Antiretroviral APOBEC3 cytidine deaminases alter HIV-1 provirus integration site profiles.

APOBEC3 (A3) proteins are host-encoded deoxycytidine deaminases that provide an innate immune barrier to retroviral infection, notably against HIV-1. Low levels of deamination are believed to contribute to the genetic evolution of HIV-1, while intense catalytic activity of these proteins can induce catastrophic hypermutation in proviral DNA leading to near-total HIV-1 restriction. So far, little is known about how A3 cytosine deaminases might impact HIV-1 proviral DNA integration sites in human chromosomal DNA. Using a deep sequencing approach, we analyze the influence of catalytic active and inactive APOBEC3F and APOBEC3G on HIV-1 integration site selections. Here we show that DNA editing is detected at the extremities of the long terminal repeat regions of the virus. Both catalytic active and non-catalytic A3 mutants decrease insertions into gene coding sequences and increase integration sites into SINE elements, oncogenes and transcription-silencing non-B DNA features. Our data implicates A3 as a host factor influencing HIV-1 integration site selection and also promotes what appears to be a more latent expression profile.

Relative Ratios of Human Seasonal Coronavirus Antibodies Predict the Efficiency of Cross-Neutralization of SARS-CoV-2 Spike Binding to ACE2.

BACKGROUND: Antibodies raised against human seasonal coronaviruses (sCoVs), which are responsible for the common cold, are known to cross-react with SARS-CoV-2 antigens. This prompts questions about their protective role against SARS-CoV-2 infections and COVID-19 severity. However, the relationship between sCoVs exposure and SARS-CoV-2 correlates of protection are not clearly identified. METHODS: We performed a cross-sectional analysis of cross-reactivity and cross-neutralization to SARS-CoV-2 antigens (S-RBD, S-trimer, N) using pre-pandemic sera from four different groups: pediatrics and adolescents, individuals 21 to 70 years of age, older than 70 years of age, and individuals living with HCV or HIV. Data was then further analysed using machine learning to identify predictive patterns of neutralization based on sCoVs serology. FINDINGS: Antibody cross-reactivity to SARS-CoV-2 antigens varied between 1.6% and 15.3% depending on the cohort and the isotype-antigen pair analyzed. We also show a range of neutralizing activity (0-45%) with median inhibition ranging from 17.6 % to 23.3 % in serum that interferes with SARS-CoV-2 spike attachment to ACE2 independently of age group. While the abundance of sCoV antibodies did not directly correlate with neutralization, we show that neutralizing activity is rather dependent on relative ratios of IgGs in sera directed to all four sCoV spike proteins. More specifically, we identified antibodies to NL63 and OC43 as being the most important predictors of neutralization. INTERPRETATION: Our data support the concept that exposure to sCoVs triggers antibody responses that influence the efficiency of SARS-CoV-2 spike binding to ACE2, which may potentially impact COVID-19 disease severity through other latent variables. FUNDING: This study was supported by a grant by the CIHR (VR2 -172722) and by a grant supplement by the CITF, and by a NRC Collaborative R&D Initiative Grant (PR031-1).

Humoral Responses and Serological Assays in SARS-CoV-2 Infections.

In December 2019, the novel betacoronavirus Severe Acute Respiratory Disease Coronavirus 2 (SARS-CoV-2) was first detected in Wuhan, China. SARS-CoV-2 has since become a pandemic virus resulting in hundreds of thousands of deaths and deep socioeconomic implications worldwide. In recent months, efforts have been directed towards detecting, tracking, and better understanding human humoral responses to SARS-CoV-2 infection. It has become critical to develop robust and reliable serological assays to characterize the abundance, neutralization efficiency, and duration of antibodies in virus-exposed individuals. Here we review the latest knowledge on humoral immune responses to SARS-CoV-2 infection, along with the benefits and limitations of currently available commercial and laboratory-based serological assays. We also highlight important serological considerations, such as antibody expression levels, stability and neutralization dynamics, as well as cross-reactivity and possible immunological back-boosting by seasonal coronaviruses. The ability to accurately detect, measure and characterize the various antibodies specific to SARS-CoV-2 is necessary for vaccine development, manage risk and exposure for healthcare and at-risk workers, and for monitoring reinfections with genetic variants and new strains of the virus. Having a thorough understanding of the benefits and cautions of standardized serological testing at a community level remains critically important in the design and implementation of future vaccination campaigns, epidemiological models of immunity, and public health measures that rely heavily on up-to-date knowledge of transmission dynamics.

The Prevalence of Delirium in An Older Acute Surgical Population and Its Effect on Outcome.

BACKGROUND: With an ageing population, an increasing number of older adults are admitted for assessment to acute surgical units. Older adults have specific factors that may influence outcomes, one of which is delirium (acute cognitive impairment). OBJECTIVES: To establish the prevalence of delirium on admission in an older acute surgical population and its effect on mortality. Secondary outcomes investigated include hospital readmission and length of hospital stay. METHOD: This observational multi-centre study investigated consecutive patients, ≥65 years, admitted to the acute surgical units of five UK hospitals during an eight-week period. On admission the Confusion Assessment Method (CAM) score was performed to detect delirium. The effect of delirium on important clinical outcomes was investigated using tests of association and logistic regression models. RESULTS: The cohort consisted of 411 patients with a mean age of 77.3 years (SD 8.1). The prevalence of admission delirium was 8.8% (95% CI 6.2-11.9%) and cognitive impairment was 70.3% (95% CI 65.6-74.7%). The delirious group were not more likely to die at 30 or 90 days (OR 1.1, 95% CI 0.2 to 5.1, p = 0.67; OR 1.4, 95% CI 0.4 to 4.1. p = 0.82) or to be readmitted within 30 days of discharge (OR 0.9, 95% CI 0.4 to 2.2, p = 0.89). Length of hospital stay was significantly longer in the delirious group (median 8 vs. 5 days respectively, p = 0.009). CONCLUSION: Admission delirium occurs in just under 10% of older people admitted to acute surgical units, resulting in significantly longer hospital stays.

Variability of Plyometric and Ballistic Exercise Technique Maintains Jump Performance.

Chandler, PT, Greig, M, Comfort, P, and McMahon, JJ. Variability of plyometric and ballistic exercise technique maintains jump performance. J Strength Cond Res 32(6): 1571-1582, 2018-The aim of this study was to investigate changes in vertical jump technique over the course of a training session. Twelve plyometric and ballistic exercise-trained male athletes (age = 23.4 ± 4.6 years, body mass = 78.7 ± 18.8 kg, height = 177.1 ± 9.0 cm) performed 3 sets of 10 repetitions of drop jump (DJ), rebound jump (RJ) and squat jump (SJ). Each exercise was analyzed from touchdown to peak joint flexion and peak joint flexion to take-off. Squat jump was analyzed from peak joint flexion to take-off only. Jump height, flexion and extension time and range of motion, and instantaneous angles of the ankle, knee, and hip joints were measured. Separate 1-way repeated analyses of variance compared vertical jump technique across exercise sets and repetitions. Exercise set analysis found that SJ had lower results than DJ and RJ for the angle at peak joint flexion for the hip, knee, and ankle joints and take-off angle of the hip joint. Exercise repetition analysis found that the ankle joint had variable differences for the angle at take-off, flexion, and extension time for RJ. The knee joint had variable differences for flexion time for DJ and angle at take-off and touchdown for RJ. There was no difference in jump height. Variation in measured parameters across repetitions highlights variable technique across plyometric and ballistic exercises. This did not affect jump performance, but likely maintained jump performance by overcoming constraints (e.g., level of rate coding).

Dietary habits and energy balance in an under 21 male international soccer team.

Soccer presents a metabolic challenge which is not necessarily matched by players' habitual dietary intake. To examine the effects of a bespoke diet, 22 players completed the Ball Sport Endurance and Sprint Test (BEAST90mod) protocol, followed by 4 days of regulated nutritional intake. The diet consisted of 10 g∙kg-1 body mass (BM) and 1.7 g∙kg-1 BM of carbohydrate and protein, respectively. On day 5, players followed a prematch nutritional strategy of 7 g∙kg-1 BM of carbohydrate and 1 g∙kg-1 BM of protein divided into three meals and then repeated the BEAST90mod. The players' pre-intervention intake consisted of 49 ± 7.1% or 3.5 g ± 1.0 g∙kg-1 BM for carbohydrate and 19 ± 3.8% of total daily energy intake or 1.3 g ± 0.5 g∙kg-1 BM for protein. Following the tailor-made dietary intervention, players ran an additional 887 ± 233 m (8.1%; d = 2.4). An acute dietary intervention provided a positive effect on a valid simulated soccer match play test.

Prevalence of multimorbidity and its association with outcomes in older emergency general surgical patients: an observational study.

OBJECTIVES: Multimorbidity is the presence of 2 or more medical conditions. This increasingly used assessment has not been assessed in a surgical population. The objectives of this study were to assess the prevalence of multimorbidity and its association with common outcome measures. DESIGN: A cross-sectional observational study. SETTING: A UK-based multicentre study, included participants between July and October 2014. PARTICIPANTS: Consecutive emergency (non-elective) general surgical patients admitted to hospital, aged over 65 years. OUTCOME MEASURES: The outcome measures were (1) the prevalence of multimorbidity and (2) the association between multimorbidity and frailty; the rate and severity of surgery; length of hospital stay; readmission to hospital within 30 days of discharge; and death at 30 and 90 days. RESULTS: Data were collected on 413 participants aged 65-98 years (median 77 years, (IQR (70-84)). 51.6% (212/413) participants were women. Multimorbidity was present in 74% (95% CI 69.7% to 78.2%) of the population and increased with age (p<0.0001). Multimorbidity was associated with increasing frailty (p for trend <0.0001). People with multimorbidity underwent surgery as often as those without multimorbidity, including major surgery (p=0.03). When comparing multimorbid people with those without multimorbidity, we found no association between length of hospital stay (median 5 days, IQR (1-54), vs 6 days (1-47), (p=0.66)), readmission to hospital (64 (21.1%) vs 18 (16.8%) (p=0.35)), death at 30 days (14 (4.6%) vs 6 (5.6%) (p=0.68)) or 90-day mortality (28 (9.2%) vs 8 (7.6%) (p=0.60)). CONCLUSIONS AND IMPLICATIONS: Multimorbidity is common. Nearly three-quarters of this older emergency general surgical population had 2 or more chronic medical conditions. It was strongly associated with age and frailty, and was not a barrier to surgical intervention. Multimorbidity showed no associations across a range of outcome measures, as it is currently defined. Multimorbidity should not be relied on as a useful clinical tool in guidelines or policies for older emergency surgical patients.

The prevalence of hyperglycaemia and its relationship with mortality, readmissions and length of stay in an older acute surgical population: a multicentre study.

BACKGROUND: The purpose of the study is to examine the prevalence of hyperglycaemia in an older acute surgical population and its effect on clinically relevant outcomes in this setting. METHODS: Using Older Persons Surgical Outcomes Collaboration (OPSOC) multicentre audit data 2014, we examined the prevalence of admission hyperglycaemia, and its effect on 30-day and 90-day mortality, readmission within 30 days and length of acute hospital stay using logistic regression models in consecutive patients, ≥65 years, admitted to five acute surgical units in the UK hospitals in England, Scotland and Wales. Patients were categorised in three groups based on their admission random blood glucose: <7.1, between 7.1 and 11.1 and ≥11.1 mmol/L. RESULTS: A total of 411 patients (77.25±8.14 years) admitted during May and June 2014 were studied. Only 293 patients (71.3%) had glucose levels recorded on admission. The number (%) of patients with a blood glucose <7.1, 7.1-11.1 and ≥11.1 mmol/L were 171 (58.4), 99 (33.8) and 23 (7.8), respectively. On univariate analysis, admission hyperglycaemia was not predictive of any of the outcomes investigated. Although the characteristics of those with no glucose level were not different from the included sample, 30-day mortality was significantly higher in those who had not had their admission glucose level checked (10.2% vs 2.7%), suggesting a potential type II error. CONCLUSION: Despite current guidelines, nearly a third of older people with surgical diagnoses did not have their glucose checked on admission highlighting the challenges in prognostication and evaluation research to improve care of older frail surgical patients.

Routine pharmacological venous thromboembolism prophylaxis in frail older hospitalised patients: where is the evidence?

It has been claimed that there are over 25,000 preventable in-hospital deaths from venous thromboembolism annually in the UK. NICE and SIGN guidelines therefore recommend that all hospitalised patients are risk assessed for venous thromboembolism. The guidelines would recommend using pharmacological thromboprophylaxis for all patients aged 60 and above with reduced mobility and acute medical illness unless obvious contra-indications exist. Meta-analysis data regarding pharmacological thromboprophylaxis for medical patients demonstrate reductions in asymptomatic deep vein thrombosis (DVT) rather than fatal pulmonary embolism and mortality. There is also the potential for increased bleeding risk with this approach. Evidence for older medical in-patients, particularly those aged over 75, is more limited being derived from subgroup analyses of larger clinical trials. In addition, based on exclusion criteria such as increased bleeding risk, frailer older adults were unlikely to have been included within such trials. This commentary will (i) critically appraise available data on the incidence of DVT and PE in older hospitalised patients; (ii) review the evidence available from meta-analyses and subgroup analyses in older medical in-patients for the use of venous thromboembolism prophylaxis; (iii) discuss those situations out-with the guidelines where venous thromboprophylaxis may not be appropriate and even potentially harmful in this patient group and (iv) suggest future research directions.