Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to ...eculizumab in complement inhibitor–naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% 95% confidence interval (CI), −4.66, 18.14), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 0.80, 1.77), percent reduction in LDH (−76.8% vs −76.0%; difference 95% CI, −0.83% −5.21, 3.56), change in FACIT-Fatigue score (7.07 vs 6.40; difference 95% CI, 0.67 −1.21, 2.55), breakthrough hemolysis (4.0% vs 10.7%; difference 95% CI, −6.7% −14.21, 0.18), and stabilized hemoglobin (68.0% vs 64.5%; difference 95% CI, 2.9 −8.80, 14.64). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.
•Ravulizumab every 8 weeks is noninferior to eculizumab every 2 weeks across all efficacy end points in C5 inhibitor–naive PNH patients.•Ravulizumab provided immediate, complete, and sustained inhibition of C5 over the entire 8-week dose interval, unlike eculizumab.
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More than 20 unrelated proteins can form amyloid fibrils in vivo which are related to various diseases, such as Alzheimer’s disease, prion disease, and systematic amyloidosis. Amyloid fibrils are an ...ordered protein aggregate with a lamellar cross-β structure. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In this study, we explored the amyloid-degrading ability of nattokinase, a fibrinolytic subtilisin-like serine protease, and determined the optimal conditions for amyloid hydrolysis. This ability is shared by proteinase K and subtilisin Carlsberg, but not by trypsin or plasmin.
INTRODUCTION:Unfulfilled expectations, assessed postoperatively, have been consistently associated with dissatisfaction after total knee arthroplasty (TKA). However, identifying these expectations ...preoperatively has been a challenge. We aimed at identifying specific expectations that are most likely to affect postoperative dissatisfaction.
METHODS:We included all patients in our institutional registry with a body mass index of <40 kg/m who underwent primary unilateral TKA and had a minimum 2-year follow-up. Preoperatively, patients completed the 19-item Hospital for Special Surgery Expectations Survey, Short Form-12, Knee Injury and Osteoarthritis Outcomes Score and EuroQol 5-D. Two years postoperatively, patients reported their dissatisfaction on five domains. We estimated logistic regression models to identify the expectation items associated with each domain.
RESULTS:A total of 2,279 TKA patients (mean age65.3 ± 9.2 years; mean body mass index30.2 ± 5.9 kg/m) met our inclusion/exclusion criteria. The association between expectations and dissatisfaction was domain specific, that is, subsets of 4 to 5 items were markedly associated with each dissatisfaction domain, and these expectations differed depending on the dissatisfaction domain examined. Of those, expectations predicting dissatisfaction on multiple domains included kneeling ability and leg straightening and participation in recreation and sports.
DISCUSSION:We identified a subset of expectations most likely to affect dissatisfaction after TKA. Our findings should inform preoperative patient education approaches on those expectations to realistically orient patient expectations and increase satisfaction.
LEVEL OF EVIDENCE:Level II
Viruses initiate infection by transferring their genetic material across a cellular membrane and into the appropriate compartment of the cell. The mechanisms by which animal viruses, especially ...nonenveloped viruses, deliver their genomes are only poorly understood. This is due in part to technical difficulties involved in direct visualization of viral gene delivery and to uncertainties in distinguishing productive and nonproductive pathways caused by the high particle-to-plaque forming unit ratio of most animal viruses. Here, we combine an imaging assay that simultaneously tracks the viral capsid and genome in live cells with an infectivity-based assay for RNA release to characterize the early events in the poliovirus (PV) infection. Effects on RNA genome delivery from inhibitors of cell trafficking pathways were probed systematically by both methods. Surprisingly, we observe that genome release by PV is highly efficient and rapid, and thus does not limit the overall infectivity or the infection rate. The results define a pathway in which PV binds to receptors on the cell surface and enters the cell by a clathrin-, caveolin-, flotillin-, and microtubule-independent, but tyrosine kinase- and actin-dependent, endocytic mechanism. Immediately after the internalization of the virus particle, genome release takes place from vesicles or tightly sealed membrane invaginations located within 100-200 nm of the plasma membrane. These results settle a long-lasting debate of whether PV directly breaks the plasma membrane barrier or relies on endocytosis to deliver its genome into the cell. We expect this imaging assay to be broadly applicable to the investigation of entry mechanisms for nonenveloped viruses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Psychological distress has been correlated with higher levels of nicotine dependence. To date, the possible association between individuals' levels of psychological distress and e-cigarette use has ...not been investigated, despite the dramatic growth of e-cigarette use in the US. We examined this possible association using a nationally representative sample of US adults.
A total of 36,697 adults from the 2014 National Health Interview Survey (NHIS) were included. The Kessler 6 scale was used to measure psychological distress. Multivariate logistic regression analysis was conducted to assess the association between level of psychological distress and e-cigarette use.
Both e-cigarette and cigarette use varied according to level of psychological distress as well as multiple socio-demographic characteristics. In a multivariate model, psychological distress was significantly associated with the following groups: (a) exclusive e-cigarette ever-use (aOR = 3.7; 95% CI = 1.6, 8.6), (b) current dual use of e-cigarettes and cigarettes (aOR = 4.6; 95% CI = 3.1, 6.7), (c) former cigarette use and ever use of e-cigarette (aOR = 3.2; 95% CI = 2.2, 4.8) and (d) current use of cigarettes only (aOR = 2.1; 95% CI = 1.7, 2.6).
These are the first data to demonstrate that, as is true for cigarettes, e-cigarette use is associated with increased levels of psychological distress. Further large-scale, longitudinal studies are needed to determine the direction of this relationship and to evaluate the long-term positive and negative consequences of such use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Low or high prepregnancy body mass index (BMI) and inadequate or excess gestational weight gain (GWG) are associated with adverse neonatal outcomes. This study estimates the contribution of these ...risk factors to preterm births (PTBs), small-for-gestational age (SGA) and large-for-gestational age (LGA) births in Canada compared to the contribution of prenatal smoking, a recognized perinatal risk factor.
We analyzed data from the Canadian Maternity Experiences Survey. A sample of 5,930 women who had a singleton live birth in 2005-2006 was weighted to a nationally representative population of 71,200 women. From adjusted odds ratios, we calculated population attributable fractions to estimate the contribution of BMI, GWG and prenatal smoking to PTB, SGA and LGA infants overall and across four obstetric groups.
Overall, 6% of women were underweight (<18.5 kg/m(2)) and 34.4% were overweight or obese (≥25.0 kg/m(2)). More than half (59.4%) gained above the recommended weight for their BMI, 18.6% gained less than the recommended weight and 10.4% smoked prenatally. Excess GWG contributed more to adverse outcomes than BMI, contributing to 18.2% of PTB and 15.9% of LGA. Although the distribution of BMI and GWG was similar across obstetric groups, their impact was greater among primigravid women and multigravid women without a previous PTB or pregnancy loss. The contributions of BMI and GWG to PTB and SGA exceeded that of prenatal smoking.
Maternal weight, and GWG in particular, contributes significantly to the occurrence of adverse neonatal outcomes in Canada. Indeed, this contribution exceeds that of prenatal smoking for PTB and SGA, highlighting its public health importance.
Background
Preterm births (PTB) and small‐for‐gestational‐age (SGA) births are distinct but related pregnancy outcomes, with differing aetiologies and short and long‐term morbidities. Few studies ...have compared a broad array of predictors among these two outcomes. The purpose of this study was to compare risk factors for PTB and SGA births using a national sample of Canadian women.
Methods
We analysed data from the Canadian Maternity Experiences Survey (n = 6421). Mothers were ≥15 years of age, gave birth to a singleton infant and were living with their infant at the time of the interview (between 5 and 14 months post‐partum). Backward stepwise multivariable logistic regression models were constructed for each outcome.
Results
Risk profiles for the two outcomes had both differences and similarities. Risk factors specific to PTB were education less than high school, having a previous medical condition, developing a new medical condition or health problem during pregnancy, being a primigravida, or being a multigravida with a previous PTB or a previous miscarriage or abortion. Risk factors unique to SGA were low pre‐pregnancy body mass index (<18 kg/m2), smoking during pregnancy and being a recent immigrant. Risk factors for both outcomes included low weight gain during pregnancy (<9.1 kg), short stature (<155 cm) and reporting life as ‘very stressful’ in the year prior to birth of the baby.
Conclusion
A greater understanding of the risk factors related to PTB and SGA may help to reduce the prevalence of these conditions and the associated risk of infant mortality and morbidity.
Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, ...mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Treatment of paroxysmal nocturnal haemoglobinuria (PNH) includes the monoclonal antibody eculizumab. This randomised, double‐blind, multi‐national cross‐over Phase III study in PNH patients aimed to ...demonstrate the equivalence of the proposed eculizumab biosimilar SB12 and reference eculizumab (Soliris, ECU). PNH patients with lactate dehydrogenase (LDH) ≥1·5× upper limit of normal were randomised into treatment sequences SB12‐ECU or ECU‐SB12. Four weekly infusions of 600 mg eculizumab were followed by fortnightly infusions of 900 mg until week 50 (ECU/SB12 cross‐over at week 26). Primary endpoints were LDH at week 26 and the time‐adjusted area under the effect curve (AUEC) of LDH over weeks 14‒26 and 40‒52. Among 46 patients (92%) who completed the study, the least squares mean (LSM) difference in LDH at week 26 (34·48; 95% confidence interval CI −47·66‒116·62 U/l) and geometric LSM ratio of time‐adjusted AUEC of LDH (1·08; 90% CI 0·95‒1·23) were within pre‐defined equivalence margins. Mean numbers of transfused red blood cell units, other secondary endpoints, pharmacokinetics, and pharmacodynamics were comparable. No patients developed anti‐drug antibodies. Treatment‐emergent adverse events were reported in 72% and 68% of patients in the SB12 and ECU treatment groups, respectively. The results demonstrate equivalence of SB12 to ECU and support SB12‐use in PNH patients.
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