Does the PI3K pathway promote or antagonize regulatory T cell development and function?

Regulatory T cells (Tregs) prevent autoimmunity and inflammation by suppressing the activation of other T cells and antigen presenting cells. The role of phosphoinositide 3-kinase (PI3K) signaling in Treg is controversial. Some studies suggest that inhibition of the PI3K pathway is essential for the development of Tregs whereas other studies have shown reduced Treg numbers and function when PI3K activity is suppressed. Here we attempt to reconcile the different studies that have explored PI3K and the downstream effectors Akt, Foxo, and mTOR in regulatory T cell development and function and discuss the implications for health and therapeutic intervention

Using the Indirect Cohort Design to Estimate the Effectiveness of the Seven Valent Pneumococcal Conjugate Vaccine in England and Wales

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2, 3 and 13 month schedule, and has led to large decreases in invasive pneumococcal disease (IPD) caused by the vaccine serotypes in both vaccinated and unvaccinated cohorts. We estimated the effectiveness of PCV-7 against IPD. METHODS AND FINDINGS: We used enhanced surveillance data, collated at the Health Protection Agency, on vaccine type (n = 153) and non vaccine type (n = 919) IPD cases eligible for PCV-7. The indirect cohort method, a case-control type design which uses non vaccine type cases as controls, was used to estimate effectiveness of various numbers of doses as well as for each vaccine serotype. Possible bias with this design, caused by differential serotype replacement in vaccinated and unvaccinated individuals, was estimated after deriving formulae to quantify the bias. The results showed good effectiveness, increasing from 56% (95% confidence interval (CI): -7-82) for a single dose given under one year of age to 93% (95% CI: 70-98) for two doses under one year of age plus a booster dose in the second year of life. Serotype specific estimates indicated higher effectiveness against serotypes 4, 14 and 18C and lower effectiveness against 6B. Under the assumption of complete serotype replacement by non vaccine serotypes in carriage, we estimated that effectiveness estimates may be overestimated by about 2 to 5%. CONCLUSIONS: This study shows high effectiveness of PCV-7 under the reduced schedule used in the UK. This finding agrees with the large reductions seen in vaccine type IPD in recent years in England and Wales. The formulae derived to assess the bias of the indirect cohort method for PCV-7 can also be used when using the design for other vaccines that affect carriage such as the recently introduced 13 valent pneumococcal conjugate vaccine

Calpains mediate p53 activation and neuronal death evoked by DNA damage.

DNA damage is an initiator of neuronal death implicated in neuropathological conditions such as stroke. Previous evidence has shown that apoptotic death of embryonic cortical neurons treated with the DNA damaging agent camptothecin is dependent upon the tumor suppressor p53, an upstream death mediator, and more distal death effectors such as caspases. We show here that the calcium-regulated cysteine proteases, calpains, are activated during DNA damage induced by camptothecin treatment. Moreover, calpain deficiency, calpastatin expression, or pharmacological calpain inhibitors prevent the death of embryonic cortical neurons, indicating the important role of calpain in DNA damage-induced death. Calpain inhibition also significantly reduced and delayed the induction of p53. Consistent with the actions of calpains upstream of p53 and the proximal nature of p53 death signaling, calpain inhibition inhibited cytochrome c release and DEVD-AFC cleavage activity. Taken together, our results indicate that calpains are a key mediator of p53 induction and consequent caspase-dependent neuronal death due to DNA damage

Recovery, rehabilitation and follow-up services following critical illness: an updated UK national cross-sectional survey and progress report.

OBJECTIVE: To comprehensively update and survey the current provision of recovery, rehabilitation and follow-up services for adult critical care patients across the UK. DESIGN: Cross-sectional, self-administered, predominantly closed-question, electronic, online survey. SETTING: Institutions providing adult critical care services identified from national databases. PARTICIPANTS: Multiprofessional critical care clinicians delivering services at each site. RESULTS: Responses from 176 UK hospital sites were included (176/242, 72.7%). Inpatient recovery and follow-up services were present at 127/176 (72.2%) sites, adopting multiple formats of delivery and primarily delivered by nurses (n=115/127, 90.6%). Outpatient services ran at 130 sites (73.9%), predominantly as outpatient clinics. Most services (n=108/130, 83.1%) were co-delivered by two or more healthcare professionals, typically nurse/intensive care unit (ICU) physician (n=29/130, 22.3%) or nurse/ICU physician/physiotherapist (n=19/130, 14.6%) teams. Clinical psychology was most frequently lacking from inpatient or outpatient services. Lack of funding was consistently the primary barrier to service provision, with other barriers including logistical and service prioritisation factors indicating that infrastructure and profile for services remain inadequate. Posthospital discharge physical rehabilitation programmes were relatively few (n=31/176, 17.6%), but peer support services were available in nearly half of responding institutions (n=85/176, 48.3%). The effects of the COVID-19 pandemic resulted in either increasing, decreasing or reformatting service provision. Future plans for long-term service transformation focus on expansion of current, and establishment of new, outpatient services. CONCLUSION: Overall, these data demonstrate a proliferation of recovery, follow-up and rehabilitation services for critically ill adults in the past decade across the UK, although service gaps remain suggesting further work is required for guideline implementation. Findings can be used to enhance survivorship for critically ill adults, inform policymakers and commissioners, and provide comparative data and experiential insights for clinicians designing models of care in international healthcare jurisdictions

Optimizing Critical Illness Recovery: Perspectives and Solutions from the Caregivers of ICU Survivors

Objectives: To understand the unmet needs of caregivers of ICU survivors, how they accessed support post ICU, and the key components of beneficial ICU recovery support systems as identified from a caregiver perspective. Design: International, qualitative study. Subjects: We conducted 20 semistructured interviews with a diverse group of caregivers in the United States, the United Kingdom, and Australia, 11 of whom had interacted with an ICU recovery program. Setting: Seven hospitals in the United States, United Kingdom, and Australia. Interventions: None. Measurements and Main Results: Content analysis was used to explore prevalent themes related to unmet needs, as well as perceived strategies to improve ICU outcomes. Post-ICU care was perceived to be generally inadequate. Desired caregiver support fell into two main categories: practical support and emotional support. Successful care delivery initiatives included structured programs, such as post discharge telephone calls, home health programs, post-ICU clinics, and peer support groups, and standing information resources, such as written educational materials and online resources. Conclusions: This qualitative, multicenter, international study of caregivers of critical illness survivors identified consistently unmet needs, means by which caregivers accessed support post ICU, and several care mechanisms identified by caregivers as supporting optimal ICU recovery

The epidemiologic and biologic basis for classifying older age as a high-risk, immunocompromising condition for pneumococcal vaccine policy

Introduction: Immunosenescence is a normal biologic process involving deterioration of protective immune responses. Consequently, older adults experience increased risk of infectious diseases, particularly pneumonia, and its leading bacterial cause, Streptococcus pneumoniae. Pneumococcal vaccine recommendations are often limited to adults with specific medical conditions despite similar disease risks among older adults due to immunosenescence. Areas covered: This article reviews epidemiologic, biologic, and clinical evidence supporting the consideration of older age due to immunosenescence as an immunocompromising condition for the purpose of pneumococcal vaccine policy and the role vaccination can play in healthy aging. Expert opinion: Epidemiologic and biologic evidence suggest that pneumococcal disease risk increases with age and is comparable for healthy older adults and younger adults with immunocompromising conditions. Because immunocompromising conditions are already indicated for pneumococcal conjugate vaccines (PCVs), a comprehensive public health strategy would also recognize immunosenescence. Moreover, older persons should be vaccinated before reaching the highest risk ages, consistent with the approach for other immunocompromising conditions. To facilitate PCV use among older adults, vaccine technical committees (VTCs) could classify older age as an immunocompromising condition based on the process of immunosenescence. With global aging, VTCs will need to consider immunosenescence and vaccine use during healthy aging

Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity

We are grateful to members of the D.S. laboratory and Dr. E. Fernández-Malavé for discussions and critical reading of the manuscript. We appreciate the support of A. Tomás-Loba, G. Sabio, P. Martín, A. Tsilingiri, A.R. Ramiro, C.L. Abram, C.A. Lowell, J.M. García-Lobo, M. Molina, and M.C. Rodríguez for providing reagents and support. We thank the staff at the Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) facilities for technical support. M.M.-L. received a Formación de Personal Universitario (FPU) fellowship (AP2010-5935) from the Spanish Ministerio de Educación. S.I. is funded by grant SAF2015-74561-JIN from the Spanish Ministerio de Ciencia, Innovación, y Universidades (MCIU) and Fondos Europeos de Desarrollo Regional (FEDER). G.D.B and D.M.R. are supported by the Wellcome Trust and the MRC Centre for Medical Mycology at the University of Aberdeen. S.L.L. is supported by the Swiss National Science Foundation (PP00P3_150758). Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from MCIU, the Agencia Estatal de Investigación, and FEDER; B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MCIU, and FEDER; the Acteria Foundation; the Constantes y Vitales prize (Atresmedia); La Marató de TV3 Foundation (201723); the European Commission (635122-PROCROP H2020), and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the MCIU and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).Peer reviewedPublisher PD

Evaluation of the World Health Organization Global Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance Network's Laboratory External Quality Assessment Programme, 2014-2019

Introduction. In 2009, the World Health Organization (WHO) established the Global Invasive Bacterial Vaccine Preventable Disease (IB-VPD) Surveillance Network (GISN) to monitor the global burden and aetiology of bacterial meningitis, pneumonia and sepsis caused by Haemophilus influenzae (Hi), Neisseria meningitidis (Nm) and Streptococcus pneumoniae (Sp).Hypothesis/Gap Statement. The GISN established an external quality assessment (EQA) programme for the characterization of Hi, Nm and Sp by culture and diagnostic PCR.Aim. To assess the performance of sentinel site laboratories (SSLs), national laboratories (NLs) and regional reference laboratories (RRLs) between 2014 and 2019 in the EQA programme.Methodology. Test samples consisted of bacterial smears for Gram-staining, viable isolates for identification and serotyping or serogrouping (ST/SG), plus simulated cerebrospinal fluid (CSF) samples for species detection and ST/SG by PCR. SSLs and NLs were only required to analyse the slides for Gram staining and identify the species of the live isolates. RRLs, and any SLs and NLs that had the additional laboratory capacity, were also required to ST/SG the viable isolates and analyse the simulated CSF samples.Results. Across the period, 69-112 SS/NL labs and eight or nine RRLs participated in the EQA exercise. Most participants correctly identified Nm and Sp in Gram-stained smears but were less successful with Hi and other species. SSLs/NLs identified the Hi, Nm and Sp cultures well and also submitted up to 56 % of Hi, 62 % of Nm and 33 % of Sp optional ST/SG results each year. There was an increasing trend in the proportion of correct results submitted over the 6 years for Nm and Sp. Some SSLs/NLs also performed the optional detection and ST/SG of the three organisms by PCR in simulated CSF from 2015 onwards; 89-100 % of the CSF samples were correctly identified and 76-93 % of Hi-, 90-100 % of Nm- and 75-100 % of Sp-positive samples were also correctly ST/SG across the distributions. The RRLs performed all parts of the EQA to a very high standard, with very few errors across all aspects of the EQA.Conclusion. The EQA has been an important tool in maintaining high standards of laboratory testing and building of laboratory capacity in the GISN

An international study exploring the experience of survivors of critical illness as volunteers within ICU recovery services

Objectives: Many clinicians have implemented follow-up and aftercare to support patients following ICU. Some of this care is supported and facilitated by peer volunteers. There is limited contemporary work that has explicitly explored volunteer roles within ICU recovery services or the experience of volunteers undertaking these roles. We sought to explore the experience of survivors of critical illness, as volunteers, involved in ICU recovery services and understand their motivation for undertaking these roles. Design: Qualitative exploration using in-depth semistructured interviews. The study design used an inductive content analysis process. We also documented the roles that were adopted by volunteers in each site involved in the study. Setting: Patients and caregivers were sampled from seven sites across three continents. Patients and Subjects: Patients and caregivers who had adopted peer-volunteering roles were undertaken. Interventions: None. Measurements and Main Results: Twelve patient and caregiver peer volunteers were interviewed. Four key themes were identified. These themes related to the experience of volunteers within ICU recovery services and their motivation for undertaking these roles: 1) self-belief and acceptance, 2) developing peer support, 3) social roles and a sense of purpose, and 4) giving back. Overwhelmingly, participants were positive about the role of the volunteer in the critical care setting. Conclusions: Peer volunteers undertake a variety of roles in ICU recovery services and during recovery more generally. These roles appear to be of direct benefit to those in these roles. Future research is needed to develop these roles and fully understand the potential impact on the service, including the impact on other patients

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

Antipsychotic drugs have been used effectively for the treatment of schizophrenia symptoms, but they are often associated with metabolic side effects such as weight gain and endocrine disruptions. To investigate the possible mechanisms of antipsychotic-induced metabolic effects, we studied the impact of chronic administration of a typical antipsychotic drug (haloperidol) and an atypical antipsychotic (risperidone) to male rats on food intake, body weight, adiposity, and the circulating concentrations of hormones and metabolites that can influence energy homeostasis. Chronic (28 days) haloperidol administration had no effect on food intake, weight gain or adiposity in male rats, whereas risperidone treatment resulted in a transient reduction in food intake and significantly reduced body weight gain compared to vehicle-treated control rats. Whereas neither antipsychotic had any effect on serum lipid profiles, glucose tolerance or the circulating concentrations of hormones controlled by the hypothalamo-pituitary-thyroid (free T4), -adrenal (corticosterone), -somatotropic (IGF-1), or -gonadotropic axes (testosterone), haloperidol increased circulating insulin levels and risperidone increased serum glucagon levels. This finding suggests that haloperidol or risperidone induce distinct metabolic effects. Since metabolic disorders such as obesity and type 2 diabetes mellitus represent serious health issues, understanding antipsychotic-induced endocrine and metabolic effects may ultimately allow better control of these side effects