The updated Banff classification allows for the diagnosis of antibody‐mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk ...in patients with consistently C4d‐negative AMR (n = 51) compared with C4d‐positive AMR patients (n = 156) and matched control subjects without AMR. All first‐year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor‐specific antibody (DSA). C4d‐negative AMR patients were not different from C4d‐positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti‐HLA/ABO‐incompatibility). C4d‐positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 interquartile range 8–32 days vs. 46 interquartile range 20–191, p < 0.001) and were three times more common (7.8% vs 2.5%). One‐ and 2‐year post–AMR‐defining biopsy graft survival in C4d‐negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d‐positive AMR patients, respectively (p = 0.4). C4d‐negative AMR was associated with a 2.56‐fold (95% confidence interval, 1.08–6.05, p = 0.033) increased risk of graft loss compared with AMR‐free matched controls. No clinical characteristics were identified that reliably distinguished C4d‐negative from C4d‐positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.
This study shows kidney transplant recipients with c4d‐negative antibody‐mediated rejection (AMR) are indistinguishable from c4d‐positive AMR recipients in terms of baseline demographic and transplant characteristics, but c4d‐negative AMR presents significantly later posttransplant and is more likely to be subclinical, and both groups have worse graft survival than AMR‐free matched controls.
C-type lectin receptors (CLRs) are carbohydrate binding pattern recognition receptors (PRRs) which play a central role in host recognition of pathogenic microorganisms. Signaling through CLRs ...displayed on antigen presenting cells dictates important innate and adaptive immune responses. Several pathogens have evolved mechanisms to exploit the receptors or signaling pathways of the CLR system to gain entry or propagate in host cells. CLR responses to high priority pathogens such as
, HIV, Ebola, and others are described and considered potential avenues for therapeutic intervention.
and HIV are the leading causes of death due to infectious disease and have a synergistic relationship that further promotes aggressive disease in co-infected persons. Immune recognition through CLRs and other PRRs are important determinants of disease outcomes for both TB and HIV. Investigations of CLR responses to
and HIV, to date, have primarily focused on single infection outcomes and do not account for the potential effects of co-infection. This review will focus on CLRs recognition of
and HIV motifs. We will describe their respective roles in protective immunity and immune evasion or exploitation, as well as their potential as genetic determinants of disease susceptibility, and as avenues for development of therapeutic interventions. The potential convergence of CLR-driven responses of the innate and adaptive immune systems in the setting of
and HIV co-infection will further be discussed relevant to disease pathogenesis and development of clinical interventions.
We investigated the cerebral folate system in post-mortem brains and matched cerebrospinal fluid (CSF) samples from subjects with definite Alzheimer's disease (AD) (
21) and neuropathologically ...normal brains (
21) using immunohistochemistry, Western blot and dot blot. In AD the CSF showed a significant decrease in 10-formyl tetrahydrofolate dehydrogenase (FDH), a critical folate binding protein and enzyme in the CSF, as well as in the main folate transporter, folate receptor alpha (FRα) and folate. In tissue, we found a switch in the pathway of folate supply to the cerebral cortex in AD compared to neurologically normal brains. FRα switched from entry through FDH-positive astrocytes in normal, to entry through glial fibrillary acidic protein (GFAP)-positive astrocytes in the AD cortex. Moreover, this switch correlated with an apparent change in metabolic direction to hypermethylation of neurons in AD. Our data suggest that the reduction in FDH in CSF prohibits FRα-folate entry via FDH-positive astrocytes and promotes entry through the GFAP pathway directly to neurons for hypermethylation. This data may explain some of the cognitive decline not attributable to the loss of neurons alone and presents a target for potential treatment.
OBJECTIVE:We studied clinical outcomes of COVID-19 infection in patients living with HIV (PLH) in comparison to non-HIV population.
DESIGN:Analysis of a multicentre research network TriNETX was ...performed including patients more than 10 years of age diagnosed with COVID-19.
METHODS:Outcomes in COVID-19 positive patients with concurrent HIV (PLH) were compared with a propensity-matched cohort of patients without HIV (non-PLH).
RESULTS:Fifty thousand one hundred and sixty-seven patients with COVID-19 were identified (49,763 non-PLH, 404 PLH). PLH were more likely to be men, African–American, obese and have concurrent hypertension, diabetes, chronic kidney disease and nicotine dependence compared with non-PLH cohort (all P values <0.05). We performed 1 : 1 matching for BMI, diabetes, hypertension, chronic lung diseases, chronic kidney disease, race, history of nicotine dependence and sex. In unmatched analysis, PLH had higher mortality at 30 days risk ratio 1.55, 95% confidence interval (95% CI)1.01–2.39 and were more likely to need inpatient services (risk ratio 1.83, 95% CI1.496–2.24). After propensity score matching, no difference in mortality was noted (risk ratio 1.33, 95% CI0.69–2.57). A higher proportion of PLH group needed inpatient services (19.31 vs. 11.39%, risk ratio 1.696, 95% CI1.21–2.38). Mean C-reactive protein, ferritin, erythrocyte sedimentation rate and lactate dehydrogenase levels after COVID-19 diagnosis were not statistically different and mortality was not different for PLH with a history of antiretroviral treatment.
CONCLUSION:Crude COVID-19 mortality is higher in PLH; however, propensity-matched analyses revealed no difference in outcomes, showing that higher mortality is driven by higher burden of comorbidities. Early diagnosis and intensive surveillance are needed to prevent a ‘Syndemic’ of diseases in this vulnerable cohort.
Background.
Organ transplant recipients comprise an immunocompromised and vulnerable cohort. Outcomes of coronavirus disease 2019 (COVID-19) in solid organ transplant (SOT) recipients remain ...understudied.
Methods.
We used a multicenter federated research network to compare clinical outcomes of COVID-19 in patients with SOT to a propensity--matched cohort of patients without SOT.
Results.
We identified 2307 SOT recipients and 231 047 nontransplant patients with COVID-19. Transplant patients were more likely to be male individuals, older, have a body mass index >30 kg/m
2
, and have comorbid hypertension, diabetes, nicotine dependence, heart failure, and ischemic heart disease compared with the nontransplant group (
P
< 0.05). One-to-one matching was performed for diabetes, hypertension, chronic lung diseases, race, nicotine dependence, heart failure, ischemic heart disease, and gender. There was no difference in the composite outcome of intubation or mechanical ventilation at 30 days (risk ratio RR, 1.04; 95% confidence interval CI, 0.86-1.26) or 60 days (RR, 1.03; 95% CI, 0.86-1.24) between the 2 groups. Hospitalization rate was higher in the transplant cohort (30.97% versus 25.47%; RR, 1.22; 95% CI, 1.11-1.34). There was no difference in mortality at 30 days (6.45% versus 5.29%; RR, 1.22; 95% CI, 0.88-1.68) or 60 days postdiagnosis (RR, 1.05; 95% CI, 0.83-1.32). More patients in the SOT group developed acute renal injury compared with non-SOT cohort (24.73% versus 14.29%; RR, 1.73; 95% CI, 1.53-1.96).
Conclusions.
Patients with SOT have high COVID-19-related mortality; however, propensity-matched analyses reveal that this increased risk is secondary to higher burden of comorbidities. SOT status independently increases risk of hospital admission and acute kidney injury.
The study of HIV infection and pathogenicity in physical reservoirs requires a biologically relevant model. The human immune system (HIS) mouse is an established model of HIV infection, but defects ...in immune tissue reconstitution remain a challenge for examining pathology in tissues. We utilized exogenous injection of the human recombinant FMS-like tyrosine kinase 3 ligand (rFLT-3 L) into the hematopoietic stem cell (HSC) cord blood HIS mouse model to significantly expand the total area of lymph node (LN) and the number of circulating human T cells. The results enabled visualization and quantification of HIV infectivity, CD4 T cell depletion and other measures of pathogenesis in the secondary lymphoid tissues of the spleen and LN. Treatment with the Caspase-1/4 inhibitor VX-765 limited CD4
T cell loss in the spleen and reduced viral load in both the spleen and axillary LN. In situ hybridization further demonstrated a decrease in viral RNA in both the spleen and LN. Transcriptomic analysis revealed that in vivo inhibition of caspase-1/4 led to an upregulation in host HIV restriction factors including SAMHD1 and APOBEC3A. These findings highlight the use of rFLT-3 L to augment human immune system characteristics in HIS mice to support investigations of HIV pathogenesis and test host directed therapies, though further refinements are needed to further augment LN architecture and cellular populations. The results further provide in vivo evidence of the potential to target inflammasome pathways as an avenue of host-directed therapy to limit immune dysfunction and virus replication in tissue compartments of HIV
persons.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A novel technique has been developed, which will open exciting new opportunities for studying the very neutron-rich nuclei involved in the r process. As a proof of principle, the γ spectra from the β ...decay of ^{76}Ga have been measured with the SuN detector at the National Superconducting Cyclotron Laboratory. The nuclear level density and γ-ray strength function are extracted and used as input to Hauser-Feshbach calculations. The present technique is shown to strongly constrain the ^{75}Ge(n,γ)^{76}Ge cross section and reaction rate.
Humanized mice have become an important workhorse model for HIV research. Advances that enabled development of a human immune system in immune deficient mouse strains have aided new basic research in ...HIV pathogenesis and immune dysfunction. The small animal features facilitate development of clinical interventions that are difficult to study in clinical cohorts, and avoid the high cost and regulatory burdens of using non-human primates. The model also overcomes the host restriction of HIV for human immune cells which limits discovery and translational research related to important co-infections of people living with HIV. In this review we emphasize recent advances in modeling bacterial and viral co-infections in the setting of HIV in humanized mice, especially neurological disease, and Mycobacterium tuberculosis and HIV co-infections. Applications of current and future co-infection models to address important clinical and research questions are further discussed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Ultrasound is widely regarded as an important adjunct to antenatal care (ANC) to guide practice and reduce perinatal mortality. We assessed the impact of ANC ultrasound use at health ...centres in resource‐limited countries.
Design
Cluster randomised trial.
Setting
Clusters within five countries (Democratic Republic of Congo, Guatemala, Kenya, Pakistan, and Zambia)
Methods
Clusters were randomised to standard ANC or standard care plus two ultrasounds and referral for complications. The study trained providers in intervention clusters to perform basic obstetric ultrasounds.
Main outcome measures
The primary outcome was a composite of maternal mortality, maternal near‐miss mortality, stillbirth, and neonatal mortality.
Results
During the 24‐month trial, 28 intervention and 28 control clusters had 24 263 and 23 160 births, respectively; 78% in the intervention clusters received at least one study ultrasound; 60% received two. The prevalence of conditions noted including twins, placenta previa, and abnormal lie was within expected ranges. 9% were referred for an ultrasound‐diagnosed condition, and 71% attended the referral. The ANC (RR 1.0 95% CI 1.00, 1.01) and hospital delivery rates for complicated pregnancies (RR 1.03 95% CI 0.89, 1.20) did not differ between intervention and control clusters nor did the composite outcome (RR 1.09 95% CI 0.97, 1.23) or its individual components.
Conclusions
Despite availability of ultrasound at ANC in the intervention clusters, neither ANC nor hospital delivery for complicated pregnancies increased. The composite outcome and the individual components were not reduced.
Tweetable
Antenatal care ultrasound did not improve a composite outcome that included maternal, fetal, and neonatal mortality.
Tweetable
Antenatal care ultrasound did not improve a composite outcome that included maternal, fetal, and neonatal mortality.
Nuclear reactions where an exotic nucleus captures a neutron are critical for a wide variety of applications, from energy production and national security, to astrophysical processes, and ...nucleosynthesis. Neutron capture rates are well constrained near stable isotopes where experimental data are available; however, moving far from the valley of stability, uncertainties grow by orders of magnitude. This is due to the complete lack of experimental constraints, as the direct measurement of a neutron-capture reaction on a short-lived nucleus is extremely challenging. Here, we report on the first experimental extraction of a neutron capture reaction rate on ^{69}Ni, a nucleus that is five neutrons away from the last stable isotope of Ni. The implications of this measurement on nucleosynthesis around mass 70 are discussed, and the impact of similar future measurements on the understanding of the origin of the heavy elements in the cosmos is presented.
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