Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting ...inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.
The paediatric massive transfusion protocol (MTP) is activated in the paediatric population for both trauma and non-trauma related indications. While it helps to improve the efficiency and efficacy ...of the delivery of blood products, it can also result in increased wastage. We aimed to evaluate the wastage rates from our paediatric MTP activations from 2013 to 2018.
As part of an audit, we retrospectively reviewed the records of the paediatric patients who had MTP activations. We collected the following data: reason for MTP activation, weight of patient, number of cycles of MTP required, blood products used, blood products wasted, deviation from our institution's recommended MTP blood product ratio, and reason for wastage.
We had 26 paediatric MTP activations within the audit period. There was an overall wastage rate of 1.5%, with wastage occurring in 3 out of 26 patients. The reason for all wastage was demise of the patient. Most patients' transfusion ratios deviated from our institution's MTP protocol.
Our wastage rates are low likely because of clear MTP activation guidelines and a flexible MTP workflow.
Regulatory T (Treg) cells are essential for immune tolerance of embryo implantation, and insufficient Treg cells are implicated in early pregnancy loss. An abortion-prone mouse model was used to ...evaluate the utility of IL-2 complexed with JES6-1 anti–IL-2 antibody (IL-2/JES6-1) to boost uterine Treg cells and improve reproductive success. IL-2/JES6-1, but not IL-2/IgG control, administered in the periconception phase to CBA/J females mated with DBA/2 males elicited a greater than twofold increase in the proportion of CD4+ T cells expressing forkhead box P3 (FOXP3), and an increase in the ratio of FOXP3+ Treg cells/FOXP3– T conventional cells, in the uterus and its draining lymph nodes at embryo implantation that was sustained into midgestation. An attenuated phenotype was evident in both thymic-derived and peripheral Treg cells with elevated cytotoxic T-lymphocyte antigen-4, CD25, and FOXP3, indicating improved suppressive function, as well as increased proliferative marker Ki-67. IL-2/JES6-1 treatment reduced fetal loss from 31% to 10%, but this was accompanied by a 6% reduction in late gestation fetal weight, despite comparable placental size and architecture. Similar effects of IL-2/JES6-1 on Treg cells and fetal growth were seen in CBA/J females with healthy pregnancies sired by BALB/c males. These findings show that expanding the uterine Treg cell pool through targeting IL-2 signaling is a strategy worthy of further investigation for mitigating immune-mediated fetal loss.
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Percutaneous transluminal angioplasty is the current standard treatment for arteriovenous fistula (AVF) stenosis. The mid- and long-term patency with plain balloon angioplasty (PBA) is however far ...from satisfactory. While paclitaxel-coated balloon angioplasty has been shown to be superior to PBA, concern over its safety profile has recently arisen after a reported possible increased mortality risk with a meta-analysis of large lower limb studies. An angioplasty balloon with a new type of drug coating, the sirolimus-coated balloon (SCB), has been proven to improve patency in the coronary arteries. However, its effect on AV access has yet to be studied.
This is an investigator-initiated, prospective, multicenter, double-blinded, randomized controlled clinical trial to assess the effectiveness of SCB compared to PBA in improving the patency of AVF after angioplasty. A total of 170 patients with mature AVF that requires PTA due to AVF dysfunction will be randomly assigned to treatment with a SCB or PBA at a 1:1 ratio, stratified by location of AVF and followed up for up to 1 year. The inclusion criteria include 1 adult patient aged 21 to 85 years who requires balloon angioplasty for dysfunctional arteriovenous fistula 2; matured AVF, defined as being in use for at least 1 month prior to the angioplasty; and 3 successful angioplasty of the underlying stenosis with PBA, defined as less than 30% residual stenosis on digital subtraction angiography (DSA) and restoration of thrill in the AVF on clinical examination. The exclusion criteria include thrombosed or partially thrombosed access circuit at the time of treatment, presence of symptomatic or angiographically significant central vein stenosis that requires treatment with more than 30% residual stenosis post angioplasty, and existing stent placement within the AVF circuit. The primary endpoint of the study is access circuit primary patency at 6 months. The secondary endpoints are target lesion primary patency; access circuit-assisted primary patency; access circuit secondary patency at 3, 6, and 12 months; target lesion restenosis rate at 6 months; total number of interventions; complication rate; and cost-effectiveness. The trial is supported by Concept Medical.
This study will evaluate the clinical efficacy and safety of SCB compared to PBA in the treatment of AVF stenosis in hemodialysis patients.
ClinicalTrials.gov NCT04409912 . Registered on 1 June 2020.
Background & Aims Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established ...tumours, we evaluated potential immune mechanisms associated with survival in HCC. Methods Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation). Results The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8+ T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation. Conclusions Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation.
To contribute to the literature of best-practice approaches to promote full mu agonist chronic opioid analgesic therapy (COAT) cessation in a population with chronic, noncancer pain by describing ...initial and extended follow-up outcomes from a limited group program that utilized a standardized, multidisciplinary curriculum containing robust complementary care access in a private practice setting.
A retrospective review of data from electronic health records and the California Prescription Drug Monitoring Program for program participants between October 2017 and December 2019.
Daily oral morphine milligram equivalent (MME) dose use upon entry, at program graduation, at 6 months post graduation, and at extended follow-up of 7 to 24 months post graduation were compared and reported for program participants.
A total of 109 program participants with incoming daily COAT use amounts as high as 600 MME (median, 60 MME; 25% quartile, 36.5 MME; 75% quartile, 90 MME; interquartile range, 53.5 MME) had a successful COAT cessation rate of 90% at program graduation, which was maintained at 6 months and extended follow-up at 95% and 97%, respectively.
This pilot study contributes to the literature by documenting a successful and potentially generalizable strategy to promote COAT cessation, and by providing unusually lengthy follow-up for postintervention COAT cessation monitoring.
Toxoplasma gondii is traditionally known as a parasite of felids, with possible infection in intermediate hosts such as dogs and humans, and thus a disease of public health significance. Published ...data on the prevalence of toxoplasmosis in dogs and cats in Singapore is scanty, and this paper documents a suspect clinical case of toxoplasmosis in a free-roaming puppy trapped from an offshore island of Singapore.
A 12-week-old puppy presented with hindlimb weakness and sarcopenia, with rapidly progressing ascending paralysis and respiratory distress, one week after trapping. Toxoplasmosis was suspected after indirect fluorescence antibody testing (IFAT) revealed anti-T. gondii antibodies. The puppy responded quickly to clindamycin treatment and was discharged from hospital after 10 days.
While rare and undocumented, veterinary clinicians in Singapore are advised to also include toxoplasmosis infection as a differential diagnosis in dogs presenting with similar clinical signs. This is especially so for dogs which have access to the outdoors.
Improved understanding of psychological features associated with full mu agonist long-term opioid therapy (LTOT) cessation may offer advantages for clinicians. This preliminary study presents changes ...in psychological outcomes in patients with chronic, non-cancer pain (CNCP) after LTOT cessation via a 10-week multidisciplinary program which included treatment with buprenorphine. Paired
-tests pre- and post-LTOT cessation were compared in this retrospective cohort review of data from electronic medical records of 98 patients who successfully ceased LTOT between the dates of October 2017 to December 2019. Indicators of quality of life, depression, catastrophizing, and fear avoidance, as measured by the 36-Item Short Form Survey, the Patient Health Questionnaire-9-Item Scale, the Pain Catastrophizing Scale, and the Fear Avoidance Belief Questionnaires revealed significant improvement. Scores did not significantly improve for daytime sleepiness, generalized anxiety, and kinesiophobia, as measured by the Epworth Sleepiness Scale, the Generalized Anxiety Disorder 7-Item Scale, and the Tampa Scale of Kinesiophobia. The results suggest that successful LTOT cessation may be interconnected with improvements in specific psychological states.
Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in
. Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients ...confirmed with biallelic
mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation
(NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.
Trauma team activation criteria have a variable performance in the paediatric population. We aimed to identify predictors for high-level resource utilisation during trauma resuscitation in the ED.
A ...retrospective study was conducted in the ED of a tertiary paediatric hospital. Patient data were collected from trauma surveillance registry and analysis was performed to identify significant predictors. We then assessed the sensitivity and specificity of proposed models with respect to observed patient outcomes.
Among 11 282 cases, the mean age was 6.1±4.9 (SD) years old. Fall was the most common mechanism of injury in 7364 (65.3%) patients. Eighty-eight (0.8%) patients required at least one high-level resource. Significant predictors for high-resource utilisation were overall GCS of <14 (relative risk (RR) 38.841, 95% CI 21.328 to 70.739, p<0.001), high-risk mechanisms of fall from height and motor vehicle collision (RR 7.863, 95% CI 4.687 to 13.192, p<0.001), as well as age-specific tachycardia (RR 1.796, 95% CI 1.145 to 2.817, p=0.0108). A model consisting of GCS and high-risk mechanism would under-triage 21 (0.2%) patients and over-triage 681 (6.0%) patients. When age-specific tachycardia was added, 8 (0.1%) less patients would be under-triaged but an additional 3251 (28.9%) patients would be over-triaged.
As utilisation of high-level resources in paediatric trauma was rare, it was difficult to find an appropriate balance between under-triage and over-triage. Between the two, minimising the proportion of under-triage is more important as patient safety is paramount in paediatric trauma care.
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