131 research outputs found
Nonlinearity and disorder: Classification and stability of nonlinear impurity modes
We study the effects produced by competition of two physical mechanisms of
energy localization in inhomogeneous nonlinear systems. As an example, we
analyze spatially localized modes supported by a nonlinear impurity in the
generalized nonlinear Schr\"odinger equation and describe three types of
nonlinear impurity modes --- one- and two-hump symmetric localized modes and
asymmetric localized modes --- for both focusing and defocusing nonlinearity
and two different (attractive or repulsive) types of impurity. We obtain an
analytical stability criterion for the nonlinear localized modes and consider
the case of a power-law nonlinearity in detail. We discuss several scenarios of
the instability-induced dynamics of the nonlinear impurity modes, including the
mode decay or switching to a new stable state, and collapse at the impurity
site.Comment: 18 pages, 22 figure
Dynamical simulations of polaron transport in conjugated polymers with the inclusion of electron-electron interactions
Dynamical simulations of polaron transport in conjugated polymers in the
presence of an external time-dependent electric field have been performed
within a combined extended Hubbard model (EHM) and Su-Schrieffer-Heeger (SSH)
model. Nearly all relevant electron-phonon and electron-electron interactions
are fully taken into account by solving the time-dependent Schr\"{o}dinger
equation for the -electrons and the Newton's equation of motion for the
backbone monomer displacements by virtue of the combination of the adaptive
time-dependent density matrix renormalization group (TDDMRG) and classical
molecular dynamics (MD). We find that after a smooth turn-on of the external
electric field the polaron is accelerated at first and then moves with a nearly
constant velocity as one entity consisting of both the charge and the lattice
deformation. An ohmic region (3 mV/ 9
mV/) where the stationary velocity increases linearly with the
electric field strength is observed for the case of =2.0 eV and =1.0 eV.
The maximal velocity is well above the speed of sound. Below 3 mV/
the polaron velocity increases nonlinearly and in high electric fields with
strength 10.0 mV/ the polaron will become unstable and
dissociate. The relationship between electron-electron interaction strengths
and polaron transport is also studied in detail. We find that the the on-site
Coulomb interactions will suppress the polaron transport and small
nearest-neighbor interactions values are also not beneficial to the
polaronic motion while large values favor the polaron transport
Tight-binding parameters for charge transfer along DNA
We systematically examine all the tight-binding parameters pertinent to
charge transfer along DNA. The molecular structure of the four DNA bases
(adenine, thymine, cytosine, and guanine) is investigated by using the linear
combination of atomic orbitals method with a recently introduced
parametrization. The HOMO and LUMO wavefunctions and energies of DNA bases are
discussed and then used for calculating the corresponding wavefunctions of the
two B-DNA base-pairs (adenine-thymine and guanine-cytosine). The obtained HOMO
and LUMO energies of the bases are in good agreement with available
experimental values. Our results are then used for estimating the complete set
of charge transfer parameters between neighboring bases and also between
successive base-pairs, considering all possible combinations between them, for
both electrons and holes. The calculated microscopic quantities can be used in
mesoscopic theoretical models of electron or hole transfer along the DNA double
helix, as they provide the necessary parameters for a tight-binding
phenomenological description based on the molecular overlap. We find that
usually the hopping parameters for holes are higher in magnitude compared to
the ones for electrons, which probably indicates that hole transport along DNA
is more favorable than electron transport. Our findings are also compared with
existing calculations from first principles.Comment: 15 pages, 3 figures, 7 table
Infection-related and -unrelated malignancies, HIV and the aging population
Funding Information: Conflicts of interest: JR reports personal fees from Abbvie, Bionor, BMS, Boehringer, Gilead, Merck, Janssen, Tobira, Tibotec and ViiV, outside the submitted work. OK has received honoraria, consultancy and/or lecture fees from Abbott, Gilead, GSK, Janssen, Merck, Tibotec and Viiv outside the submitted work. All other authors state no commercial or other associations that may pose a conflict of interest. Funding: Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), 5th Framework (QLK2-2000-00773), 6th Framework (LSHP-CT-2006-018632) and 7th Framework (FP7/2007?2013; EuroCoord n? 260694) programmes. Current support also includes unrestricted grants from Janssen R&D, Merck and Co. Inc., Pfizer Inc. and GlaxoSmithKline LLC. The participation of centres in Switzerland was supported by The Swiss National Science Foundation (Grant 108787). The authors have no financial disclosures to make. Author contributions: LS developed the project, analysed the data, and was responsible for writing the manuscript. ?HB and OK contributed to the study design and analysis, interpretation of the data and writing of the manuscript. JL proposed the project and contributed to the study design, ideas for analysis, interpretation of the data and writing of the manuscript. BL, PD, AC, JR, BK, JT and IK contributed to national coordination, study design and writing of the manuscript. AM supervised the project and contributed to the study design and analysis, interpretation of the data and writing of the manuscript. Publisher Copyright: © 2016 British HIV AssociationObjectives: HIV-positive people have increased risk of infection-related malignancies (IRMs) and infection-unrelated malignancies (IURMs). The aim of the study was to determine the impact of aging on future IRM and IURM incidence. Methods: People enrolled in EuroSIDA and followed from the latest of the first visit or 1 January 2001 until the last visit or death were included in the study. Poisson regression was used to investigate the impact of aging on the incidence of IRMs and IURMs, adjusting for demographic, clinical and laboratory confounders. Linear exponential smoothing models forecasted future incidence. Results: A total of 15 648 people contributed 95 033 person-years of follow-up, of whom 610 developed 643 malignancies [IRMs: 388 (60%); IURMs: 255 (40%)]. After adjustment, a higher IRM incidence was associated with a lower CD4 count [adjusted incidence rate ratio (aIRR) CD4 count < 200 cells/μL: 3.77; 95% confidence interval (CI) 2.59, 5.51; compared with ≥ 500 cells/μL], independent of age, while a CD4 count < 200 cells/μL was associated with IURMs in people aged < 50 years only (aIRR: 2.51; 95% CI 1.40–4.54). Smoking was associated with IURMs (aIRR: 1.75; 95% CI 1.23, 2.49) compared with never smokers in people aged ≥ 50 years only, and not with IRMs. The incidences of both IURMs and IRMs increased with older age. It was projected that the incidence of IRMs would decrease by 29% over a 5-year period from 3.1 (95% CI 1.5–5.9) per 1000 person-years in 2011, whereas the IURM incidence would increase by 44% from 4.1 (95% CI 2.2–7.2) per 1000 person-years over the same period. Conclusions: Demographic and HIV-related risk factors for IURMs (aging and smoking) and IRMs (immunodeficiency and ongoing viral replication) differ markedly and the contribution from IURMs relative to IRMs will continue to increase as a result of aging of the HIV-infected population, high smoking and lung cancer prevalence and a low prevalence of untreated HIV infection. These findings suggest the need for targeted preventive measures and evaluation of the cost−benefit of screening for IURMs in HIV-infected populations.publishersversionPeer reviewe
Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study
Objectives Mortality among HIV patients with tuberculosis (TB) remains high in Eastern Europe (EE), but details of TB and HIV management remain scarce. Methods In this prospective study, we describe the TB treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART). Results A total of 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95%CI 41.5\u201374.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%. Conclusions Our results show that internationally recommended MDR-TB treatment regimens were infrequently used and that ART use and viral suppression was well below the target of 90%, reflecting the challenging patient population and the environment in which health care is provided. Urgent improvement of management of patients with TB/HIV in EE, in particular for those with MDR-TB, is needed and includes widespread access to rapid TB diagnostics, better access to and use of second-line TB drugs, timely ART initiation with viral load monitoring, and integration of TB/HIV care
Легочные осложнения у детей и подростков после трансплантации гемопоэтических стволовых клеток
Relevance. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) makes it possible to treat severe malignant and non-malignant hematopoietic disorders system. Pulmonary complications (PC) occur in 40–60 % of patients after allo-HSCT. However to date, the effect of HSCT on functional and morphological pulmonary changes in recipients remains insufficiently studied.The objective of current study was to evaluate risk factors affecting long-term survival in children and adolescents after allo-HSCT.Methods and materials. The current study was both retrospective and prospective. The analysis included 362 patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), aged 5 months to 18 years, who received allo-HSCT at Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation in 2000–2018. All the patients underwent chest computed tomography (CT). When detecting CT changes, we performed fibrobronchoscopy (FBS) with microbiological examination of bronchoalveolar lavage (BAL).Results. PC were diagnosed in 124 patients (64 %) who received allo-HSCT in 2014–2018. Decrease of overall survival (OS) is associated with PC development during the first year after allo-HSCT(р<0,001).The development of early PC in remission of the underlying disease significantly affected OS (p=0.001).The probability of PC development is 2.26 times higher in patients older than 9 years (p=0.006). When comparing the intensity of conditioning regimens (MACvsRIC) in remission of the underlying disease, we did not get significant differences in the incidence of PC (p>0.05). Graft source, donor type, HLA-compatibility, recipient gender did not affect the incidence of PC (p>0.05). When using graft-versus-host disease (GVHD) prophylaxis (ptCYvsATG), the 5-year OS in patients without PC was 78.8 % and 62.8 %respectively. The 5-year OS in patients with PC was 51.8 % and 42.4 % respectively (р=0.007). Decrease of OS in patients with PC is associated with chGVHD(58.3 %,) (р=0.03).Conclusion. Pulmonary complications (infectious and non-infectious) in allo-HSCT recipients are more likely to occur in the first year after transplantation. Among bacterial pathogens, the predominance of Gr(-) flora remains. The incidence of pulmonary complications was significantly lower when using ptCY as a prevention of GVHD. Введение. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) позволяет излечить тяжелые злокачественные и незлокачественные заболевания системы крови. Легочные осложнения (ЛО) после алло-ТГСК встречаются у 40–60% пациентов. Однако до настоящего времени остается недостаточно изученным влияние ТГСК на функциональные и морфологические изменения в легких у реципиентов.Цель – изучить факторы риска, влияющие на долгосрочную выживаемость у детей и подростков после алло-ТГСК.Методы и материалы. Настоящее исследование было как ретроспективным, так и проспективным. В анализ включены 362 пациента с острым лимфобластным лейкозом (ОЛЛ) и острым миелоидным лейкозом (ОМЛ), в возрасте от 5 месяцев до 18 лет, получивших алло-ТГСК в НИИ ДОГиТ им. Р. М. Горбачёвой в период с 2000 по 2018 г. Всем пациентам проводилась компьютерная томография (КТ) грудной клетки. При обнаружении изменений на КТ мы выполняли диагностическую фибробронхоскопию (ФБС) с микробиологическим исследованием бронхоальвеолярного лаважа (БАЛ). Результаты. ЛО диагностированы у 124 (64 %) пациентов из 193 пациентов, получавших алло-ТГСК с 2014 по 2018 г. Снижение общей выживаемости (ОВ) ассоциировано с развитием ЛО в течение первого года после алло-ТГСК (р<0,001). Развитие ранних легочных осложнений в ремиссии основного заболевания значимо влияло на ОВ (р=0,001). Шанс развития ЛО в 2,26 раза выше у пациентов старше 9 лет (р=0,006). При сравнении интенсивности режимов кондиционирования (миелоаблативные (МАК) режимы и режимы со сниженной интенсивностью доз (РИК)) в ремиссии основного заболевания нами не было получено значимых различий в частоте возникновения легочных осложнений (р>0,05). Источник трансплантата, тип донора, совместимость по генам HLA-системы, пол реципиента не оказывали влияния на частоту развития легочных осложнений (р>0,05). При использовании режима профилактики реакции «трансплантат против хозяина» (РТПХ) (птЦФ против АТГ) 5-летняя ОВ у пациентов без ЛО составила 78,8 и 62,8 % соответственно. У пациентов с ЛО 5-летняя ОВ – 51,8 и 42,4 % соответственно (р=0,007). Ухудшение общей выживаемости у пациентов с ЛО ассоциировано с хРТПХ (58,3 %) (р=0,03).Заключение. Легочные осложнения (инфекционные и неинфекционные) у реципиентов алло-ТГСК чаще возникают в первый год после выполнения трансплантации. Среди бактериальных возбудителей сохраняется преобладание Гр(-)-флоры. Частота развития легочных осложнений была значительно ниже при использовании птЦФ в качестве профилактики РТПХ.
Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study
Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection
Анализ факторов риска и эффективности Дефибротида для лечения синдрома обструкции синусоидов/веноокклюзионной болезни печени после аллогенной трансплантации гемопоэтических стволовых клеток у детей и взрослых
Introduction. Sinusoidal obstructive syndrome (SOS)/veno-occlusive liver disease (VOD) is one of the most dangerous complication of allogeneic hematopoietic stem cell transplantation (alloHSCT).The objective of our study was to analyze risk factors associated with SOS/VOD in children and adults after alloHSCT.Methods and materials. The study included 76 patients who were diagnosed with the development of SOS/VOD after alloHSCT performed in Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation between 2001 and 2019. 25 patients (32.9 %) were younger than 18 years, 51 patients (68.1 %) — 18 years and older. Among them, 17 patients were treated with defibrotide at a dose of 25 mg/kg per day, median therapy duration — 21 day.Results. One-year overall survival (OS) was significantly higher when partial and complete response to the therapy was achieved — 45 %, than when there was no response — 0 % in the general group (p = 0.001). According to the results of multivariate analysis of unrelated alloHSCT HR 2.040 (95 %CI 1.112-3.744, р = 0.021), acute GVHD HR 0.496 (95 % CI 0.272-0.903, р = 0.022), moderate/severe SOS/VOD HR 2.423 (95 % CI 1.298-4.524, p = 0.005) statistically significantly influenced the 1-year OS. Defibrotide and accompanying therapy did not significantly influence the 1-year OS in children and adults (n=76) - 53 % and 54 % (p=0.86), respectively. In a multivariate analysis. unrelated alloHSCT HR 8.172 (95 %CI 2.176-30.696, р=0.002) and moderate and severe SOS/VOD HR 9.077 (95 % CI 2.425-33.978, р=0.001) significantly influenced the 1-year OS in the pediatric group.Conclusion. The understanding of risk factors of adverse prognosis in patients SOS/VOD facilitates selection of patients who will benefit the most from therapy with defibrotide. Early administration of defibrotide in the course of VOD/SOS is crucial to achieve response.Введение. Синдром обструкции синусоидов (СОС)/веноокклюзионная болезнь печени (ВОБ) — одно из фатальных осложнений аллогенной трансплантации гемопоэтических стволовых клеток (аллоТГСК).Целью исследования является оценка факторов риска и эффективности применения Дефибротида при СОС/ ВОБ у детей и взрослых после аллоТГСК.Методы и материалы. В исследование включены 76 пациентов НИИДОГИТ им. Р. М. Горбачёвой после аллоТГСК, у которых в период с 2001 по 2019 г. было выявлено развитие СОС/ВОБ печени. В возрасте до 18 лет наблюдали 25 (32,9 %) пациентов, 51 (68,1 %) пациент — 18 лет и старше. Из них 17 пациентов получили Дефибротид в дозе 25 мг/кг в сутки, медиана длительности терапии составила 21 день.Результаты. Однолетняя общая выживаемость (ОВ) была значимо выше при достижении частичного и полного ответа на терапию — 45 %, чем при отсутствии ответа — 0 % в общей группе (р = 0,001). По результатам многофакторного анализа аллоТГСК от неродственного донора ОР 2,040 (95 % ДИ 1,112 — 3,744, р = 0,021), наличие острой реакции «трансплантат против хозяина» (оРТПХ) ОР 0,496 (95 % ДИ 0,272 — 0,903, р = 0,022), степень СОС/ВОБ ОР 2,423 (95 % ДИ 1,298 — 4,524, р = 0,005) статистически значимо влияли на 1-летнюю ОВ. При применении Дефибротида и сопроводительной терапии 1-летняя ОВ не различалась в группе взрослых и детей (n=76) и составила 53 и 54 % соответственно (Р = 0,86). В многофакторном анализе аллоТГСК от неродственного донора — ОР 8,172 (95 % ДИ 2,176 — 30,696, р = 0,002) и СОС/ВОБ 2 — 3-й степени — ОР 9,077 (95 % ДИ 2,425 — 33,978, р = 0,001) — статистически значимо влияли на 1-летнюю ОВ в педиатрической группе.Заключение. Обнаружение неблагоприятных факторов риска позволит сделать диагностику СОС/ВОБ более своевременной и безотлагательно начать терапию, что имеет ключевое значение для эффективного лечения данного осложнения аллоТГСК
Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study
Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe
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