COVID-19 and Liver Disease: An Evolving Landscape.

The COVID-19 pandemic has resulted in significant worldwide morbidity and mortality. In this review, we examine the intricate relationships between COVID-19 and liver diseases. While respiratory manifestations of COVID-19 are well known, its impact and consequences in patients with liver diseases remain an area of ongoing investigation. COVID-19 can induce liver injury through various mechanisms and is associated with higher mortality in individuals with preexisting chronic liver disease. Mortality increases with the severity of chronic liver disease and the level of care required. The outcomes in patients with autoimmune hepatitis remain unclear, whereas liver transplant recipients are more likely to experience symptomatic COVID-19 but have comparable outcomes to the general population. Despite suboptimal immunological response, COVID-19 vaccinations are safe and effective in liver disease, although cases of autoimmune hepatitis-like syndrome have been reported. In conclusion, COVID-19 has significant implications in liver diseases; early recognition and treatments are important for improving patient outcomes.

Genetic Diversity, Compartmentalization, and Age of HIV Proviruses Persisting in CD4+ T Cell Subsets during Long-Term Combination Antiretroviral Therapy.

The HIV reservoir, which comprises diverse proviruses integrated into the genomes of infected, primarily CD4+ T cells, is the main barrier to developing an effective HIV cure. Our understanding of the genetics and dynamics of proviruses persisting within distinct CD4+ T cell subsets, however, remains incomplete. Using single-genome amplification, we characterized subgenomic proviral sequences (nef region) from naive, central memory, transitional memory, and effector memory CD4+ T cells from five HIV-infected individuals on long-term combination antiretroviral therapy (cART) and compared these to HIV RNA sequences isolated longitudinally from archived plasma collected prior to cART initiation, yielding HIV data sets spanning a median of 19.5 years (range, 10 to 20 years) per participant. We inferred a distribution of within-host phylogenies for each participant, from which we characterized proviral ages, phylogenetic diversity, and genetic compartmentalization between CD4+ T cell subsets. While three of five participants exhibited some degree of proviral compartmentalization between CD4+ T cell subsets, combined analyses revealed no evidence that any particular CD4+ T cell subset harbored the longest persisting, most genetically diverse, and/or most genetically distinctive HIV reservoir. In one participant, diverse proviruses archived within naive T cells were significantly younger than those in memory subsets, while for three other participants we observed no significant differences in proviral ages between subsets. In one participant, "old" proviruses were recovered from all subsets, and included one sequence, estimated to be 21.5 years old, that dominated (>93%) their effector memory subset. HIV eradication strategies will need to overcome within- and between-host genetic complexity of proviral landscapes, possibly via personalized approaches.IMPORTANCE The main barrier to HIV cure is the ability of a genetically diverse pool of proviruses, integrated into the genomes of infected CD4+ T cells, to persist despite long-term suppressive combination antiretroviral therapy (cART). CD4+ T cells, however, constitute a heterogeneous population due to their maturation across a developmental continuum, and the genetic "landscapes" of latent proviruses archived within them remains incompletely understood. We applied phylogenetic techniques, largely novel to HIV persistence research, to reconstruct within-host HIV evolutionary history and characterize proviral diversity in CD4+ T cell subsets in five individuals on long-term cART. Participants varied widely in terms of proviral burden, genetic diversity, and age distribution between CD4+ T cell subsets, revealing that proviral landscapes can differ between individuals and between infected cell types within an individual. Our findings expose each within-host latent reservoir as unique in its genetic complexity and support personalized strategies for HIV eradication.

Sex-specific energy management strategies in response to training for increased foraging effort prior to reproduction in captive zebra finches.

Free-living animals often engage in behaviour that involves high rates of workload and results in high daily energy expenditure (DEE), such as reproduction. However, the evidence for elevated DEE accompanying reproduction remains equivocal. In fact, many studies have found no difference in DEE between reproducing and non-reproducing females. One of the hypotheses explaining the lack of difference is the concept of an 'energetic ceiling'. However, it is unclear whether the lack of increase in energy expenditure is due to the existence of an energetic ceiling and/or compensation by males during parental care. To investigate whether an energetic ceiling exists, we experimentally manipulated foraging effort in captive zebra finches, Taeniopygia guttata, creating two groups with high and low foraging efforts followed by both groups breeding in the low foraging effort common garden condition. DEE was measured in both sexes throughout the experiment. We show sex-specific energy management strategies in response to training for increased foraging effort prior to reproduction. Specifically, males and females responded differently to the high foraging effort treatment and subsequently to chick rearing in terms of energy expenditure. Our results also suggest that there is an energetic ceiling in females and that energetic costs incurred prior to reproduction can be carried over into subsequent stages of reproduction in a sex-specific manner.

Physiological adjustments to high foraging effort negatively affect fecundity but not final reproductive output in captive zebra finches.

Foraging at elevated rates to provision offspring is thought to be an energetically costly activity and it has been suggested that there are physiological costs associated with the high workload involved. However, for the most part, evidence for costs of increased foraging and/or reproductive effort is weak. Furthermore, despite some experimental evidence demonstrating negative effects of increased foraging and parental effort, the physiological mechanisms underlying costs associated with high workload remain poorly understood. To examine how high workload affects haematology, oxidative stress and reproductive output, we experimentally manipulated foraging effort in captive zebra finches, Taeniopygia guttata, using a previously described technique, and allowed individuals to breed first in low foraging effort conditions and then in high foraging effort conditions. We found that birds upregulated haematocrit and haemoglobin concentration in response to training. Birds subjected to increased workload during reproduction had lower fecundity, although final reproductive output was not significantly different than that of controls. Offspring of parents subjected to high workload during reproduction also had higher oxidative stress when they were 90 days of age. Total antioxidant capacity and reactive oxygen metabolites of birds responded differently in the two breeding attempts, but we did detect an overall increase in oxidative stress in response to training in either attempt, which could explain the lower fecundity observed in birds subjected to increased workload during reproduction.

Comparing outcomes of cholecystectomies in white vs. minority patients.

BACKGROUND: This study aimed to investigate the disparity between white and minority patients undergoing cholecystectomies, including presentation, outcomes, and financial burden. METHODS: This was an IRB approved retrospective review of all cholecystectomies at an academic medical center from 2013 to 2018. Data collected include demographics, insurance type, charge of admission, and clinical outcomes. RESULTS: 1539 patients underwent cholecystectomies. Of those, 36.9% were white and 63.1% were minority. Minority patients presented at a younger age than white patients (45.5 vs 53.9, p < 0.01) and required emergent admission (76.2% vs 68.4%, p < 0.01). No significant difference was found for clinical outcomes between white and minority. Minority patients were more commonly uninsured (32.1%). Among the uninsured, self-pay had a higher charge than emergency MediCal (by 5.46 per 1000 dollars). CONCLUSION: Minority patients are more commonly disadvantaged at presentation and charged more due to insurance status despite similar outcomes after cholecystectomies.

HIV Proviral Burden, Genetic Diversity, and Dynamics in Viremic Controllers Who Subsequently Initiated Suppressive Antiretroviral Therapy.

Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy (ART). Understanding the burden, genetic diversity, and longevity of persisting proviruses in diverse individuals with HIV is critical to this goal, but these characteristics remain understudied in some groups. Among them are viremic controllers-individuals who naturally suppress HIV to low levels but for whom therapy is nevertheless recommended. We reconstructed within-host HIV evolutionary histories from longitudinal single-genome amplified viral sequences in four viremic controllers who eventually initiated ART and used this information to characterize the age and diversity of proviruses persisting on therapy. We further leveraged these within-host proviral age distributions to estimate rates of proviral turnover prior to ART. This is an important yet understudied metric, since pre-ART proviral turnover dictates reservoir composition at ART initiation (and thereafter), which is when curative interventions, once developed, would be administered. Despite natural viremic control, all participants displayed significant within-host HIV evolution pretherapy, where overall on-ART proviral burden and diversity broadly reflected the extent of viral replication and diversity pre-ART. Consistent with recent studies of noncontrollers, the proviral pools of two participants were skewed toward sequences that integrated near ART initiation, suggesting dynamic proviral turnover during untreated infection. In contrast, proviruses recovered from the other two participants dated to time points that were more evenly spread throughout infection, suggesting slow or negligible proviral decay following deposition. HIV cure strategies will need to overcome within-host proviral diversity, even in individuals who naturally controlled HIV replication before therapy. IMPORTANCE HIV therapy is lifelong because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure. Elite controllers-individuals who naturally suppress HIV to undetectable levels-are being intensely studied as models of HIV remission, but viremic controllers, individuals who naturally suppress HIV to low levels, remain understudied even though they too may hold valuable insights. We combined phylogenetics and mathematical modeling to reconstruct proviral seeding and decay from infection to therapy-mediated suppression in four viremic controllers. We recovered diverse proviruses persisting during therapy that broadly reflected HIV's within-host evolutionary history, where the estimated half-lives of the persistent proviral pool during untreated infection ranged from <1 year to negligible. Cure strategies will need to contend with proviral diversity and between-host heterogeneity, even in individuals who naturally control HIV.

Haematological traits co-vary with migratory status, altitude and energy expenditure: a phylogenetic, comparative analysis.

Aerobic capacity is assumed to be a main predictor of workload ability and haematocrit (Hct) and haemoglobin (Hb) have been suggested as key determinants of aerobic performance. Intraspecific studies have reported increases in Hct and Hb in response to increased workload. Furthermore, Hct and Hb vary markedly among individuals and throughout the annual cycle in free-living birds and it has been suggested that this variation reflects adaptive modulation of these traits to meet seasonal changes in energy demands. We used a comparative dataset of haematological traits, measures of metabolic rate (57 species), and life-history traits (160 species) to test several hypotheses for adaptive variation in haematology in relation to migration and altitude. We then extended these general ideas to test relationships between Hct and basal metabolic rate, daily energy expenditure and activity energy expenditure, using the 57 species that we have metabolic rate information for. We found that at the interspecific level, full migrants have higher Hct and Hb than partial migrants and non-migrants, and that altitude is positively correlated with Hb but not Hct. Hct is positively associated with activity energy expenditure (energy spent specifically on costly activities), suggesting that haematological traits could be adaptively modulated based on life-history traits and that Hct is a potential physiological mediator of energetic constraint.

Prevalence and Correlates of Pre-Treatment HIV Drug Resistance among HIV-Infected Children in Ethiopia.

Pediatric human immunodeficiency virus (HIV) care in resource-limited settings remains a major challenge to achieving global HIV treatment and virologic suppression targets, in part because the administration of combination antiretroviral therapies (cART) is inherently complex in this population and because viral load and drug resistance genotyping are not routinely available in these settings. Children may also be at elevated risk of transmission of drug-resistant HIV as a result of suboptimal antiretroviral administration for prevention of mother-to-child transmission. We investigated the prevalence and the correlates of pretreatment HIV drug resistance (PDR) among HIV-infected, cART-naive children in Ethiopia. We observed an overall PDR rate of 14%, where all cases featured resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs): ~9% of participants harbored resistance solely to NNRTIs while ~5% harbored resistance to both NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs). No resistance to protease inhibitors was observed. No sociodemographic or clinical parameters were significantly associated with PDR, though limited statistical power is noted. The relatively high (14%) rate of NNRTI resistance in cART-naive children supports the use of non-NNRTI-based regimens in first-line pediatric treatment in Ethiopia and underscores the urgent need for access to additional antiretroviral classes in resource-limited settings.