Abstract
Human cytomegalovirus (HCMV) infections are among the most common complications arising in transplant patients, elevating the risk of various complications including loss of graft and death. ...HCMV infections are also responsible for more congenital infections worldwide than any other agent. Congenital HCMV (cCMV) infections are the leading nongenetic cause of sensorineural hearing loss and a source of significant neurological disabilities in children. While there is overlap in the clinical and laboratory approaches to diagnosis of HCMV infections in these settings, the management, follow-up, treatment, and diagnostic strategies differ considerably. As yet, no country has implemented a universal screening program for cCMV. Here, we summarize the issues, limitations, and application of diagnostic strategies for transplant recipients and congenital infection, including examples of screening programs for congenital HCMV that have been implemented at several centers in Japan, Italy, and the United States.
Members of the family
have enveloped, spherical virions with characteristic complex structures consisting of symmetrical and non-symmetrical components. The linear, double-stranded DNA genomes of ...125-241 kbp contain 70-170 genes, of which 43 have been inherited from an ancestral herpesvirus. In general, herpesviruses have coevolved with and are highly adapted to their hosts, which comprise many mammalian, avian and reptilian species. Following primary infection, they are able to establish lifelong latent infection, during which there is limited viral gene expression. Severe disease is usually observed only in the foetus, the very young, the immunocompromised or following infection of an alternative host. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family
, which is available at ictv.global/report/herpesviridae.
Familial aggregation of psoriatic arthritis Chandran, V; Schentag, C T; Brockbank, J E ...
Annals of the rheumatic diseases,
05/2009, Letnik:
68, Številka:
5
Journal Article
Recenzirano
The aim of this study was to determine the recurrence risk of psoriatic arthritis (PsA) and uncomplicated psoriasis in first-degree relatives (FDRs) of patients with PsA.
All available FDRs (full ...siblings, parents and children) of 100 consecutive consenting patients attending a PsA clinic were evaluated for the presence of psoriasis and PsA using a standard protocol. The protocol included a screening questionnaire, physical examination by a rheumatologist, and radiographic and laboratory assessment. The prevalence of PsA and psoriasis in FDRs of the index cases was determined, and the recurrence risk ratio (lambda) was calculated, assuming a population prevalence of PsA of 0.25%, and a population prevalence of psoriasis of 2%.
The 100 probands had 533 relatives. Eighty-four of them were deceased and 53 were unavailable (age <16 years). Of the remaining 396 FDRs, 107 did not participate (living too far away/did not consent). Thus, 289/396 (73%) of the available FDRs participated in the study. There were 130 siblings, 108 parents and 51 children. The prevalence of PsA and psoriasis among FDRs was 7.6% and 15.2%, respectively. The lambda(1 )was 30.4 for PsA and 7.6 for psoriasis. The prevalence of PsA and psoriasis in siblings was 7.7% and 17.7%, respectively. The lambda(S) was 30.8 for PsA and 8.8 for psoriasis.
The recurrence risk ratio for both PsA and psoriasis is high in FDRs and siblings of patients with PsA. These results confirm that both PsA and psoriasis have a strong heritable component.
BACKGROUND: As part of assessing the possibility of transfusion transmission of human herpesvirus 8 (HHV‐8 or Kaposi's sarcoma‐associated herpesvirus), HHV‐8 seroprevalence was estimated among US ...blood donors, the performance of HHV‐8 serologic tests was compared, and the presence of HHV‐8 DNA was tested for in donated blood.
STUDY DESIGN AND METHODS: Replicate panels of 1040 plasma specimens prepared from 1000 US blood donors (collected in 1994 and 1995) and 21 Kaposi's sarcoma patients were tested for antibodies to HHV‐8 in six laboratories. HHV‐8 PCR was performed on blood samples from 138 donors, including all 33 who tested seropositive in at least two laboratories and 22 who tested positive in at least one.
RESULTS: The estimated HHV‐8 seroprevalence among US blood donors was 3.5 percent (95% CI, 1.2%‐9.8%) by a conditional dependence latent‐class model, 3.0 percent (95% CI, 2.0%‐4.6%) by a conditional independence latent‐class model, and 3.3 percent (95% CI, 2.3%‐4.6%) by use of a consensus‐derived gold standard (specimens positive in two or more laboratories); the conditional dependence model best fit the data. In this model, laboratory specificities ranged from 96.6 to 100 percent. Sensitivities ranged widely, but with overlapping 95 percent CIs. HHV‐8 DNA was detected in blood from none of 138 donors evaluated.
CONCLUSIONS: Medical and behavioral screening does not eliminate HHV‐8‐seropositive persons from the US blood donor pool, but no viral DNA was found in donor blood. Further studies of much larger numbers of seropositive individuals will be required to more completely assess the rate of viremia and possibility of HHV‐8 transfusion transmission. Current data do not indicate a need to screen US blood donors for HHV‐8.
Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we ...conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C∗06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10−364). Stepwise analysis revealed multiple HLA-C∗06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C∗12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10−8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10−11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.
Background/Objectives
Federally‐mandated consultant pharmacist‐conducted retrospective medication regimen reviews (MRRs) are designed to improve medication safety in nursing homes (NH). However, MRRs ...are potentially ineffective. A new model of care that improves access to and efficiency of consultant pharmacists is needed. The objective of this study was to determine the impact of pharmacist‐led telemedicine services on reducing high‐risk medication adverse drug events (ADEs) for NH residents using medication reconciliation and prospective MRR on admission plus ongoing clinical decision support alerts throughout the residents’ stay.
Design
Quality improvement study using a stepped‐wedge design comparing the novel service to usual care in a one‐year evaluation from November 2016 to October 2017.
Setting
Four NHs (two urban, two suburban) in Southwestern Pennsylvania.
Participants
All residents in the four NHs were screened. There were 2,127 residents admitted having 652 alerts in the active period.
Intervention
Upon admission, pharmacists conducted medication reconciliation and prospective MRR for residents and also used telemedicine for communication with cognitively‐intact residents. Post‐admission, pharmacists received clinical decision support alerts to conduct targeted concurrent MRRs and telemedicine.
Measurement
Main outcome was incidence of high‐risk medication, alert‐specific ADEs. Secondary outcomes included all‐cause hospitalization, 30‐day readmission rates, and consultant pharmacists' recommendations.
Results
Consultant pharmacists provided 769 recommendations. The intervention group had a 92% lower incidence of alert‐specific ADEs than usual care (9 vs 31; 0.14 vs 0.61/1,000‐resident‐days; adjusted incident rate ratio (AIRR) = 0.08 (95% confidence interval (CI) = 0.01–0.40; P = .002). All‐cause hospitalization was similar between groups (149 vs 138; 2.33 vs 2.70/1,000‐resident‐days; AIRR = 1.06 (95% CI = 0.72–1.58); P = .75), as were 30‐day readmissions (110 vs 102; 1.72 vs 2.00/1,000‐resident‐days; AIRR = 1.21 (95% CI = 0.76–1.93); P = .42).
Conclusions
This is the first evaluation of the impact of pharmacist‐led patient‐centered telemedicine services to manage high‐risk medications during transitional care and throughout the resident's NH stay, supporting a new model of patient care.
To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow ...cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)
HLA-DRA
sublining fibroblasts, IL1B
pro-inflammatory monocytes, ITGAX
TBX21
autoimmune-associated B cells and PDCD1
peripheral helper T (T
) cells and follicular helper T (T
) cells. We defined distinct subsets of CD8
T cells characterized by GZMK
, GZMB
, and GNLY
phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1
HLA-DRA
fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
Human herpesvirus 8 (HHV-8), the causal agent of Kaposi's sarcoma, is transmitted sexually among homosexual men, but little is known of its transmission among women. Although HHV-8 has been detected ...in blood, there has been no clear evidence of blood-borne transmission.
We identified risk factors for HHV-8 infection in 1295 women in Baltimore, Detroit, New York, and Providence, Rhode Island, who reported high-risk sexual behavior or drug use. HHV-8 serologic studies were performed with two enzyme-linked immunosorbent assays.
In univariate analyses, HHV-8 was associated with black race, Hispanic ethnic background, a lower level of education, and infection with syphilis, the human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). The risk of seropositivity for HHV-8 increased with the frequency of injection-drug use (P<0.001); HHV-8 seroprevalence among the women who used drugs daily was three times that among women who never injected drugs. Among the women with a low risk of sexual transmission, HHV-8 seroprevalence was 0 percent in those who had never injected drugs and 36 percent in those who had injected drugs (P<0.001). However, injection-drug use was linked less strongly to HHV-8 infection than to infection with HBV or HCV. In a multivariate analysis, independent predictors of HHV-8 seropositivity included HIV infection (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.2), syphilis infection (odds ratio, 1.8; 95 percent confidence interval, 1.1 to 2.8), and daily injection-drug use (odds ratio, 3.2; 95 percent confidence interval, 1.4 to 7.6).
Both injection-drug use and correlates of sexual activity were risk factors for HHV-8 infection in the women studied. The independent association of HHV-8 infection with injection-drug use suggests that HHV-8 is transmitted through needle sharing, albeit less efficiently than HBV, HCV, or HIV.
Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two ...pharmacophoresa zinc binding group and a Cys-reactive warheadwere designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement of both the catalytic Zn2+ and Cys165 was confirmed. A second-generation series improved on affinity by incorporating known reversible inhibitor pharmacophores; the mechanism was confirmed by exhaustive dialysis, mass spectrometry, and in vitro evaluation against the C165S mutant. Finally, a third-generation inhibitor was shown to have good cellular activity and low toxicity. In addition to our findings, an alternative method of modeling time-dependent inhibition that simplifies assay setup and allows comparison of inhibition models is discussed.
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