Analgesic Peptides: From Natural Diversity to Rational Design.

Pain affects one-third of the global population and is a significant public health issue. The use of opioid drugs, which are the strongest painkillers, is associated with several side effects, such as tolerance, addiction, overdose, and even death. An increasing demand for novel, safer analgesic agents is a driving force for exploring natural sources of bioactive peptides with antinociceptive activity. Since the G protein-coupled receptors (GPCRs) play a crucial role in pain modulation, the discovery of new peptide ligands for GPCRs is a significant challenge for novel drug development. The aim of this review is to present peptides of human and animal origin with antinociceptive potential and to show the possibilities of their modification, as well as the design of novel structures. The study presents the current knowledge on structure-activity relationship in the design of peptide-based biomimetic compounds, the modification strategies directed at increasing the antinociceptive activity, and improvement of metabolic stability and pharmacodynamic profile. The procedures employed in prolonged drug delivery of emerging compounds are also discussed. The work summarizes the conditions leading to the development of potential morphine replacements.

Chitosan and Sodium Hyaluronate Hydrogels Supplemented with Bioglass for Bone Tissue Engineering.

The aim of the study was to produce biocomposites based on chitosan and sodium hyaluronate hydrogels supplemented with bioglasses obtained under different conditions (temperature, time) and to perform an in vitro evaluation of their cytocompatibility using both indirect and direct methods. Furthermore, the release of ions from the composites and the microstructure of the biocomposites before and after incubation in simulated body fluid were assessed. Tests on extracts from bioglasses and hydrogel biocomposites were performed on A549 epithelial cells, while MG63 osteoblast-like cells were tested in direct contact with the developed biomaterials. The immune response induced by the biomaterials was also evaluated. The experiments were carried out on both unstimulated and lipopolysaccharide (LPS) endotoxin-stimulated human peripheral blood cells in the presence of extracts of the biocomposites and their components. Extracts of the materials produced do not exhibit toxic effects on A549 cells, and do not increase the production of proinflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin (IL-6) by blood cells in vitro. In direct contact with MG63 osteoblast-like cells, biocomposites containing the reference bioglass and those containing SrO are more cytocompatible than biocomposites with ZnO-doped bioglass. Using two testing approaches, the effects both of the potentially toxic agents released and of the surface of the tested materials on the cell condition were assessed. The results pave the way for the development of highly porous hydrogel-bioglass composite scaffolds for bone tissue engineering.

Association of bone mineral density and potential risk factors for osteoporosis in patients with severe haemophilia A.

INTRODUCTION: In people with haemophilia (PWH), recurrent episodes of bleeding lead to joint deterioration and bone resorption. To date, the effects of various other factors on bone mineral density (BMD) reduction have found conflicting results. AIM: The aim of this study was to analyse the relationships between BMD, bone mineral content (BMC), and trabecular bone score (TBS) parameters based on the dual X-ray absorptiometry method (DXA) and potential risk factors for osteoporosis in patients with severe haemophilia A. METHODS: Fifty-five men with severe haemophilia A, aged 18-68 years, and 59 healthy volunteer men were enrolled in this study. Densitometric-derived lumbar spine and femoral neck BMD, BMC, and TBS were measured. Blood analyses were performed for morphology parameters, liver and kidney function parameters, and viral status. Serum levels of oestradiol (E2 ), testosterone (T), dehydroepiandrosterone sulphate (DHEA-S), parathormone, and vitamin D were measured. RESULTS: Patients showed significantly lower BMD compared to controls (p < .003). The result below the expected range for age was nearly double (6.82% vs. 3.92%) in PWH under 50 years old compared to controls. Haemophilic patients also exhibited significantly higher vitamin D3 deficiency (p < .0001), which was strongly associated with low TBS. Additionally, low body mass index and high neutrophil/lymphocyte ratio were correlated with low BMC and BMD. CONCLUSIONS: This study confirms the prevalence of low BMD and BMC in patients with haemophilia in Poland. Factors that contribute to low BMD are primarily vitamin D deficiency, low BMI, high neutrophil/lymphocyte ratio, and low testosterone/oestradiol ratio.

Bioactive Glasses Enriched with Strontium or Zinc with Different Degrees of Structural Order as Components of Chitosan-Based Composite Scaffolds for Bone Tissue Engineering.

The development of innovative biomaterials with improved integration with bone tissue and stimulating regeneration processes is necessary. Here, we evaluate the usefulness of bioactive glasses from the SiO2-P2O5-CaO system enriched with 2 wt.% SrO or ZnO in the manufacturing of chitosan-based scaffolds. Bioglasses produced using the sol-gel method were subjected to thermal treatment in different regimes. Chitosan/bioglass composites were produced with a weight ratio. Bioglasses were evaluated via TG-DTA, FTIR, and SEM-EDS before and after incubation in simulated body fluid (SBF). The release of ions was tested. The cytocompatibility of the composites in contact with MG63 osteoblast-like cells was evaluated. The results showed that the presence of the crystalline phase decreased from 41.2-44.8% for nonmodified bioglasses to 24.2-24.3% for those modified with ZnO and 22.0-24.2% for those modified with SrO. The samples released Ca2+, Zn2+, and/or Sr2+ ions and were bioactive according to the SBF test. The highest cytocompatibility was observed for the composites containing nonmodified bioglasses, followed by those enriched with SrO bioglasses. The least cytocompatible were the composites containing ZnO bioglasses that released the highest amount of Zn2+ ions (0.58 ± 0.07 mL/g); however, those that released 0.38 ± 0.04 mL/g were characterised by acceptable cytocompatibility. The study confirmed that it is feasible to control the biological performance of chitosan/bioglass composites by adjusting the composition and heat treatment parameters of bioglasses.

Calcination and ion substitution improve physicochemical and biological properties of nanohydroxyapatite for bone tissue engineering applications.

Nanohydroxyapatite (nanoHAP) is widely used in bone regeneration, but there is a need to enhance its properties to provide stimuli for cell commitment and osteoconduction. This study examines the effect of calcination at 1200 °C on the physicochemical and biological properties of nanoHAP doped with magnesium (Mg2+), strontium (Sr2+), and zinc (Zn2+). A synergistic effect of dual modification on nanoHAP biological properties was investigated. The materials were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), BET analysis, Fourier-transform spectroscopy, and thermal analysis methods. Furthermore, ion release tests and in vitro biological characterization, including cytocompatibility, reactive oxygen species production, osteoconductive potential and cell proliferation, were performed. The XRD results indicate that the ion substitution of nanoHAP has no effect on the apatite structure, and after calcination, ß-tricalcium phosphate (ß-TCP) is formed as an additional phase. SEM analysis showed that calcination induces the agglomeration of particles and changes in surface morphology. A decrease in the specific surface area and in the ion release rate was observed. Combining calcination and nanoHAP ion modification is beneficial for cell proliferation and osteoblast response and provide additional stimuli for cell commitment in bone regeneration.

Molnupiravir compared to nirmatrelvir/ritonavir for COVID-19 in high-risk patients with haematological malignancy in Europe. A matched-paired analysis from the EPICOVIDEHA registry.

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

Bioactive Materials for Bone Regeneration: Biomolecules and Delivery Systems.

Novel tissue regeneration strategies are constantly being developed worldwide. Research on bone regeneration is noteworthy, as many promising new approaches have been documented with novel strategies currently under investigation. Innovative biomaterials that allow the coordinated and well-controlled repair of bone fractures and bone loss are being designed to reduce the need for autologous or allogeneic bone grafts eventually. The current engineering technologies permit the construction of synthetic, complex, biomimetic biomaterials with properties nearly as good as those of natural bone with good biocompatibility. To ensure that all these requirements meet, bioactive molecules are coupled to structural scaffolding constituents to form a final product with the desired physical, chemical, and biological properties. Bioactive molecules that have been used to promote bone regeneration include protein growth factors, peptides, amino acids, hormones, lipids, and flavonoids. Various strategies have been adapted to investigate the coupling of bioactive molecules with scaffolding materials to sustain activity and allow controlled release. The current manuscript is a thorough survey of the strategies that have been exploited for the delivery of biomolecules for bone regeneration purposes, from choosing the bioactive molecule to selecting the optimal strategy to synthesize the scaffold and assessing the advantages and disadvantages of various delivery strategies.

Effect of Selected Crosslinking and Stabilization Methods on the Properties of Porous Chitosan Composites Dedicated for Medical Applications.

Chitosan is one of the most commonly employed natural polymers for biomedical applications. However, in order to obtain stable chitosan biomaterials with appropriate strength properties, it is necessary to subject it to crosslinking or stabilization. Composites based on chitosan and bioglass were prepared using the lyophilization method. In the experimental design, six different methods were used to obtain stable, porous chitosan/bioglass biocomposite materials. This study compared the crosslinking/stabilization of chitosan/bioglass composites with ethanol, thermal dehydration, sodium tripolyphosphate, vanillin, genipin, and sodium ß-glycerophosphate. The physicochemical, mechanical, and biological properties of the obtained materials were compared. The results showed that all the selected crosslinking methods allow the production of stable, non-cytotoxic porous composites of chitosan/bioglass. The composite with genipin stood out with the best of the compared properties, taking into account biological and mechanical characteristics. The composite stabilized with ethanol is distinct in terms of its thermal properties and swelling stability, and it also promotes cell proliferation. Regarding the specific surface area, the highest value exposes the composite stabilized by the thermal dehydration method.

Quantitative and Qualitative Airborne Mycobiota Surveillance in High-Risk Hospital Environment.

(1) Background: The primary aim of the presented study was to assess the prevalence of fungi in the indoor air of selected hospital wards, and the additional goal was to evaluate the susceptibility of cultured isolates of Aspergillus fumigatus to triazoles. (2) Methods: Three hematology departments and a hospital for lung diseases were surveyed in 2015 and/or 2019. Air samples were taken with a MicroBio MB1 air sampler on Sabouraud agar. The susceptibility of Aspergillus fumigatus isolates to voriconazole, posaconazole and itraconazole was tested with a microdilution method, according to EUCAST. (3) Results: The amount of fungi cultured from rooms equipped with sterile air circulation, as well as flow devices for air disinfection, was significantly lower compared to that from unprotected rooms. The areas most contaminated with fungi were corridors and bathrooms. The dominant species were Cladosporium and Penicillium. A. fumigatus was rare in hematological departments (6/61, 9.8% examinations performed in 2014 and 2/40, 5% in 2019), whereas in the hospital for lung diseases an outbreak of A. fumigatus spores with up to 300 CFU/m3 was noted in March 2015. No triazole-resistant A. fumigatus isolate was detected. (4) Conclusions: Regular microbiological testing of the hospital environment can contribute to the detection of spore outbreaks, and thus enable the implementation of corrective procedures (e.g., additional disinfection, changing of HEPA filters).

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry.

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Molnupiravir is effective in patients with haematological malignancies.

Patients with hematologic malignancies are particularly vulnerable to severe infectious complications. SARS-CoV-2 infection is associated with a high risk of severe course and death in this patient population. In addition, immune deficits associated with both the blood cancer and the treatment used make vaccination against SARS-CoV-2 less effective than in immunocompetent individuals. Molnupiravir is one of the first oral antiviral drugs to demonstrate a significant benefit in reducing hospitalisation and death in COVID-19 in the general population. In this context, 175 haematology patients with diagnosed COVID-19, and treated with MOL between January and April 2022, came under our scrutiny with a view to defining their clinical characteristics and outcomes. The most common underlying conditions were lymphomas (45%), multiple myelomas (21%) and acute leukaemias or myelodysplastic syndrome (35%). Of all, 77% of the patients were vaccinated, and half of them received a booster. At 28 days after the breakthrough COVID-19 diagnosis, 35 (20%) subjects required hospital admission. Out of those patients, seven (4%) died during the follow-up due to the progression of COVID. Our results corroborate what has been established to date with regard to the positive clinical and safety outcomes of MOL in haematology patients with mild or moderate COVID-19.

COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA).

Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.

Bioactive glasses enriched with zinc and strontium: synthesis, characterization, cytocompatibility with osteoblasts and antibacterial properties.

Purpose: The aim of the presented work was to characterize the new obtained bioglasses and assess their biological performance in vitro. Bioglasses were produced using the sol-gel method in the SiO2-P2O5-CaO system, for the purpose as composite ingredients. Their chemical composition was enriched with ZnO to introduce antibacterial properties and SrO with osteoinductive effect. The properties of bioglasses were compared and the effect of chemical composition and particle size on their biological properties was assessed. Methods: The bioglasses were evaluated via TG-DTA, FTIR, SEM-EDS analyses before and after incubation in SBF solution. LDH and WST-1 tests were used to determine the level of cytotoxicity of the tested bioglasses on hFOB1.19 osteoblasts. Results: The results show that the developed bioglasses release Ca2+, are bioactive in SBF solution, not cytotoxic and show antibacterial activity in contact with Pseudomonas aeruginosa and Staphylococcus aureus strains. Bioglasses enriched with ZnO show the highest bactericidal activity. All tested bioglasses enhanced hFOB 1.19 cells proliferation. Particle size has a lower effect on biological performance of the bioglasses than their chemical composition. Conclusions: The conducted research showed that bioglass modification with SrO and ZnO can be considered particularly for the development of biomaterials supporting bone regeneration and the treatment of infected bone defects.

Dual Modification of Porous Ca-P/PLA Composites with APTES and Alendronate Improves Their Mechanical Strength and Cytobiocompatibility towards Human Osteoblasts.

Synthetic implants are used to treat large bone defects that are often unable to regenerate, for example those caused by osteoporosis. It is necessary that the materials used to manufacture them are biocompatible and resorbable. Polymer-ceramic composites, such as those based on poly(L-lactide) (PLLA) and calcium phosphate ceramics (Ca-P), are often used for these purposes. In this study, we attempted to investigate an innovative strategy for two-step (dual) modification of composites and their components to improve the compatibility of composite components and the adhesion between PLA and Ca-P whiskers, and to increase the mechanical strength of the composite, as well as improve osteological bioactivity and prevent bone resorption in composites intended for bone regeneration. In the first step, Ca-P whiskers were modified with a saturated fatty acid namely, lauric acid (LA), or a silane coupling agent γ-aminopropyltriethoxysilane (APTES). Then, the composite, characterized by the best mechanical properties, was modified in the second stage of the work with an active chemical compound used in medicine as a first-line drug in osteoporosis-sodium alendronate, belonging to the group of bisphosphonates (BP). As a result of the research covered in this work, the composite modified with APTES and alendronate was found to be a promising candidate for future biomedical engineering applications.

The Preliminary Assessment of New Biomaterials Necessitates a Comparison of Direct and Indirect Cytotoxicity Methodological Approaches.

BACKGROUND: Cytotoxicity testing is a primary method to establish the safety of biomaterials, e.g., biocomposites. Biomaterials involve a wide range of medical materials, which are usually solid materials and are used in bone regeneration, cardiology, or dermatology. Current advancements in science and technology provide several standard cytotoxicity testing methods that are sufficiently sensitive to detect various levels of cellular toxicity, i.e., from low to high. The aim was to compare the direct and indirect methodology described in the ISO guidelines UNE-EN ISO 10993-5:2009 Part 5. METHODS: Cell proliferation was measured using WST-1 assay, and cytotoxicity was measured using LDH test kit. RESULTS: The results indicate that the molecular surface of biomaterials have impact on the cytotoxicity and proliferation profile. Based on these results, we confirm that the indirect method does not provide a clear picture of the cell condition after the exposure to the surface, and moreover, cannot provide complete results about the effects of the material. CONCLUSIONS: Comparison of both methods shows that it is pivotal to investigate biomaterials at the very early stages using both indirect and direct methods to access the influence of the released toxins and surface of the material on the cell condition.

Cytotoxicity and Antibacterial Activity of Mineral Trioxide Aggregate Cement with Radiopacity Introduced by ZrO2.

The article presents the results of in vitro studies on cytotoxicity and antibacterial activity of new MTA-type cements, developed on the basis of the sintered tricalcium silicate enriched with ZnO, along with an agent introducing the radiopacity in the form of ZrO2. The new materials have been developed to ensure that their physical and chemical properties are suited for endodontic applications. The cements were evaluated via characterisation of setting time, compressive strength, as well as translucency on X-ray images, and bioactivity in the simulated body fluid (SBF). The µCT was used to test the influence of the ZrO2 grains in the powder component on the microstructure of the produced cement. Then, the cytotoxic action of the cements was evaluated by applying a reference L-929 cell line. The conditions of the culture upon contact with the tested materials or with extracts from the cements were assessed using image analysis or an MTT colorimetric assay. Two strains of streptococci, Streptococcus mutans and Streptococcus sanguinis, were used to study the antibacterial activity of the tested cements with ZrO2 acting as the agent introducing the radiopacity. The new cements are characterised by appropriate properties as far as retrograde root canal filling is concerned.

Effects of Sterilization and Hydrolytic Degradation on the Structure, Morphology and Compressive Strength of Polylactide-Hydroxyapatite Composites.

Composites based on polylactide (PLA) and hydroxyapatite (HA) were prepared using a thermally induced phase separation method. In the experimental design, the PLA with low weight-average molar mass (Mw) and high Mw were tested with the inclusion of HA synthesized as whiskers or hexagonal rods. In addition, the structure of HA whiskers was doped with Zn, whereas hexagonal rods were mixed with Sr salt. The composites were sterilized and then incubated in phosphate-buffered saline for 12 weeks at 37 °C, followed by characterization of pore size distribution, molecular properties, density and mechanical strength. Results showed a substantial reduction of PLA Mw for both polymers due to the preparation of composites, their sterilization and incubation. The distribution of pore size effectively increased after the degradation process, whereas the sterilization, furthermore, had an impact on pore size distribution depending on HA added. The inclusion of HA reduced to some extent the degradation of PLA quantitatively in the weight loss in vitro compared to the control without HA. All produced materials showed no cytotoxicity when validated against L929 mouse skin fibroblasts and hFOB 1.19 human osteoblasts. The lack of cytotoxicity was accompanied by the immunocompatibility with human monocytic cells that were able to detect pyrogenic contaminants.

Breakthrough COVID-19 in vaccinated patients with hematologic malignancies: results from the EPICOVIDEHA survey.

Limited data are available on breakthrough COVID-19 in patients with hematologic malignancy (HM) after anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Adult patients with HM, ≥1 dose of anti-SARS-CoV-2 vaccine, and breakthrough COVID-19 between January 2021 and March 2022 were analyzed. A total of 1548 cases were included, mainly lymphoid malignancies (1181 cases, 76%). After viral sequencing in 753 cases (49%), the Omicron variant was prevalent (517, 68.7%). Most of the patients received ≤2 vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received COVID-19-specific treatment. After 30-day follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with the Omicron variant was 7.9%, comparable to other variants, with a significantly lower 30-day mortality rate than in the prevaccine era (31%). In the univariable analysis, older age (P < .001), active HM (P < .001), and severe and critical COVID-19 (P = .007 and P < .001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (P < .001). In the multivariable model, older age, active disease, critical COVID-19, and 2-3 comorbidities were correlated with a higher mortality, whereas monoclonal antibody administration, alone (P < .001) or combined with antivirals (P = .009), was protective. Although mortality is significantly lower than in the prevaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals.