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Nonhepatic hyperammonemia syndrome is a rare cause of neurologic dysfunction and cerebral edema and has most commonly been reported in posttransplant patients. Only recently has opportunistic infection with Ureaplasma species and Mycoplasma hominis been found to be key to the pathogenesis. We describe the cases of 3 immunosuppressed patients who developed hyperammonemia syndrome with new-onset refractory status epilepticus and diffuse cerebral edema. PCR was positive for M hominis in 1 patient and Ureaplasma parvum in the other 2. Despite early diagnostic suspicion and aggressive management with empirical antibiotics, seizure control, hypertonic saline, and ammonia elimination, none of our patients survived this life-threatening infection. Nonhepatic hyperammonemia and new-onset seizures can be presenting features of disseminated Ureaplasma species and M hominis infections in posttransplant patients. Immunosuppression in the absence of organ transplantation is likely sufficient to trigger this entity, as was the case in our third patient. When suspected, empiric combination antibiotics should be used due to high likelihood of resistance. The diagnostic test of choice is PCR. Patients with hyperammonemia syndrome associated with these infections typically have a poor prognosis. Early recognition and aggressive multimodal interventions may be key to ameliorating the high mortality and severe neurologic sequelae from this entity., (© 2022 American Academy of Neurology.)

Intrathecal methotrexate (IT MTX) resulting in severe adverse events including life-threatening cerebral edema is not well described. We report a rare case of death in a 37-year-old BRCA1+ woman with metastatic triple-negative breast cancer status post mastectomy following administration of IT MTX for leptomeningeal carcinomatosis. Within the 24 hours after intraoperative IT MTX delivery, she developed neurologically devastating diffuse cerebral edema leading to uncal and cerebellar tonsillar herniation. This case report highlights a rare but devastating side effect of IT MTX., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Older age and frailty are risk factors for poor clinical outcomes following SARS-CoV-2 infection. As such, COVID-19 vaccination has been prioritised for individuals with these factors, but there is concern that immune responses might be impaired due to age-related immune dysregulation and comorbidity. We aimed to study humoral and cellular responses to COVID-19 vaccines in residents of long-term care facilities (LTCFs)., Methods: In this observational cohort study, we assessed antibody and cellular immune responses following COVID-19 vaccination in members of staff and residents at 74 LTCFs across the UK. Staff and residents were eligible for inclusion if it was possible to link them to a pseudo-identifier in the COVID-19 datastore, if they had received two vaccine doses, and if they had given a blood sample 6 days after vaccination at the earliest. There were no comorbidity exclusion criteria. Participants were stratified by age (<65 years or ≥65 years) and infection status (previous SARS-CoV-2 infection [infection-primed group] or SARS-CoV-2 naive [infection-naive group]). Anticoagulated edetic acid (EDTA) blood samples were assessed and humoral and cellular responses were quantified., Findings: Between Dec 11, 2020, and June 27, 2021, blood samples were taken from 220 people younger than 65 years (median age 51 years [IQR 39-61]; 103 [47%] had previously had a SARS-CoV-2 infection) and 268 people aged 65 years or older of LTCFs (median age 87 years [80-92]; 144 [43%] had a previous SARS-CoV-2 infection). Samples were taken a median of 82 days (IQR 72-100) after the second vaccination. Antibody responses following dual vaccination were strong and equivalent between participants younger then 65 years and those aged 65 years and older in the infection-primed group (median 125 285 Au/mL [1128 BAU/mL] for <65 year olds vs 157 979 Au/mL [1423 BAU/mL] for ≥65 year olds; p=0·47). The antibody response was reduced by 2·4-times (467 BAU/mL; p≤0·0001) in infection-naive people younger than 65 years and 8·1-times (174 BAU/mL; p≤0·0001) in infection-naive residents compared with their infection-primed counterparts. Antibody response was 2·6-times lower in infection-naive residents than in infection-naive people younger than 65 years (p=0·0006). Impaired neutralisation of delta (1.617.2) variant spike binding was also apparent in infection-naive people younger than 65 years and in those aged 65 years and older. Spike-specific T-cell responses were also significantly enhanced in the infection-primed group. Infection-naive people aged 65 years and older (203 SFU per million [IQR 89-374]) had a 52% lower T-cell response compared with infection-naive people younger than 65 years (85 SFU per million [30-206]; p≤0·0001). Post-vaccine spike-specific CD4 T-cell responses displayed single or dual production of IFN-γ and IL-2 were similar across infection status groups, whereas the infection-primed group had an extended functional profile with TNFα and CXCL10 production., Interpretation: These data reveal suboptimal post-vaccine immune responses within infection-naive residents of LTCFs, and they suggest the need for optimisation of immune protection through the use of booster vaccination., Funding: UK Government Department of Health and Social Care., Competing Interests: LS reports grants from the Department of Health and Social Care during the study and is a member of the Social Care Working Group, which reports to the Scientific Advisory Group for Emergencies. AH is a member of the New and Emerging Respiratory Virus Threats Advisory Group at the Department of Health. All other authors declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant., Competing Interests: MR received funding for the COV-BOOST trial under contract via University Hospital Southampton NHS Foundation Trust, Funded by the UK NIHR/Vaccine Task Force (NIHR203292). Post-marketing surveillance reports on pneumococcal and meningococcal infection have been provided to vaccine manufacturers for which a cost recovery charge was made to GSK and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dowell, Powell, Davis, Scott, Logan, Willett, Bruton, Ayodele, Jinks, Gunn, Spalkova, Sylla, Nicol, Zuo, Ireland, Okike, Baawuah, Beckmann, Ahmad, Garstang, Brent, Brent, White, Collins, Davis, Lim, Cohen, Kenny, Linley, Poh, Amirthalingam, Brown, Ramsay, Azad, Wright, Waiblinger, Moss and Ladhani.)

Background: Residents of long-term care facilities (LTCFs) have been prioritised for COVID-19 vaccination because of the high COVID-19 mortality in this population. Several countries have implemented an extended interval of up to 12 weeks between the first and second vaccine doses to increase population coverage of single-dose vaccination. We aimed to assess the magnitude and quality of adaptive immune responses following a single dose of COVID-19 vaccine in LTCF residents and staff., Methods: From the LTCFs participating in the ongoing VIVALDI study (ISRCTN14447421), staff and residents who had received a first dose of COVID-19 vaccine (BNT162b2 [tozinameran] or ChAdOx1 nCoV-19), had pre-vaccination and post-vaccination blood samples (collected between Dec 11, 2020, and Feb 16, 2021), and could be linked to a pseudoidentifier in the COVID-19 Data Store were included in our cohort. Past infection with SARS-CoV-2 was defined on the basis of nucleocapsid-specific IgG antibodies being detected through a semiquantitative immunoassay, and participants who tested positive on this assay after but not before vaccination were excluded from the study. Processed blood samples were assessed for spike-specific immune responses, including spike-specific IgG antibody titres, T-cell responses to spike protein peptide mixes, and inhibition of ACE2 binding by spike protein from four variants of SARS-CoV-2 (the original strain as well as the B.1.1.7, B.1.351, and P.1 variants). Responses before and after vaccination were compared on the basis of age, previous infection status, role (staff or resident), and time since vaccination., Findings: Our cohort comprised 124 participants from 14 LTCFs: 89 (72%) staff (median age 48 years [IQR 35·5-56]) and 35 (28%) residents (87 years [77-90]). Blood samples were collected a median 40 days (IQR 25-47; range 6-52) after vaccination. 30 (24%) participants (18 [20%] staff and 12 [34%] residents) had serological evidence of previous SARS-CoV-2 infection. All participants with previous infection had high antibody titres following vaccination that were independent of age ( r s =0·076, p=0·70). In participants without evidence of previous infection, titres were negatively correlated with age ( r s =-0·434, p<0·0001) and were 8·2-times lower in residents than in staff. This effect appeared to result from a kinetic delay antibody generation in older infection-naive participants, with the negative age correlation disappearing only in samples taken more than 42 days post-vaccination ( r s =-0·207, p=0·20; n=40), in contrast to samples taken after 0-21 days ( r s =-0·774, p=0·0043; n=12) or 22-42 days ( r s =-0·437, p=0·0034; n=43). Spike-specific cellular responses were similar between older and younger participants. In infection-naive participants, antibody inhibition of ACE2 binding by spike protein from the original SARS-CoV-2 strain was negatively correlated with age ( r s =-0·439, p<0·0001), and was significantly lower against spike protein from the B.1.351 variant (median inhibition 31% [14-100], p=0·010) and the P.1 variant (23% [14-97], p<0·0001) than against the original strain (58% [27-100]). By contrast, a single dose of vaccine resulted in around 100% inhibition of the spike-ACE2 interaction against all variants in people with a history of infection., Interpretation: History of SARS-CoV-2 infection impacts the magnitude and quality of antibody response after a single dose of COVID-19 vaccine in LTCF residents. Residents who are infection-naive have delayed antibody responses to the first dose of vaccine and should be considered for an early second dose where possible., Funding: UK Government Department of Health and Social Care., Competing Interests: AI-S is an employee of the UK Department of Health and Social Care, which funded the study. AH is a member of the New and Emerging Respiratory Virus Threats Advisory Group at the Department of Health. AC reports grants from the UK Department of Health and Social Care during the conduct of the study. LS reports grants from the UK Department of Health and Social Care during the conduct of the study and is a member of the Social Care Working Group, which reports to the Scientific Advisory Group for Emergencies. All other authors declare no competing interests., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Background: Most data evaluating the relationship of post-mechanical thrombectomy (MT) blood pressure (BP) management and outcomes of patients with large vessel occlusion (LVO) focus on early BP control within the first 24 h. We investigated the correlation of daily BP trends up to the third day following MT with patient outcomes., Methods: We retrospectively reviewed our prospectively maintained database for LVO patients treated with MT from February 2015 to December 2017. Recorded BP values for 72 h post-reperfusion were reviewed. Daily peak systolic and diastolic blood pressures (SBP, DBP) were extracted for each day post-procedure. The association and importance between BP increments of 10 mmHg and mortality, hemorrhage, and functional independence (FI = mRS ≤ 2) was analyzed in a multivariable logistic regression and random forest (RF) analyses modeling., Results: A total of 212 thrombectomies were included. An increase in peak 24-h SBP was independently associated with higher likelihood of symptomatic hemorrhage (OR 1.2, p = 0.048) and decreased functional independence (OR 0.85, p = 0.03). Higher day 2 and day 3 peak SBP was strongly correlated with decreased functional independence and higher mortality. Third day SBP < 140 was independently associated with higher likelihood of functional independence (OR 4.3, p = 0.0004). Post-MT patients with and without functional independence demonstrated a similar relative decrease in peak SBP between the first 2 days following thrombectomy (p = 0.26); however, those without functional independence experienced a significant rebound increase in peak SBP on the third day following MT (mean change from day 2 to 3: FI - 3.5 mmHg, non-FI + 3.9 mmHg; p = 0.005)., Conclusion: High daily maximum SBP and a rebound SBP on the third day following MT is independently associated with increased likelihood of functional dependence.

Background and Purpose- The National Institutes of Health (NIH) StrokeNet provides a nationwide infrastructure to advance stroke research. Capitalizing on this unique opportunity, the NIH StrokeNet Training Core (NSTC) was established with the overarching goal of enhancing the professional development of a diverse spectrum of professionals who are embedded in the stroke clinical trials network of the NIH StrokeNet. Methods- This special report provides a descriptive account of the rationale, organization, and activities of the NSTC since its inception in 2013. Current processes and their evolution over time for facilitating training of NIH StrokeNet trainees have been highlighted. Data collected for monitoring training are summarized. Outcomes data (publications and grants) collected by NSTC was supplemented by publicly available resources. Results- The NSTC comprises of cross-network faculty, trainees, and education coordinators. It helps in the development and monitoring of training programs and organizes educational and career development activities. Trainees are provided directed guidance towards their mandated research projects, including opportunities to present at the International Stroke Conference. The committee has focused on developing sustainable models of peer-to-peer interaction and cross-institutional mentorships. A total of 124 professionals (43.7% female, 10.5% underrepresented minorities) have completed training between 2013 and 2018, of whom 55% were clinical vascular neurologists. Of the total, 85% transitioned to a formal academic position and 95% were involved in stroke research post-training. Altogether, 1659 indexed publications have been authored or co-authored by NIH StrokeNet Trainees, of which 58% were published during or after their training years. Based on data from 109 trainees, 33% had submitted 72 grant proposals as principal or co-principal investigators of which 22.2% proposals have been funded. Conclusions- NSTC has provided a foundation to foster nationwide training in stroke research. Our data demonstrate strong contribution of trainees towards academic scholarship. Continued innovation in educational methodologies is required to adapt to unique training opportunities such as the NIH StrokeNet.

Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: In the United States, about half of acute ischemic stroke patients treated with tPA (tissue-type plasminogen activator) receive treatment within 60 minutes of hospital arrival. We aimed to determine the proportion of patients receiving tPA within 60 minutes (door-to-needle time [DTNT] ≤60) and 45 minutes (DTNT ≤45) of hospital arrival by race/ethnicity and sex and to identify temporal trends in DTNT ≤60 and DTNT ≤45., Methods: Among 65 654 acute ischemic stroke admissions in the National Institute of Neurological Disorders and Stroke-funded FL-PR CReSD study (Florida-Puerto Rico Collaboration to Reduce Stroke Disparities) from 2010 to 2015, we included 6181 intravenous tPA-treated cases (9.4%). Generalized estimating equations were used to determine predictors of DTNT ≤60 and DTNT ≤45., Results: DTNT ≤60 was achieved in 42% and DTNT ≤45 in 18% of cases. After adjustment, women less likely received DTNT ≤60 (odds ratio, 0.81; 95% confidence interval, 0.72-0.92) and DTNT ≤45 (odds ratio, 0.73; 95% confidence interval, 0.57-0.93). Compared with Whites, Blacks less likely had DTNT ≤45 during off hours (odds ratio, 0.68; 95% confidence interval, 0.47-0.98). Achievement of DTNT ≤60 and DTNT ≤45 was highest in South Florida (50%, 23%) and lowest in West Central Florida (28%, 11%)., Conclusions: In the FL-PR CReSD, achievement of DTNT ≤60 and DTNT ≤45 remains low. Compared with Whites, Blacks less likely receive tPA treatment within 45 minutes during off hours. Treatment within 60 and 45 minutes is lower in women compared with men and lowest in West Central Florida compared with other Florida regions and Puerto Rico. Further research is needed to identify reasons for delayed thrombolytic treatment in women and Blacks and factors contributing to regional disparities in DTNT., (© 2017 American Heart Association, Inc.)

Opinion Statement: Preconditioning is the premise that controlled preemptive exposure to sub-lethal doses of a stressor and can condition an organism or organ to later withstand a lethal dose. This process relies on marshaling endogenous survival resources that have evolved as part of an organism's evolutionary struggle to overcome at times harsh environmental conditions. This preconditioning response occurs through activation of myriad complex mechanisms that run the gamut from alterations in gene expression to the de novo synthesis and post-translational modification of proteins, and it may occur across exposure to a wide variety of stressors (i.e., ischemia, hypoxia, hypothermia, drugs). This review will focus on preconditioning in relation to an ischemic stressor (ischemic preconditioning) and how this process may be harnessed as a protective method to ameliorate targeted acute neurologic diseases especially. There has been considerable eagerness to translate ischemic preconditioning to the bedside, and to that end there have been recent trials examining its efficacy in various clinical settings. However, some of these trials have reached diverging conclusions with a protective effect seen in studies targeting acute kidney injury solely while no benefit was seen in larger trials targeting combined endpoints including cardio-, neuro-, and renoprotection in a cohort of patients undergoing cardiac surgery. While an extensive body of pre-clinical research offers ischemic preconditioning as a robust and highly faithful protective phenomenon, its clinical utility remains unproven. This current state may be due to persisting gaps in our understanding of how best to harness its power. This review will provide an overview of the biological mechanisms proposed to underlie ischemic preconditioning, explore initial disease targets, examine the challenges we must overcome to optimally engage this system, and report findings of recent clinical trials.

Tuber rot disease is a major constraint to white yam (Dioscorea rotundata) production, accounting for 50-60% of annual yield losses in Nigeria. The main method of control using synthetic fungicides is being discouraged due to human and environmental health hazards. The potential of Oryza sativa husk (OSH) and Quercus phillyraeoides (QP) extracts for the in vitro and in vivo control of six virulent rot-causing fungal pathogens, Lasiodiplodia theobromae, Aspergillus niger, Rhizoctonia solani, Penicillium oxalicum, Sclerotium rolfsii, and Fusarium oxysporum was evaluated, using five different extract concentrations of 0.5%, 1.0%, 1.5%, 2.5%, and 3.5% w/v. These fungi were isolated from rotted tubers of D. rotundata, across three agroecological zones in Nigeria-the Humid rainforest, Derived savanna, and southern Guinea savanna. All treatments were subjected to three methods of inoculation 48 hours before the application of both extracts and stored at 28 ± 2°C for 6 months. Radial mycelial growth of the test pathogens was effectively inhibited at concentrations ≤ 3.5% w/v in vitro for both OSH and QP extracts. Rotting was significantly reduced (P ≤ 0.05) to between 0 to 18.8% and 0% to 20.9% for OSH and QP extracts respectively. The extracts significantly (P ≤ 0.05) inhibited percent rot of the test pathogens at 3.5% concentration w/v in vivo. Rot incidence was, however, lower in replicate tubers that were inoculated, treated with extracts and exposed than treatments that were covered. Phytochemical analysis of OSH and QP extracts revealed the presence of secondary metabolites such as alkaloids, flavonoids, saponins, tannins, ferulic acid, phlobatanins, Terpenoids, phenols, anthraquinone and pyroligneous acid. The efficacy of both extracts in reducing rot in this study recommends their development as prospective biopesticide formulation and use in the management of post-harvest rot of yam tubers.

While phylogenetic and cluster analyses are often used to define clonal groups within bacterial species, the identification of clonal groups that are associated with specific ecological niches or host species remains a challenge. We used Listeria monocytogenes, which causes invasive disease in humans and different animal species and which can be isolated from a number of environments including food, as a model organism to develop and implement a two-step statistical approach to the identification of phylogenetic clades that are significantly associated with different source populations, including humans, animals, and food. If the null hypothesis that the genetic distances for isolates within and between source populations are identical can be rejected (SourceCluster test), then particular clades in the phylogenetic tree with significant overrepresentation of sequences from a given source population are identified (TreeStats test). Analysis of sequence data for 120 L. monocytogenes isolates revealed evidence of clustering between isolates from the same source, based on the phylogenies inferred from actA and inlA (P = 0.02 and P = 0.07, respectively; SourceCluster test). Overall, the TreeStats test identified 10 clades with significant (P < 0.05) or marginally significant (P < 0.10) associations with defined sources, including human-, animal-, and food-associated clusters. Epidemiological and virulence phenotype data supported the fact that the source-associated clonal groups identified here are biologically valid. Overall, our data show that (i) the SourceCluster and TreeStats tests can identify biologically meaningful source-associated phylogenetic clusters and (ii) L. monocytogenes includes clonal groups that have adapted to infect specific host species or colonize nonhost environments.

Stress granules (SGs) are cytoplasmic aggregates of stalled translational preinitiation complexes that accumulate during stress. GW bodies/processing bodies (PBs) are distinct cytoplasmic sites of mRNA degradation. In this study, we show that SGs and PBs are spatially, compositionally, and functionally linked. SGs and PBs are induced by stress, but SG assembly requires eIF2alpha phosphorylation, whereas PB assembly does not. They are also dispersed by inhibitors of translational elongation and share several protein components, including Fas-activated serine/threonine phosphoprotein, XRN1, eIF4E, and tristetraprolin (TTP). In contrast, eIF3, G3BP, eIF4G, and PABP-1 are restricted to SGs, whereas DCP1a and 2 are confined to PBs. SGs and PBs also can harbor the same species of mRNA and physically associate with one another in vivo, an interaction that is promoted by the related mRNA decay factors TTP and BRF1. We propose that mRNA released from disassembled polysomes is sorted and remodeled at SGs, from which selected transcripts are delivered to PBs for degradation.

TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.