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certain retailers, particularly adult-only retailers.Iron overload (IO) affected the survival of patients with myelodysplastic syndrome (MDS). Deferasirox (DFX) is widely used in patients with MDS for iron chelation therapy, but is not suitable for MDS patients with severe thrombocytopenia. Eltrombopag (ELT) is a type of thrombopoietin receptor (TPOR) analog used in the treatment of thrombocytopenia. Therefore, we sought to explore the synergistic effects and possible mechanisms of DFX combination with ELT in MDS cells. In our study, the combination of DFX with ELT synergistically inhibited proliferation, induced apoptosis and arrested cell cycle of MDS cells. Through the RNA-sequence and gene set enrichment analysis (GSEA), iron metabolism-related pathway played important roles in apoptosis of SKM-1 cells treated with DFX plus ELT. Transferrin receptor (TFRC) was significantly highly expressed in combination group than that in single agent groups, without affecting TPOR. Furthermore, the apoptosis of the combination group MDS cells could be partially reversed by ferric ammonium citrate (FAC), accompanied with decreased expression of TFRC. These results suggested that the combination of DFX and ELT synergistically induced apoptosis of MDS cells by enhancing iron deprivation-related pathway.The evaluation criteria for dosage of low-molecular-weight heparin (LMWH) for pregnant women at high risk of venous thromboembolism (VTE) remain unclear. A retrospective study was performed to investigate the relative appropriate LMWH administration strategy and dosage for pregnant women at risk of VTE. 219 pregnant women with perinatal and postpartum VTE were reviewed and divided into group A (fixed dose group n=73, 5000 IU dalteparin daily for all women), group B (weight group n=73, 2500 IU dalteparin daily for women less than 50 kg; 5000 IU dalteparin daily for women more than 50 kg), and group C (anti-factor Xa (FXa) + weight group n=73, 5000 IU once daily for women less than 50 kg; 7500 IU once daily for women weighing 50-80 kg; 10,000 IU once daily for women weighing over 80 kg). Further dose administration was adjusted according to peak anti-FXa level, maintaining the peak at the 0.5-1.0 IU/mL range. Women in group C presented lower incidence of VTE and other pregnancy complications than group A and group B. Adjusting the dosage of LMWH according to both weight and anti-FXa level of pregnant women not only prevented VTE but also reduced the risk of postpartum hemorrhage induced by LMWH administration. In addition, adjusting the dose of LMWH according to anti-FXa level and body weight also affected the recurrence of VTE and the occurrence of postpartum hemorrhage in pregnant women.The patient preference predictor (PPP) is a proposed computer-based algorithm that would predict the treatment preferences of decisionally incapacitated patients. Incorporation of a PPP into the decision-making process has the potential to improve implementation of the substituted judgement standard by providing more accurate predictions of patients' treatment preferences than reliance on surrogates alone. Yet, critics argue that methods for making treatment decisions for incapacitated patients should be judged on a number of factors beyond simply providing them with the treatments they would have chosen for themselves. These factors include the extent to which the decision-making process recognises patients' freedom to choose and relies on evidence the patient themselves would take into account when making treatment decisions. These critics conclude that use of a PPP should be rejected on the grounds that it is inconsistent with these factors, especially as they relate to proper respect for patient autonomy. In this paper, we review and evaluate these criticisms. We argue that they do not provide reason to reject use of a PPP, thus supporting efforts to develop a full-scale PPP and to evaluate it in practice.The COVID-19 pandemic has exacerbated inequalities, including among the healthcare workforce. Based on recent literature and drawing on our experiences of working in operating theatres and critical care in the UK's National Health Service during the pandemic, we review the role of personal protective equipment and consider the ethical implications of its design, availability and provision at a time of unprecedented demand. Several important inequalities have emerged, driven by factors such as individuals purchasing their own personal protective equipment (either out of choice or to address a lack of provision), inconsistencies between guidelines issued by different agencies and organisations, and the standardised design and procurement of equipment required to protect a diverse healthcare workforce. These, we suggest, have resulted largely because of a lack of appropriate pandemic planning and coordination, as well as insufficient appreciation of the significance of equipment design for the healthcare setting. As with many aspects of the pandemic, personal protective equipment has created and revealed inequalities driven by economics, gender, ethnicity and professional influence, creating a division between the 'haves' and 'have-nots' of personal protective equipment. As the healthcare workforce continues to cope with ongoing waves of COVID-19, and with the prospect of more pandemics in the future, it is vital that these inequalities are urgently addressed, both through academic analysis and practical action.
Patients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants.
An online questionnaire was sent out to a population-based registry in The Netherlands. this website Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint.
There was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results.
The PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk-benefit assessment of new treatments for ALS.
The PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk-benefit assessment of new treatments for ALS.
To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients.
Archived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen.
IgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25-87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration.
This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.
This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.
To determine the proportional genetic contribution to the variability of cerebral β-amyloid load in older adults using the classic twin design.
Participants (n=206) comprising 61 monozygotic (MZ) twin pairs (68 (55.74%) females; mean age (SD) 71.98 (6.43) years), and 42 dizygotic (DZ) twin pairs (56 (66.67%) females; mean age 71.14 (5.15) years) were drawn from the Older Australian Twins Study. Participants underwent detailed clinical and neuropsychological evaluations, as well as MRI, diffusion tensor imaging (DTI) and amyloid PET scans. Fifty-eight participants (17 MZ pairs, 12 DZ pairs) had PET scans with
Carbon-Pittsburgh Compound B, and 148 participants (44 MZ pairs, 30 DZ pairs) with
Fluorine-NAV4694. Cortical amyloid burden was quantified using the centiloid scale globally, as well as the standardised uptake value ratio (SUVR) globally and in specific brain regions. Small vessel disease (SVD) was quantified using total white matter hyperintensity volume on MRI, and peak width of skeletonised mean diffusivity on DTI. Heritability (
) and genetic correlations were measured with structural equation modelling under the best fit model, controlling for age, sex, tracer and scanner.
The heritability of global amyloid burden was moderate (0.41 using SUVR; 0.52 using the centiloid scale) and ranged from 0.20 to 0.54 across different brain regions. There were no significant genetic or environmental correlations between global amyloid burden and markers of SVD.
Amyloid deposition, the hallmark early feature of Alzheimer's disease, is under moderate genetic influence, suggesting a major environmental contribution that may be amenable to intervention.
Amyloid deposition, the hallmark early feature of Alzheimer's disease, is under moderate genetic influence, suggesting a major environmental contribution that may be amenable to intervention.Complete genome sequencing has identified millions of DNA changes that differ between humans and chimpanzees. Although a subset of these changes likely underlies important phenotypic differences between humans and chimpanzees, it is currently difficult to distinguish causal from incidental changes and to map specific phenotypes to particular genome locations. To facilitate further genetic study of human-chimpanzee divergence, we have generated human and chimpanzee autotetraploids and allotetraploids by fusing induced pluripotent stem cells (iPSCs) of each species. The resulting tetraploid iPSCs can be stably maintained and retain the ability to differentiate along ectoderm, mesoderm, and endoderm lineages. RNA sequencing identifies thousands of genes whose expression differs between humans and chimpanzees when assessed in single-species diploid or autotetraploid iPSCs. Analysis of gene expression patterns in interspecific allotetraploid iPSCs shows that human-chimpanzee expression differences arise from substantial contributions of both cis-acting changes linked to the genes themselves and trans-acting changes elsewhere in the genome.
