This note reports the first occurrence of Monticellius indicum Mehra, 1939, in the heart of the Hawksbill turtle, Eretmochelys imbricata Linnaeus, 1766, in the state of Espírito Santo, Brazil. This ...parasite has only previously been reported, to our knowledge, in Chelonia mydas from India, Brazil, and Costa Rica.
Objective. Patients with RA suffer from a higher risk of periodontal attachment loss and increased oral inflammation. We hypothesize that there are pathogenetic and immunological interactions between ...these diseases that go beyond impaired manual dexterity accompanying advanced RA. The primary objective of the present study was to determine whether a loss of alveolar bone can be detected in RA patients during the early course of the disease.
Methods. In this cross-sectional, epidemiological case–control study, 22 patients with early RA (ERA) were compared with 22 matched healthy controls. Oral and periodontal status, clinical activity, and socio-demographic parameters were determined. Oral microbiota were analysed using real-time quantitative PCR specific for leading oral pathogens.
Results. More advanced forms of periodontitis were found in ERA patients compared with controls. ERA patients had a greater number of missing teeth ERA 5.7 (s.d. 5.0), controls 1.9 (s.d. 1.0), P = 0.002, deeper periodontal pockets clinical attachment level: ERA 3.4 (s.d. 0.5 mm), controls 2.7 (s.d. 0.3 mm), P < 0.000, and greater bleeding on probing ERA 18.6% (s.d. 9.0%), controls 10.5% (s.d. 5.1%), P = 0.001 despite comparable oral hygiene. Tannerella forsythia (6.77-fold, P = 0.033) subgingivally and Streptococcus anginosus (3.56-fold, P = 0.028) supragingivally were the characteristic pathogens in ERA.
Conclusion. Increased loss of periodontal attachment and alveolar bone can be detected in patients with ERA, therefore we propose that the consulting rheumatologists inform the patients that they have a higher risk of periodontal disease. It would be beneficial if these patients were referred directly for intensive dental care.
Purpose
Supporting the provision of intensive care medicine through telehealth potentially improves process quality. This may improve patient recovery and long-term outcomes. We investigated the ...effectiveness of a multifaceted telemedical programme on the adherence to German quality indicators (QIs) in a regional network of intensive care units (ICUs) in Germany.
Methods
We conducted an investigator-initiated, large-scale, open-label, stepped-wedge cluster randomised controlled trial enrolling adult ICU patients with an expected ICU stay of ≥ 24 h. Twelve ICU clusters in Berlin and Brandenburg were randomly assigned to three sequence groups to transition from control (standard care) to the intervention condition (telemedicine). The quality improvement intervention consisted of daily telemedical rounds guided by eight German acute ICU care QIs and expert consultations. Co-primary effectiveness outcomes were patient-specific daily adherence (fulfilled yes/no) to QIs, assessed by a central end point adjudication committee. Analyses used mixed-effects logistic modelling adjusted for time. This study is completed and registered with ClinicalTrials.gov (NCT03671447).
Results
Between September 4, 2018, and March 31, 2020, 1463 patients (414 treated on control, 1049 on intervention condition) were enrolled at ten clusters, resulting in 14,783 evaluated days. Two randomised clusters recruited no patients (one withdrew informed consent; one dropped out). The intervention, as implemented, significantly increased QI performance for “sedation, analgesia and delirium” (adjusted odds ratio (99.375% confidence interval CI) 5.328, 3.395–8.358), “ventilation” (OR 2.248, 1.198–4.217), “weaning from ventilation” (OR 9.049, 2.707–30.247), “infection management” (OR 4.397, 1.482–13.037), “enteral nutrition” (OR 1.579, 1.032–2.416), “patient and family communication” (OR 6.787, 3.976–11.589), and "early mobilisation" (OR 3.161, 2.160–4.624). No evidence for a difference in adherence to “daily multi-professional and interdisciplinary clinical visits” between both conditions was found (OR 1.606, 0.780–3.309). Temporal trends related and unrelated to the intervention were detected. 149 patients died during their index ICU stay (45 treated on control, 104 on intervention condition).
Conclusion
A telemedical quality improvement program increased adherence to seven evidence-based German performance indicators in acute ICU care. These results need further confirmation in a broader setting of regional, non-academic community hospitals and other healthcare systems.
Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies
, but it has shown limited efficacy against solid tumours. Solid tumours may have ...cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy
. We found that the loss of genes in the interferon-γ receptor (IFNγR) signalling pathway (IFNGR1, JAK1 or JAK2) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFNγR signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours.
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid ...tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.
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•CAR T cells under chronic antigen stimulation show hallmarks of T cell exhaustion•CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition•CAR T cells with NK-like transition were identified in patients after treatment•Unlike WT CAR T cells, ID3 and SOX4 knockout CAR T cells retain anti-tumor immunity
Continuous antigen exposure drives CAR T cell exhaustion and promotes CD8+ T-to-NK-like T cell transition. Transcription factors ID3 and SOX4 are upregulated during CAR dysfunction and regulate genes associated with exhaustion, including NK receptors. Knocking out ID3 and SOX4 in CAR T cells slows dysfunction and improves anti-tumor immunity.
Active galactic nuclei, which are powered by long-term accretion onto central supermassive black holes, produce relativistic jets with lifetimes of at least one million years, and the observation of ...the birth of such a jet is therefore unlikely. Transient accretion onto a supermassive black hole, for example through the tidal disruption of a stray star, thus offers a rare opportunity to study the birth of a relativistic jet. On 25 March 2011, an unusual transient source (Swift J164449.3+573451) was found, potentially representing such an accretion event. Here we report observations spanning centimetre to millimetre wavelengths and covering the first month of evolution of a luminous radio transient associated with Swift J164449.3+573451. The radio transient coincides with the nucleus of an inactive galaxy. We conclude that we are seeing a newly formed relativistic outflow, launched by transient accretion onto a million-solar-mass black hole. A relativistic outflow is not predicted in this situation, but we show that the tidal disruption of a star naturally explains the observed high-energy properties and radio luminosity and the inferred rate of such events. The weaker beaming in the radio-frequency spectrum relative to γ-rays or X-rays suggests that radio searches may uncover similar events out to redshifts of z ≈ 6.
Background Pancreatic fistula (PF) is one of the most common complications after pancreaticoduodenectomy. There have been no large prospective randomized trials evaluating PF rates comparing ...invagination versus duct to mucosa pancreaticojejunostomy. We tested the hypothesis that a duct to mucosa pancreaticojejunostomy would reduce the PF rate. Study Design Between August 2006 and May 2008, 197 patients at two institutions underwent pancreaticoduodenectomy by a total of 8 experienced pancreatic surgeons as part of this prospective randomized trial (clinical trial no. NCT00359320 ). All patients were stratified by pancreatic texture and randomized to either an invagination or a duct to mucosa pancreaticojejunal anastomosis. Recorded variables included pancreatic duct diameter, operative time, blood loss, complications, and pathology. Primary end point was PF rate, as defined by the International Study Group on Pancreatic Fistula. Secondary end points included PF grade, postoperative length of hospital stay, other morbidities, and mortality. Results Rate of PF for the entire cohort was 17.8%. There were 23 fistulas (24%) in the duct to mucosa cohort and 12 fistulas (12%) in the invagination cohort (p < 0.05). The greatest risk factor for a PF was pancreas texture: PF developed in only 8 patients (8%) with hard glands, and in 27 patients (27%) with a soft gland. There were two perioperative deaths (both in the duct to mucosa group), with the proximate causes of death being PF, followed by bleeding and sepsis. Conclusions This dual-institution prospective randomized trial reveals considerably fewer fistulas with invagination compared with duct to mucosa pancreaticojejunostomy after pancreaticoduodenectomy. Results confirm increased PF rates in soft as compared with hard glands. Additional studies are needed to define the optimal technique of pancreatic reconstruction after pancreaticoduodenectomy.
Background There is increasing evidence that fatty acid deficiencies or imbalances may contribute to childhood neurodevelopmental disorders. Methods We conducted a randomized, double-blind, ...placebo-controlled 6-week pilot trial investigating the effects of 1.5 g/d of omega-3 fatty acids (.84 g/d eicosapentaenoic acid, .7 g/d docosahexaenoic acid) supplementation in 13 children (aged 5 to 17 years) with autistic disorders accompanied by severe tantrums, aggression, or self-injurious behavior. The outcome measure was the Aberrant Behavior Checklist (ABC) at 6 weeks. Results We observed an advantage of omega-3 fatty acids compared with placebo for hyperactivity and stereotypy, each with a large effect size. Repeated-measures ANOVA indicated a trend toward superiority of omega-3 fatty acids over placebo for hyperactivity. No clinically relevant adverse effects were elicited in either group. Conclusions The results of this study provide preliminary evidence that omega-3 fatty acids may be an effective treatment for children with autism.
CD8+ T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell ...development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8+ T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1+ progenitor Tex cells to more differentiated TCF-1− Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy.
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•SWI/SNF complexes direct distinct epigenetic checkpoints in CD8+ T cell exhaustion•PBAF protects the pool of stem-cell-like progenitor exhausted CD8+ T cells•PBAF coordinates epigenetic transitions between exhausted CD8+ T cell subsets•Depleting PBAF in CD8+ T cells improves tumor control with immunotherapy
Epigeneic factors regulate key transitions in CD8+ T cell exhaustion. Baxter et al. find that two versions of SWI/SNF chromatin-remodeling complexes direct distinct epigenetic checkpoints in the development of exhaustion. Whereas BAF is required for early responses, PBAF protects the stem-cell-like population responsive to PD-1 checkpoint blockade.
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