Calprotectin is a granulocyte neutrophil-predominant cytosolic protein. Fecal concentrations are elevated in intestinal inflammation and may predict relapse in quiescent inflammatory bowel disease. ...We aim to investigate fecal calprotectin (FC) as a biomarker in predicting the clinical course of acute severe ulcerative colitis (ASUC).
In 90 patients with ASUC requiring intensive in-patient medical therapy (January 2005-September 2007), we investigated the discriminant ability of FC to predict colectomy and corticosteroid and infliximab nonresponse. All patients received parenteral corticosteroids as first-line treatment; 21 (23.3%) were also treated with infliximab (5 mg/kg), after failure of corticosteroid therapy.
Of 90 patients, 31 (34.4%) required colectomy, including 11 (52.4%) of those treated with infliximab. Overall FC was high (1,020.0 microg/g interquartile range: 601.5-1,617.5). FC was significantly higher in patients requiring colectomy (1,200.0 vs. 887.0; P=0.04), with a trend toward significance when comparing corticosteroid nonresponders and responders (1,100.0 vs. 863.5; P=0.08), as well as between infliximab nonresponders and responders (1,795.0 vs. 920.5; P=0.06). Receiver-operator characteristic curve analysis yielded an area under the curve of 0.65 to predict colectomy (P=0.04), with a maximum likelihood ratio of 9.23, specificity 97.4%, and sensitivity 24.0% at a cutoff point of 1,922.5 microg/g. Kaplan-Meier analyses showed that using 1,922.5 microg/g over a median follow-up of 1.10 years, 87% of patients will need subsequent colectomy.
This is the first data set to demonstrate that FC levels are dramatically elevated in severe UC. These data raise the possibility that this biomarker can predict response to first or second-line medical therapy in this setting.
We present the first experimental study of plasmoid formation in a magnetic reconnection layer undergoing rapid radiative cooling, a regime relevant to extreme astrophysical plasmas. Two exploding ...aluminum wire arrays, driven by the Z machine, generate a reconnection layer (S_{L}≈120) in which the cooling rate far exceeds the hydrodynamic transit rate (τ_{hydro}/τ_{cool}>100). The reconnection layer generates a transient burst of >1 keV x-ray emission, consistent with the formation and subsequent rapid cooling of the layer. Time-gated x-ray images show fast-moving (up to 50 km s^{-1}) hotspots in the layer, consistent with the presence of plasmoids in 3D resistive magnetohydrodynamic simulations. X-ray spectroscopy shows that these hotspots generate the majority of Al K-shell emission (around 1.6 keV) prior to the onset of cooling, and exhibit temperatures (170 eV) much greater than that of the plasma inflows and the rest of the reconnection layer, thus providing insight into the generation of high-energy radiation in radiatively cooled reconnection events.
Thoracic imaging tests for the diagnosis of COVID‐19 McInnes, Matthew DF; Salameh, Jean-Paul; Leeflang, Mariska MG ...
Cochrane database of systematic reviews,
09/2020, Letnik:
2020, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Background
The diagnosis of infection by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) presents major challenges. Reverse transcriptase polymerase chain reaction (RT‐PCR) testing ...is used to diagnose a current infection, but its utility as a reference standard is constrained by sampling errors, limited sensitivity (71% to 98%), and dependence on the timing of specimen collection. Chest imaging tests are being used in the diagnosis of COVID‐19 disease, or when RT‐PCR testing is unavailable.
Objectives
To determine the diagnostic accuracy of chest imaging (computed tomography (CT), X‐ray and ultrasound) in people with suspected or confirmed COVID‐19.
Search methods
We searched the COVID‐19 Living Evidence Database from the University of Bern, the Cochrane COVID‐19 Study Register, and The Stephen B. Thacker CDC Library. In addition, we checked repositories of COVID‐19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 5 May 2020.
Selection criteria
We included studies of all designs that produce estimates of test accuracy or provide data from which estimates can be computed. We included two types of cross‐sectional designs: a) where all patients suspected of the target condition enter the study through the same route and b) where it is not clear up front who has and who does not have the target condition, or where the patients with the target condition are recruited in a different way or from a different population from the patients without the target condition. When studies used a variety of reference standards, we included all of them.
Data collection and analysis
We screened studies and extracted data independently, in duplicate. We also assessed the risk of bias and applicability concerns independently, in duplicate, using the QUADAS‐2 checklist and presented the results of estimated sensitivity and specificity, using paired forest plots, and summarised in tables. We used a hierarchical meta‐analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs).
Main results
We included 84 studies, falling into two categories: studies with participants with confirmed diagnoses of COVID‐19 at the time of recruitment (71 studies with 6331 participants) and studies with participants suspected of COVID‐19 (13 studies with 1948 participants, including three case‐control studies with 549 cases and controls). Chest CT was evaluated in 78 studies (8105 participants), chest X‐ray in nine studies (682 COVID‐19 cases), and chest ultrasound in two studies (32 COVID‐19 cases). All evaluations of chest X‐ray and ultrasound were conducted in studies with confirmed diagnoses only. Twenty‐five per cent (21/84) of all studies were available only as preprints, 15/71 studies in the confirmed cases group and 6/13 of the studies in the suspected group.
Among 71 studies that included confirmed cases, 41 studies had included symptomatic cases only, 25 studies had included cases regardless of their symptoms, five studies had included asymptomatic cases only, three of which included a combination of confirmed and suspected cases. Seventy studies were conducted in Asia, 2 in Europe, 2 in North America and one in South America. Fifty‐one studies included inpatients while the remaining 24 studies were conducted in mixed or unclear settings. Risk of bias was high in most studies, mainly due to concerns about selection of participants and applicability.
Among the 13 studies that included suspected cases, nine studies were conducted in Asia, and one in Europe. Seven studies included inpatients while the remaining three studies were conducted in mixed or unclear settings.
In studies that included confirmed cases the pooled sensitivity of chest CT was 93.1% (95%CI: 90.2 ‐ 95.0 (65 studies, 5759 cases); and for X‐ray 82.1% (95%CI: 62.5 to 92.7 (9 studies, 682 cases). Heterogeneity judged by visual assessment of the ROC plots was considerable. Two studies evaluated the diagnostic accuracy of point‐of‐care ultrasound and both reported zero false negatives (with 10 and 22 participants having undergone ultrasound, respectively). These studies only reported True Positive and False Negative data, therefore it was not possible to pool and derive estimates of specificity.
In studies that included suspected cases, the pooled sensitivity of CT was 86.2% (95%CI: 71.9 to 93.8 (13 studies, 2346 participants) and specificity was 18.1% (95%CI: 3.71 to 55.8). Heterogeneity judged by visual assessment of the forest plots was high.
Chest CT may give approximately the same proportion of positive results for patients with and without a SARS‐CoV‐2 infection: the chances of getting a positive CT result are 86% (95% CI: 72 to 94) in patient with a SARS‐CoV‐2 infection and 82% (95% CI: 44 to 96) in patients without.
Authors' conclusions
The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results. Our findings indicate that chest CT is sensitive but not specific for the diagnosis of COVID‐19 in suspected patients, meaning that CT may not be capable of differentiating SARS‐CoV‐2 infection from other causes of respiratory illness. This low specificity could also be the result of the poor sensitivity of the reference standard (RT‐PCR), as CT could potentially be more sensitive than RT‐PCR in some cases. Because of limited data, accuracy estimates of chest X‐ray and ultrasound of the lungs for the diagnosis of COVID‐19 should be carefully interpreted.
Future diagnostic accuracy studies should avoid cases‐only studies and pre‐define positive imaging findings. Planned updates of this review will aim to: increase precision around the accuracy estimates for CT (ideally with low risk of bias studies); obtain further data to inform accuracy of chest X rays and ultrasound; and continue to search for studies that fulfil secondary objectives to inform the utility of imaging along different diagnostic pathways.
We report a unique case of high‐grade B‐cell lymphoma, not otherwise specified in a 5‐year‐old child. Whole‐genome sequencing revealed a DDX3X::MLLT10 fusion, usually seen in T‐cell acute ...lymphoblastic leukaemia (ALL). This suggests the novel idea that MLLT10 fusions are capable of driving B‐cell malignancies. An IGH deletion usually only seen in adults was also found. These unique genetic findings provide novel insights into B‐cell lymphomagenesis. The child remains in remission 7 year post chemotherapy, which demonstrates that novel complex molecular findings do not always denote high‐risk disease.
Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), ...anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.
Background
The respiratory illness caused by SARS‐CoV‐2 infection continues to present diagnostic challenges. Our 2020 edition of this review showed thoracic (chest) imaging to be sensitive and ...moderately specific in the diagnosis of coronavirus disease 2019 (COVID‐19). In this update, we include new relevant studies, and have removed studies with case‐control designs, and those not intended to be diagnostic test accuracy studies.
Objectives
To evaluate the diagnostic accuracy of thoracic imaging (computed tomography (CT), X‐ray and ultrasound) in people with suspected COVID‐19.
Search methods
We searched the COVID‐19 Living Evidence Database from the University of Bern, the Cochrane COVID‐19 Study Register, The Stephen B. Thacker CDC Library, and repositories of COVID‐19 publications through to 30 September 2020. We did not apply any language restrictions.
Selection criteria
We included studies of all designs, except for case‐control, that recruited participants of any age group suspected to have COVID‐19 and that reported estimates of test accuracy or provided data from which we could compute estimates.
Data collection and analysis
The review authors independently and in duplicate screened articles, extracted data and assessed risk of bias and applicability concerns using the QUADAS‐2 domain‐list. We presented the results of estimated sensitivity and specificity using paired forest plots, and we summarised pooled estimates in tables. We used a bivariate meta‐analysis model where appropriate. We presented the uncertainty of accuracy estimates using 95% confidence intervals (CIs).
Main results
We included 51 studies with 19,775 participants suspected of having COVID‐19, of whom 10,155 (51%) had a final diagnosis of COVID‐19. Forty‐seven studies evaluated one imaging modality each, and four studies evaluated two imaging modalities each. All studies used RT‐PCR as the reference standard for the diagnosis of COVID‐19, with 47 studies using only RT‐PCR and four studies using a combination of RT‐PCR and other criteria (such as clinical signs, imaging tests, positive contacts, and follow‐up phone calls) as the reference standard.
Studies were conducted in Europe (33), Asia (13), North America (3) and South America (2); including only adults (26), all ages (21), children only (1), adults over 70 years (1), and unclear (2); in inpatients (2), outpatients (32), and setting unclear (17).
Risk of bias was high or unclear in thirty‐two (63%) studies with respect to participant selection, 40 (78%) studies with respect to reference standard, 30 (59%) studies with respect to index test, and 24 (47%) studies with respect to participant flow.
For chest CT (41 studies, 16,133 participants, 8110 (50%) cases), the sensitivity ranged from 56.3% to 100%, and specificity ranged from 25.4% to 97.4%. The pooled sensitivity of chest CT was 87.9% (95% CI 84.6 to 90.6) and the pooled specificity was 80.0% (95% CI 74.9 to 84.3). There was no statistical evidence indicating that reference standard conduct and definition for index test positivity were sources of heterogeneity for CT studies.
Nine chest CT studies (2807 participants, 1139 (41%) cases) used the COVID‐19 Reporting and Data System (CO‐RADS) scoring system, which has five thresholds to define index test positivity. At a CO‐RADS threshold of 5 (7 studies), the sensitivity ranged from 41.5% to 77.9% and the pooled sensitivity was 67.0% (95% CI 56.4 to 76.2); the specificity ranged from 83.5% to 96.2%; and the pooled specificity was 91.3% (95% CI 87.6 to 94.0). At a CO‐RADS threshold of 4 (7 studies), the sensitivity ranged from 56.3% to 92.9% and the pooled sensitivity was 83.5% (95% CI 74.4 to 89.7); the specificity ranged from 77.2% to 90.4% and the pooled specificity was 83.6% (95% CI 80.5 to 86.4).
For chest X‐ray (9 studies, 3694 participants, 2111 (57%) cases) the sensitivity ranged from 51.9% to 94.4% and specificity ranged from 40.4% to 88.9%. The pooled sensitivity of chest X‐ray was 80.6% (95% CI 69.1 to 88.6) and the pooled specificity was 71.5% (95% CI 59.8 to 80.8).
For ultrasound of the lungs (5 studies, 446 participants, 211 (47%) cases) the sensitivity ranged from 68.2% to 96.8% and specificity ranged from 21.3% to 78.9%. The pooled sensitivity of ultrasound was 86.4% (95% CI 72.7 to 93.9) and the pooled specificity was 54.6% (95% CI 35.3 to 72.6).
Based on an indirect comparison using all included studies, chest CT had a higher specificity than ultrasound. For indirect comparisons of chest CT and chest X‐ray, or chest X‐ray and ultrasound, the data did not show differences in specificity or sensitivity.
Authors' conclusions
Our findings indicate that chest CT is sensitive and moderately specific for the diagnosis of COVID‐19. Chest X‐ray is moderately sensitive and moderately specific for the diagnosis of COVID‐19. Ultrasound is sensitive but not specific for the diagnosis of COVID‐19. Thus, chest CT and ultrasound may have more utility for excluding COVID‐19 than for differentiating SARS‐CoV‐2 infection from other causes of respiratory illness.
Future diagnostic accuracy studies should pre‐define positive imaging findings, include direct comparisons of the various modalities of interest in the same participant population, and implement improved reporting practices.
Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK ...TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.
Background
Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes.
...Objectives
To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty. DESIGN: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate doserange effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers.
Setting
Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center.
Participants
Target enrollment is 150 subjects aged 70–85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 (“mild”) or 6 (“moderate”), a 6MWT of 200–400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL.
Intervention
A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days.
Measurements
The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial.
Results
The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board.
Conclusion
This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty.
Increased salt tolerance is needed for crops grown in areas at risk of salinisation. This requires new genetic sources of salt tolerance, and more efficient techniques for identifying salt-tolerant ...germplasm, so that new genes for tolerance can be introduced into crop cultivars. Screening a large number of genotypes for salt tolerance is not easy. Salt tolerance is achieved through the control of salt movement into and through the plant, and salt-specific effects on growth are seen only after long periods of time. Early effects on growth and metabolism are likely due to osmotic effects of the salt, that is to the salt in the soil solution. To avoid the necessity of growing plants for long periods of time to measure biomass or yield, practical selection techniques can be based on physiological traits. We illustrate this with current work on durum wheat, on selection for the trait of sodium exclusion. We have explored a wide range of genetic diversity, identified a new source of sodium exclusion, confirmed that the trait has a high heritability, checked for possible penalties associated with the trait, and are currently developing molecular markers. This illustrates the potential for marker-assisted selection based on sound physiological principles in producing salt-tolerant crop cultivars.
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