Current recommendations for treating patients with thromboembolism and concomitant thrombocytopenia are based on anecdotal data and expert opinion, rather than clinical studies. Our aim was to use an ...in-vitro model employing thromboelastography (TEG) to evaluate clot formation as a surrogate indicator of clinical tendency to hemorrhage, and investigate the interactions of plasma at varying concentrations of platelets in the presence of anticoagulants.
Platelet-rich and platelet-poor plasma isolated from whole blood were mixed together to obtain platelet concentrations ranging from less than 10-150 × 10 platelets/l. Clotting was initiated with tissue factor and measured by TEG.
Different tissue factor concentrations were required to model clinical clotting profiles for plasma that contained heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux. No tissue factor was required for rivaroxaban or dabigatran-clotting reactions. The time to initiate coagulation (R) was significantly delayed at platelet concentrations less than 30 × 10/l for UFH and LMWH, less than 20 × 10/l for fondaparinux, and less than 10 × 10/l for rivaroxaban and dabigatran. The strength of the clot was significantly compromised at all platelet concentrations in the presence of UFH, LMWH or fondaparinux. In contrast, rivaroxaban and dabigatran compromised clot strength at platelet concentrations less than 10 × 10/l.
All anticoagulants tested compromised coagulation at specific platelet concentration thresholds. Rivaroxaban and dabigatran had reduced impact on clot formation at low-platelet concentrations compared with heparinoids, suggesting that the factor-specific inhibitors may be more favorable than traditional heparin-based treatment of thromboembolism in the presence of thrombocytopenia.
Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To ...determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10(-9)), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10(-5)), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10(-5)), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10(-5)), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.
There have been significant developments in diagnostic and therapeutic options for patients with neuroendocrine tumors (NETs). Key phase 3 studies include the CLARINET trial, which evaluated ...lanreotide in patients with nonfunctioning enteropancreatic NETs; the RADIANT-2 and RADIANT-4 studies, which evaluated everolimus in functioning and nonfunctioning NETs of the gastrointestinal tract and lungs; the TELESTAR study, which evaluated telotristat ethyl in patients with refractory carcinoid syndrome; and the NETTER-1 trial, which evaluated Lu-DOTATATE in NETs of the small intestine and proximal colon (midgut). Based on these and other advances, the North American Neuroendocrine Tumor Society convened a multidisciplinary panel of experts with the goal of updating consensus-based guidelines for evaluation and treatment of midgut NETs. The medical aspects of these guidelines (focusing on systemic treatment, nonsurgical liver-directed therapy, and postoperative surveillance) are summarized in this article. Surgical guidelines are described in a companion article.
According to the established model of murine innate lymphoid cell (ILC) development, helper ILCs develop separately from natural killer (NK) cells. However, it is unclear how helper ILCs and NK cells ...develop in humans. Here we elucidated key steps of NK cell, ILC2, and ILC3 development within human tonsils using ex vivo molecular and functional profiling and lineage differentiation assays. We demonstrated that while tonsillar NK cells, ILC2s, and ILC3s originated from a common CD34−CD117+ ILC precursor pool, final steps of ILC2 development deviated independently and became mutually exclusive from those of NK cells and ILC3s, whose developmental pathways overlapped. Moreover, we identified a CD34−CD117+ ILC precursor population that expressed CD56 and gave rise to NK cells and ILC3s but not to ILC2s. These data support a model of human ILC development distinct from the mouse, whereby human NK cells and ILC3s share a common developmental pathway separate from ILC2s.
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•Human NK cells, ILC2s, and ILC3s develop from tonsil CD34−CD117+ ILC precursors•A CD56+ subset of CD34−CD117+ precursors generates NK cells and ILC3s but not ILC2s•Human ILC development is distinct from the established murine model
Human innate lymphoid cells (ILCs) develop from tissue-resident ILC precursors (ILCPs) in secondary lymphoid tissues. Here, Chen et al. describe a model of human ILC development in tonsils in which NK cells and group 3 ILCs derive from a CD56+ subset of ILCPs that cannot differentiate into group 2 ILCs.
Patients undergoing breast cancer surgery frequently experience chronic postoperative pain. The primary objective of this randomized study was to determine if thoracic paravertebral block (TPVB) ...reduced the incidence of chronic pain after a modified radical mastectomy (MRM) when compared with general anesthesia (GA).
One hundred eighty women undergoing MRM were randomized to 1 of 3 study groups: group 1: standardized GA, group 2: GA with a single-injection TPVB and placebo paravertebral infusion, and group 3: GA with a continuous TPVB. Outcomes assessed postoperatively included acute postoperative pain and analgesic consumption and, at 3 and 6 months, the incidence and severity of chronic pain and physical and mental health-related quality of life (HRQOL).
There was no significant difference in the incidence of chronic pain at 3 months (P = 0.13) and 6 months (P = 0.79) after the MRM between the study groups. The relative risk of developing chronic pain (P = 0.25) was also similar between the groups. There was no difference in acute pain (P = 0.22) or postoperative analgesic consumption (P = 0.67) between the groups. Nevertheless, differences were observed in chronic pain-related secondary outcome variables. The TPVB groups reported lower chronic pain scores (P < 0.05), exhibited fewer symptoms and signs of chronic pain (P ≤ 0.01), and also experienced better physical and mental HRQOL than did the GA group. Chronic pain scores also decreased with time in all study groups (P < 0.05).
There is no significant difference in the incidence or relative risk of chronic pain at 3 and 6 months after an MRM when TPVB is used in conjunction with GA. Nevertheless, patients who receive a TPVB report less severe chronic pain, exhibit fewer symptoms and signs of chronic pain, and also experience better physical and mental HRQOL.
Abstract Background Osteoporosis is a common condition among elderly. Genetic mapping studies repeatedly located the distal short arms of X-chromosome as the quantitative trait loci (QTL) for BMD in ...mice. Fine mapping of a syntenic segment on Xp22 in a Caucasian female population suggested a moderate association between lumbar spine (LS) BMD and 2 intronic SNPs in the Pirin ( PIR ) gene, which encodes an iron-binding nuclear protein. This study aimed to examine genetic variations in the PIR gene by a comprehensive tagging method and its sex-specific effects on BMD and osteoporotic risk. Methods Two thousand men and 2000 women aged 65 or above were recruited from the community. BMDs at the LS, femoral neck, total hip and whole body were measured and followed up at 4-year. Genotyping was performed for tagSNPs of PIR gene including adjacent regions, and the PIR haplotypes were inferred using PHASE program. Results Analysis by linear regression showed a significant association between SNP rs5935970 and LS-BMD, while haplotype T-T-A was significantly associated with BMD of all measured sites. However, none of such associations were found in men. Linear Mixed Model also confirmed the same sex-specific and site-specific effect for longitudinal BMD changes. Conclusion In addition to confirming the association between BMDs and the PIR gene, we also revealed that this finding is sex-specific, possibly due to an X-linked effect. This study demonstrated the importance of considering sex and genetic interactions in studies of disease predisposition and complex traits.
Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia ...A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors.
To report the efficacy and safety results from the NuProtect study.
PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study.
Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events.
Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.
•We explored cranial neuropathy recovery in T4 NPC after chemoradiation with IMRT.•With a median follow-up time of 6.4 years, the crude recovery rate was 79%.•CN III, IV, and VI had the highest ...5-year full recovery rate.•Smoking, CN II involvement, and >2 months of neuropathy were negative predictors for recovery.•Re-palsy of recovered nerves should prompt an evaluation for local recurrence.
Cranial neuropathy is a common presenting symptom of advanced T4 nasopharyngeal carcinoma (NPC). Data on neurological outcomes after modern intensity-modulated radiotherapy (IMRT) and chemotherapy are scarce.
Case records of consecutive T4 NPC patients who received definitive IMRT in two tertiary oncology centers in 2004–2019 were reviewed. Patterns of cranial neuropathies at disease presentation were recorded. Time to neurological recovery and the rate of subsequent re-palsy were estimated by the Kaplan-Meier method. Clinical predictors were analyzed using multivariable Cox regression.
During the study period, 257 T4 NPC patients presented with 504 individual cranial neuropathies. The median time from neuropathy onset to NPC diagnosis was two months (IQR, 1–4 months). Cranial nerves (CN) VI (56.4%), V2 (47.9%), and V3 (29.2%) were most frequently involved. At a median follow-up of 6.4 years, the crude partial and full recovery rates of neuropathies were 111 (22%) and 289 (57.3%), respectively. CN III, IV, and VI had the highest 5-year full recovery rate (72.7%), followed by CN V1-3 (60.3%), XII (48.6%), and II (18.2%) (p < 0.001). Positive smoking history, optic nerve involvement, and longer duration of neuropathy were independent negative predictors for neurological recovery. After full recovery, re-palsy was observed in 6.9% (20/289) of the nerves, 60% of which co-occurred with local NPC recurrences.
Durable recovery of most cranial neuropathies in advanced T4 NPC was observed in the era of modern IMRT and effective systemic chemotherapy. Both patient and disease factors affected the chance of neurological recovery. Re-palsy of recovered nerves should prompt careful evaluation for local recurrence.
Summary
In this study we report the largest descriptive cohort of congenital antithrombin (AT) deficiency in children, its clinical presentation, molecular basis and genotype‐phenotype correlation. ...Paediatric patients diagnosed with AT deficiency at two tertiary care children's hospitals over a 10‐year period were retrospectively reviewed. SERPINC1 gene sequencing was offered to subjects who did not already have the test performed. Molecular modelling and stability simulations were performed for the novel mutations identified. Twenty‐nine subjects from 18 pedigrees were identified. Mean age (± standard deviation) at diagnosis and mean duration of follow‐up were 8·4 (± 6·6) years and 6·6 (± 5·7) years respectively. Most recent mean AT activity and AT antigen levels (n = 20) were 0·53 (± 0·09) iu/ml and 0·60 (± 0·17) iu/ml respectively. Ten subjects were diagnosed secondary to low AT activity measured following venous thrombo‐embolism (VTE). All 10 subjects had additional risk factors at the time of VTE. None of the 19 subjects diagnosed with AT deficiency in the setting of positive family history have had VTE with 7·4 (± 5·8) years follow‐up. Mutation analysis has been completed on 19 subjects from 16 pedigrees. Nine unique mutations, including 4 novel mutations were identified.
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