Delightfully Sober

It’s a Friday night and you’ve found yourself once again in Campustown. But there’s a catch…you’re sober. You’ve agreed to be the designated driver for the night, and the bottom line is that you’re not drinking. To some, this sounds like a boring night waiting to happen—but it doesn’t have to be. If you’re unsure, check out these quick tips on how to make the most of your sober night out

Intravenous immunoglobulin treatment for encephalitis in children aged 6 months to 16 years: the IgNiTE RCT

Background: There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking. Objective: To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness. Design: Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children. Setting: Twenty-one NHS Hospitals in the UK. Participants: Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis. Intervention: Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment. Main outcome measure: Participants were followed up for 12 months (+/– 4 weeks) after randomisation. The primary outcome measure was a ‘good recovery’ defined as a score of ≤ 2 on the Paediatric Glasgow Outcome Score Extended at 12 months after randomisation. Secondary outcomes: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and intravenous immunoglobulin safety data. Results: We planned to recruit 308 children over a 42-month period. After enrolment of 18 participants (8 male; 44%) over 21 months (from December 2015 to September 2017), funding was withdrawn due to slow recruitment and the study was terminated. Ten participants were randomised to the intravenous immunoglobulin group, and eight to the placebo group, and all 18 participants were included in the analysis. At 12 months after randomisation, 9 participants [50%; intravenous immunoglobulin n = 5 (50%), placebo n = 4 (50%)] made good recovery and 5 participants [28%; intravenous immunoglobulin n = 3 (30%), placebo n = 2 (25%)] made a poor recovery. Three participants in the placebo group (43%) experienced a total of 10 serious adverse events compared with none in the intravenous immunoglobulin group but none of the adverse events were judged to be related to the study treatment. No deaths occurred during the study period. Conclusion: ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was halted prematurely due to slow recruitment. Given the small sample size, the study was underpowered to evaluate the effect of intravenous immunoglobulin when compared with placebo in childhood encephalitis. The study findings, albeit from a small sample size, support existing evidence that encephalitis results in poor neurological outcomes for many children. Lessons learned from the ImmunoglobuliN in the Treatment of Encephalitis trial would be valuable for the success of future trials set up to address the efficacy of early treatment with intravenous immunoglobulin in all-cause encephalitis in children. Study limitations and future work: The study was underpowered to evaluate the efficacy of intravenous immunoglobulin in the treatment of childhood encephalitis due to the small sample size achieved. Future trials should seek to address this important question. Trial registration: This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Objective: To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness. // Design: Phase 3b multicentre, double-blind, randomised placebo-controlled trial. // Setting: Twenty-one hospitals in the UK. // Participants: Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308. // Intervention: Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment. // Main outcome measure: The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended. // Secondary outcome measures: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data. // Results: 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG. // Conclusions: The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis. // Trial registration number: Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925

Efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute pain after orthopedic trauma: a practice management guideline from the Eastern Association for the Surgery of Trauma and the Orthopedic Trauma Association

OBJECTIVES: Fracture is a common injury after a traumatic event. The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) to treat acute pain related to fractures is not well established. METHODS: Clinically relevant questions were determined regarding NSAID use in the setting of trauma-induced fractures with clearly defined patient populations, interventions, comparisons and appropriately selected outcomes (PICO). These questions centered around efficacy (pain control, reduction in opioid use) and safety (non-union, kidney injury). A systematic review including literature search and meta-analysis was performed, and the quality of evidence was graded per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The working group reached consensus on the final evidence-based recommendations. RESULTS: A total of 19 studies were identified for analysis. Not all outcomes identified as critically important were reported in all studies, and the outcome of pain control was too heterogenous to perform a meta-analysis. Nine studies reported on non-union (three randomized control trials), six of which reported no association with NSAIDs. The overall incidence of non-union in patients receiving NSAIDs compared with patients not receiving NSAIDs was 2.99% and 2.19% (p=0.04), respectively. Of studies reporting on pain control and reduction of opioids, the use of NSAIDs reduced pain and the need for opioids after traumatic fracture. One study reported on the outcome of acute kidney injury and found no association with NSAID use. CONCLUSIONS: In patients with traumatic fractures, NSAIDs appear to reduce post-trauma pain, reduce the need for opioids and have a small effect on non-union. We conditionally recommend the use of NSAIDs in patients suffering from traumatic fractures as the benefit appears to outweigh the small potential risks

Interventions to improve or facilitate linkage to or retention in pre-ART (HIV) care and initiation of ART in low- and middle-income settings--a systematic review.

INTRODUCTION: Several approaches have been taken to reduce pre-antiretroviral therapy (ART) losses between HIV testing and ART initiation in low- and middle-income countries, but a systematic assessment of the evidence has not yet been undertaken. The aim of this systematic review is to assess the potential for interventions to improve or facilitate linkage to or retention in pre-ART care and initiation of ART in low- and middle-income settings. METHODS: An electronic search was conducted on Medline, Embase, Global Health, Web of Science and conference databases to identify studies describing interventions aimed at improving linkage to or retention in pre-ART care or initiation of ART. Additional searches were conducted to identify on-going trials on this topic, and experts in the field were contacted. An assessment of the risk of bias was conducted. Interventions were categorized according to key domains in the existing literature. RESULTS: A total of 11,129 potentially relevant citations were identified, of which 24 were eligible for inclusion, with the majority (n=21) from sub-Saharan Africa. In addition, 15 on-going trials were identified. The most common interventions described under key domains included: health system interventions (i.e. integration in the setting of antenatal care); patient convenience and accessibility (i.e. point-of-care CD4 count (POC) testing with immediate results, home-based ART initiation); behaviour interventions and peer support (i.e. improved communication, patient referral and education) and incentives (i.e. food support). Several interventions showed favourable outcomes: integration of care and peer supporters increased enrolment into HIV care, medical incentives increased pre-ART retention, POC CD4 testing and food incentives increased completion of ART eligibility screening and ART initiation. Most studies focused on the general adult patient population or pregnant women. The majority of published studies were observational cohort studies, subject to an unclear risk of bias. CONCLUSIONS: Findings suggest that streamlining services to minimize patient visits, providing adequate medical and peer support, and providing incentives may decrease attrition, but the quality of the current evidence base is low. Few studies have investigated combined interventions, or assessed the impact of interventions across the HIV cascade. RESULTS from on-going trials investigating POC CD4 count testing, patient navigation, rapid ART initiation and mobile phone technology may fill the quality of evidence gap. Further high-quality studies on key population groups are required, with interventions informed by previously reported barriers to care

SARS-CoV-2 seroprevalence in pregnant women in Kilifi, Kenya from March 2020 to March 2022

BackgroundSeroprevalence studies are an alternative approach to estimating the extent of transmission of SARS-CoV-2 and the evolution of the pandemic in different geographical settings. We aimed to determine the SARS-CoV-2 seroprevalence from March 2020 to March 2022 in a rural and urban setting in Kilifi County, Kenya.MethodsWe obtained representative random samples of stored serum from a pregnancy cohort study for the period March 2020 to March 2022 and tested for antibodies against the spike protein using a qualitative SARS-CoV-2 ELISA kit (Wantai, total antibodies). All positive samples were retested for anti-SARS-CoV-2 anti-nucleocapsid antibodies (Euroimmun, ELISA kits, NCP, qualitative, IgG) and anti-spike protein antibodies (Euroimmun, ELISA kits, QuantiVac; quantitative, IgG).ResultsA total of 2,495 (of 4,703 available) samples were tested. There was an overall trend of increasing seropositivity from a low of 0% [95% CI 0–0.06] in March 2020 to a high of 89.4% [95% CI 83.36–93.82] in Feb 2022. Of the Wantai test-positive samples, 59.7% [95% CI 57.06–62.34] tested positive by the Euroimmun anti-SARS-CoV-2 NCP test and 37.4% [95% CI 34.83–40.04] tested positive by the Euroimmun anti-SARS-CoV-2 QuantiVac test. No differences were observed between the urban and rural hospital but villages adjacent to the major highway traversing the study area had a higher seroprevalence.ConclusionAnti-SARS-CoV-2 seroprevalence rose rapidly, with most of the population exposed to SARS-CoV-2 within 23 months of the first cases. The high cumulative seroprevalence suggests greater population exposure to SARS-CoV-2 than that reported from surveillance data

Hopes, Dreams, but No Plans : Aging Parents of Individuals with Intellectual and Developmental Disabilities

Individuals living with an intellectual or developmental disability (IDD) are often reliant on others for most of their lives. As a result, the parents of individuals with IDD are positioned in a unique caretaking role as they age alongside their dependent children. Drawing from in-depth interviews with 14 older parents of individuals with IDD, the present study discusses the ways in which these aging parents attempt to make future plans for both themselves and their children within the neoliberal framework of the United States. This paper argues that because parents of individuals with IDD are reliant on an inherently unpredictable system of public services for support, the capability to plan for their old age is limited

Hemostasis and tumor immunity

Abstract Significant data have accumulated demonstrating a reciprocal relationship between cancer and the hemostatic system whereby cancer promotes life‐threatening hemostatic system dysregulation (e.g., thromboembolism, consumptive coagulopathy), and hemostatic system components directly contribute to cancer pathogenesis. The mechanistic underpinnings of this relationship continue to be defined, but it is becoming increasingly clear that many of these mechanisms involve crosstalk between the hemostatic and immune systems. This is perhaps not surprising given that there is ample evidence for bidirectional crosstalk between the hemostatic and immune systems at multiple levels that likely evolved to coordinate the response to injury, host defense, and tissue repair. Much of the data linking hemostasis and immunity in cancer biology focus on innate immune system components. However, the advent of adaptive immunity‐based cancer therapies such as immune checkpoint inhibitors has revealed that the relationship of hemostasis and immunity in cancer extends to the adaptive immune system. Adaptive immunity‐based cancer therapies appear to be associated with an increased risk of thromboembolic complications, and hemostatic system components appear to regulate adaptive immune functions through diverse mechanisms to affect tumor progression. In this review, the evidence for crosstalk between hemostatic and adaptive immune system components is discussed, and the implications of this relationship in the context of cancer therapy are reviewed. A better understanding of these relationships will likely lead to strategies to make existing adaptive immune based therapies safer by decreasing thromboembolic risk and may also lead to novel targets to improve adaptive immune‐based cancer treatments

Synthesis of Antibiotic Scaffolds Inspired by the Tan 1057-D Biologically Active Natural Product Through the Utilization of Ullmann Copper(I) and Gold Cyclization Chemistry

honors thesisCollege of ScienceChemistryRyan E. LooperAs bacterial resistance to drugs continues to rise, the search for new antibiotics is of paramount importance. One key element to finding successful antibiotics is to uncover small molecules that act through novel mechanisms of action in order to decrease the risk of cross-resistance and provide antibiotics with longer clinical lifetimes. Based on previous work conducted in our research group, the TAN-1057 antibiotic family shows promise as new candidates in part due to their inhibition of protein synthesis at the point of tRNA acyl-transfer in the ribosome. This project involves the synthesis of the TAN-1057 D heterocyclic core, as well as the elucidation of TAN- 1057 D interactions in the ribosome. A modular synthetic strategy has been implemented to construct the heterocyclic core of TAN-1057 D. This strategy was chosen in order to streamline analog development via facile functional group additions and control of the heterocyclic ring oxidation state. The core has been synthesized through the utilization of Ullmann copper(I) chemistry, and manipulation of the core is currently in progress to allow for analog development. The installation of functional group handles will allow for a wide variety of analogs to be synthesized, and then undergo biological testing. Upon completion of TAN-1057 D derivatives, we will be able to explore the mechanism of action of the parent compound and gather insight into the structural characteristics of a future drug candidate