Efficacy and safety of ferric derisomaltose (FDI) compared with iron sucrose (IS) in patients with iron deficiency anemia after bariatric surgery

Purpose Iron deficiency is common following bariatric surgery, and treatment with intravenous iron is often required. This post hoc analysis of data from two randomized, open-label, multicenter trials evaluated the efficacy and safety of ferric derisomaltose (FDI; formerly iron isomaltoside 1000) versus iron sucrose (IS) over 4 weeks in adults with iron deficiency anemia (IDA) resulting from prior bariatric surgery. Materials and methods Data were pooled for participants who received FDI or IS in the PROVIDE or FERWON-IDA trials for the treatment of IDA post bariatric surgery. Efficacy outcomes included changes in hemoglobin (Hb) and iron parameters; safety outcomes included the incidence of adverse drug reactions (ADRs), serious or severe hypersensitivity reactions (HSRs), and hypophosphatemia. Results The analysis included 159 patients. Mean (standard deviation) cumulative iron doses were 1199 (± 347) mg for FDI and 937 (± 209) mg for IS. Compared with IS, FDI resulted in a faster and more pronounced Hb response, and a higher proportion of responders (Hb level increase ≥ 2 g/dL from baseline) at all time points. The incidence of ADRs was similar with FDI and IS (15.1% and 18.2%, respectively), with no serious ADRs or serious or severe HSRs reported. The incidence of hypophosphatemia was low and similar in both treatment groups, with no cases of severe hypophosphatemia observed. Conclusions In patients with IDA resulting from bariatric surgery, FDI produced a faster and more pronounced Hb response than IS. Both FDI and IS were well tolerated. Graphical abstract

CHANGES IN SERUM LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR WITH ELECTROCONVULSIVE THERAPY AND PHARMACOTHERAPY AND ITS CLINICAL CORRELATES IN MALE SCHIZOPHRENIA PATIENTS

Objectives: It has been postulated that neurotrophin dysregulation leads to disorganization in neuronal networks, which results in schizophrenia. The current study sets out to evaluate if the finding of lower BDNF levels in schizophrenia patients could be confirmed in an independent cohort, and to investigate if the BDNF levels can be altered with different treatment modalities such as electroconvulsive therapy (ECT) and/or antipsychotic pharmacotherapy (PT). Methods: A total of 54 male patients with schizophrenia and 35 healthy controls were included in the study. Schizophrenia patients were subdivided into two groups as the ones who underwent ECT+PT and only PT. Clinical and sociodemographic data questionnaire, Positive and Negative Syndrome Scale (PANSS) and blood sample collection for BDNF assessment were applied to all patients (on first and last days of admissions) and healthy participants (on the day of the interview). Then, clinical parameters and blood sample outcomes were statistically analyzed. Results: Mean BDNF levels of healthy individuals was significantly higher than mean pre and post-treatment BDNF levels in both PT only and ECT+PT groups. While serum BDNF levels did not increase after ECT+PT, there was a trend level increase in the PT only group. There was no significant correlation between the change in serum BDNF levels with total PANSS scores in either group after treatment. Conclusions: We could confirm previously suggested data of lower serum BDNF levels in schizophrenia patients compared to healthy population but we couldn’t find significant increase in serum BDNF levels with ECT+PT or only PT as some previous studies suggested.

Protective Effect of Flavonoids from a Deep-Sea-Derived Arthrinium sp. against ox-LDL-Induced Oxidative Injury through Activating the AKT/Nrf2/HO-1 Pathway in Vascular Endothelial Cells

Oxidized low-density lipoprotein (ox-LDL)-induced oxidative injury in vascular endothelial cells is crucial for the progression of cardiovascular diseases, including atherosclerosis. Several flavonoids have been shown cardiovascular protective effects. Recently, our research group confirmed that the novel flavonoids isolated from the deep-sea-derived fungus Arthrinium sp., 2,3,4,6,8-pentahydroxy-1-methylxanthone (compound 1) and arthone C (compound 2) effectively scavenged ROS in vitro. In this study, we further investigated whether these compounds could protect against ox-LDL-induced oxidative injury in endothelial cells and the underlying mechanisms. Our results showed that compounds 1 and 2 inhibited ox-LDL-induced apoptosis and adhesion factors expression in human umbilical vein vascular endothelial cells (HUVECs). Mechanistic studies showed that these compounds significantly inhibited the ROS level increase and the NF-κB nuclear translocation induced by ox-LDL. Moreover, compounds 1 and 2 activated the Nrf2 to transfer into nuclei and increased the expression of its downstream antioxidant gene HO-1 by inducing the phosphorylation of AKT in HUVECs. Importantly, the AKT inhibitor MK-2206 2HCl or knockdown of Nrf2 by RNA interference attenuated the inhibition effects of these compounds on ox-LDL-induced apoptosis in HUVECs. Meanwhile, knockdown of Nrf2 abolished the effects of the compounds on ox-LDL-induced ROS level increase and the translocation of NF-κB to nuclei. Collectively, the data showed that compounds 1 and 2 protected endothelial cells against ox-LDL-induced oxidative stress through activating the AKT/Nrf2/HO-1 pathway. Our study provides new strategies for the design of lead compounds for related cardiovascular diseases treatment.

Ichthyoplankton Species Composition and Assemblages From the Estuary to the Hukou Section of the Changjiang River

Estuary river–lake (ERL) complex is critical for the development of ichthyoplankton, which plays an essential role in the breeding, nursing, and recruitment of freshwater fish species. In this study, different ERL sections were selected to investigate the ichthyoplankton assemblage from the Changjiang River estuary to its Hukou section between May 2018 and August 2020. During the study period, fish larvae of 40, 35, 54, and 46 fish species were sampled in the Rugao (RG), Nanjing (NJ) (nearby estuary), Anqing (AQ), and Hukou (HK) (connected river–lake) sections in the Changjiang River, respectively. Results on ichthyoplankton surveys revealed fluctuating assemblage patterns in the different river sections; larval fish species composition presented ecological habitat-dependent characteristics, which supported the importance of ERL complex for ichthyoplankton development. Furthermore, the density of fish larvae was negatively correlated with water transparency but positively correlated with water temperature, the daily rate of water level increase, and runoff in the limitative range. A generalized additive model analysis indicated that the hydrological factors significantly affecting larval fish abundance are water temperature, transparency, the daily rate of water level increase, and runoff (p < 0.05). These results also indicated that river estuaries and river–lake connected complexes are essential for ichthyoplankton recruitment and migration. In combination with the historical record, ichthyoplankton assemblage’s patterns in the Changjiang River lower reaches were preliminarily elucidated, although additional works are needed such as assessing effects on their survival and recruitment.

Comparative pharmacoeconomic analysis of the use of erythropoiesis-stimulating drugs for the treatment of anemia in cancer patients

Introduction. Currently, a number of pharmacoeconomic studies describing use of erythropoietin stimulating agent (ESA) in cancer patients with anemia have been published, however, most of the publications on this topic are foreign. At the same time, there are practically no studies comparing the economic efficiency of various ESA preparations with each other. Some of works by foreign colleagues reflect that the clinical efficacy of using ESA namely the degree of increase in Hb, significantly depends on the patient’s body weight: the higher the weight, the greater the dose of EPO is required for a single administration and a course of therapy.Aim. Сomparative pharmacoeconomic analysis of epoetin alfa usage for the treatment of anemia in adult cancer patients with weight 80 kg.Materials and methods. The following drugs were selected for comparative analysis: epoetin alfa, epoetin beta, darbepoetin. Clinical efficacy was assessed in terms of the rate of in Hb level increase. Pharmacoeconomic analysis was carried out using the cost-effectiveness method (CEA).Results. Тhe usage of epoetin alfa 12,000 IU for 8 weeks therapy course in cancer patients weighting over 80 kg had a better cost-effectiveness ratio compared to epoetin alfa (10,000 IU, 30,000 IU, 40,000 IU) and darbepoetin, giving way in price only to the cheapest epoetin beta which can be administered 4 injections simultaneously. Its the infringement of patients rights to avoid additional pain. Its the infringement of patients rights to avoid additional pain. At the 16th week of therapy, the usage of epoetin alfa 12,000 IU had an advantage over all ESA.Conclusions. Тhe usage of russian epoetin alfa 12,000 IU for the treatment of anemia in adult cancer patients weighing over 80 kg approximately in real clinical practice in Russian Federation is an economically justified approach to the medical care organization.

Estimating the impact of influenza on the epidemiological dynamics of SARS-CoV-2

As in past pandemics, co-circulating pathogens may play a role in the epidemiology of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In particular, experimental evidence indicates that influenza infection can up-regulate the expression of ACE2—the receptor of SARS-CoV-2 in human cells—and facilitate SARS-CoV-2 infection. Here we hypothesized that influenza impacted the epidemiology of SARS-CoV-2 during the early 2020 epidemic of COVID-19 in Europe. To test this hypothesis, we developed a population-based model of SARS-CoV-2 transmission and of COVID-19 mortality, which simultaneously incorporated the impact of non-pharmaceutical control measures and of influenza on the epidemiological dynamics of SARS-CoV-2. Using statistical inference methods based on iterated filtering, we confronted this model with mortality incidence data in four European countries (Belgium, Italy, Norway, and Spain) to systematically test a range of assumptions about the impact of influenza. We found consistent evidence for a 1.8–3.4-fold (uncertainty range across countries: 1.1 to 5.0) average population-level increase in SARS-CoV-2 transmission associated with influenza during the period of co-circulation. These estimates remained robust to a variety of alternative assumptions regarding the epidemiological traits of SARS-CoV-2 and the modeled impact of control measures. Although further confirmatory evidence is required, our results suggest that influenza could facilitate the spread and hamper effective control of SARS-CoV-2. More generally, they highlight the possible role of co-circulating pathogens in the epidemiology of COVID-19.

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

Nerve trauma-induced toll-like receptor 7 (TLR7) expression level increase in primary sensory neurons in the damaged dorsal root ganglion (DRG) avails to neuropathic pain, but the reason is still unknown. In the current study, we showed that unilateral lumbar 4 (L4) spinal nerve ligation (SNL) upregulated CCAAT/enhancer-binding protein-β (C/EBPβ) expression in ipsilateral L4 DRG. Preventing this elevation attenuated the SNL-induced upregulation of TLR7 in the ipsilateral L4 DRG and inhibited cold/thermal hyperalgesia and mechanical allodynia. Mimicking nerve trauma-induced C/EBPβ upregulation generated an elevated level of TLR7 in injected DRG, augmented responses to cold/thermal/mechanical stimuli while causing ipsilateral spontaneous pain with no SNL. Mechanistically, SNL upregulated binding of increased C/EBPβ to Tlr7 promoter in ipsilateral L4 DRG. Accorded that C/EBPβ could trigger the activation of Tlr7 promoter and co-expressed with Tlr7 mRNA in individual DRG neurons, our findings strongly suggest the role of C/EBPβ in nerve trauma-mediated TLR7 upregulation in damaged primary sensory neurons.

Dynamics of fortnightly water level variations along a tide-dominated estuary with negligible river discharge

Observations indicate that the fortnightly fluctuations in the mean amplitude of water level increase in the upstream direction along the lower half of a tide-dominated estuary (the Guadiana Estuary), with negligible river discharge, but remain constant upstream. Analytical solutions reproducing the semi-diurnal wave propagation shows that this pattern results from reflection effects at the estuary head. The phase difference between velocity and elevation increases from the mouth to the head (where the wave has a standing nature) as the timing of high and low water levels come progressively closer to slack water. Thus, the tidal (flood–ebb) asymmetry in discharge is reduced in the upstream direction. It becomes negligible along the upper estuary half as the mean sea level remains constant despite increased friction due to wave shoaling. Observations of a flat mean water level along a significant portion of an upper estuary suggest a standing wave character and, thus, indicate significant reflection of the propagating semi-diurnal wave at the head. Details of the analytical model show that changes in the mean depth or length of semi-arid estuaries, in particular for macrotidal locations, affect the fortnightly tide amplitude and, thus, the upstream mass transport and inundation regime. This has significant potential impacts on the estuarine environment in terms of ecosystem management.

A Dose Escalation Phase Ia Study of Anti-CD20 Antibody Drug Conjugate, MRG001 in Relapsed/Refractory Advanced Non-Hodgkin Lymphom

Background: MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE), an anti-microtubulin agent. In preclinical studies, MRG001 demonstrated significant tumor growth inhibition in rituximab-resistant non-Hodgkin's lymphoma (NHL) models. MRG001 is being evaluated in a first-in-human, open-label, multicenter Phase I study for the safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity in patients with CD20-positive relapsed or refractory (R/R) B-cell NHL. Methods: MRG001 was evaluated as a monotherapy for the treatment of patients with confirmed CD20-positive R/R B-cell NHL. The study consists of Phase Ia dose escalation and Ib dose expansion. In the Phase Ia dose-escalation study utilizing a "3+3" design, patients with pathologically confirmed R/R NHL received single agent MRG001 intravenously once every 3 weeks (Q3W) for a maximum of 6 treatment cycles. Six dose levels ranging from 0.15 to 2.5 mg/kg were evaluated for safety, PK and preliminary antitumor activity to determine the MTD/RP2D. Results: From June 25, 2019 to May 31, 2021, a total of 21 subjects with DLBCL (n=8), FL (n=12), and MZL (n=1) who met the eligibility criteria had received at least two cycles of MRG001. As of May 31, 2021, 18 subjects were off treatment and 3 subjects were still on treatment. There were 3 subjects enrolled into the 0.15, 0.3 , 0.6, 1.2 and 2.5 mg/kg cohort respectively, and 6 subjects enrolled into the 1.8 mg/kg cohort. Of the 21 subjects enrolled, 12 subjects were male and 9 subjects were female, with age ranging from 27 to 75 years old. Among the 18 subjects who were off treatment, 5 had completed 6 cycles of treatment, and 13 had drug discontinuation (12 due to progression of disease and 1 subject due to withdrawal of the informed consent for personal reasons). Commonly observed drug-related TEAEs were decreased white blood cell/neutrophil/lymphocyte counts, ALT/AST elevation, pyrexia, hypertension, increased LDH, QT prolongation, and thrombocytopenia.TEAEs (29 cases) ≥ Grade 3 were reported in 9 subjects, including 23 drug-related TEAEs in 8 subjects. The most commonly reported Grade 3 or above TRAEs were leukopenia/neutropenia, lymphopenia, hypertension, and ALT elevation. In the 2.5 mg/kg cohort, two subjects experienced drug-related toxicities that met the DLT definition per protocol, including 1 subject with Grade 3 hyperlipidemia and 1 subject with Grade 4 neutropenia that lasted 5 days. There was no death due to AEs. PK samples of total antibody, MRG001 and MMAE were measured at predefined time points and the results showed that the C max and AUC of total antibody, MRG001 and MMAE increased with dose level increase. The T max of MMAE was non-linear to dose level increase, similar trends could be observed in two other parameters including C max and AUC 0-t, which suggested that MMAE was continuously released from MRG001. Among 21 pts who had at least one tumor assessment, 1 CR (5%), 4 PR (19%), 9 SD (43%), and 7 PD (33%). The investigator assessed ORR was 24% and the DCR was 67%. In the starting dose 0.15 mg/kg cohort, one subject with FL acheived PR. Among six subjects (4 with DLBCL and 2 with FL) enrolled in the 1.8 mg/kg cohort, one DLBCL subject achieved CR and another subject with DLBCL achieved PR, ORR was 33.33% (2 out of 6). Three subjects were enrolled in the 2.5 mg/kg cohort, two subjects with FL had PR, both of them had DLT on cycle 1 and had dose reduction to 1.8 mg/kg from cycle 2, ORR was 66.7% (2 out of 3). Conclusion: The dose escalation study of MRG001 has shown manageable safety profiles and encouraging preliminary antitumor activity in patients with NHL. Based on the safety, tolerability, and pharmacokinetic parameters of MRG001, 1.8 mg/kg was determined to be the RP2D and further investigation of MRG001 in patients with NHL is warranted. Disclosures Peng: Lepu Biopharma Co., Ltd.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Li: Shanghai Miracogen Inc.: Current Employment.

Impact of Coastal Flood on Building, Infrastructure, and Community Adaptation in Bukit Bestari Tanjungpinang

Coastal flood in Indonesia, namely as banjir rob, is a phenomenon that increases seawater to inundate around the tidal area. In Tanjungpinang, cases of coastal floods become a serious problem for people living in this area. This research aims to model the coastal flood inundation by modeling water inundation with a maximum level increase scenario. Its model was used to estimate coastal floods' impact on houses, buildings, and infrastructures with scenario 2 meters of sea-level rise. On the other hand, the budget loss for restoration was estimated to study the effort of community adaptations with the ECLAC RAB method and observation to understand community adaptation. It was found that the spatial model succeeded in zoning inundation areas, which had a significant impact on houses, buildings, worship places, schools, and industrial at many 4112 units. From this case, the budget loss for the restoration of the physical environment was estimated at around 61994014.75 USD. In addition, the survey revealed the existing condition before and after the coastal flood. Several community efforts for adaptation were developing houses on stilt and hoarding the lowest land on-site location for build houses.