Abstract
Background
In human immunodeficiency virus (HIV)–positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased ...risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART.
Methods
Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children <18 years at ART initiation, with sustained viral suppression (VS) (≤400 copies/mL) for ≥1 year were included. The prevalence of PIR (defined as World Health Organization advanced/severe immunosuppression for age) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of acquired immunodeficiency syndrome (AIDS) or death on suppressive ART were calculated by PIR status.
Results
Of 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P ≤ .03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P < .001).
Conclusions
One in eight children in our cohort experienced PIR despite sustained VS. While the overall rate of AIDS/death was low, children with PIR had a 4-fold increase in risk of event as compared with immune responders.
One in eight children living with human immunodeficiency virus in Europe and Thailand experienced poor immune response at 1 year of virally suppressive antiretroviral therapy. These children had a 4-fold increased risk of AIDS or death compared with immune responders.
We report measurements of the flux-integrated $\overline{\nu}_\mu$ and $\overline{\nu}_\mu+\nu_\mu$ charged-current cross-sections on water and hydrocarbon targets using the T2K anti-neutrino beam ...with a mean beam energy of 0.86 GeV. The signal is defined as the (anti-)neutrino charged-current interaction with one induced $\mu^\pm$ and no detected charged pion or proton. These measurements are performed using a new WAGASCI module recently added to the T2K setup in combination with the INGRID Proton Module. The phase space of muons is restricted to the high-detection efficiency region, $p_{\mu}>400~{\rm MeV}/c$ and $\theta_{\mu}<30^{\circ}$, in the laboratory frame. An absence of pions and protons in the detectable phase spaces of $p_{\pi}>200~{\rm MeV}/c$, $\theta_{\pi}<70^{\circ}$ and $p_{\rm p}>600~{\rm MeV}/c$, $\theta_{\rm p}<70^{\circ}$ is required. In this paper, both the $\overline{\nu}_\mu$ cross-sections and $\overline{\nu}_\mu+\nu_\mu$ cross-sections on water and hydrocarbon targets and their ratios are provided by using the D’Agostini unfolding method. The results of the integrated $\overline{\nu}_\mu$ cross-section measurements over this phase space are $\sigma_{\rm H_{2}O}=(1.082\pm0.068(\rm stat.)^{+0.145}_{-0.128}(\rm syst.)) \times 10^{-39}\,{\rm cm^{2} / nucleon}$, $\sigma_{\rm CH}=(1.096\pm0.054(\rm stat.)^{+0.132}_{-0.117}(\rm syst.)) \times 10^{-39}\,{\rm cm^{2} / nucleon}$, and $\sigma_{\rm H_{2}O}/\sigma_{\rm CH} = 0.987\pm0.078(\rm stat.)^{+0.093}_{-0.090}(\rm syst.)$. The $\overline{\nu}_\mu+\nu_\mu$ cross-section is $\sigma_{\rm H_{2}O} = (1.155\pm0.064(\rm stat.)^{+0.148}_{-0.129}(\rm syst.)) \times 10^{-39}\,{\rm cm^{2} / nucleon}$, $\sigma_{\rm CH}=(1.159\pm0.049(\rm stat.)^{+0.129}_{-0.115}(\rm syst.)) \times 10^{-39}\,{\rm cm^{2} / nucleon}$, and $\sigma_{\rm H_{2}O}/\sigma_{\rm CH}=0.996\pm0.069(\rm stat.)^{+0.083}_{-0.078}(\rm syst.)$.
Aberrant expression of trk receptor kinases and enhanced expression of various neurotrophins (NTs) have been implicated in the development and progression of human prostatic carcinoma and pancreatic ...ductal adenocarcinoma. We examined the antitumor efficacy of administration of NT neutralizing antibodies on the growth of established human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice.
In initial studies, tumor-bearing nude mice were treated with a mixture of NT antibodies 100 microg each of anti-nerve growth factor (NGF), anti-brain-derived neurotrophic factor, anti-NT-3, and anti-NT-4/5 or normal rabbit IgG (400 microg) intratumorally and peritumorally three times/week over a 15-day dosing period. In subsequent studies, tumor-bearing nude mice were treated with individual NT antibodies (100 microg), affinity-purified anti-NGF (0.1, 1.0, or 10.0 microg), or normal rabbit IgG (100 microg) using the same dosing schedule.
Treatment with the antibody mixture inhibited significantly the growth of TSU-Pr1 and AsPC-1 xenografts as compared with IgG-treated controls (maximal inhibition of 53 and 53%, respectively), whereas this treatment caused significant regression in PC-3 xenografts. Treatment of TSU-Pr1 xenografts with either anti-NGF or anti-NT-3 resulted in maximal tumor growth inhibition of 67 and 64%, respectively, whereas anti-brain-derived neurotrophic factor and anti-NT-4/5 did not inhibit tumor growth in this tumor model. Administration of various concentrations (0.1, 1.0, or 10.0 microg) of affinity-purified anti-NGF resulted in maximal TSU-Pr1 tumor growth inhibition of 49, 62, and 66%, respectively.
These data add further support for the therapeutic potential of disrupting trk-signaling events in select types of nonneuronal human cancers, specifically prostatic and pancreatic carcinomas.
Healthcare workers exposed to coronavirus 2019 (COVID-19) patients could be psychologically distressed. This study aims to assess the magnitude of psychological distress and associated factors among ...hospital staff during the COVID-19 pandemic in a large tertiary hospital located in north-east Italy.
All healthcare and administrative staff working in the Verona University Hospital (Veneto, Italy) during the COVID-19 pandemic were asked to complete a web-based survey from 21 April to 6 May 2020. Symptoms of post-traumatic distress, anxiety and depression were assessed, respectively, using the Impact of Event Scale (IES-R), the Self-rating Anxiety Scale (SAS) and the Patient Health Questionnaire (PHQ-9). Personal socio-demographic information and job characteristics were also collected, including gender, age, living condition, having pre-existing psychological problems, occupation, length of working experience, hospital unit (ICUs and sub-intensive COVID-19 units vs. non-COVID-19 units). A multivariable logistic regression analysis was performed to identify factors associated with each of the three mental health outcomes.
A total of 2195 healthcare workers (36.9% of the overall hospital staff) participated in the study. Of the participants, 35.7% were nurses, 24.3% other healthcare staff, 16.4% residents, 13.9% physicians and 9.7% administrative staff. Nine per cent of healthcare staff worked in ICUs, 8% in sub-intensive COVID-19 units and 7.6% in other front-line services, while the remaining staff worked in hospital units not directly engaged with COVID-19 patients. Overall, 63.2% of participants reported COVID-related traumatic experiences at work and 53.8% (95% CI 51.0%-56.6%) showed symptoms of post-traumatic distress; moreover, 50.1% (95% CI 47.9%-52.3%) showed symptoms of clinically relevant anxiety and 26.6% (95% CI 24.7%-28.5%) symptoms of at least moderate depression. Multivariable logistic regressions showed that women, nurses, healthcare workers directly engaged with COVID-19 patients and those with pre-existing psychological problems were at increased risk of psychopathological consequences of the pandemic.
The psychological impact of the COVID-19 pandemic on healthcare staff working in a highly burdened geographical of north-east Italy is relevant and to some extent greater than that reported in China. The study provides solid grounds to elaborate and implement interventions pertaining to psychology and occupational health.
Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to ...selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration IC50 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.
Recent studies have reported collagen cross-linking after exposure to riboflavin followed by ultraviolet-A (UVA) exposure. This study is the first to investigate the effect of a riboflavin-containing ...primer on adhesive interface stability and dentinal matrix metalloproteinase activity. Human dentin was etched with 35% phosphoric acid, treated with 0.1% riboflavin, exposed to UVA for 2 min, and bonded with a two-step etch-and-rinse adhesive. Adhesive was applied to control specimens without riboflavin/UVA. Specimens were subjected to microtensile bond strength tests and pulled to failure after storage for 24 hrs, 6 mos, or 1 yr. Interfacial nanoleakage was evaluated by light and transmission electron microscopy. To investigate dentinal matrix metalloproteinase activity, we performed correlative zymographic assays on protein extracts obtained from phosphoric-acid-etched dentin powder with or without riboflavin/UVA treatment and XP Bond. Ultraviolet-activated riboflavin treatment increased the immediate bond strength to dentin at all aging intervals (p < 0.05 vs. control) and decreased interfacial nanoleakage in aged specimens (1 yr; p < 0.05). Zymograms revealed that riboflavin/UVA pre-treatment inhibited dentinal matrix metalloproteinase activity (especially MMP-9). In conclusion, dentinal collagen cross-linking induced by riboflavin/UVA increased immediate bond strength, stabilized the adhesive interface, and inhibited dentin matrix metalloproteinases, thereby increasing the durability of resin-dentin bonds.
Safe and effective antithrombotic therapy requires understanding of mechanisms that contribute to pathological thrombosis but have a lesser impact on hemostasis. We found that the extrinsic tissue ...factor (TF) coagulation initiation complex can selectively activate the antihemophilic cofactor, FVIII, triggering the hemostatic intrinsic coagulation pathway independently of thrombin feedback loops. In a mouse model with a relatively mild thrombogenic lesion, TF-dependent FVIII activation sets the threshold for thrombus formation through contact phase-generated FIXa. In vitro, FXa stably associated with TF-FVIIa activates FVIII, but not FV. Moreover, nascent FXa product of TF-FVIIa can transiently escape the slow kinetics of Kunitz-type inhibition by TF pathway inhibitor and preferentially activates FVIII over FV. Thus, TF synergistically primes FIXa-dependent thrombin generation independently of cofactor activation by thrombin. Accordingly, FVIIa mutants deficient in direct TF-dependent thrombin generation, but preserving FVIIIa generation by nascent FXa, can support intrinsic pathway coagulation. In ex vivo flowing blood, a TF-FVIIa mutant complex with impaired free FXa generation but activating both FVIII and FIX supports efficient FVIII-dependent thrombus formation. Thus, a previously unrecognized TF-initiated pathway directly yielding FVIIIa-FIXa intrinsic tenase complex may be prohemostatic before further coagulation amplification by thrombin-dependent feedback loops enhances the risk of thrombosis.
•A coagulation initiating pathway is revealed in which the TF-FVIIa-nascent FXa complex activates FVIII apart from thrombin feedback.•Direct activation of the intrinsic pathway by TF may preserve hemostasis under anticoagulant therapy targeting thrombin amplification.
Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase ...activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr−/−) mice were crossed with the KrasG12D/+; Trp53R172H/+; Ptf1aCre/+ (KPC) model of metastatic PDA. Ddr1−/−; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1−/−; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1−/− mice were crossed with the KrasG12D/+; Ptf1aCre/+ neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1−/− models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1−/− animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy generally associated with poor prognosis. Allogeneic hematopoietic cell transplantation (alloHCT) continues to be the most ...potent anti-leukemia treatment for adult patients with intermediate and high-risk AML. However, disease relapse after alloHCT remains unacceptably high and is the primary cause of treatment failure and mortality following alloHCT. It is therefore that post-transplant early cellular or pharmacologic maintenance or preemptive strategies to enhance the graft-versus-leukemia effect or to eradicate persistent minimal residual disease have been of renewed interest, particularly with the availability of more sensitive technologies to measure residual AML. Although preliminary studies have demonstrated improved outcomes with the use of post-alloHCT remission therapies, prospective randomized trials are required to determine their clinical efficacy and role in the treatment of AML. On behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use and efficacy of available pharmacologic post-remission therapies, including hypomethylating agents, deacetylase inhibitors, and tyrosine kinase inhibitors, as well as cellular therapies, including preemptive and prophylactic donor lymphocyte infusions for the prevention of relapse of AML.
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