5366 research outputs found
Sort by
Effects of intravitreal injection of siRNA against caspase-2 on retinal and optic nerve degeneration in air blast induced ocular trauma.
No full textOcular repeated air blast injuries occur from low overpressure blast wave exposure, which are often repeated and in quick succession. We have shown that caspase-2 caused the death of retinal ganglion cells (RGC) after blunt ocular trauma. Here, we investigated if caspase-2 also mediates RGC apoptosis in a mouse model of air blast induced indirect traumatic optic neuropathy (b-ITON). C57BL/6 mice were exposed to repeated blasts of overpressure air (3 × 2 × 15 psi) and intravitreal injections of siRNA against caspase-2 (siCASP2) or against a control enhanced green fluorescent protein (siEGFP) at either 5 h after the first 2 × 15 psi ("post-blast") or 48 h before the first blast exposure ("pre-blast") and repeated every 7 days. RGC counts were unaffected by the b-ITON or intravitreal injections, despite increased degenerating ON axons, even in siCASP2 "post-blast" injection groups. Degenerating ON axons remained at sham levels after b-ITON and intravitreal siCASP2 "pre-blast" injections, but with less degenerating axons in siCASP2 compared to siEGFP-treated eyes. Intravitreal injections "post-blast" caused greater vitreous inflammation, potentiated by siCASP2, with less in "pre-blast" injected eyes, which was abrogated by siCASP2. We conclude that intravitreal injection timing after ocular trauma induced variable retinal and ON pathology, undermining our candidate neuroprotective therapy, siCASP2
Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial.
No full textImportance
In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes.
Objective
To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure.
Design, Setting, and Participants
This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020.
Interventions
Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210).
Main Outcomes and Measures
The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates.
Results
Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device.
Conclusions and Relevance
Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference.
Trial Registration
ClinicalTrials.gov Identifier: NCT02654327
Chronic Kidney Disease and Cognitive Impairment.
No full textChronic kidney disease (CKD) is associated with a high risk of cognitive impairment (CI). Both vascular and metabolic factors are implicated in the causation of CI in CKD. The traditional risk factors for CI are more prevalent in CKD and interact reciprocally. CI in CKD is associated with reduced functional capacity, poor quality of life and mortality. Cognition declines significantly after initiation of haemodialysis (HD). Repeated cerebral insults related to intra-dialytic haemodynamic instability may be responsible for the rapid, step-wise decline in cognition observed in HD patients. Cognitive interventions used in the general population have not been adequately tested in CKD. Exercise interventions are likely to be beneficial based on biological plausibility and pilot trial data. Cooled HD may be beneficial in HD patients but needs substantive trial data to support it. Cognition testing should be routinely offered to CKD patients. There is a need for further research into the underlying causes of CI in CKD with a view to developing therapeutic interventions
Correspondence on prevailing dermatology-related topics on the rapidly growing TikTok social media platform.
No full textWe found the Roche et al article on prevailing dermatology-related topics on the rapidly growing TikTok social media (SoMe) platform informative, particularly with respect to the popularity of dermatological search terms such as #roaccuatane (57.7 million in August 2021). Zheng et al expatiated on this further by providing guidance on how dermatologists can navigate such platforms using hashtags (#) which Nikookam et al postulated as a way of providing quality educational dermatology-related content for the public and budding dermatologists alike
6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150).
No full textVIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1-23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy.This trial was registered at www.clinicaltrials.gov as #NCT03069352
The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery.
No full textMultisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL6 may be preferable to IL1 or TNF-α . We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease
Cardio-metabolic outcomes in South Asians compared to White Europeans in the United Kingdom: a matched controlled population-based cohort study.
No full textBACKGROUND
There appears to be an inequality in the risk of cardio-metabolic disease between those from a South Asian (SA) background when compared to those of White Europeans (WE) descendance, however, this association has not been explored in a large European cohort. This population-based open retrospective cohort explores the incidence of cardio-metabolic disease in those without pre-existing cardiometabolic disease taken from a large UK primary care database from 1st January 2007 to 31st December 2017.
METHODS
A retrospective open cohort matched population-based study using The Health Improvement Network (THIN) database. The outcomes of this study were the incidences of cardio-metabolic events (type 2 diabetes mellitus, hypertension, ischemic heart disease, stroke, heart failure, and atrial fibrillation).
RESULTS
A total of 94,870 SA patients were matched with 189,740 WE patients. SA were at an increased risk of developing: T2DM (adjusted hazard ratio (aHR) 3.1; 95% CI 2.97-3.23); HTN (1.34; 95% CI: 1.29-1.39); ischaemic heart disease (IHD) (1.81; 95% CI: 1.68-1.93) and heart failure (HF) (1.11; 95% CI: 1.003-1.24). However, they were at a lower risk of atrial fibrillation (AF) (0.53; 95% CI: 0.48-0.59) when compared to WE. Of those of SA origin, the Bangladeshi community were at the greatest risk of T2DM, HTN, IHD and HF, but were at the lowest risk of AF in when compared to Indians and Pakistanis.
CONCLUSION
Considering the high risk of cardio-metabolic diseases in the SA cohort, differential public health measures should be considered in these patients to reduce their risk of disease, which may be furthered tailored depending on their country of origin
Relationship between Depression and Anxiety, Health Status and Lung Function in Patients with Alpha-1 Antitrypsin Deficiency.
No full textAlpha-1 Antitrypsin deficiency (AATD) is a genetic condition that can lead to Chronic Obstructive Pulmonary Disease. The burden of psychological disease, its impact and contributing factors in patients with AATD are largely unknown. This study determined the prevalence of depression and anxiety in AATD and its clinical impact. All subjects with PiZZ/PiZnull ( = 635) and PiSZ ( = 111) genotypes within the AATD registry who had sufficient data to calculate pulmonary physiological and health status (HS) decline were grouped as those with or without a diagnosis of depression and/or anxiety. Univariate and multivariate analyses were performed on physiological, demographic and HS parameters. Depression and/or anxiety was present in 16.4% overall in both PiSZ and PiZZ/PiZnull cohorts and was associated with lower baseline pulmonary function and worse HS. In the multivariable analysis of the PiZZ/PiZnull cohort, a greater average decline in FEV% predicted was observed in those with depression and/or anxiety than those without (-1.53 SD ± 2.26 per year, -0.99 ± 1.79, respectively; = 0.03) but there was no difference in HS decline ( = 0.33). No differences were seen in the PiSZ cohort. Dyspnoea (mMRC score) was generally worse in those with depression and/or anxiety than those without. Comorbidity burden did not differ between those with or without depression and/or anxiety. Disease severity and progression may be contributing to the prevalence of psychological factors in PiZZ/PiZnull patients. Patients who are declining rapidly should be actively monitored for psychological co-morbidity and treated by cognitive or pharmacological means.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1991904
Current practice and registration patterns among United Kingdom Haemophilia Centre Doctors' Organisation centers for patients with unclassified bleeding disorders.
No full textBACKGROUND
Bleeding of unknown cause (BUC) and unclassified bleeding disorders (UBD) are increasingly recognized. There is no guidance on diagnosis and management.
OBJECTIVES
To examine UK haemophilia centre registration patterns and current practice for UBD patients.
METHODS
In a two-step process, the UK National Haemophilia Database (NHD) was reviewed for registration patterns of UBD patients and a survey of UK haemophilia centers was conducted (January/February 2021) to capture current practice for diagnosis and management of patients with UBD.
RESULTS/DISCUSSION
Overall, registrations with the NHD for UBD patients has sharply risen from 2012 to 2020 and in 2019 accounted for 2.65% of registered patients. For the survey, the response rate was 52/67 (78%). Practice was widely variable; 35/52 (67%) centers register UBD; among these 35 centers, terminology included UBD (28 centers), undiagnosed bleeding disorder (four centers), and BUC (three centers); 34/52 (65%) centers use a formal bleeding assessment tool. For management of dental extraction and high bleeding risk surgery in a fictional UBD patient we found that tranexamic acid was widely used; however, beyond this a variety of hemostatic products were advised including blood products, recombinant factor VIIa/prothrombin complex concentrate, and desmopressin. There was general consensus (≈90%) on avoiding regional anesthesia in pregnancy, but no agreement on the need for fetal precautions to avoid bleeding at delivery (50% would advise these). There was a disparity of opinion on chemical thromboprophylaxis, and management of patients without prior hemostatic challenges and offspring of these patients.
CONCLUSION
This study provides a snapshot of current practice and real-world data in this area. Future studies need to address the gaps in evidence