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"Fields, Gregory A"
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Multiple Aging Mechanisms in Ferroelectric Deuterated Potassium Dihydrogen Phosphate
The anomalously large dielectric aging in ferroelectric partially deuterated potassium dihydrogen phosphate (DKDP) is found to have multiple distinct mechanisms. Two components cause decreases in dielectric response over a limited range of fields around the aging field. A large fraction of this aging occurs on time scales of ~1000s after a field change, as expected for a hydrogen/deuterium diffusion mechanism. A slower component can give almost complete loss of domain-wall dielectric response at the aging field after weeks of aging. There is also a particularly unusual aging in which the dielectric response increases with time after rapid cooling.
Paper
Lymphocytic infiltration in stage II microsatellite stable colorectal tumors: A retrospective prognosis biomarker analysis
Recognized clinical risk factors for progression (emergency presentation, poorly differentiated tumor, depth of tumor invasion, and adjacent organ involvement) are insufficient to identify those patients with stage II CRC at higher risk of disease progression [4,5]. [...]a meta-analysis aimed to assess the predictive ability of these signatures revealed that although gene expression signatures may be associated with prognosis, their ability to accurately predict patients’ risk of progression was limited, probably due to the molecular heterogeneity of tumors [7]. [...]the identification of new biomarkers to inform clinical decision-making for adjuvant chemotherapy is needed [8]. Methods Patients and samples The discovery dataset (named ICO/CLX) included a previously described set of 100 patients with colon cancer diagnosed at stage II and MSS paired normal-tumor samples (Colonomics study, “CLX”: www.colonomics.org; NCBI BioProject PRJNA188510). Raw sequence data were filtered based on the TCRβ V, D, and J gene definitions provided by the international ImMunoGeneTics information system (IMGT) database and binned using a modified nearest-neighbor algorithm to merge closely related sequences and remove both PCR and sequencing errors.
Journal Article
Long-Term Endocrine and Exocrine Insufficiency After Pancreatectomy
Purpose
To identify peri-operative risk factors and time to onset of pancreatic endocrine/exocrine insufficiency.
Methods
We retrospectively analyzed a single institutional series of patients who underwent pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) between 2000 and 2015. Endocrine/exocrine insufficiencies were defined as need for new pharmacologic intervention. Cox proportional modeling was used to identify peri-operative variables to determine their impact on post-operative pancreatic insufficiency.
Results
A total of 1717 patient records were analyzed (75.47% PD, 24.53% DP) at median follow-up 17.88 months. Average age was 62.62 years, 51.78% were male, and surgery was for malignancy in 74.35% of patients. Post-operative endocrine insufficiency was present in 20.15% (
n
= 346). Male gender (
p
= 0.015), increased body mass index (BMI) (
p
< 0.001), tobacco use (
p
= 0.011), family history of diabetes (DM) (
p
< 0.001), personal history of DM (
p ≤
0.001), and DP (
p ≤
0.001) were correlated with increased risk. Mean time to onset was 20.80 ± 33.60 (IQR: 0.49–28.37) months. Post-operative exocrine insufficiency was present in 36.23% (
n
= 622). Race (
p
= 0.014), lower BMI (
p
< 0.001), family history of DM (
p
= 0.007
)
, steatorrhea (
p
< 0.001), elevated pre-operative bilirubin (
p
= 0.019), and PD (
p ≤
0.001) were correlated with increased risk. Mean time to onset was 14.20 ± 26.90 (IQR: 0.89–12.69) months.
Conclusions
In this large series of pancreatectomy patients, 20.15% and 36.23% of patients developed post-operative endocrine and exocrine insufficiency at a mean time to onset of 20.80 and 14.20 months, respectively. Patients should be educated regarding post-resection insufficiencies and providers should have heightened awareness long-term.
Journal Article
Atrial fibrillation after cardiac surgery: identifying candidate predictors through a Delphi process
ObjectivesThis study was undertaken to identify potential predictors of atrial fibrillation after cardiac surgery (AFACS) through a modified Delphi process and expert consensus. These will supplement predictors identified through a systematic review and cohort study to inform the development of two AFACS prediction models as part of the PARADISE project (NCT05255224). Atrial fibrillation is a common complication after cardiac surgery. It is associated with worse postoperative outcomes. Reliable prediction of AFACS would enable risk stratification and targeted prevention. Systematic identification of candidate predictors is important to improve validity of AFACS prediction tools.DesignThis study is a Delphi consensus exercise.SettingThis study was undertaken through remote participation.ParticipantsThe participants are an international multidisciplinary panel of experts selected through national research networks.InterventionsThis is a two-stage consensus exercise consisting of generating a long list of variables, followed by refinement by voting and retaining variables selected by at least 40% of panel members.ResultsThe panel comprised 15 experts who participated in both stages, comprising cardiac intensive care physicians (n=3), cardiac anaesthetists (n=2), cardiac surgeons (n=1), cardiologists (n=4), cardiac pharmacists (n=1), critical care nurses (n=1), cardiac nurses (n=1) and patient representatives (n=2). Our Delphi process highlighted candidate AFACS predictors, including both patient factors and those related to the surgical intervention. We generated a final list of 72 candidate predictors. The final list comprised 3 demographic, 29 comorbidity, 4 vital sign, 13 intraoperative, 10 postoperative investigation and 13 postoperative intervention predictors.ConclusionsA Delphi consensus exercise has the potential to highlight predictors beyond the scope of existing literature. This method proved effective in identifying a range of candidate AFACS predictors. Our findings will inform the development of future AFACS prediction tools as part of the larger PARADISE project.Trial registration numberNCT05255224.
Journal Article
Unmasking the tonic-aversive state in neuropathic pain
Tonic pain, a chief clinical problem, is difficult to study in rodent models that measure threshold changes of evoked reactions to acutely applied stimuli. These authors used conditioned place preference to assess tonic pain in rats and measure the efficacy of agents that relieve it.
Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.
Journal Article
Intratumoral expression of IL-12 and CD40 ligand (CD154) from plasmids generates antitumor responses that eliminate tumoral T regs
Intratumoral immunotherapy (ITIT) strives to generate effective antitumor immunity by directly stimulating the immune system in tumors to reverse local tumor-mediated immune suppression. In vivo expression of Interleukin-12 (IL-12) using in vivo plasmid transfection as an intratumoral cancer immunotherapy entered Phase II clinical trials for metastatic melanoma but to limited clinical success. We sought to improve the efficacy of in vivo IL-12 electroporation by the addition of a CD154 (CD40 ligand)- expressing plasmid to the IL-12 encoding plasmid treatment and assessing efficacy against solid tumors. Mice with intradermal B16F10 melanoma or MC38 murine colon carcinoma tumors received 2 weekly intratumoral (IT) injections of plasmids encoding IL-12 and CD154, followed by in vivo electroporation. The addition of CD154 to IL-12 was superior to IL-12 alone and resulted in frequent tumor clearance of treated tumors, marked by an increase in CD8 T cells and a drastic reduction in T regulatory cells in the tumor microenvironment. Tumor treatment responses were abrogated in mice which lack conventional DC1 cells (BatF3 KO) or lack CD8 T cells. These findings highlight the potential of adding CD154 to IL-12 plasmid electroporation as a cancer immunotherapy and suggest that other combinations would be therapeutically valuable.
Journal Article
In situ vaccination with cowpea mosaic virus elicits systemic antitumor immunity and potentiates immune checkpoint blockade
BackgroundIn situ vaccination (ISV) is a cancer immunotherapy strategy in which immunostimulatory reagents are introduced directly into a tumor to stimulate antitumor immunity both against the treated tumor and systemically against untreated tumors. Recently, we showed that cowpea mosaic virus (CPMV) is a potent multi-toll-like receptor (TLR) agonist with potent efficacy for treating tumors in mice and dogs by ISV. However, ISV with CPMV alone does not uniformly treat all mouse tumor models tested, however this can be overcome through strategic combinations. More insight is needed to delineate potency and mechanism of systemic antitumor immunity and abscopal effect.MethodWe investigated the systemic efficacy (abscopal effect) of CPMV ISV with a two-tumor mouse model using murine tumor lines B16F10, 4T1, CT26 and MC38. Flow cytometry identified changes in cell populations responsible for systemic efficacy of CPMV. Transgenic knockout mice and depleting antibodies validated the role of relevant candidate cell populations and cytokines. We evaluated these findings and engineered a multicomponent combination therapy to specifically target the candidate cell population and investigated its systemic efficacy, acquired resistance and immunological memory in mouse models.ResultsISV with CPMV induces systemic antitumor T-cell-mediated immunity that inhibits growth of untreated tumors and requires conventional type-1 dendritic cells (cDC1s). Furthermore, using multiple tumor mouse models resistant to anti-programmed death 1 (PD-1) therapy, we tested the hypothesis that CPMV along with local activation of antigen-presenting cells with agonistic anti-CD40 can synergize and strengthen antitumor efficacy. Indeed, this combination ISV strategy induces an influx of CD8+ T cells, triggers regression in both treated local and untreated distant tumors and potentiates tumor responses to anti-PD-1 therapy. Moreover, serial ISV overcomes resistance to anti-PD-1 therapy and establishes tumor-specific immunological memory.ConclusionsThese findings provide new insights into in situ TLR activation and cDC1 recruitment as effective strategies to overcome resistance to immunotherapy in treated and untreated tumors.
Journal Article
Prognostic model for atrial fibrillation after cardiac surgery: a UK cohort study
ObjectiveTo develop a validated clinical prognostic model to determine the risk of atrial fibrillation after cardiac surgery as part of the PARADISE project (NIHR131227).MethodsProspective cohort study with linked electronic health records from a cohort of 5.6 million people in the United Kingdom Clinical Practice Research Datalink from 1998 to 2016. For model development, we considered a priori candidate predictors including demographics, medical history, medications, and clinical biomarkers. We evaluated associations between covariates and the AF incidence at the end of follow-up using logistic regression with the least absolute shrinkage and selection operator. The model was validated internally with the bootstrap method; subsequent performance was examined by discrimination quantified with the c-statistic and calibration assessed by calibration plots. The study follows TRIPOD guidelines.ResultsBetween 1998 and 2016, 33,464 patients received cardiac surgery among the 5,601,803 eligible individuals. The final model included 13-predictors at baseline: age, year of index surgery, elevated CHA2DS2-VASc score, congestive heart failure, hypertension, acute coronary syndromes, mitral valve disease, ventricular tachycardia, valve surgery, receiving two combined procedures (e.g., valve replacement + coronary artery bypass grafting), or three combined procedures in the index procedure, statin use, and ethnicity other than white or black (statins and ethnicity were protective). This model had an optimism-corrected C-statistic of 0.68 both for the derivation and validation cohort. Calibration was good.ConclusionsWe developed a model to identify a group of individuals at high risk of AF and adverse outcomes who could benefit from long-term arrhythmia monitoring, risk factor management, rhythm control and/or thromboprophylaxis.
Journal Article
Characteristics and Timing of Initial Virus Shedding in Severe Acute Respiratory Syndrome Coronavirus 2, Utah, USA
Virus shedding in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can occur before onset of symptoms; less is known about symptom progression or infectiousness associated with initiation of viral shedding. We investigated household transmission in 5 households with daily specimen collection for 5 consecutive days starting a median of 4 days after symptom onset in index patients. Seven contacts across 2 households implementing no precautionary measures were infected. Of these 7, 2 tested positive for SARS-CoV-2 by reverse transcription PCR on day 3 of 5. Both had mild, nonspecific symptoms for 1-3 days preceding the first positive test. SARS-CoV-2 was cultured from the fourth-day specimen in 1 patient and from the fourth- and fifth-day specimens in the other. We also describe infection control measures taken in the households that had no transmission. Persons exposed to SARS-CoV-2 should self-isolate, including from household contacts, wear a mask, practice hand hygiene, and seek testing promptly.
Journal Article