SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have ...been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful.
: Animal, in vitro and clinical data relevant to the biology of the renin-angiotensin system (RAS), its interaction with the kallikrein-kinin system (KKS) and SARS-CoV-2, and clinical studies were reviewed.
SARS-CoV-2 hijacks ACE2to invade and damage cells, downregulating ACE2, reducing its protective effects and exacerbating injurious Ang II effects. However, retrospective observational studies do not show higher risk of infection with ACEI or ARB use. Nevertheless, study of the RAS and KKS in the setting of coronaviral infection may yield therapeutic targets.
Understanding the long-term maintenance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity is critical for predicting protection against reinfection. In an age- and ...gender-matched cohort of 24 participants, the association of disease severity and early immune responses on the maintenance of humoral immunity 12 months post-infection is examined. All severely affected participants maintain a stable subset of SARS-CoV-2 receptor-binding domain (RBD)-specific memory B cells (MBCs) and good neutralizing antibody breadth against the majority of the variants of concern, including the Delta variant. Modeling these immune responses against vaccine efficacy data indicate a 45%–76% protection against symptomatic infection (variant dependent). Overall, these findings indicate durable humoral responses in most participants after infection, reasonable protection against reinfection, and implicate baseline antigen-specific CD4+ T cell responses as a predictor of maintenance of antibody neutralization breadth and RBD-specific MBC levels at 12 months post-infection.
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•SARS-CoV-2-specific humoral immunity is sustained at 12 months post-infection•Severe disease is associated with more durable immune responses•Immune responses are equivalent to a vaccine protective efficacy of 45%–76%•Early CD4 T cell responses predict durable neutralization and memory B cells
One year after SARS-CoV-2 infection, despite declining antibody titers, Balachandran et al. report a disease-severity-associated maintenance of antibody functions and memory B cell magnitudes. The convalescent serum could neutralize most VOCs, and the initial CD4 T cell levels predict the antibody neutralization breadth and memory B cell durability.
People with immunocompromising conditions are at increased risk of SARS-CoV-2 infection and mortality, however early in the pandemic it was challenging to collate data on this heterogenous ...population. We conducted a registry study of immunocompromised individuals with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection from March-October 2020 in Sydney, Australia to understand clinical and laboratory outcomes in this population prior to the emergence of the Delta variant. 27 participants were enrolled into the study including people with a haematologic oncologic conditions (n = 12), secondary immunosuppression (N = 8) and those with primary or acquired immunodeficiency (i.e. HIV; N = 7). All participants had symptomatic COVID-19 with the most common features being cough (64%), fever (52%) and headache (40%). Five patients demonstrated delayed SARS-CoV-2 clearance lasting three weeks to three months. The mortality rate in this study was 7% compared to 1.3% in the state of New South Wales Australia during the same period. This study provides data from the first eight months of the pandemic on COVID-19 outcomes in at-risk patient groups.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Na0.25K0.25Bi0.5TiO3 (NKBT) perovskite particles are synthesized by solid-state method and used as a filler for polyvinylidene fluoride-co-hexafluoropropylene (PVDF-HFP) co-polymer. X-ray diffraction ...analysis of NKBT powders shows that the particles have a rhombohedral perovskite crystal structure (R3c symmetry). Raman spectroscopy reveals that the co-polymer crystallizes predominantly into the mixture of polar β- and γ-crystals, while there is also a contribution of the non-polar α-crystal phase. The introduction of the NKBT into the PVDF-HFP results with an increase in effective dielectric permittivity and this effect depends on the inorganic content in the composite. The most interesting result of the present study is that the introduction of NKBT particles induces the appearance of an additional transition peak in the dielectric spectra of the co-polymer matrix. At the fixed frequency of ~2 kHz, the observed process appears at ~10 °C (about 45° above the glass transition temperature) and its magnitude strongly depends on the amount of the NKBT in the composite. Dielectric spectroscopy measurements of the composites are carried out in the wide range of frequencies (from 0.1 Hz to 1 MHz) and temperatures (from −100 to 100 °C). They reveal that the novel process can be clearly distinguished in the frequency range between 160 Hz and ~50 kHz.
•Na0.25K0.25Bi0.5TiO3 (NKBT) perovskite particles are synthesized by solid state method.•PVDF-HFP/NKBT composite films were prepared by solution mixing.•NKBT particles induce an increase in effective dielectric permittivity of the films.•An additional transition peak was observed in the dielectric spectra of the composite film.•The magnitude of the novel transition depends on the NKBT content.
Despite widespread HIV screening and treatment programs across sub-Saharan Africa, many countries are not on course to meet the Joint United Nations Program on HIV/AIDS 90–90–90 targets. As mental ...health disorders such as depression are prevalent among people living with HIV, investment in understanding and addressing comorbid depression is increasing. This manuscript aims to assess depression and HIV management in sub-Saharan Africa using a 90–90–90 lens through a discussion of: depression and the HIV care continuum; the state of depression screening and treatment; and innovations such as task-shifting strategies for depression management. Due to the lack of mental health infrastructure and human resources, task-shifting approaches that integrate mental health management into existing primary and community health programs are increasingly being piloted and adopted across the region. Greater integration of such mental health care task-shifting into HIV programs will be critical to realizing the 90–90–90 goals and ending the HIV epidemic.
Hepatitis C virus (HCV) can be cleared naturally in a subset of individuals. However, the asymptomatic nature of acute HCV infection makes the study of the early immune response and defining the ...correlates of protection challenging. Despite this, there is now strong evidence implicating the humoral immune response, specifically neutralising antibodies, in determining the clearance or chronicity outcomes of primary HCV infection. In general, immunoglobulin G (IgG) plays the major role in viral neutralisation. However, there are limited investigations of anti-HCV envelope protein 2 (E2) isotypes (IgM, IgG, IgA) and IgG subclasses (IgG1-4) in early HCV infection. In this study, using a rare cohort of 14 very recently HCV-infected individuals (4-45 days) with varying disease outcome (
= 7 clearers), the timing and potency of anti-HCV E2 isotypes and IgG subclasses were examined longitudinally, in relation to neutralising antibody activity. Clearance was associated with anti-E2 IgG, specifically IgG1 and IgG3, and appeared essential to prevent the emergence of new HCV variants and the chronic infection outcome. Interestingly, these IgG responses were accompanied by IgM antibodies and were associated with neutralising antibody activity in the subjects who cleared infection. These findings provide novel insights into the early humoral immune response characteristics associated with HCV disease outcome.
Summary Studies of individuals who were highly exposed but seronegative (HESN) for HIV infection led to the discovery that homozygosity for the Δ32 deletion mutation in the CCR5 gene prevents viral ...entry into target cells, and is associated with resistance to infection. Additionally, evidence for protective immunity has been noted in some HESN groups, such as sex workers in The Gambia. Population studies of individuals at high risk for hepatitis C virus infection suggest that an HESN phenotype exists. The body of evidence, which suggests that protective immunity allows clearance of hepatitis C virus without seroconversion is growing. Furthermore, proof-of-principle evidence from in-vitro studies shows that genetic polymorphisms can confer resistance to establishment of infection. This Review discusses the possibility that genetic mutations confer resistance against hepatitis C virus, and also explores evidence for protective immunity, including via genetically programmed variations in host responses. The data generally strengthens the notion that investigations of naturally arising polymorphisms within the hepatitis C virus interactome, and genetic association studies of well characterised HESN individuals, could identify potential targets for vaccine design and inform novel therapies.
Depression is common among people living with HIV (PLWH). Measurement-based care models that measure depression severity and antidepressant side effects, and use an algorithm to guide antidepressant ...prescription by non-specialized health workers represent an evidence-based treatment for severe depression in sub-Saharan Africa. We conducted in-depth interviews from June to December 2018 with eleven patients enrolled in Project SOAR-Mental Health, a pilot project integrating depression treatment into HIV care in Malawi. Patients treated with amitriptyline or fluoxetine participated in interviews exploring antidepressant acceptability through patient knowledge, side effect severity, pill burden, adherence, perceived efficacy, and tolerability. Patients described a lack of detailed antidepressant education from their providers. Variable, typically self-limiting side effects were reported from both amitriptyline and fluoxetine. While most side effects were mild, three patients reported functional impairment. Patients reported high adherence, though the additional pill burden was a challenge. Most patients found the antidepressants efficacious, tolerable, beneficial and acceptable. Although patient psychoeducation is notably lacking as a facet of clinical management, antidepressant prescription by primary care providers appears acceptable for comorbid severe depression in PLWH initiating HIV care in sub-Saharan Africa. Health workers should be mindful of dosing to minimise side effects and considerate of the additional pill burden.
Trial registration: ClinicalTrials.gov ID NCT03555669. Retrospectively registered on 13 June 2018.
This study aims to prepare drotaverine hydrochloride superporous hydrogel hybrid systems (DSHH systems) to prolong its residence time in the stomach, provide extended release and reduce its frequency ...of administration. Drotaverine hydrochloride (DRH) is a spasmolytic drug that suffers from brief residence due to intestinal hypermotility during diarrheal episodes associated with gastrointestinal colics resulting in low bioavailability and repeated dosing. Eight DSHH systems were prepared using gas blowing technique. The prepared DSHH systems were evaluated regarding their morphology, incorporation efficiency, density, porosity, swelling ratio, viscoelastic property, erosion percentage and release kinetics. The FH8 formula containing equal proportion of chitosan (3%) /polyvinyl alcohol (3%) as strengthener and crosslinked with tripolyphosphate showed the highest incorporation efficiency (91.83 ± 1.33%), good swelling ratio (28.32 ± 3.15% after 24 h), optimum viscoelastic properties (60.19 ± 3.82 kPa) and sustained release profile (88.03 ± 2.15% after 24 h). A bioequivalence study was done to compare the bioavailability of the candidate formula
versus
Spasmocure®. Statistical analysis showed significant (
P
< 0.05) increase in bioavailability 2.7 folds with doubled Tmax (4 h) compared to the marketed product (2 h). These results declared that the superporous hydrogel hybrid systems could be a potential gastroretentive approach for the sustained delivery of drugs with short residence time with enhanced viscoelasticity.
Graphical abstract
The long‐term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection are still being understood. The molecular and phenotypic properties of SARS‐CoV‐2 ...antigen–specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen‐specific memory B‐cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID‐19). Here, we performed single‐cell molecular analysis of the SARS‐CoV‐2 receptor‐binding domain (RBD)–specific MBC population in three patients after severe COVID‐19 and four patients after mild/moderate COVID‐19. We analyzed the transcriptomic and B‐cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor‐alpha (TNF‐α) signaling via nuclear factor‐kappa B in the severe group, involving CD80, FOS, CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80hiTNFAIP3hi and CD11chiCD95hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long‐term RBD‐specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID‐19 severity.
We performed an in‐depth single‐cell gene expression analysis of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) receptor‐binding domain–specific memory B cells in three patients after severe coronavirus disease 2019 (COVID‐19) and four patients after mild/moderate COVID‐19. We analyzed the transcriptome and B‐cell repertoire at ~2 months and ~4 months after symptom onset. The transcriptomic analysis revealed that in the severe group, genes associated with activation, in particular, those associated with tumor necrosis factor‐alpha signaling via nuclear factor‐kappa B were maintained, whereas in the mild/moderate group these declined over time.
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