Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1

STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING(-/-)) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING(-/-) mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal to STING(-/-) mice by the i.v. route. Corneally infected STING(-/-) mice also showed increased periocular disease and increased corneal and trigeminal ganglia titers, although there was no difference in brain titers. They also showed elevated expression of tumor necrosis factor alpha (TNF-α) and CXCL9 relative to control mice but surprisingly modest changes in type I interferon expression. Finally, we also showed that HSV strains lacking the ability to counter autophagy and the PKR-driven antiviral state had near-wild-type virulence following intracerebral infection of STING(-/-) mice. Together, these data show that while STING is an important component of host resistance to HSV in the cornea, its previously shown immutable role in mediating host survival by the i.v. route was not recapitulated following a mucosal infection route. Furthermore, our data are consistent with the idea that HSV counters STING-mediated induction of the antiviral state and autophagy response, both of which are critical factors for survival following direct infection of the nervous system

Beyond the COVID-19 Pandemic: Tips for Players and Athletes COVID-RECOVER

First paragraph: The aim of this guidance is to provide a framework for athletes to cope, thrive and engage in personal growth during the current pandemic. The COVID-19 pandemic has likely led to wide-scale disruption of your sporting trajectories for 2020. This has included the cancellation or postponement of sporting events, limits to group training due to social distancing, restrictions on use of sporting facilities and loss of face-to-face access to coaches and support personnel. In the context of a threat to public health, arguably sports competition sinks into lesser importance, but for athletes like you, for whom sport is a fulltime job or major life goal, or for those who identify sports competition as a key part of their identity, it is important to share recommendations based on evidence and theory on how to support athletes and players through this time. The unprecedented situation means that evidence from similar or related contexts and relevant theories needs to be used to extrapolate to COVID-19 and all its challenges. Each of the guidelines below should be viewed like a menu to choose from and try, test and review, and be seen as a road to discovery instead of passive prescription of activities. Our team of practitioners and researchers have collated the knowledge below based on four premises: 1. Psychological Strengths: As a performer on the sporting stage, you have, in all likelihood, developed many skills and habits to support your on-field performance. Pre-performance routines for penalty taking, for example, may include relaxation and focusing components which aid emotional regulation. This can be also applied to help you cope in world outside of sport (i.e. outside the bubble). Awareness of your repertoire of psychological skills and the ability to use them across different contexts is highly important. 2. Resilience: The capacity to mobilise resources both in advance and after a major challenge, is developed through our sporting challenges. In the face of a trauma, it is likely that resilience is the default rather than the exception. As an athlete, you have the ability to respond in an optimistic way to major stressors and engage in post-traumatic growth. Further, you have successful experiences from memory to call upon on which By doing this, you build a firm foundation on which to build your beliefs that you have sufficient resources to cope with COVID-19. 3. Individual Responses: It is important to acknowledge that athletes in different sports and at different levels of competition have developed diverse sets of abilities and competencies. Dual-career athletes (e.g. student-athletes) may have invested much of their effort in their sport despite study or work commitments, and injured athletes may be over-identifying with their sport as a predictable response to injury, in both cases making these athletes very vulnerable to major stressors. 4. Perception of Control: Loss of control is a major source of anxiety in a pandemic (see Mansell, 2020). Developing autonomy and a sense of control is a key part to feeling safe and secure. With COVID-19, the new habits that could help protect you such as physical isolation, hand hygiene, and avoiding touching your face can help you gain control in an uncertain world. And finding new ways to exercise, to work and to interact can open up a world of exciting possibilities. Athletes have shown an ability to develop positive habits and maintain self-control, skills transferable to meeting the present challenging circumstances

Beyond the COVID-19 Pandemic: Tips for Players and Athletes COVID-RECOVER

First paragraph: The aim of this guidance is to provide a framework for athletes to cope, thrive and engage in personal growth during the current pandemic. The COVID-19 pandemic has likely led to wide-scale disruption of your sporting trajectories for 2020. This has included the cancellation or postponement of sporting events, limits to group training due to social distancing, restrictions on use of sporting facilities and loss of face-to-face access to coaches and support personnel. In the context of a threat to public health, arguably sports competition sinks into lesser importance, but for athletes like you, for whom sport is a fulltime job or major life goal, or for those who identify sports competition as a key part of their identity, it is important to share recommendations based on evidence and theory on how to support athletes and players through this time. The unprecedented situation means that evidence from similar or related contexts and relevant theories needs to be used to extrapolate to COVID-19 and all its challenges. Each of the guidelines below should be viewed like a menu to choose from and try, test and review, and be seen as a road to discovery instead of passive prescription of activities. Our team of practitioners and researchers have collated the knowledge below based on four premises: 1. Psychological Strengths: As a performer on the sporting stage, you have, in all likelihood, developed many skills and habits to support your on-field performance. Pre-performance routines for penalty taking, for example, may include relaxation and focusing components which aid emotional regulation. This can be also applied to help you cope in world outside of sport (i.e. outside the bubble). Awareness of your repertoire of psychological skills and the ability to use them across different contexts is highly important. 2. Resilience: The capacity to mobilise resources both in advance and after a major challenge, is developed through our sporting challenges. In the face of a trauma, it is likely that resilience is the default rather than the exception. As an athlete, you have the ability to respond in an optimistic way to major stressors and engage in post-traumatic growth. Further, you have successful experiences from memory to call upon on which By doing this, you build a firm foundation on which to build your beliefs that you have sufficient resources to cope with COVID-19. 3. Individual Responses: It is important to acknowledge that athletes in different sports and at different levels of competition have developed diverse sets of abilities and competencies. Dual-career athletes (e.g. student-athletes) may have invested much of their effort in their sport despite study or work commitments, and injured athletes may be over-identifying with their sport as a predictable response to injury, in both cases making these athletes very vulnerable to major stressors. 4. Perception of Control: Loss of control is a major source of anxiety in a pandemic (see Mansell, 2020). Developing autonomy and a sense of control is a key part to feeling safe and secure. With COVID-19, the new habits that could help protect you such as physical isolation, hand hygiene, and avoiding touching your face can help you gain control in an uncertain world. And finding new ways to exercise, to work and to interact can open up a world of exciting possibilities. Athletes have shown an ability to develop positive habits and maintain self-control, skills transferable to meeting the present challenging circumstances

Plasma lutein and zeaxanthin concentrations associated with musculoskeletal health and incident frailty in The Irish Longitudinal Study on Ageing (TILDA)

peer-reviewedIntroduction Lutein and zeaxanthin are diet-derived carotenoids that are proposed to help mitigate frailty risk and age-related declines in musculoskeletal health via their anti-oxidant and anti-inflammatory properties. Therefore, this study aimed to investigate the association between lutein and zeaxanthin status and indices of musculoskeletal health and incident frailty among community-dwelling adults aged ≥50 years in the Irish Longitudinal Study on Ageing (TILDA). Methods Cross-sectional analyses (n = 4513) of plasma lutein and zeaxanthin concentrations and grip strength, usual gait speed, timed up-and-go (TUG), probable sarcopenia (defined as grip strength <27 kg in men, <16 kg in women), and bone mass (assessed using calcaneal broadband ultrasound stiffness index) were performed at Wave 1 (2009–2011; baseline). In the longitudinal analyses (n = 1425–3100), changes in usual gait speed (at Wave 3, 2014–2015), grip strength (Wave 4, 2016) and TUG (at Wave 5, 2018), incident probable sarcopenia (at Wave 4) and incident frailty (Fried's phenotype, Frailty Index, FRAIL Scale, Clinical Frailty Scale-classification tree, at Wave 5) were determined. Data were analysed using linear and ordinal logistic regression, adjusted for confounders. Results Cross-sectionally, plasma lutein and zeaxanthin concentrations were positively associated with usual gait speed (B [95 % CI] per 100-nmol/L higher concentration: Lutein 0.59 [0.18, 1.00], Zeaxanthin 1.46 [0.37, 2.55] cm/s) and inversely associated with TUG time (Lutein −0.07 [−0.11, −0.03], Zeaxanthin −0.14 [−0.25, −0.04] s; all p 0.05). Plasma lutein concentration was positively associated with bone stiffness index (0.54 [0.15, 0.93], p 0.05). Conclusion Higher plasma lutein and zeaxanthin concentrations at baseline were associated with a reduced likelihood of incident frailty after ~8 years of follow up. Baseline plasma lutein and zeaxanthin concentrations were also positively associated with several indices of musculoskeletal health cross-sectionally but were not predictive of longitudinal changes in these outcomes over 4–8 years.Horizon 2020 Marie Skłodowska-Curie ActionsThis work was supported by the Teagasc Research Leaders 2025 programme co-funded by Teagasc and the European Union's Horizon 2020 - Research and Innovation Framework Programme under the H2020 Marie Skłodowska-Curie Actions grant agreement number 754380. TILDA is funded by Atlantic Philanthropies, the Irish Department of Health and Irish Life. Roman Romero-Ortuno is funded by a grant from Science Foundation Ireland under grant number 18/FRL/6188

Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans

The association between the maternal diet and the maternal and infant gut microbiome: A systematic review

During pregnancy, changes occur to influence the maternal gut microbiome, and potentially the fetal microbiome. Diet has been shown to impact the gut microbiome. Little research has been conducted examining diet during pregnancy with respect to the gut microbiome. To meet inclusion criteria, dietary analyses must have been conducted as part of the primary aim. The primary outcome was the composition of the gut microbiome (infant or maternal), as assessed using culture-independent sequencing techniques. This review identified seven studies for inclusion, five examining the maternal gut microbiome and two examining the fetal gut microbiome. Microbial data were attained through analysis of stool samples by 16S rRNA gene-based microbiota assessment. Studies found an association between the maternal diet and gut microbiome. High-fat diets (% fat of total energy), fat-soluble vitamins (mg/day) and fibre (g/day) were the most significant nutrients associated with the gut microbiota composition of both neonates and mothers. High-fat diets were significantly associated with a reduction in microbial diversity. High-fat diets may reduce microbial diversity, while fibre intake may be positively associated with microbial diversity. The results of this review must be interpreted with caution. The number of studies was low, and the risk of observational bias and heterogeneity across the studies must be considered. However, these results show promise for dietary intervention and microbial manipulation in order to favour an increase of health-associated taxa in the gut of the mother and her offspring

Determinants of woody encroachment and cover in African savannas

Savanna ecosystems are an integral part of the African landscape and sustain the livelihoods of millions of people. Woody encroachment in savannas is a widespread phenomenon but its causes are widely debated. We review the extensive literature on woody encroachment to help improve understanding of the possible causes and to highlight where and how future scientific efforts to fully understand these causes should be focused. Rainfall is the most important determinant of maximum woody cover across Africa, but fire and herbivory interact to reduce woody cover below the maximum at many locations. We postulate that woody encroachment is most likely driven by CO2 enrichment and propose a two-system conceptual framework, whereby mechanisms of woody encroachment differ depending on whether the savanna is a wet or dry system. In dry savannas, the increased water-use efficiency in plants relaxes precipitation-driven constraints and increases woody growth. In wet savannas, the increase of carbon allocation to tree roots results in faster recovery rates after disturbance and a greater likelihood of reaching sexual maturity. Our proposed framework can be tested using a mixture of experimental and earth observational techniques. At a local level, changes in precipitation, burning regimes or herbivory could be driving woody encroachment, but are unlikely to be the explanation of this continent-wide phenomenon

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707