodsA retrospective cohort was set in 18 medical-surgical ICUs, enrolling consecutive adults, positive by SARS-CoV 2 RNA by reverse transcriptase polymerase chain reaction or positive rapid antigen test, and undergoing endotracheal intubation. All were followed until hospital discharge or death. The combined outcome was hospital mortality or terminal extubation with hospice discharge. Twenty-five clinical and laboratory variables available 48 hours prior to intubation were entered into multiple logistic regression (MLR) and the resulting model was used to predict mortality of validation cohort patients. AUROC was calculated for C-TIME, APACHE IVa and SOFA.ResultsThe median age of the 2,440 study patients was 66 years; 61.6 percent were men, and 50.5 percent were Hispanic, Native American or African American. Age, gender, COPD, minimum mean arterial pressure, Glasgow Coma scale score, and PaO2/FiO2 ratio, maximum creatinine and bilirubin, receiving factor Xa inhibitors, days receiving non-invasive respiratory support and days receiving corticosteroids prior to intubation were significantly associated with the outcome variable. The validation cohort comprised 1,179 patients. C-TIME had the highest AUROC of 0.75 (95%CI 0.72-0.79), vs 0.67 (0.64-0.71) and 0.59 (0.55-0.62) for APACHE and SOFA, respectively (Chi2 P<0.0001).ConclusionsC-TIME is the only mortality prediction score specifically developed and validated for COVID-19 patients who require mechanical ventilation. It has acceptable discriminant accuracy and goodness-of-fit to assist decision-making just prior to intubation. The C-TIME mortality prediction calculator can be freely accessed on-line at https://phoenixmed.arizona.edu/ctime.