Targeting immune checkpoints is a novel approach in cancer therapy. This strategy may trigger immune related adverse events (irAE). We hypothesize that the incidence of irAE will be greater in ...patients receiving immune checkpoint inhibitors (ICI) targeting only immune cells compared to those that also target tumor cells (PD-L1). In addition, we compared the specific irAE profile and overall response rate (ORR) for each ICI by target(s).
We reviewed all ICI cancer clinical trials (90; 174 arms) that reported irAE and were published through MEDLINE. 114 arms from 73 trials were eligible for this meta-analysis (including 11,328 patients). We collected and compared arm-specific data including ICI target, number of patients with irAE of any grade, grade 3+ and grade 5, specific irAE, and ORR. The R package “meta” was used to conduct a meta-analysis to calculate and compare the percentage of patients with irAE and ORR.
The incidence (% of patients) of any grade irAE per ICI target was reported for 40 arms (3418 patients) treated with ICI. Most arms (80%) and patients (53%) studied were on phase 1/2 clinical trials. Patients were treated for solid malignancy on 39 arms (97%), mainly melanoma (40%). Two arms included ICI combinations. The incidence of any grade irAE was higher in patients who received ICI targeting CTLA-4 (53.8%) than PD-1 (26.5%) and PD-L1 ICI (17.1%) (P<0.001). Comparative specific irAE rates were calculated for each ICI target.
Our systematic review supported our mechanistic-driven hypothesis. We encourage investigators to report the incidence of irAE in future ICI combination trials.
A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
Purpose
Coronavirus disease (COVID-19) has rapidly emerged as a global health threat. The purpose of this article is to share our local experience of stepping up infection control measures in ...ophthalmology to minimise COVID-19 infection of both healthcare workers and patients.
Methods
Infection control measures implemented in our ophthalmology clinic are discussed. The measures are based on detailed risk assessment by both local ophthalmologists and infection control experts.
Results
A three-level hierarchy of control measures was adopted. First, for administrative control, in order to lower patient attendance, text messages with an enquiry phone number were sent to patients to reschedule appointments or arrange drug refill. In order to minimise cross-infection of COVID-19, a triage system was set up to identify patients with fever, respiratory symptoms, acute conjunctivitis or recent travel to outbreak areas and to encourage these individuals to postpone their appointments for at least 14 days. Micro-aerosol generating procedures, such as non-contact tonometry and operations under general anaesthesia were avoided. Nasal endoscopy was avoided as it may provoke sneezing and cause generation of droplets. All elective clinical services were suspended. Infection control training was provided to all clinical staff. Second, for environmental control, to reduce droplet transmission of COVID-19, installation of protective shields on slit lamps, frequent disinfection of equipment, and provision of eye protection to staff were implemented. All staff were advised to measure their own body temperatures before work and promptly report any symptoms of upper respiratory tract infection, vomiting or diarrhoea. Third, universal masking, hand hygiene, and appropriate use of personal protective equipment (PPE) were promoted.
Conclusion
We hope our initial experience in stepping up infection control measures for COVID-19 infection in ophthalmology can help ophthalmologists globally to prepare for the potential community outbreak or pandemic. In order to minimise transmission of COVID-19, ophthalmologists should work closely with local infection control teams to implement infection control measures that are appropriate for their own clinical settings.
Emergence of a new SARS-CoV-2 variant in the UK Tang, Julian W; Tambyah, Paul A; Hui, David SC
Journal of infection/The Journal of infection,
04/2021, Volume:
82, Issue:
4
Journal Article
Summary Objective To study the effect of intra-articular injection of meloxicam (Mobic) on the development of osteoarthritis (OA) in rats and examine concomitant changes in nociceptive behavior and ...the expression of mitogen-activated protein kinases (MAPKs) in articular cartilage chondrocytes. Methods OA was induced in Wistar rats by right anterior cruciate ligament transection (ACLT); the left knee was not treated. The OA + meloxicam (1.0 mg) group was injected intra-articularly in the ACLT knee with 1.0 mg of meloxicam once a week for 5 consecutive weeks starting 5 weeks after ACLT. The OA + meloxicam (0.25 mg) group was treated similarly with 0.25 mg meloxicam. The sham group underwent arthrotomy only and received vehicle of 0.1 mL sterile 0.9% saline injections, whereas the naive rats in meloxicam-only groups were treated similarly with 1.0- and 0.25-mg meloxicam. Nociception was measured as secondary mechanical allodynia and hind paw weight-bearing distribution at before (pre-) and 5, 10, 15, and 20 weeks post-ACLT. Histopathology of the cartilage and synovia was examined 20 weeks after ACLT. Immunohistochemical analysis was performed to examine the effect of meloxicam on MAPKs (p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK)) expression in the articular cartilage chondrocytes. Results OA rats receiving intra-articular meloxicam treatment showed significantly less cartilage degeneration and synovitis than saline-treated controls. Nociception were improved in the OA + meloxicam groups compared with the OA group. Moreover, meloxicam attenuated p38 and JNK but enhanced ERK expression in OA-affected cartilage. Conclusions Intra-articular injection of meloxicam (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cellular p38 and JNK, but enhances ERK expression.
Thioamides antithyroid‐drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD‐induced agranulocytosis is important for clinical management. ...We performed a genome‐wide association study (GWAS) involving 20 patients with ATD‐induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single‐nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD‐induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8–103.7; P = 1.3 × 10‐24) and replication (OR = 37; 95% CI = 3.7–367.4; P = 9.6 × 10‐7). HLA‐B*38:02:01 was in complete linkage disequilibrium with rs185386680. High‐resolution HLA typing confirmed that HLA‐B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)‐induced agranulocytosis (OR = 265.5; 95% CI = 27.9–2528.0; P = 2.5 × 10‐14), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA‐B*38:02:01 in predicting CMZ/MMI‐induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
Black phosphorous (BP), the most thermodynamically stable allotrope of phosphorus, is a high-mobility layered semiconductor with direct band-gap determined by the number of layers from 0.3 eV (bulk) ...to 2.0 eV (single layer). Therefore, BP is considered as a natural candidate for broadband optical applications, particularly in the infrared (IR) and mid-IR part of the spectrum. The strong light-matter interaction, narrow direct band-gap, and wide range of tunable optical response make BP as a promising nonlinear optical material, particularly with great potentials for infrared and mid-infrared opto-electronics. Herein, we experimentally verified its broadband and enhanced saturable absorption of multi-layer BP (with a thickness of ~10 nm) by wide-band Z-scan measurement technique, and anticipated that multi-layer BPs could be developed as another new type of two-dimensional saturable absorber with operation bandwidth ranging from the visible (400 nm) towards mid-IR (at least 1930 nm). Our results might suggest that ultra-thin multi-layer BP films could be potentially developed as broadband ultra-fast photonics devices, such as passive Q-switcher, mode-locker, optical switcher etc.
Soils are a crucial component of the Earth system; they comprise a large portion of terrestrial carbon stocks, mediate the supply and demand of nutrients, and influence the overall response of ...terrestrial ecosystems to perturbations. In this paper, we develop a new soil biogeochemistry model for the Community Land Model, version 4 (CLM4). The new model includes a vertical dimension to carbon (C) and nitrogen (N) pools and transformations, a more realistic treatment of mineral N pools, flexible treatment of the dynamics of decomposing carbon, and a radiocarbon (14C) tracer. We describe the model structure, compare it with site-level and global observations, and discuss the overall effect of the revised soil model on Community Land Model (CLM) carbon dynamics. Site-level comparisons to radiocarbon and bulk soil C observations support the idea that soil C turnover is reduced at depth beyond what is expected from environmental controls for temperature, moisture, and oxygen that are considered in the model. In better agreement with observations, the revised soil model predicts substantially more and older soil C, particularly at high latitudes, where it resolves a permafrost soil C pool. In addition, the 20th century-C dynamics of the model are more realistic than those of the baseline model, with more terrestrial C uptake over the 20th century due to reduced N downregulation and longer turnover times for decomposing C.
Summary
Background
Bullous pemphigoid (BP) is the most common autoimmune‐mediated subepidermal blistering skin disease and is associated with significant morbidity and mortality.
Objectives
To ...determine the 3‐year mortality rate, risk factors and causes of death in patients with BP in Singapore, compared with the general population.
Methods
We conducted a retrospective cohort study of all newly diagnosed patients with BP seen at the National Skin Centre from 1 April 2004 to 31 December 2009. Demographic and clinical data on comorbidities and treatment were recorded. Mortality information was obtained from the National Registry of Diseases.
Results
In total 359 patients were included in our study. The 1‐, 2‐, 3‐year mortality rates were 26·7%, 38·4% and 45·7%, respectively. The 3‐year standardized mortality risk for patients with BP was 2·74 (95% confidence interval 2·34–3·19) times higher than for the age‐ and sex‐matched general population. Parkinson disease, heart failure and chronic renal disease were associated with increased mortality, while combination treatment with low‐to‐moderate‐dose corticoste‐roids and immunomodulatory agents such as doxycycline and/or nicotinamide was associated with lower mortality. Overall, infections were the most common cause of death (59·8%), with the main causes of death being pneumonia (42·7%), cardiovascular disease (14·6%) and stroke (11·6%).
Conclusions
This study confirms an increased 3‐year mortality rate for patients with BP in Singapore. Risk factors for increased mortality include medical comorbidities, especially neurological, cardiac and renal diseases. Treatment with combination therapy, including the use of low‐to‐moderate‐dose corticosteroid, appeared to decrease mortality risk in patients with BP.
What's already known about this topic?
Bullous pemphigoid (BP) is the most common subepidermal blistering skin disease and is associated with significant morbidity.
Patients with BP have an increased mortality rate compared with the general population in Western cohorts.
What does this study add?
This is the first comprehensive study to demonstrate increased mortality risk in Asian patients with BP.
Mortality risk factors include Parkinson disease, heart failure and chronic renal disease.
Combination treatment with low‐to‐moderate‐dose corticosteroids and immunomodulatory agents, such as doxycycline and/or nicotinamide, was associated with lower mortality.
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