Publications by authors named "Kenneth Smith"

651 Publications

Reply to: Rethink the classical view of cerebrospinal fluid production.

Nat Rev Neurol 2021 Jul 12. Epub 2021 Jul 12.

Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1038/s41582-021-00539-zDOI Listing
July 2021

Optimal management of patients with operable pancreatic head cancer: A Markov decision analysis.

J Surg Oncol 2021 Jul 7. Epub 2021 Jul 7.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Introduction: Neoadjuvant therapy (NAT) is an emerging strategy for operable pancreatic ductal adenocarcinoma (PDAC). While NAT increases multimodal therapy completion, it risks functional decline and treatment dropout. We used decision analysis to determine optimal management of localized PDAC and consider risks faced by elderly patients.

Methods: A Markov cohort decision analysis model evaluated treatment options for a 60-year-old patient with resectable PDAC: (1) upfront pancreaticoduodenectomy or (2) NAT. One-way and probabilistic sensitivity analyses were performed. A subanalysis considered the scenario of a 75-year-old patient.

Results: For the base case, NAT offered an incremental survival gain of 4.6 months compared with SF (overall survival: 26.3 vs. 21.7 months). In one-way sensitivity analyses, findings were sensitive to recurrence-free survival for NAT patients undergoing adjuvant, probability of completing NAT, and probability of being resectable at exploration after NAT. On probabilistic analysis, NAT was favored in a majority of trials (97%) with a median survival benefit of 5.1 months. In altering the base case for the 75-year-old scenario, NAT had a survival benefit of 3.8 months.

Conclusions: This analysis demonstrates a significant benefit to NAT in patients with localized PDAC. This benefit persists even in the elderly cohort.
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http://dx.doi.org/10.1002/jso.26589DOI Listing
July 2021

Insufficient Anthrax Lethal Toxin Neutralization Is Associated with Antibody Subclass and Domain Specificity in the Plasma of Anthrax-Vaccinated Individuals.

Microorganisms 2021 Jun 2;9(6). Epub 2021 Jun 2.

Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.

Anthrax vaccine adsorbed (AVA) is a significant line of defense against bioterrorist attack from spores. However, in a subset of individuals, this vaccine may produce a suboptimal quantity of anti-protective antigen (PA), antibodies that are poorly neutralizing, and/or antibody titers that wane over time, necessitating annual boosters. To study individuals with such poor responses, we examine the properties of anti-PA in a subset of vaccinated individuals that make significant quantities of antibody but are still unable to neutralize toxin. In this cohort, characterized by poorly neutralizing antibody, we find that increased IgG4 to IgG1 subclass ratios, low antibody avidity, and insufficient antibody targeting domain 4 associate with improper neutralization. Thus, future vaccines and vaccination schedules should be formulated to improve these deficiencies.
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http://dx.doi.org/10.3390/microorganisms9061204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229884PMC
June 2021

Muscle and tendon adaptations to moderate load eccentric vs. concentric resistance exercise in young and older males.

Geroscience 2021 Jul 1. Epub 2021 Jul 1.

MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham Biomedical Research Centre, University of Nottingham's Royal Derby Hospital Centre, Nottingham, UK.

Resistance exercise training (RET) is well-known to counteract negative age-related changes in both muscle and tendon tissue. Traditional RET consists of both concentric (CON) and eccentric (ECC) contractions; nevertheless, isolated ECC contractions are metabolically less demanding and, thus, may be more suitable for older populations. However, whether submaximal (60% 1RM) CON or ECC contractions differ in their effectiveness is relatively unknown. Further, whether the time course of muscle and tendon adaptations differs to the above is also unknown. Therefore, this study aimed to establish the time course of muscle and tendon adaptations to submaximal CON and ECC RET. Twenty healthy young (24.5 ± 5.1 years) and 17 older males (68.1 ± 2.4 years) were randomly allocated to either isolated CON or ECC RET which took place 3/week for 8 weeks. Tendon biomechanical properties, muscle architecture and maximal voluntary contraction were assessed every 2 weeks and quadriceps muscle volume every 4 weeks. Positive changes in tendon Young's modulus were observed after 4 weeks in all groups after which adaptations in young males plateaued but continued to increase in older males, suggesting a dampened rate of adaptation with age. However, both CON and ECC resulted in similar overall changes in tendon Young's modulus, in all groups. Muscle hypertrophy and strength increases were similar between CON and ECC in all groups. However, pennation angle increases were greater in CON, and fascicle length changes were greater in ECC. Notably, muscle and tendon adaptations appeared to occur in synergy, presumably to maintain the efficacy of the muscle-tendon unit.
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http://dx.doi.org/10.1007/s11357-021-00396-0DOI Listing
July 2021

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2.

Nature 2021 Jun 30. Epub 2021 Jun 30.

Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Cambridge, UK.

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.
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http://dx.doi.org/10.1038/s41586-021-03739-1DOI Listing
June 2021

Exploring the impact of COVID-19 on the willingness of older adults to participate in physiology research: views from past and potential volunteers.

Appl Physiol Nutr Metab 2021 Jun 28. Epub 2021 Jun 28.

University of Nottingham, School of Medicine, Derby, Derbyshire, United Kingdom of Great Britain and Northern Ireland;

We explored the views of older (≥65 years) past and potential volunteers in regard to participating in physiology research during the COVID-19 pandemic. Using an online questionnaire and focus groups, we found that past volunteers (n=55) were more likely to take part in both acute (p<0.05) and chronic (p<0.05) physiology studies, compared to potential future volunteers (n=57). Both cohorts demonstrated a positive attitude towards volunteering during the COVID-19 pandemic, although concern was evident. Novelty • Volunteers demonstrated a positive attitude and also concern towards participating in physiology research during COVID-19.
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http://dx.doi.org/10.1139/apnm-2021-0204DOI Listing
June 2021

Should older adult pneumococcal vaccination recommendations change due to decreased vaccination in children during the pandemic? A cost-effectiveness analysis.

Vaccine 2021 07 21;39(31):4278-4282. Epub 2021 Jun 21.

University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address:

Background: The COVID-19 pandemic is causing declines in childhood immunization rates. We examined potential COVID-19-related changes in pediatric 13-valent pneumococcal conjugate vaccine (PCV13) use, subsequent impact on childhood and adult pneumococcal disease rates, and how those changes might affect the favorability of PCV13 use in non-immunocompromised adults aged ≥65 years.

Methods: A Markov model estimated pediatric disease resulting from decreased PCV13 use in children aged <5 years; absolute decreases from 10 to 50% for 1-2 years duration were examined, assuming no catch-up vaccination and that decreased vaccination led to proportionate increases in PCV13 serotype pneumococcal disease in children and seniors. Integrating pediatric model output into a second Markov model examining 65-year-olds, we estimated the cost effectiveness of older adult pneumococcal vaccination strategies while accounting for potential epidemiologic changes from decreased pediatric vaccination.

Results: One year of 10-50% absolute decreases in PCV13 use in <5-year-olds increased pneumococcal disease by an estimated 4-19% in seniors; 2 years of decreased use increased senior rates by 8-38%. In seniors, a >53% increase in pneumococcal disease was required to favor PCV13 use in non-immunocompromised seniors at a $200,000 per quality-adjusted life-year gained threshold, which corresponded to absolute decreases in pediatric PCV13 vaccination of >50% over a 2-year period. In sensitivity analyses, senior PCV13 vaccination was unfavorable if absolute decreases in pediatric PCV13 receipt were within plausible ranges, despite model assumptions favoring PCV13 use in seniors.

Conclusion: COVID-19-related decreases in pediatric PCV13 use would need to be both substantial and prolonged to make heightened PCV13 use in non-immunocompromised seniors economically favorable.
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http://dx.doi.org/10.1016/j.vaccine.2021.06.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215512PMC
July 2021

Higher-Valency Pneumococcal Conjugate Vaccines: An Exploratory Cost-Effectiveness Analysis in U.S. Seniors.

Am J Prev Med 2021 07 29;61(1):28-36. Epub 2021 Apr 29.

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Introduction: Use of the 13-valent pneumococcal conjugate vaccine in nonimmunocompromised adults aged ≥65 years is controversial. Higher-valency conjugate vaccines (15-valent and 20-valent ) are under development; their potential cost effectiveness in older adults is unknown, particularly when potential indirect (herd immunity) effects from childhood vaccination are considered.

Methods: A Markov model estimated the cost effectiveness of current U.S. recommendations and alternative strategies using currently available and in-development pneumococcal conjugate vaccines in seniors. Separately, strategies using a hypothetical 20-valent vaccine adding the 7 most common disease-causing non-13-valent vaccine serotypes were considered. Sensitivity analyses were performed and alternative scenarios were examined. Data were gathered and the analyses were performed in 2020.

Results: In analyses considering only existing and in-development vaccines, sole 20-valent vaccine use cost $172,491/quality-adjusted life year gained compared with current U.S. recommendations under baseline assumptions (equal serotype effectiveness and no childhood vaccination indirect effects). Strategies using 15-valent vaccine were more costly and less effective. When 13-valent/20-valent vaccines were assumed ineffective against pneumococcal serotype 3 and 15-valent vaccine was fully effective, 15-valent vaccine cost $237,431/quality-adjusted life year gained. With indirect effects considered, 15-valent or 20-valent vaccine cost >$449,000/quality-adjusted life year gained. When adding hypothetical 20-valent vaccine under baseline assumptions, hypothetical 20-valent vaccine cost $139,348/quality-adjusted life year gained.

Conclusions: In-development pneumococcal conjugate vaccines may be economically unreasonable in older adults, regardless of serotype effectiveness assumptions, particularly when considering potential indirect effects from use of those vaccines in children. Adult vaccines containing high-risk serotypes not contained in childhood vaccines may be more promising.
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http://dx.doi.org/10.1016/j.amepre.2021.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221100PMC
July 2021

Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE).

ChemMedChem 2021 Jun 6. Epub 2021 Jun 6.

Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA.

Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5-0.25) and minimum adjunctive concentration (MAC=128-32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our "in house" permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.
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http://dx.doi.org/10.1002/cmdc.202100321DOI Listing
June 2021

Age-related alterations in muscle architecture are a signature of sarcopenia: the ultrasound sarcopenia index.

J Cachexia Sarcopenia Muscle 2021 Jun 1. Epub 2021 Jun 1.

Center for Research in Myology UMRS974, Sorbonne Université, INSERM, Myology Institute, Paris, France.

Background: The assessment of muscle mass is a key determinant of the diagnosis of sarcopenia. We introduce for the first time an ultrasound imaging method for diagnosing sarcopenia based on changes in muscle geometric proportions.

Methods: Vastus lateralis muscle fascicle length (Lf) and thickness (Tm) were measured at 35% distal femur length by ultrasonography in a population of 279 individuals classified as moderately active elderly (MAE), sedentary elderly (SE) (n = 109), mobility impaired elderly (MIE) (n = 43), and in adult young controls (YC) (n = 60). The ratio of Lf/Tm was calculated to obtain an ultrasound index of the loss of muscle mass associated with sarcopenia (USI). In a subsample of elderly male individuals (n = 76) in which corresponding DXA measurements were available (MAE, n = 52 and SE, n = 24), DXA-derived skeletal muscle index (SMI, appendicular limb mass/height ) was compared with corresponding USI values.

Results: For both young and older participants, USI values were found to be independent of sex, height and body mass. USI values were 3.70 ± 0.52 for YC, 4.50 ± 0.72 for the MAE, 5.05 ± 1.11 for the SE and 6.31 ± 1.38 for the MIE, all significantly different between each other (P < 0.0001). Based on the USI Z-scores, with reference to the YC population, the 219 elderly participants were stratified according to their muscle sarcopenic status. Individuals with USI values within a range of 3.70 < USI ≥ 4.23 were classified as non-sarcopenic (prevalence 23.7%), those with USI values within 4.23 < USI ≥ 4.76 were classified as pre-sarcopenic (prevalence 23.7%), those with USI values within 4.76 < USI ≥ 5.29 were classified as moderately sarcopenic (prevalence 15.1%), those with USI values within range 5.29 < USI ≥ 5.82 were classified as sarcopenic (prevalence 27.9%), and those with USI values >5.82 were classified as severely sarcopenic (prevalence 9.6%). The DXA-derived SMI was found to be significantly correlated with USI (r = 0.61, P < 0.0001). Notably, the USI cut-off value for moderate sarcopenia (4.76 a.u.) was found to coincide with the DXA cut-off value of sarcopenia (7.26 kg/m ).

Conclusions: We propose a novel, practical, and inexpensive imaging marker of the loss of muscle mass associated with sarcopenia, called the ultrasound sarcopenic index (USI), based on changes in muscle geometric proportions. These changes provide a useful 'signature of sarcopenia' and allow the stratification of individuals according to the presence and severity of muscle sarcopenia. We are convinced that the USI will be a useful clinical tool for confirming the diagnosis of sarcopenia, of which the assessment of muscle mass is a key-component.
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http://dx.doi.org/10.1002/jcsm.12720DOI Listing
June 2021

The physiological impact of high-intensity interval training in octogenarians with comorbidities.

J Cachexia Sarcopenia Muscle 2021 May 31. Epub 2021 May 31.

MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Royal Derby Hospital Centre, University of Nottingham, Derby, UK.

Background: Declines in cardiorespiratory fitness (CRF) and fat-free mass (FFM) with age are linked to mortality, morbidity and poor quality of life. High-intensity interval training (HIIT) has been shown to improve CRF and FFM in many groups, but its efficacy in the very old, in whom comorbidities are present is undefined. We aimed to assess the efficacy of and physiological/metabolic responses to HIIT, in a cohort of octogenarians with comorbidities (e.g. hypertension and osteoarthritis).

Methods: Twenty-eight volunteers (18 men, 10 women, 81.2 ± 0.6 years, 27.1 ± 0.6 kg·m ) with American Society of Anaesthesiology (ASA) Grade 2-3 status each completed 4 weeks (12 sessions) HIIT after a control period of equal duration. Before and after each 4 week period, subjects underwent body composition assessments and cardiopulmonary exercise testing. Quadriceps muscle biopsies (m. vastus lateralis) were taken to quantify anabolic signalling, mitochondrial oxidative phosphorylation, and cumulative muscle protein synthesis (MPS) over 4-weeks.

Results: In comorbid octogenarians, HIIT elicited improvements in CRF (anaerobic threshold: +1.2 ± 0.4 ml·kg ·min , P = 0.001). HIIT also augmented total FFM (47.2 ± 1.4 to 47.6 ± 1.3 kg, P = 0.04), while decreasing total fat mass (24.8 ± 1.3 to 24 ± 1.2 kg, P = 0.0002) and body fat percentage (33.1 ± 1.5 to 32.1 ± 1.4%, P = 0.0008). Mechanistically, mitochondrial oxidative phosphorylation capacity increased after HIIT (i.e. citrate synthase activity: 52.4 ± 4 to 67.9 ± 5.1 nmol·min ·mg , P = 0.005; membrane protein complexes (C): C-II, 1.4-fold increase, P = 0.002; C-III, 1.2-fold increase, P = 0.03), as did rates of MPS (1.3 ± 0.1 to 1.5 ± 0.1%·day , P = 0.03). The increase in MPS was supported by up-regulated phosphorylation of anabolic signalling proteins (e.g. AKT, p70S6K, and 4E-BP1; all P < 0.05). There were no changes in any of these parameters during the control period. No adverse events were reported throughout the study.

Conclusions: The HIIT enhances skeletal muscle mass and CRF in octogenarians with disease, with up-regulation of MPS and mitochondrial capacity likely underlying these improvements. HIIT can be safely delivered to octogenarians with disease and is an effective, time-efficient intervention to improve muscle mass and physical function in a short time frame.
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http://dx.doi.org/10.1002/jcsm.12724DOI Listing
May 2021

Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease.

Immunity 2021 06 16;54(6):1257-1275.e8. Epub 2021 May 16.

R&D Department, Hycult Biotech, 5405 PD Uden, the Netherlands.

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8 T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.
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http://dx.doi.org/10.1016/j.immuni.2021.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125900PMC
June 2021

Combined in vivo muscle mass, muscle protein synthesis and muscle protein breakdown measurement: a 'Combined Oral Stable Isotope Assessment of Muscle (COSIAM)' approach.

Geroscience 2021 May 27. Epub 2021 May 27.

MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, Clinical, Metabolic and Molecular Physiology, School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Uttoxeter Road, Derby, DE22 3DT, UK.

Optimising approaches for measuring skeletal muscle mass and turnover that are widely applicable, minimally invasive and cost effective is crucial in furthering research into sarcopenia and cachexia. Traditional approaches for measurement of muscle protein turnover require infusion of expensive, sterile, isotopically labelled tracers which limits the applicability of these approaches in certain populations (e.g. clinical, frail elderly). To concurrently quantify skeletal muscle mass and muscle protein turnover i.e. muscle protein synthesis (MPS) and muscle protein breakdown (MPB), in elderly human volunteers using stable-isotope labelled tracers i.e. Methyl-[D]-creatine (D-Cr), deuterium oxide (DO), and Methyl-[D]-3-methylhistidine (D-3MH), to measure muscle mass, MPS and MPB, respectively. We recruited 10 older males (71 ± 4 y, BMI: 25 ± 4 kgm, mean ± SD) into a 4-day study, with DXA and consumption of DO and D-Cr tracers on day 1. D-3MH was consumed on day 3, 24 h prior to returning to the lab. From urine, saliva and blood samples, and a single muscle biopsy (vastus lateralis), we determined muscle mass, MPS and MPB. D-Cr derived muscle mass was positively correlated to appendicular fat-free mass (AFFM) estimated by DXA (r = 0.69, P = 0.027). Rates of cumulative myofibrillar MPS over 3 days were 0.072%/h (95% CI, 0.064 to 0.081%/h). Whole-body MPB over 6 h was 0.052 (95% CI, 0.038 to 0.067). These rates were similar to previous literature. We demonstrate the potential for D-Cr to be used alongside DO and D-3MH for concurrent measurement of muscle mass, MPS, and MPB using a minimally invasive design, applicable for clinical and frail populations.
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http://dx.doi.org/10.1007/s11357-021-00386-2DOI Listing
May 2021

Is further research on adult pneumococcal vaccine uptake improvement programs worthwhile? Α value of information analysis.

Vaccine 2021 06 25;39(27):3608-3613. Epub 2021 May 25.

University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States. Electronic address:

Background: Pneumococcal vaccination policy for US adults is evolving, but previous research has shown that programs to increase vaccine uptake are economically favorable, despite parameter uncertainty. Using value of information (VOI) analysis and prior analyses, we examine the value of further research on vaccine uptake program parameters.

Methods: In US 50-64-year-olds, current vaccine recommendations with and without an uptake program were analyzed. In older adults, current recommendations and an alternative strategy (polysaccharide vaccine for all, adding conjugate vaccine only for the immunocompromised) with and without uptake programs were examined. Uptake program parameters were derived from a clinical trial (absolute uptake increase 12.3% [range 0-25%], per-person cost $1.78 [range $0.70-$2.26]), with other parameters obtained from US databases. VOI analyses incorporated probabilistic sensitivity analysis outputs into R-based regression techniques.

Results: In 50-64-year-olds, an uptake program cost $54,900/QALY gained compared to no uptake program. For ages ≥65, the program cost $287,000/QALY gained with the alternative strategy and $765,000/QALY with current recommendations. In younger adults, population-level expected value of perfect information (EVPI) was $59.7 million at $50,000/QALY gained and $2.8 million at $100,000/QALY gained. In older adults, EVPI values ranged from ~$1 million to $34.5 million at $100,000 and $200,000/QALY thresholds. The population expected value of partial perfect information (EVPPI) for combined uptake program cost and uptake improvement parameters in the younger population was $368,700 at $50,000/QALY and $43,900 at $100,000/QALY gained thresholds. In older adults, population EVPPI for vaccine uptake program parameters was $0 at both thresholds, reaching a maximum value of $445,000 at a $225,000/QALY threshold. Other model parameters comprised larger components of the global EVPI.

Conclusion: VOI results do not support further research on pneumococcal vaccine uptake programs in adults at commonly cited US cost-effectiveness benchmarks. Further research to reduce uncertainty in other aspects of adult pneumococcal vaccination is justifiable.
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http://dx.doi.org/10.1016/j.vaccine.2021.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296468PMC
June 2021

A collagen extraction and deuterium oxide stable isotope tracer method for the quantification of bone collagen synthesis rates in vivo.

Physiol Rep 2021 May;9(10):e14799

Clinical, Metabolic and Molecular Physiology, University of Nottingham, Royal Derby Hospital, Derby, UK.

The development of safe and practical strategies to prevent weakening of bone tissue is vital, yet attempts to achieve this have been hindered by a lack of understanding of the short-term (days-weeks) physiology of bone collagen turnover. To address this, we have developed a method to quantify bone collagen synthesis in vivo, using deuterium oxide (D O) tracer incorporation techniques combined with gas chromatography pyrolysis isotope-ratio mass spectrometry (GC-pyrolysis-IRMS). Forty-six male and female rats from a selectively bred model ingested D O for 3 weeks. Femur diaphyses (FEM), tibia proximal (T-PRO), and distal (T-DIS) epiphyses-metaphyses and tibia mid-shaft diaphyses (T-MID) were obtained from all rats after necropsy. After demineralisation, collagen proteins were isolated and hydrolysed and collagen fractional synthetic rates (FSRs) determined by incorporation of deuterium into protein-bound alanine via GC-pyrolysis-IRMS. The collagen FSR for the FEM (0.131 ± 0.078%/day; 95% CI [0.106-0.156]) was greater than the FSR at T-MID (0.055 ± 0.049%/day; 95% CI [0.040-0.070]; p < 0.001). The T-PRO site had the highest FSR (0.203 ± 0.123%/day; 95% CI [0.166-0.241]) and T-DIS the lowest (0.027 ± 0.015%/day; 95% CI [0.022-0.031]). The three tibial sites exhibited different FSRs (p < 0.001). Herein, we have developed a sensitive method to quantify in vivo bone collagen synthesis and identified site-specific rates of synthesis, which could be applicable to studies of human bone collagen turnover.
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http://dx.doi.org/10.14814/phy2.14799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157767PMC
May 2021

Cost-Effectiveness of Prophylactic Cranial Irradiation Versus MRI Surveillance for Extensive-Stage Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2021 May 11. Epub 2021 May 11.

Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. Electronic address:

Purpose: Owing to conflicting prospective data, controversy exists regarding prophylactic cranial irradiation (PCI) in extensive-stage small cell lung cancer (ES-SCLC). We evaluated the cost-effectiveness of PCI versus magnetic resonance imaging (MRI) surveillance for patients with ES-SCLC based on currently available evidence and in the context of the proposed Centers for Medicare & Medicaid Services alternative payment model.

Methods And Materials: A Markov state transition model was constructed to perform a cost-effectiveness analysis comparing MRI surveillance alone with PCI for ES-SCLC. Clinical parameters were obtained from clinical trial data, and cost data were based on 2019 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio (ICER) with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness-to-pay threshold of $100,000 per QALY gained. One-way and probabilistic sensitivity analyses were performed to consider model uncertainty.

Results: In the base-case scenario, PCI was not cost-effective in this model, with an ICER of $168,456 per QALY gained compared with MRI surveillance alone, assuming that overall survival was 10 months for MRI surveillance alone and 12.5 months for PCI. One-way sensitivity analysis showed that results were most sensitive to the variation of overall survival and cognitive decline rates between the 2 groups. In a scenario analysis in which all patients received hippocampal-avoidance PCI, the model results became nearly cost-effective with PCI.

Conclusions: PCI was not found to be cost-effective within this model compared with MRI surveillance alone, owing to the neurocognition decline effect of PCI based on available evidence. Hippocampal-avoidance PCI may be a potential cost-effective strategy for ES-SCLC, with confirmation expected after an ongoing prospective clinical trial (The Southwest Oncolology Group MRI Brain Surveillance Alone Versus MRI Surveillance And Prophylactic Cranial Irradiation [MAVERICK]), which includes assessments of cognitive function.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.049DOI Listing
May 2021

c-Rel employs multiple mechanisms to promote the thymic development and peripheral function of regulatory T cells in mice.

Eur J Immunol 2021 May 7. Epub 2021 May 7.

Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.

The NF-κB transcription factor c-Rel is a critical regulator of Treg ontogeny, controlling multiple points of the stepwise developmental pathway. Here, we found that the thymic Treg defect in c-Rel-deficient (cRel ) mice is quantitative, not qualitative, based on analyses of TCR repertoire and TCR signaling strength. However, these parameters are altered in the thymic Treg-precursor population, which is also markedly diminished in cRel mice. Moreover, c-Rel governs the transcriptional programme of both thymic and peripheral Tregs, controlling a core of genes involved with immune signaling, and separately in the periphery, cell cycle progression. Last, the immune suppressive function of peripheral cRel tTregs is diminished in a lymphopenic model of T cell proliferation and is associated with decreased stability of Foxp3 expression. Collectively, we show that c-Rel is a transcriptional regulator that controls multiple aspects of Treg development, differentiation, and function via distinct mechanisms.
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http://dx.doi.org/10.1002/eji.202048900DOI Listing
May 2021

Cost-effectiveness of ethanol lock prophylaxis to prevent central line-associated bloodstream infections in children with intestinal failure in the United States.

JPEN J Parenter Enteral Nutr 2021 Apr 28. Epub 2021 Apr 28.

Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Introduction: Central line-associated bloodstream infections (CLABSIs) lead to significant morbidity and mortality in children with intestinal failure (IF). Ethanol lock prophylaxis (ELP) greatly reduces CLABSI frequency with minimal side effects. However, in the United States, a recently approved orphan drug designation for dehydrated alcohol has greatly increased 70% ethanol cost from about $10/day to $1000/day. We examined the cost-effectiveness of ELP in relation to these changes.

Methods: We simulated a previously developed IF Markov model over 1 year. Costs were measured in 2020 US dollars and effectiveness in quality-adjusted life-years (QALYs). CLABSI rate with and without ELP was estimated from the largest available comparative observational study. The primary outcome was incremental cost-effectiveness ratio (ICER) between treatments. Secondary outcomes included CLABSI frequency. Sensitivity analyses on all model parameters were performed.

Results: In the base model, children with IF not using ELP accumulated $131,815 in costs and 0.32 QALYs per patient compared with $437,884 and 0.33 QALYs per patient in those using ELP. The ICER was nearly $17 million/QALY gained. ELP resulted in a 40% reduction in CLABSI frequency. ELP became cost-effective at $68/day and cost-saving at $63/day. Sensitivity analysis identified no other plausible parameter variation to reach the benchmark of $100,000/QALY gained.

Conclusions: At the current price, ELP is not cost-effective for CLABSI prevention in children with IF in the United States. This study highlights the critical need for the approval of an affordable lock therapy option to prevent CLABSIs in these children.
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http://dx.doi.org/10.1002/jpen.2130DOI Listing
April 2021

Single-cell multi-omics analysis of the immune response in COVID-19.

Nat Med 2021 05 20;27(5):904-916. Epub 2021 Apr 20.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16C1QA/B/C) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34 hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8 T cells and an increased ratio of CD8 effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.
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http://dx.doi.org/10.1038/s41591-021-01329-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121667PMC
May 2021

Premedication prior to PEG-asparaginase is cost-effective in pediatric patients with acute lymphoblastic leukemia.

Pediatr Blood Cancer 2021 Aug 16;68(8):e29051. Epub 2021 Apr 16.

University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further PEG-asparaginase with Erwinia. Erwinia is associated with more frequent dosing, increased expense, and limited availability. Premedication may reduce rates of allergic reactions.

Procedures: This Markov model evaluated the cost-effectiveness of three strategies: premedication plus therapeutic drug monitoring (TDM), TDM alone, and no premedication or TDM. We modeled two scenarios: a standard-risk (SR) B-ALL patient receiving two asparaginase doses and a high-risk (HR) patient receiving seven asparaginase doses. The model incorporated costs of asparaginase, premedication, TDM and clinic visits, and lost parental wages associated with each additional Erwinia dose. We incorporated a five-year time horizon with a societal perspective. Outcomes were Erwinia substitutions avoided and differences in quality-adjusted life years (QALYs). Probabilistic and one-way sensitivity analyses evaluated model uncertainty.

Results: In both scenarios, premedication was the least costly strategy. In SR and HR scenarios, premedication with monitoring resulted in 8% and 7% fewer changes to Erwinia compared with monitoring alone and 3% and 2% fewer changes compared with no premedication/monitoring, respectively. Premedication resulted in the most QALYs gained in the SR patients. Individual variation of model inputs did not change premedication/monitoring favorability for either scenario. In probabilistic sensitivity analyses, premedication/monitoring was favored in >87% of iterations in both scenarios.

Conclusion: Compared with other strategies, premedication use and asparaginase level monitoring in children with B-ALL is potentially cost-saving.
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http://dx.doi.org/10.1002/pbc.29051DOI Listing
August 2021

Weight Loss through Lifestyle Intervention Improves Mobility in Older Adults.

Gerontologist 2021 Apr 5. Epub 2021 Apr 5.

Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background And Objectives: The high prevalence of overweight or obesity in older adults is a public health concern because obesity affects health, including risk of mobility disability.

Research Design And Methods: The Mobility and Vitality Lifestyle Program (MOVE UP), delivered by community health workers (CHW), enrolled 303 community-dwelling adults to assess the impact of a 32-session behavioral weight management intervention. Participants completed the program at 26 sites led by 22 CHWs. Participation was limited to people aged 60-75 who had a BMI 27-45 kg/m 2. The primary outcome was performance on the Short Physical Performance Battery (SPPB) over 12 months.

Results: Participants were age (sd) 67.7 (4.1) and mostly female (87%); 22.7% were racial minorities. The mean (sd) BMI at baseline was 34.7 (4.7). Participants attended a median of 24 of 32 sessions; 240 (80.3%) completed the 9- or 13-month outcome assessment. Median weight loss in the sample was 5% of baseline body weight. SPPB total scores improved by +0.31 units (p < .006), gait speed by +0.04 m/sec (p < .0001), and time to complete chair stands by -0.95 sec (p < .0001). Weight loss ≥ 5% was associated with a gain of +0.73 in SPPB score. Increases in activity (by self-report or device) were not independently associated with SPPB outcomes but did reduce the effect of weight loss.

Discussion And Implications: Promoting weight management in a community group setting may be an effective strategy for reducing risk of disability in older adults.
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http://dx.doi.org/10.1093/geront/gnab048DOI Listing
April 2021

Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression.

Sci Transl Med 2021 03;13(587)

Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 0AW, UK.

Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.
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http://dx.doi.org/10.1126/scitranslmed.abd5666DOI Listing
March 2021

High Dietary Fat Consumption Impairs Axonal Mitochondrial Function .

J Neurosci 2021 May 30;41(19):4321-4334. Epub 2021 Mar 30.

Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom.

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca levels and impairs impulse conduction within the saphenous nerve in prediabetic PN. Diabetes and prediabetes are leading causes of peripheral neuropathy (PN) worldwide. PN has no cure, but development in diabetes and prediabetes is associated with dyslipidemia, including elevated levels of saturated fatty acids. Saturated fatty acids impair mitochondrial dynamics and function in cultured neurons, indicating a role for mitochondrial dysfunction in PN progression; however, the effect of elevated circulating fatty acids on the peripheral nervous system is unknown. In this study, we identify early pathogenic events in sensory nerve axons of mice with high-fat diet-induced PN, including alterations in mitochondrial function, axonal conduction, and intra-axonal calcium, that provide important insight into potential PN mechanisms associated with prediabetes and dyslipidemia .
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http://dx.doi.org/10.1523/JNEUROSCI.1852-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143198PMC
May 2021

Quantitative Top-Down Proteomics in Complex Samples Using Protein-Level Tandem Mass Tag Labeling.

J Am Soc Mass Spectrom 2021 Jun 16;32(6):1336-1344. Epub 2021 Mar 16.

Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma 73019, United States.

Labeling approaches using isobaric chemical tags (e.g., isobaric tagging for relative and absolute quantification, iTRAQ and tandem mass tag, TMT) have been widely applied for the quantification of peptides and proteins in bottom-up MS. However, until recently, successful applications of these approaches to top-down proteomics have been limited because proteins tend to precipitate and "crash" out of solution during TMT labeling of complex samples making the quantification of such samples difficult. In this study, we report a top-down TMT MS platform for confidently identifying and quantifying low molecular weight intact proteoforms in complex biological samples. To reduce the sample complexity and remove large proteins from complex samples, we developed a filter-SEC technique that combines a molecular weight cutoff filtration step with high-performance size exclusion chromatography (SEC) separation. No protein precipitation was observed in filtered samples under the intact protein-level TMT labeling conditions. The proposed top-down TMT MS platform enables high-throughput analysis of intact proteoforms, allowing for the identification and quantification of hundreds of intact proteoforms from cell lysates. To our knowledge, this represents the first high-throughput TMT labeling-based, quantitative, top-down MS analysis suitable for complex biological samples.
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http://dx.doi.org/10.1021/jasms.0c00464DOI Listing
June 2021

A hyperspectral imaging system for mapping haemoglobin and cytochrome-c-oxidase concentration changes in the exposed cerebral cortex.

IEEE J Sel Top Quantum Electron 2021 Jul-Aug;27(4). Epub 2021 Jan 22.

Department of Medical Physics and Biomedical Engineering, University College London, London WC1E 6BT, UK.

We present a novel hyperspectral imaging (HSI) system using visible and near-infrared (NIR) light on the exposed cerebral cortex of animals, to monitor and quantify changes in the oxygenation of haemoglobin and in cellular metabolism via measurement of the redox states of cytochrome-c-oxidase (CCO). The system, named hNIR, is based on spectral scanning illumination at 11 bands (600, 630, 665, 784, 800, 818, 835, 851, 868, 881 and 894 nm), using a supercontinuum laser coupled with a rotating Pellin-Broca prism. Image reconstruction is performed with the aid of a Monte Carlo framework for photon pathlength estimation and post-processing correction of partial volume effects. The system is validated on liquid optical phantoms mimicking brain tissue haemodynamics and metabolism, and finally applied on the exposed cortex of mice undergoing alternating oxygenation challenges. The results of the study demonstrate the capacity of hNIR to map and quantify the haemodynamic and metabolic states of the exposed cortex at microvascular levels. This represents (to the best of our knowledge) the first example of simultaneous mapping and quantification of cerebral haemoglobin and CCO using visible and NIR HSI, which can potentially become a powerful tool for better understanding brain physiology.
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http://dx.doi.org/10.1109/JSTQE.2021.3053634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116887PMC
January 2021

Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.

Nature 2021 05 11;593(7857):136-141. Epub 2021 Mar 11.

Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK.

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b2. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.
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http://dx.doi.org/10.1038/s41586-021-03412-7DOI Listing
May 2021

Homozygous mutation associated with infantile inflammatory bowel disease.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892;

Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1β stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.
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http://dx.doi.org/10.1073/pnas.2009217118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958356PMC
March 2021

The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity.

Mol Psychiatry 2021 Mar 4. Epub 2021 Mar 4.

Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London, United Kingdom.

Dysfunctional mitochondria characterise Parkinson's Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those. Both in vitro and in vivo data show that neurotoxins, which phenotypically mimic PD, increase TSPO to enhance cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signalling, forming positive feedback, which represses the transcription factor EB (TFEB) and the controlled production of lysosomes. Finally, genetic variances in the transcriptome confirm that TSPO is required to alter the autophagy-lysosomal pathway during neurotoxicity.
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http://dx.doi.org/10.1038/s41380-021-01050-zDOI Listing
March 2021

Spray-Capillary-Based Capillary Electrophoresis Mass Spectrometry for Metabolite Analysis in Single Cells.

Anal Chem 2021 03 1;93(10):4479-4487. Epub 2021 Mar 1.

Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States.

Single-cell capillary electrophoresis mass spectrometry (CE-MS) is a promising platform to analyze cellular contents and probe cell heterogeneity. However, current single-cell CE-MS methods often rely on offline microsampling processes and may demonstrate low sampling precision and accuracy. We have recently developed an electrospray-assisted device, , for low-volume sample extraction. With the spray-capillary, low-volume samples (pL-nL) are drawn into the sampling end of the device, which can be used directly for CE separation and online MS detection. Here, we redesigned the spray-capillary by utilizing a capillary with a <15 μm tapered tip so that it can be directly inserted into single cells for sample collection and on-capillary CE-MS analysis. We evaluated the performance of the modified spray-capillary by performing single-cell microsampling on single onion cells with varying sample injection times and direct MS analysis or online CE-MS analysis. We have demonstrated, for the first time, online sample collection and CE-MS for the analysis of single cells. This application of the modified spray-capillary device facilitates the characterization and relative quantification of hundreds of metabolites in single cells.
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http://dx.doi.org/10.1021/acs.analchem.0c04624DOI Listing
March 2021
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