Age-related Defects in CD4 T Cell Cognate Helper Function Lead to Reductions in Humoral Responses

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals

Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen

Using a T cell receptor transgenic (TCR Tg) mouse model, we have shown that TCR Tg CD4 cells from aged mice retain a naive phenotype, but exhibit reduced proliferation and IL-2 production in response to the antigen compared with cells from young mice. We hypothesize that age-related decreases in T cell function may be partly related to the age of the T cells. Because thymic output is decreased with age, peripheral T cells in older individuals are likely to be older than those in younger individuals. To investigate this possibility, we have manipulated the age of CD4 T cells in the periphery of young and aged mice. The production of new T cells was induced by depleting peripheral CD4 T cells or by creating bone marrow chimeras. In both young and aged individuals where we induced the production of new T cells, these newly generated cells exhibited robust responses to antigen ex vivo and in vivo, exhibiting good expansion, IL-2 production, and cognate helper function. Our results suggest that age-related defects in response to antigenic stimulation, in part, are caused by the age of the CD4 T cells

Prevention of child behavior problems through universal implementation of a group behavioral family intervention.

The aim of this mental health promotion initiative was to evaluate the effectiveness of a universally delivered group behavioral family intervention (BFI) in preventing behavior problems in children. This study investigates the transferability of an efficacious clinical program to a universal prevention intervention delivered through child and community health services targeting parents of preschoolers within a metropolitan health region. A quasiexperimental two-group (BFI, n=804 vs. Comparison group, n=806) longitudinal design followed preschool aged children and their parents over a 2-year period. BFI was associated with significant reductions in parent-reported levels of dysfunctional parenting and parent-reported levels of child behavior problems. Effect sizes on child behavior problems ranged from large (.83) to moderate (.47). Positive and significant effects were also observed in parent mental health, marital adjustment, and levels of child rearing conflict. Findings are discussed with respect to their implication for significant population reductions in child behavior problems as well as the pragmatic challenges for prevention science in encouraging both the evaluation and uptake of preventive initiatives in real world settings

A clinical practice guideline for the management of patients with acute spinal cord injury: recommendations on the use of methylprednisolone sodium succinate

Introduction: The objective of this guideline is to outline the appropriate use of methylprednisolone sodium succinate (MPSS) in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MPSS in acute SCI. A multidisciplinary Guideline Development Group used this information, in combination with their clinical expertise, to develop recommendations for the use of MPSS. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: The main conclusions from the systematic review included the following: (1) there were no differences in motor score change at any time point in patients treated with MPSS compared to those not receiving steroids; (2) when MPSS was administered within 8 hours of injury, pooled results at 6- and 12-months indicated modest improvements in mean motor scores in the MPSS group compared with the control group; and (3) there was no statistical difference between treatment groups in the risk of complications. Our recommendations were: (1) "We suggest not offering a 24-hour infusion of high-dose MPSS to adult patients who present after 8 hours with acute SCI"; (2) "We suggest a 24-hour infusion of high-dose MPSS be offered to adult patients within 8 hours of acute SCI as a treatment option"; and (3) "We suggest not offering a 48-hour infusion of high-dose MPSS to adult patients with acute SCI." Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in SCI patients

A clinical practice guideline for the management of patients with acute spinal cord injury and central cord syndrome: recommendations on the timing (<= 24 hours versus > 24 hours) of decompressive surgery

Objective: To develop recommendations on the timing of surgical decompression in patients with traumatic spinal cord injury (SCI) and central cord syndrome. Methods: A systematic review of the literature was conducted to address key relevant questions. A multidisciplinary guideline development group used this information, along with their clinical expertise, to develop recommendations for the timing of surgical decompression in patients with SCI and central cord syndrome. Based on GRADE, a strong recommendation is worded as "we recommend," whereas a weak recommendation is presented as "we suggest." Results: Conclusions from the systematic review included (1) isolated studies reported statistically significant and clinically important improvements following early decompression at 6 months and following discharge from inpatient rehabilitation; (2) in one study on acute central cord syndrome without instability, a marginally significant improvement in total motor scores was reported at 6 and 12 months in patients managed with early versus late surgery; and (3) there were no significant differences in length of acute care/rehabilitation stay or in rates of complications between treatment groups. Our recommendations were: "We suggest that early surgery be considered as a treatment option in adult patients with traumatic central cord syndrome" and "We suggest that early surgery be offered as an option for adult acute SCI patients regardless of level." Quality of evidence for both recommendations was considered low. Conclusions: These guidelines should be implemented into clinical practice to improve outcomes in patients with acute SCI and central cord syndrome by promoting standardization of care, decreasing the heterogeneity of management strategies, and encouraging clinicians to make evidence-informed decisions

A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Role of Baseline Magnetic Resonance Imaging in Clinical Decision Making and Outcome Prediction

Introduction: The objective of this guideline is to outline the role of magnetic resonance imaging (MRI) in clinical decision making and outcome prediction in patients with traumatic spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MRI in patients with traumatic SCI. This review focused on longitudinal studies that controlled for baseline neurologic status. A multidisciplinary Guideline Development Group (GDG) used this information, their clinical expertise, and patient input to develop recommendations on the use of MRI for SCI patients. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as “we recommend,” whereas a weaker recommendation is indicated by “we suggest.” Results: Based on the limited available evidence and the clinical expertise of the GDG, our recommendations were: (1) “We suggest that MRI be performed in adult patients with acute SCI prior to surgical intervention, when feasible, to facilitate improved clinical decision-making” (quality of evidence, very low) and (2) “We suggest that MRI should be performed in adult patients in the acute period following SCI, before or after surgical intervention, to improve prediction of neurologic outcome” (quality of evidence, low). Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and prognostication for patients with SCI

A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Type and Timing of Rehabilitation.

Introduction: The objective of this study is to develop guidelines that outline the appropriate type and timing of rehabilitation in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to rehabilitation in patients with acute SCI. A multidisciplinary guideline development group used this information, and their clinical expertise, to develop recommendations for the type and timing of rehabilitation. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest. Results: Based on the findings from the systematic review, our recommendations were: (1) We suggest rehabilitation be offered to patients with acute spinal cord injury when they are medically stable and can tolerate required rehabilitation intensity (no included studies; expert opinion); (2) We suggest body weight-supported treadmill training as an option for ambulation training in addition to conventional overground walking, dependent on resource availability, context, and local expertise (low evidence); (3) We suggest that individuals with acute and subacute cervical SCI be offered functional electrical stimulation as an option to improve hand and upper extremity function (low evidence); and (4) Based on the absence of any clear benefit, we suggest not offering additional training in unsupported sitting beyond what is currently incorporated in standard rehabilitation (low evidence). Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in patients with SCI by promoting standardization of care, decreasing the heterogeneity of management strategies and encouraging clinicians to make evidence-informed decisions

A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Type and Timing of Anticoagulant Thromboprophylaxis.

Introduction: The objective of this study is to develop evidence-based guidelines that recommend effective, safe and cost-effective thromboprophylaxis strategies in patients with spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions relating to thromboprophylaxis in SCI. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: Based on conclusions from the systematic review and expert panel opinion, the following recommendations were developed: (1) "We suggest that anticoagulant thromboprophylaxis be offered routinely to reduce the risk of thromboembolic events in the acute period after SCI;" (2) "We suggest that anticoagulant thromboprophylaxis, consisting of either subcutaneous low-molecular-weight heparin or fixed, low-dose unfractionated heparin (UFH) be offered to reduce the risk of thromboembolic events in the acute period after SCI. Given the potential for increased bleeding events with the use of adjusted-dose UFH, we suggest against this option;" (3) "We suggest commencing anticoagulant thromboprophylaxis within the first 72 hours after injury, if possible, in order to minimize the risk of venous thromboembolic complications during the period of acute hospitalization." Conclusions: These guidelines should be implemented into clinical practice in patients with SCI to promote standardization of care, decrease heterogeneity of management strategies and encourage clinicians to make evidence-informed decisions

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (&lt;50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community